Vaccination has proven to be one of the most effective strategies against the COVID 19 pandemic. Several studies have evaluated and confirmed its effectiveness in different populations, particularly in reducing severe outcomes such as hospitalization and death. However, the potential of vaccination to protect against infection itself has been overlooked. The aim of this study was to determine the effectiveness of the booster dose in a sample of Colombian patients during the fourth wave of COVID-19 pandemic, which was associated with the emergence and predominance of the Omicron variant. A cross-sectional study was conducted on individuals who underwent RT-PCR testing for COVID-19 detection in a dedicated laboratory in Bogotá, Colombia, between December 30th 2021 and February 7th 2022. A total of 1,468 subjects were included in the study. The comparison between fully vaccinated individuals with a booster dose and those without the booster dose revealed a 28% reduction in the odds of infection (OR = 0.719 CI 0.531 - 0.971). Age (OR = 1,009 CI 1,001 - 1,018) and low economic status (OR= 1,812 CI 1,416- 2,319) were associated with an increased risk of infection.These findings suggest the need for booster vaccination in the general population to improve the prevention rates of SARS-CoV-2 infection and mitigate severe outcomes.

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high rate of mortality in kidney transplant recipients (KTRs). The current vaccine strategy for KTRs seems to be unable to provide effective protection against coronavirus disease 2019 (COVID-19) [2] and the occurrence of severe COVID-19 in some vaccinated KTRs suggested a lack of immunity. We analized here the antibody response in a group of 32 kidney transplant recipients (KTR) followed at the Nephrology and Dialysis unit of the Hospital Pio XI of Desio, Italy, compared with a group of 23 healthy workers classified as Late responders (HCW-LR) (10 males age 27-62) and 13 females (age 46-64). We observed that the patients need additional vaccine boosters due to their immunocompromised status and therapy to protect them from infections related to viral variants, in accordance with the literature.

Little is known about the long-term durability of the induced immune response in subjects af-fected by obesity, particularly in those with an abdominal distribution of adipose tissue. We evaluated SARS-CoV-2-specific antibody response after BNT162b2 vaccine booster dose, com-paring individuals with abdominal obesity (AO) with those without, discerning between indi-viduals previously infected or not. IgG-TrimericS were measured in 511 subjects at baseline, 21 days after vaccine dose-1 and at one, three, six and nine months after dose-2 and at one and three months after booster dose. Nucleocapsid antibodies were assessed at baseline and at the end of the study to detect SARS-CoV-2 infection. To evaluate the three-months difference in absolute variation of IgG-TrmicericS levels from booster dose we used multivariable linear regression that showed interaction between AO and SARS-CoV-2 infection status (p=0.016). AO is associated with higher absolute IgG-TrimericS variation in prior infected individuals, regardless of possi-ble confounders and IgG-TrimericS levels at booster dose (p=0.0125). No interaction was evinced using BMI in the same regression model (p=0.418). The robust response in the development of antibodies after booster dose, observed in people with OA and previous infection, may support the recommendations to undergo the booster dose also in this population group.

Our aim was to evaluate the immune response of healthcare workers included in the RIPOVAC study, after receiving a booster dose (third dose), in terms of intensity and persistence of induced antibodies. In the second phase of RIPOVAC study, between December 2021 and January 2022, eight months after the second dose, 389 voluntary, immunocompetent, non-pregnant healthcare workers received a booster dose of SARS-CoV-2 vaccine, and a serum sample was obtained. Two groups of patients were established: with and without previous SARS-CoV-2 infection. In order to quantify anti-S1 IgG (AU/mL) we used CMIA (Abbott). All the health workers were anti-S IgG positive 8 months after receiving the booster dose of the vaccine, with a mean of 17040 AU/mL. In 53 patients without previous infection, antibody levels had increased by a mean of 10762 AU/mL. This figure is 7 times higher than the one produced after the second dose (1506 AU/mL). The booster dose produces a robust elevation of the antibody level, which persists at 8 months with levels up to values significantly higher than those reached after the second dose, that allow to predict a persistence of more than one year. The study demonstrates the efficacy of the booster dose of anti-SARS-CoV-2 vaccines.

Given the concerns of waning immunity from the primary COVID-19 vaccines and the first booster dose, we conducted an on-line cross-sectional study in May 2022 to investigate willingness to receive a second COVID-19 booster dose or a new COVID-19 vaccine and its associated factors. Overall, 22.7% of participants were willing to be vaccinated, 39.3% were unsure, but tend to be willing, 25.8% were unsure, 4.9% were unsure, but tend to be unwilling, and 7.4% were unwilling to be vaccinated. The main reasons against accepting a second COVID‐19 booster dose or a new COVID-19 vaccine COVID-19 dose included concerns about the side effects, the opinion that further vaccination is unnecessary, and effectiveness uncertainties. Males, younger individuals, participants without a previous COVID-19 diagnosis, and those with good/very good self-perceived physical health were significantly more frequently willing to receive a second COVID‐19 booster dose or a new COVID-19 vaccine. Also, increased fear of the COVID-19, increased trust in COVID-19 vaccination and decreased fear of a second booster dose or a new COVID-19 vaccine were associated with increased willingness. Our results show some hesitancy and unwillingness toward further COVID-19 vaccination and indicate that fear of COVID-19 and trust in COVID-19 vaccination affect public opinion

Objective: We report a case of acute pancytopenia and liver injury after concomitant administration of low-dose methotrexate (MTX), and high-dose esomeprazole and metamizole. Case summary: A 71-year-old patient with chronic systemic idiopathic erosive arthritis was admitted after a pelvic ring fracture. After hospital admission, she received MTX in addition to esomeprazole and metamizole. Subsequent laboratory tests revealed pancytopenia and elevated liver enzymes. The follow-up clinical examinations were unremarkable, with the exception of sub-febrile temperatures. Further investigations did not detect a definitive etiology. Due to the suspicion of methotrexate-induced hematotoxicity and hepatotoxicity, antagonizing therapy with calcium folinate was administered, after which the blood counts and liver parameters normalized. Discussion: Due to the administration of high-dose metamizole immediately before the administration of low-dose MTX, the pre-existing hematotoxic pharmacodynamic effect of MTX was acutely enhanced by that of metamizole, although folic acid was administered preemptively. In addition, the concomitant administration of high-dose esomeprazole and normal dose torasemide resulted in a pharmacokinetic interaction with MTX by decreasing its renal secretion and elimination, further enhancing the concentration-dependent hematotoxic and hepatotoxic side effects of MTX. Conclusions: The relatively high demand for analgesics in patients with chronic rheumatic diseases already being treated with MTX and proton pump inhibitors necessitates that clinicians consider drug-drug interactions as potential causes of adverse drug reactions after the administration of metamizole or nonsteroidal anti-inflammatory drugs. In this category of patients, it is strongly recommended to switch to analgesics of other classes.

Arthrospira platensis, commercially known as Spirulina, is a fresh-water cyanobacterium that is gaining even more attention in the last years due to its high biological and nutritional value. For this reason, it has been employed in several food applications, to obtain or enhance functional and technological properties of cheese, yogurt, bread, cookies or pasta. The aim of this work was to evaluate the potential boosting effect of two different concentrations (0.25% and 0.50%) of Arthrospira platensis on the fermentation capability of several starter LAB strains, 1 probiotic and 4 commercial mix culture. These strains were used to ferment three different substrates and their fermentation behaviors were evaluated by impedance analyses together with rheological and color measurements. It was demonstrated that the booster effect took place, but it was variable and dependent not only on the strain or mix culture used, but also on the substrate and Arthrospira platensis concentration. Also, rheological and color modifications were found to be dependent of these factors.

Observe the synergistic effect and dose-effect relationship of Trimethoprim (TMP) on bactericidal activity with Flos Lonicerae in vitro. Microamount chessboard dilution method was conducted to determine the minimal inhibitory concentration (MIC) of Trimethoprim, Flos Lonicerae, as well as the combination of Trimethoprim and Flos Lonicerae separately against Staphylococcus aureus, Escherichia coli in vitro and Salmonella. The pour plate count method was used to determine the combined bactericidal activity of Flos Lonicerae combined with Different concentrations TMP. The results showed that the MIC values of the combination of Flos Lonicerae with TMP was much less than the MIC values of the independent use of Flos Lonicerae or TMP, The FIC values of the combination of Flos Lonicerae with TMP were between 0.5 and 1, there was additive effect between them. The bactericidal rates were fitted with least square method, the 95% confidence intervals of the optimal blending quantity about the combination of Flos Lonicerae with TMP on the test organisms were 231μg·mL^-1-249μg·mL^-1, 237μg·mL^-1-259μg·mL^-1, and 235 -259μg·mL^-1

Computed tomography (CT) is a widely employed imaging modality with diverse clinical applications in pediatric and adult populations, offering numerous advantages. Despite several alternatives to imaging modalities with ionising radiation, CT scans have demonstrated persistent global popularity, contributing to a substantial amount of effective radiation doses for patients. This exposure results in hazards, including stochastic effects that amplify the radiation-induced cancer risk proportionally to the radiation dose received. CT-related radiation comprises a substantial portion of cumulative effective doses within diagnostic radiology, specifically impacting younger patient cohorts undergoing repeated investigations for chronic diseases over time. Scientific literature over recent decades has explored various methods to mitigate radiation doses during medical imaging. One notable strategy involves implementing low-dose and ultralow-dose CT protocols, maintaining diagnostic efficacy in acute and non-acute medical and surgical conditions. Utilising innovative image reconstruction algorithms, such as iterative reconstruction and emerging deep-learning algorithms based on artificial intelligence, plays a pivotal role in achieving an approximately 80% reduction in patient radiation compared to standard doses. This review article discusses the significance of low-dose protocols across a spectrum of acute and chronic medical conditions affecting different body systems.

Background: External beam radiation therapy requires a sophisticated and laborious planning procedure. To improve the efficiency and quality of the planning procedure, machine learning predictions of the dose distributions have been introduced to speed up the planning procedure and to serve as quality assurance. The most recent dose prediction models are based on deep learning U-Nets that give good approximations of the dose in 3D almost instantly. It is our purpose to train a 3D dose prediction for glioblastoma VMAT treatment and test its robustness and sensitivity for the purpose of quality assurance of automatic contouring. Methods: From a cohort of 125 glioblastoma (GBM) patients, VMAT plans were created according to a clinical protocol. The initial model was trained on a concatenated 3D U-Net. A total of 60 cases were used for training, 15 for validation and 20 for testing. The prediction model was tested for sensitivity to dose changes according to realistic contour variations. Additionally, the model was tested for robustness by exposing it to a worst-case test set containing out-of-distribution cases.Results: The initially trained prediction model had a dose score of 0.94 Gy and a mean DVH score for all structures of 1.95 Gy. In terms of sensitivity, the model was able to predict the dose changes that occurred due to the contour variations with a mean error of 1.38 Gy.Conclusions: We obtained a 3D VMAT dose prediction model for GBM with limited data, providing good sensitivity to realistic contour variations. We tested and improved the model's robustness, by targeted updating the training set, making it a useful technique for dose awareness in the contouring evaluation and quality assurance.

Neuroinflammation, defined as inflammatory reactions mediated by cytokines, chemokines, reactive oxygen species, and secondary messengers in the central nervous system (CNS) including the brain and spinal cord is the basis of many neurological disorders. Recently, erythropoietin (EPO) has been considered and studied as a modulator of neuroinflammation. On this article minireview of pathophysiology of neuroinflammation and the neuroprotective effects of EPO is discussed and a case of subacute huge subdural hematoma with double mydriasis operated urgently, treated with low daily dose (vs high dose once or twice a month in the literature) of EPO and recovered fully and discharged home with good consciousness is reported. In addition, the probable unfavorable outcome of erythropoietin administration in patients with neuroinflammation in COVID-19 is considered.

The SARS-CoV-2 Omicron variant and its sublineages continue to cause COVID-19—associated pediatric hospitalizations, severe disease, and death globally. BNT162b2 and CoronaVac are among the top most widely used COVID-19 vaccines. Much less is known on the Wuhan-Hu-1 strain based vaccines in the pediatric population compared to adults. Given the worldwide need for booster vaccinations to stimulate the immune response against new Omicron variants of SARS-CoV-2, we characterized the humoral and cellular immune response against Omicron variant BA.1 in a pediatric population aged 10 to 16 years who received heterologous vaccination based on two doses CoronaVac, two doses CoronaVac (2x) plus one booster doses BNT162b2 [CoronaVac(2x) + BNT162b2 (1x)], two doses CoronaVac plus two booster doses BNT162b2 [CoronaVac(2x) + BNT162b2 (2x)], and three doses BNT162b2. We observed that [CoronaVac(2x) + BNT162b2 (2x)] vaccination showed higher anti-S1 and neutralizing antibody titers and CD4 and CD8 T cell immunity specific to the Omicron variant compared to immunization with two doses CoronaVac alone. Furthermore, from all groups tested, immunity against Omicron was highest in individuals who received three doses BNT162b2. We conclude that booster vaccination with BNT162b2 promotes greater immunity against SARS-CoV-2 in the pediatric population compared to two doses CoronaVac alone.

In this study, the degradation characteristics of radio-frequency (RF) low-noise amplifier (LNA) based on silicon-germanium (SiGe) heterojunction bipolar transistors (HBTs) due to total ionizing dose (TID) are investigated. The small-signal equivalent model of a SiGe HBT is utilized to analyze circuit-level performance including the input and the output matching and noise figure (NF). As a target circuit, an LNA with a cascode common-emitter stage with emitter degeneration is studied and the equation of each performance parameter is derived. The RF LNA fabricated using commercial 350 nm SiGe technology was exposed to X-ray irradiation with the total dose up to 3 Mrad (SiO2). The experimental results exhibit that modeled device parameters estimate the degraded circuit performance. In addition, the relative impact of each parameter on the circuit metrics is revealed, which is expected from the derived design equations. The key device parameters for modeling TID-induced circuit degradations include the base resistance, the transconductance, and the base-to-emitter capacitance.

Sepsis is a major health problem and accounts for 20 per cent of deaths worldwide. It is the most expensive condition treated in United States hospitals at $27 billion per year or about $20,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only marginal impact. Mortality is about 27 per cent for hospitalized patients and about 42 per cent for patients in intensive care.There are two phases of sepsis – a hyper inflammatory phase and a subsequent hypo inflammatory phase.During the hyper inflammatory phase the metabolic rate increases associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and migration of those leucocytes to infected and damaged tissues and an increased supply and consumption of glucose to fuel this immune system.During the subsequent hypo inflammatory phase the metabolic rate declines and this is associated with a decrease in body temperature and a generalized decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life threatening circumstances. Thus adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened then mitochondrial production of ATP is partially or substantially suppressed in favor of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischemic, or damaged tissues.However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery.It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients leading to a substantial ATP deficit. This is the fundamental issue of sepsis.This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyper glycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypo metabolic (hypo inflammatory) phase of sepsis should significantly improve survival.

Celecoxib as adjuvant therapy has been shown in a small randomized trial for Covid-19 to prevent clinical deterioration and rapidly improve thoracic computerized axial tomography (CT-chest)¹. Multiple descriptive trials of high dose famotidine (both inpatient and outpatient) have demonstrated clinical response^2,3,4. We describe the rapid clinical responses after increasing the celecoxib dosage to 400mg bid with high dose famotidine 80mg qid in both a critical inpatient who on baseline required 40 liters per minute high flow nasal insufflation and an outpatient who declined admission but had critical Covid-19 biomarkers.

More than 600 Healthcare workers died due to COVID-19 infection until January 2022 in Ecuador. Even though the COVID-19 vaccines are safe, local, and systemic reactions were reported among physicians. This study aims to analyze the Adverse events (AEs) of COVID-19 vaccines with an emphasis on homologous and heterologous booster doses. An electronic survey was performed in Quito- Ecuador, directed to physicians who were vaccinated with the three doses of COVID-19 vaccines. 210 participants were analyzed after administering any doses of the vaccines. At least one AE was identified in 60.0% (126/210) of the sample after the first dose, 52.40% (110/210) after the second dose, and 75.2% (158/210) after the booster dose. The most frequent AEs were localized pain, myalgia, headache, and fever. At least one drug was used in 44.3% of the population after the first dose, 37.1% after the second dose, and 63.8% in the booster dose. Heterol-ogous booster produces more AEs compared with homologous booster (80.1% vs. 53.8%), and 77.3% of participants reported that interfered with daily activities. Similar studies agree that reactogenicity occurs mainly with heterologous vaccination compared to ho-mologous vaccination. This situation affected physicians’ performance in daily activities and led them to use medication for the symptoms

Background: COVID-19 booster uptake remained poor among healthcare workers (HCW) despite evidence of improved immunity against Delta and Omicron variants. While most studies used a questionnaire to assess hesitancy, this study aimed to identify factors affecting true booster hesitancy by examining actual vaccine uptake across time. Method: COVID-19 vaccination database records among HCW working at 7 Singaporean public primary care clinics between January to December 2021 were extracted, with gender, profession, place of practice, vaccination type and dates. Time to booster was calculated from the date of vaccination minus date of eligibility. Chi-square test was used to compare relationship between 1st dose and booster hesitancy, Kaplan-Meier method and Log-rank test were adopted to evaluate differences in cumulative booster uptake. Multivariate cox regression was used to investigate predictors for timely booster vaccination. Vaccination rate was charted across time and corroborated with media releases pertaining to legislative changes. Results: 877 of 891 (98.9%) primary care HCW were fully vaccinated, 73.8% of eligible HCW had taken the booster. HCW were less booster hesitant [median 16 (5-31.3) days] compared to the 1st dose [median 39 (13-119.3) days]. 1st dose hesitant HCW were more likely to be booster hesitant (OR=3.66, 95%CI 2.61-5.14). Adjusting for sex, workplace and time to 1st dose, ancillary (HR=1.53, 95%CI 1.03-2.28), medical (HR=1.8, 95%CI 1.18-2.74) and nursing (HR=1.8, 95%CI 1.18-2.37) received boosters earlier compared with administrative staff. No temporal relationship was observed between booster uptake, legislative changes and COVID-19 infection numbers. Conclusion: Vaccine hesitancy among HCW had improved from booster to 1st dose, with timely booster vaccination among medical and nursing staff. Tailored education, risk messaging and strategic legislation might help to reduce delayed booster vaccination.

Background: The coronavirus disease-19 (COVID-19) has spread globally with more than 80,000 people infected, and nearly 3000 patients died. Currently, we are in an urgent need for effective treatment strategy to control the clinical deterioration of COVID-19 patients. Methods: The clinical data of 10 COVID-19 patients receiving short-term moderate-dose corticosteroid (160mg/d) plus immunoglobulin (20g/d) were studied in the North Yard of The First Hospital of Changsha, Hunan from January 17^th to February 27^th, 2020. Epidemiological, clinical, laboratory, radiological findings were analyzed. Results: After treatment with combination of low-dose corticosteroid (40-80mg/d) and immunoglobulin (10g/d), patients’ lymphocyte count (0.88±0.34 vs 0.59±0.18, P<0.05), oxygenation index including SPO₂ (94.90±2.51 vs 90.50±5.91, P<0.05) and PaO₂/FiO₂ (321.36±136.91 vs 129.30±64.97, P<0.05) were significantly lower than pre-treatment, and CT showed that the pulmonary lesion deteriorated in all patients. While after treatment of short-term moderate-dose corticosteroid plus immunoglobulin, patients’ APACHE Ⅱ score (9.10±6.15 vs 5.50±9.01, P<0.05), body temperature (37.59±1.16 vs 36.46±0.25, P<0.05), lymphocyte count (0.59±0.18 vs 1.36±0.51, P<0.05), Lactate dehydrogenase (419.24±251.31 vs 257.40±177.88, P<0.05), and C-reactive protein (49.94±26.21 vs 14.58±15.25, P<0.05) significantly improved compared with post-treatment with low-dose therapy. In addition, oxygenation index including SPO₂ (90.50±5.91 vs 97.50±1.18, P<0.05), PaO₂ (60.47±14.53 vs 99.07±34.31, P<0.05), and PaO₂/FiO₂ (129.30±64.97 vs 340.86±146.72, P<0.05) significant improved. Furthermore, CT showed that pulmonary lesions obviously improved in 7 patients. After systematic therapy, 4 out of 10 COVID-19 patients recovered and discharged. Conclusions: Short-term moderate-dose corticosteroid plus immunoglobulin is effective for reversing the continued deterioration of COVID-19 patients who failed to respond to the low-dose therapy. Funding: This work was supported by the Innovative Major Emergency Project Funding against the New Coronavirus Pneumonia in Hunan Province (Dr. Ji-Yang Liu, number 2020SK3014; Dr. Yuan-Lin Xie, number 2020SK3013).

This was a retrospective cohort study, which aimed to investigate the factors associated with hesitancy to receive the third dose of coronavirus disease 2019 (COVID-19) vaccine. A paper-based questionnaire survey was administered to all participants. Accordingly, the study included participants who provided answer in the questionnaire whether they have an intent to receive the third dose of vaccine. Data on sex, age, area of residence, adverse reactions after the second vaccination, whether the third vaccination was desired, and reasons to accept or hesitate booster vaccination were retrieved. Among the 2439 participants with mean (±SD) age of 52.6±18.9 years, and median IgG-S antibody titer of 324.9 (AU/mL), 97.9% of participants indicated their intent to accept a third vaccination dose. The logistic regression revealed that younger age (OR=0.98; 95% CI: 0.96-1.00) and higher antibody level (OR=2.52; 95% CI: 1.27-4.99) are positively associated with the third vaccine hesitancy. The efficacy of the COVID-19 vaccine and concerns about adverse reactions had significant impact on the third vaccination behavior. A rapid increase in the booster dose rate is needed to control the pandemic, and specific approaches should be taken in these groups that are likely to hesitate the third vaccine, subsequently increasing booster contact rate.

Bacillus Calmette-Guérin (BCG) is the only widely used prophylactic tuberculosis (TB) vaccine that can prevent severe TB in infants. However, it provides poor protection in adults, and therefore, there in ongoing research on new TB vaccines and immunization strategies with more durable immune effects. The recombinant BCG and BCG prime-protein booster are two important vaccine strategies that have recently been developed based on BCG and could improve immune responses. In this study, three immune strategies based on four protective antigens, namely, ESAT-6, CFP-10, nPPE18, and nPstS1, were applied to construct recombinant rBCG-EPCP009, EPCP009 subunit protein, and BCG prime-EPCP009 booster vaccine candidates. The short- and long-term immune effects after vaccination in Balb/c mice were evaluated based on humoral immunity, cellular immunity, and the ability of spleen cells to inhibit in vitro mycobacterial growth. At 8 and 12 weeks after the initial immunization, splenocytes from mice inoculated with the BCG prime-EPCP009 protein booster secreted higher levels of PPD- and EPCP009-specific IFN-γ, IL-2, TNF-α, IL-17, GM-CSF, and IL-12 and had a higher IFN-γ⁺CD4⁺ TEM:IL-2⁺CD8⁺ TCM cell ratio than splenocytes from mice inoculated with the rBCG-EPCP009 and EPCP009 proteins. In addition, the EPCPE009-specific IgG2a/IgG1 ratio was slightly higher in the BCG prime-EPCP009 protein booster group than in the other two groups. The in vitro mycobacterial inhibition assay showed that the splenocytes of mice from the BCG prime-EPCP009 protein booster group exhibited stronger inhibition of Mycobacterium tuberculosis （M. tuberculosis）growth than the splenocytes of mice from the other two groups. These results indicate that the BCG prime-EPCP009 protein booster exhibited superior immunogenicity and M. tuberculosis growth inhibition to the parental BCG, rBCG-EPCP009, and EPCP009 proteins under in vitro conditions. Thus, the BCG prime-EPCP009 protein booster may be important for the development of a more effective adult TB vaccine.

The calculation of effective doses is crucial in many medical and radiation fields, in order to ensure safety and compliance with regulatory limits. Traditionally, Monte Carlo codes using detailed human body computational phantoms have been used for such calculations. Monte Carlo dose calculations can be time-consuming and require expertise in different processes when building the computational phantom and dose calculations. This study employs various machine learning (ML) algorithms to predict the organ doses and effective dose conversion coefficients (DCCs) for different anthropomorphic phantoms. A comprehensive data set comprising neutron energy bins, organ labels, masses, and densities is compiled from Monte Carlo studies, and is used to train and evaluate the supervised ML models. This study includes a broad range of phantoms, including those from the International Commission of Radiation Protection (ICRP-110, ICRP-116 phantom), the Visible-Human Project (VIP-man phantom), and the Medical Internal Radiation Dose Committee (MIRD-Phantom), with row data prepared using numerical data and organ categorical labeled data. Extreme gradient boosting (XGB), gradient boosting (GB), and the random forest-based Extra Trees regressor are employed to assess the performance of the ML models against published ICRP neutron DCC values using the mean square error, mean absolute error, and R² metrics. The results demonstrate that the ML predictions significantly vary in lower energy ranges and vary less in higher neutron energy ranges, while showing good agreement with ICRP values at mid-range energies. Moreover, the categorical data models align closely with the reference doses, suggesting the potential of ML in predicting effective doses for custom phantoms based on regional populations, such as the Saudi voxel-based model. This study paves the way for efficient dose prediction using ML, particularly in scenarios requiring rapid results without extensive computational resources or expertise. The findings also indicate potential improvements in data representation and the inclusion of larger data sets to refine model accuracy and prevent overfitting. Thus, ML methods can serve as valuable techniques for the continued development of personalized dosimetry.

Zero-dose children, or children who have not received any routine vaccination, are a priority population for global health policy makers as these children are at high risk of mortality from vaccine-preventable illnesses. We conducted a narrative review to identify potential interventions, both within and outside of the health sector, to reach zero-dose children. We reviewed peer-reviewed and grey literature and identified 59 relevant resources. Additionally, we interviewed six key informants to enhance synthesis of our findings. Data were organized into three priority settings: (1) urban slums, (2) remote or rural communities, and (3) conflict settings. We found that zero-dose children in the three-priority settings face differing barriers to vaccina-tion and, therefore, require context-specific interventions, such as leveraging slum health commit-tees for urban slums or integrating with existing humanitarian response services for conflict set-tings. Three predominant themes emerged for grouping the various interventions: (1) community engagement, (2) health systems strengthening and integration, and (3) technological innovations. The barriers to reaching zero-dose children are multifaceted and nuanced to each setting, there-fore, no one intervention is enough. Technological interventions especially must be coupled with community engagement and health systems strengthening efforts. Evaluations of the suggested interventions are needed to guide scale up, as the evidence-base around these interventions is rel-atively small.

Vaccines are crucial for controlling the COVID-19 pandemic, and booster doses are becoming increasingly important. This study aimed to assess the efficacy of the ChAdOx1 nCoV-19 vaccine from AstraZeneca as a third dose in healthcare workers at different time intervals (one, three, and six months). Two methods to measure immune response—ELISA (EUROIMMUN Medizinische Labordiagnostika AG, Luebeck, Germany) and ELISpot (Mabtech AB, Macka Strand, Sweden)—were used. A total of 170 participants were included in the study. The results showed that while IgG levels decreased at six months compared to levels at one and three months, they were still significantly higher than the baseline. Furthermore, neutralizing levels at three and six months after the third dose were not significantly different. These findings suggest that the immune response induced by the vaccine is robust and effective for several months. These results have significant implications for public health policymakers, as they provide strong support for booster vaccinations. The ChAdOx1 nCoV-19 vaccine appears to be a reliable option for preventing the spread of COVID-19, and this study provides valuable information for healthcare workers and policymakers in managing the pandemic.

Purpose: Novel coronavirus disease (COVID-19) is the current global concern. Radiotherapy (RT), commonly employed in cancer management, has been considered one of the potential treatments for COVID-19 pneumonia. Here, we present the final report of the pilot trial evaluating the efficacy and safety of low-dose whole-lung irradiation (LD-WLI) in patients with COVID-19 pneumonia. Methods and Materials: We enrolled patients with moderate COVID-19 pneumonia who were older than 60 years. Participants were treated with LD-WLI in a single fraction of 0.5 or 1.0Gy along with the national protocol of COVID-19. The primary endpoints were improvement of SpO₂, the number of hospital/ICU stay days, and the number of intubations after RT and the secondary endpoints were alterations of the c-reactive peptide, interleukin-6, ferritin, procalcitonin, and D-dimer. The response rate (RR) was defined as a rise in SpO₂ upon RT with rising or constant trend in the next two days, and clinical recovery (CR) included patients who were discharged from the hospital or acquired SpO₂ ≥93% on room air. Results: Between 21 May 2020 and 2 July 2020, ten patients were enrolled. The median age was 75 years, 80% were male, and 80% had comorbidities. The first five patients received a single 0.5Gy-WLI, and others received 1.0Gy. Patients were followed for 2-14 days (median 5.5 days). Following one day, nine patients experienced an improvement in SpO₂. Five patients were discharged (median 6^th day, range 2^nd-14^th day), and four patients died (median 7^th day, range 3^rd-10^th day). Overall, the RR and CR were 60.0% and 55.5%, respectively. The RR and CR rates of 0.5- and 1.0Gy group were 80% vs 40% and 75% vs 40%, respectively. No acute radiation-induced toxicity was recorded. Conclusions: LD-WLI with a single 0.5Gy fraction seems to be a more appropriate dose to warrant further evaluation in a large-scale, randomized trial.

Most studies on vaccines of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on antibody, but cellular immunities are also critical. We aimed to evaluate the immune reactions of hemodialysis (HD) patients after the administration of the booster dose from the perspective of both humoral and cellular immunities. Hemodialysis patients (HD group) and age- and sex-matched non-dialysis individuals (control group) receiving three doses of BNT162b2 vaccine were measured for anti-SARS-CoV-2 immunoglobulin (IgG) and T-SPOTⓇ.COVID test (T-SPOT) before, 3 weeks, and 3 months after the booster dose. The HD group had significantly higher SARS-CoV-2 IgG levels 3 weeks and 3 months after the booster dose than the control group, although both groups had no difference in SARS-CoV-2 IgG levels before the booster dose. Moreover, the HD group had significantly higher T-SPOT levels before and 3 weeks after the booster dose than the control group, but the difference was not significantly different 3 months after the booster dose. Furthermore, the incidence rates of local and systemic adverse reactions were significantly higher in the HD group than in the control group. HD patients obtained higher SARS-CoV-2 IgG levels and SARS-COV-2-specific T-cell responses after the booster dose than control.

Vitamin D deficiency and insufficiency are highly prevalent in CKD affecting over 80% of hemodialysis (HD) patients and require therapeutic intervention. Nephrological societies suggest the administration of cholecalciferol according to the guidelines for the general population. The aim of the observational study was to evaluate the efficacy and safety of the therapy with a high dose of cholecalciferol in HD patients with 25(OH)D deficiency and insufficiency to reach the target serum 25(OH)D level &gt; 30 ng/mL. 22 patients (16 M), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration of 13.05 (9.00–17.90) ng/mL were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session). All patients achieved the target value &gt;30 ng/mL, with a mean time of 2.86 ± 1.87 weeks. In the first week, the target level of 25(OH)D (100%) was reached by 2 patients (9.09%), in the second week – by 15 patients (68.18%), in the fourth week – by 18 patients (81.18%) and in the ninth week by all 22 patients (100%). A significant increase in 1,25(OH)2D levels was observed during the study, however, only 2 patients (9.09%) achieved a concentration of 1,25(OH)2D above 25 ng/mL – the lower limit of the reference range. The intact PTH concentrations remained unchanged during the observation period. No episodes of hypercalcemia, and one new episode of hyperphosphatemia were observed. In conclusion, our study showed that the administration of a high therapeutic dose of cholecalciferol allowed for a quick, effective, and safe leveling of 25(OH)D concentration in HD patients.

Background: The uptake of COVID-19 booster vaccines has been significantly low. Therefore, it is questionable whether combining the COVID-19 booster vaccines with Influenza vaccines can increase the population's interest in taking such vaccines and manage the health pandemic effectively. Methodology: In this systematic review and meta-analysis, a synthesis of the findings and summary of a total of 30 research articles based on the topic, ‘combining influenza and COVID-19 booster vaccination strategy’ was undertaken. The research articles were identified from three databases, namely, PubMed, Cochran Library, and Google Scholar using specific keywords and inclusion criteria. However, research articles that were not peer-reviewed and not published in English were excluded from the systematic review and meta-analysis. The average risk ratio of the included articles was 0.78% based on a 95% CI. On the other hand, the heterogeneity between such studies was I² = 35%, while the statistical significance of their findings occurred at p < 0.05. The average p-value of the included research studies was p = 0.62, implying that the null hypothesis was not rejected in almost all the studies. Results: A synthesis of the chosen research articles revealed that when influenza and COVID-19 booster vaccines are combined, there is potential for an increase in the uptake of the latter, mainly because many populations have already been accustomed to taking influenza vaccines on an annual basis. Conclusions: In this way, through such findings, medical health experts can make informed decisions to increase the population's willingness to receive the COVID-19 booster vaccines.

ABSTRACT Objectives: Typical Diagnostic Reference Levels (DRL) in terms of Computed Tomography Dose Index (CTDI) and patient dose in terms of Effective Dose (ED ) and Size Specific Dose Estimate (SSDE) were estimated in Computed Tomography (CT) guided biopsy procedures. Materials and Methods: A total of 226 CT biopsy procedures - Iliac bone, liver, lung, mediastinum and para-aortic tissue - were retrospectively analyzed and Typical DRL extracted based on ICRP 135 instructions. Results: For helical mode acquisitions, DRLs in terms of CTDIvol were 9.7 mGy for Iliac bone, 8.9 mGy for liver, 8.8 mGy for lung, 7.9 mGy for mediastinal mass and 9 mGy for para-aortic lymph nodes biopsy procedures. For biopsy acquisitions, DRL values were 7.3 mGy, 7.7 mGy, 5.6 mGy, 5.6 mGy and 7.4 mGy respectively. Also, SSDE median values ranged from 7.6 mGy to 10 mGy for biopsy acquisitions and 11,3 mGy to 12,6 mGy for helical acquisitions, as well as the median values for effective dose ranged from 1.6 mSv to 5,7 mSv for biopsy scans and 3.9 to 9.3 mSv for helical scans. Conclusions: The use of DLR as an optimization tool for CT-guided biopsy procedures revealed that helical scans across the entire anatomical region greatly affect radiation dose compared to biopsy acquisitions.

This commentary is focused on radioactive contaminations in the Urals, where the consequences were more severe in the long term than those after the Chernobyl accident. The difference is that the latter was a technogenic catastrophe, but the former - a radioactive contamination tolerated since 70 years with several accidents in between. In earlier publications of Russian researchers no cancer frequency elevation was reported after exposures below 0.5 Sv or generally in the populations exposed to low doses. Later on, the same scientists started to claim similar relative risks for cancer and other diseases among exposed people in the Urals and in atomic bomb survivors from Hiroshima and Nagasaki. Apparently, an unofficial directive has been behind this ideological shift noticed around the year 2005. Trimming of statistics has been not unusual in the former Soviet Union. Potential motives included fostering radiophobia, stirring anti-nuclear protests in other countries and strangulation of nuclear energy aimed at the boosting of fossil fuel prices. Recent publications claiming cardiovascular risks after low-dose low-rate exposures and recommending more stringent standards of radiological protection are discussed here in some detail. Such recommendations for dose rates compatible with the natural radiation background are obviously nonsensical.

To date, radiation adaptation response has been reported as a low-dose related phenomenon and has been associated with radiation hormesis. Well-known cancers are caused by non-radiation active reactants, in addition to radiation. A model of suppression for radiation-specific cancers was previously reported, but the model did not target radiation-nonspecific cancers. In this paper, we describe kinetic models of radiation-induced suppressors for general radiation non-specific cancers, estimating the dose that induces the maximum hormesis effect while satisfying the condition that the risk is approximately proportional to dose above 100 mSv. It was found that the radiation hormesis effect is maximal at about 20 mSv when the rate constant for generation is the same as the rate constant for decomposition. When the two rate constants are different, the dose at which the radiation hormesis effect is maximized depends on both rate constants, but the dose increases as the two rate constants approach each other, reaching a maximum of about 20 mSv. This conclusion may lead to the discovery of unknown cancer suppressors at low doses and the development of cancer suppression methods in the future.

The aim of the present study was to assess the efficacy of All Cosmos Industries (ACI) bio-organic and bio-chemical fertilizers and ACI N-Fixer (N-Bio Booster) on the paddy yields based on the field trial plots at Langkat, Medan, Indonesia. This application of ACI bio-organic fertilizer (NPK 5/5/5) and ACI bio-chemical (NPK 15/15/15) fertilizer and ACI N-Fixer tests were conducted at the paddy farm at Langkat from May-October 2018. This study employed a factorial randomized complete block design which consisted of two factors, namely: Factor I with four types of fertilizers while Factor II consisted of two paddy varieties (Inpari 30 and Inpari 32). Overall, the filled grains in the ACI treatments are significantly (P< 0.05) higher than those in the control treatments that used Normal Chemical Compound NPK. Overall, total weight per meter² (368-617g) in ACI treatments are also significantly (P< 0.05) higher than those (319-371g) in the control treatments. At harvesting time at 105 days after transplanting, significantly higher (P< 0.05) colony counts (13-15 x 10⁶ CFU/mL) (for ACI treatments), than those (8 x 10⁶ CFU/mL) in the controls positively indicated higher total yields of paddy grains per hectare. It was found that the application of ACI bio-organic and bio-chemical fertilizers and ACI N-Fixer can improve paddy yields of the two rice varieties, between 16.4-38.2% (up to 5.75 MT/ha), in the field trial plots at Langkat. These commercial fertilizers play an imperative role in refining the soil fertility and thereby can increase the yield of rice production. Therefore, it is highly recommended that ACI bio-organic and ACI bio-chemical fertilizers and ACI N-Fixer (N-Bio Booster) can be employed to increase the paddy yield in this region.

Patients with lean NAFLD make up an increasing subset of liver diseases. The association between lean NAFLD and feutin-A, which serves as a hepatokine and adipokine, has never been examined. Our study aimed to explore the association of serum fetuin-A among lean and nonlean patients. The study comprised 606 adults from the community, stratified into lean or nonlean (BMI </≥ 24 kg/m2) and NAFLD or non-NAFLD (scoring of ultrasonographic fatty liver indicator, US-FLI ≥ 2/<2). Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD among the tertiles of fetuin-A after adjustment. The least square means were computed by general linear models to estimate marginal means of the serum fetuin-A concentrations in relation to the NAFLD groups. The OR of having NAFLD for the highest versus the lowest tertile of fetuin-A was 2.62 (95% CI: 1.72-3.98; P for trend<0.001). Stratifying by BMI, the OR of having lean NAFLD for the highest versus the lowest tertile of fetuin-A was 2.09 (95% CI: 1.09-3.98; P for trend 0.026), while nonlean NAFLD had no significant association with the fetuin-A gradient after adjustments. Fetuin-A was positively associated with lean NAFLD after adjusting for central obesity and insulin resistance.

Hispanic/Latino communities have suffered a disproportionate burden due to the COVID-19 pandemic. Although Puerto Rico has one of the highest COVID-19 primary series vaccination rates nationwide, this estimate contrasts with the low uptake of booster doses (32.7%). This study aimed to assess health belief correlates of COVID-19 vaccine booster uptake. PR-CEAL recruited 787 participants via an online survey between December 2021 and January 2022. Sociodemographic characteristics and questions framed using the Health Belief Model were assessed. Analyses included adjusted Poisson regression models to estimate prevalence ratios (PR) of booster refusal. Overall, 22% of participants planned (10%) or refused (12%) the vaccine booster. Participants with lower income [PR=1.92; 95%CI=1.30, 2.84], in disagreement with vaccine benefits [PR=4.16; 95%CI=3.06, 5.64], and in agreement with booster concerns [PR=2.93; 95%CI=2.12, 4.04], efficacy [PR=2.76; 95%CI=2.00, 3.82], and safety [PR=2.97; 95%CI=2.15, 4.08] were significantly more likely to refuse the booster. Booster vaccination refusal was associated with lower perceived vaccine benefits and higher barriers among adults in Puerto Rico. Results informed CEAL team intervention strategies for public health campaigns to increase booster vaccine uptake.

Introduction: The top priority of active immunoprophylaxis of pertussis is immunisation of infants as they can develop severe multiple-organ complications or even die from this disease. Objectives: The aim of the work is the identification of factors negatively affecting vaccine immunity to pertussis in preschool children prior to the administration of the first booster. Patients and Methods: The research was conducted on 352 children from 4.5 to 5.9 years of age who were hospitalised in the University Children’s Hospital in Lublin (Poland) from 1 January 2012 to 31 December 2015. The children taking part in the study had been administered all the mandatory vaccines from their birth to the age of 2 or 2.5 years old according to the Polish Immunisation Program 2008-2009. The immunoenzymatic method ELISA was applied to assess vaccine immunity to tetanus, diphtheria, pertussis, Haemophilus influenzae type b (Hib), poliomyelitis (IPV), mumps, rubella and measles. The level of vaccine antibodies to hepatitis type B was determined chemilumiscently. Results: The protective antibody titer was not found in 41 (11.65%) children before the administration of the booster. To verify the collective impact of parameters analised on antibody titer to pertussis, the Generalized Linear Model (GLZ) was used. Gender, type of vaccine, asthma, Hib and mumps antibody titers have been shown to be predicators of vaccine immunity to pertussis. Conclusions: Immunomodulation considered on the example of titer of IgG antibody to pertussis can serve as a useful model of the assessment of development of acquired immunity after mandatory vaccinations.

Hyper-radiosensitivity (HRS) is the increased sensitivity to low doses of ionizing radiation observed in most cell lines. We previously demonstrated that HRS is permanently abolished in cells irradiated at a low dose rate (LDR), in a mechanism dependent on transforming growth factor β3 (TGF-β3). In this study, we aimed to elucidate the activation and receptor binding of TGF-β3 in this mechanism. T-47D cells were pre-treated with inhibitors of potential receptors and activators of TGF-β3, along with addition of small extracellular vesicles (sEVs) from LDR primed cells, before their radiosensitivity was assessed by the clonogenic assay. The protein content of sEVs from LDR primed cells was analyzed with mass spectrometry. Our results show that sEVs contain TGF-β3 regardless of priming status, but only sEVs from LDR primed cells remove HRS in reporter cells. Inhibition of the matrix metalloproteinase (MMP) family prevents removal of HRS, suggesting an MMP-dependent activation of TGF-β3 in the LDR primed cells. We demonstrate a functional interaction between TGF-β3 and activin receptor like kinase 1 (ALK1), by showing that TGF-β3 removes HRS through ALK1 binding, independent of ALK5 and TGF-βRII. These results are an important contribution to a more comprehensive understanding of the mechanism behind TGF-β3 mediated removal of HRS.

Objectives. Optimal treatment strategy for ischemic stroke in patients presenting with tandem occlusions the internal carotid artery remains controversial. Several studies have demonstrated better clinical outcomes after eptifibatide, which is a short half-life antiplatelet agent. This retrospective analysis was focused at safety and efficacy of administration of low-dose eptifibatide in stroke patients with tandem lesions. Methods. We evaluated results of endovascular treatment in 148 stroke patients with tandem lesions. Patients in whom balloon angioplasty alone resulted in satisfactory cerebral flow did not receive eptifibatide (33 patients); others received this drug together with stent implantation (115 patients). Eptifibatide was given in as intravenous bolus 180 g/kg, and then in modified low dose of 1 g/kg/min for 24 hours. Results. There were no statistically significant differences between both groups regarding 30-day mortality, frequency of thrombotic events and hemorrhagic complications. Analysis of clinical status at 30-day follow-up revealed that administration of eptifibatide was associated with statistically significant better outcome: a higher rate of either no neurological symptoms or only mild symptoms (4 NIHSS points maximally). Conclusions. Administration of eptifibatide in stroke patients presenting with tandem lesions is relatively safe. Moreover, treatment with this drug can improve clinical outcomes in these challenging patients.

We compared the functional and morphologic effects in the loading dose between patients with treatment-naïve neovascular age-related macular degeneration treated with either intravitreal aflibercept (IVA) or intravitreal faricimab (IVF) injection in clinical settings. This retrospective study included 30 eyes from 28 patients who started IVA treatment between June and September 2022 and 30 eyes from 29 patients who started IVF treatment between October 2022 and March 2023. The mean best corrected visual acuity (BCVA) significantly improved from pre-treatment after loading dose in the IVA group (from 0.46 ± 0.46 to 0.36 ± 0.37, p=0.0047) and not in the IVF group (from 0.46 ± 0.41 to 0.44 ± 0.45, p=0.60). The mean central retinal thickness (CRT) significantly improved in both groups. The proportion of eyes with residual exudative change was greater in the IVF group than in the IVA group at 2 months after the first treatment. (p=0.026) We further analyzed the patients who obtained complete resolution of exudative changes after the loading dose. The IVA group had a significant improvement in BCVA, whereas the IVF group did not p=0.0047 and 0.20, respectively) Although IVA and IVF significantly improved the CRT, the BCVA improved significantly in IVA group and not in IVF group.

Ecdysterone is a phytosteroid widely discussed for its various pharmacological, growth-promoting and anabolic effects mediated by activation of estrogen receptor beta (ERbeta). Performance-enhancement in sports was demonstrated recently, and ecdysterone was consequently included in the Monitoring Program to detect potential patterns of misuse in sport. Only few studies on the pharmacokinetics of ecdysterone in humans have been reported so far. In this study, post-administration urines in twelve volunteers (single dose of 50 mg of ecdysterone) were analyzed using dilute-and-inject liquid chromatography-tandem mass spectrometry. Identification and quantitation of ecdysterone and of two metabolites, 14-deoxy ecdysterone and 14-deoxy poststerone was achieved. Ecdysterone was the most abundant analyte present in post-administration urines, detected for more than 2 days with a maximum concentration (Cmax) in the 2.8-8.5 h urines (Cmax = 4.4-30.0 µg/mL). The metabolites 14-deoxy ecdysterone and 14-deoxy poststerone were detected later reaching the maximum concentrations at 8.5-39.5 h (Cmax = 0.1-6.0 µg/mL) and 23.3-41.3 h (Cmax = 0.1-1.5 µg/mL), respectively. Cumulative urinary excretion yielded average values of 18%, 2.3% and 1.5% for ecdysterone, 14-deoxy ecdysterone and 14-deoxy poststerone, respectively. Ecdysterone and 14-deoxy ecdysterone were excreted following first order kinetics with half-lives calculated with three hours, while pharmacokinetics of 14-deoxy poststerone needs further evaluation.

While there is a coordinated effort around reaching zero dose children and closing existing equity gaps in immunization delivery, it’s important that there is agreement and clarity around how ‘zero dose status’ is defined and what is gained and lost by using different indicators for zero dose status. There are two popular approaches used in research, program design, and advocacy to define zero dose status: one uses a single vaccine to serve as a proxy for zero dose status, while another uses a subset of vaccines to identify children who have missed all routine vaccines. We provide a global analysis utilizing the most recent publicly available DHS and MICS data to compare the number, proportion, and profile of children 12 to 23 months who are ‘penta-zero dose’ (have not received the pentavalent vaccine), ‘truly’ zero dose (have not received the BCG, polio, pentavalent, and measles vaccines), and ‘misclassified’ zero dose children (those who are penta-zero dose but have received at least one other vaccine). Our analysis includes 194,829 observations from 82 low- and middle-income countries. Globally, 14.2% of children are penta-zero dose and 7.5% are truly zero dose, suggesting that 46.5% of penta-zero dose children have had at least one contact with the immunization system. While there are similarities in the profile of children that are penta-zero dose and truly zero dose, there are key differences between the proportion of key characteristics among truly zero dose and misclassified zero dose children, including access to maternal and child health services. By understanding the extent of connection zero dose children may have with the health and immunization system and contrasting it with how much the use of a more feasible definition of zero dose may underestimate the level of vulnerability in the zero dose population, we provide insights that can help immunization programs design strategies that better target the most disadvantaged populations. If the vulnerability profiles of the truly zero dose children are qualitatively different from that of the penta zero dose children, then failing to distinguish the truly zero dose populations, and how to optimally reach them, may lead to the development of misguided or inefficient strategies for vaccinating the most disadvantaged population of children.

An increase in Spodoptera species was reported in Bt soybean fields expressing Cry1Ac insecticidal proteins in Brazil, requiring additional management with chemical insecticides. Here, we evaluated the dose effects of flubendiamide and thiodicarb on Spodoptera cosmioides (Walker, 1858), Spodoptera eridania (Stoll, 1782), Spodoptera albula (Walker, 1857) and Spodoptera frugiperda (J. E. Smith, 1797) (Lepidoptera: Noctuidae) that survived on MON 87751 × MON 87708 × MON 87701 × MON 89788, expressing Cry1A.105, Cry2Ab2 and Cry1Ac; MON 87701 × MON 89788 soybean, expressing Cry1Ac; and non-Bt soybean. On unsprayed Cry1A.105/Cry2Ab2/Cry1Ac soybean, only S. frugiperda showed ~60% mortality after 10 d, whereas S. cosmioides, S. eridania and S. albula showed >81% mortality. Surviving larvae of all species on this Bt soybean showed &gt;80% mortality when exposed to the field label dose of flubendiamide (70 mL/ha) or thiodicarb (400 g/ha) or at 50% of these doses. In contrast, all four species had <25% and <19% mortality on Cry1Ac and non-Bt soybean, respectively. Surviving S. cosmioides, S. eridania and S. albula on these soybean types presented >83% mortality post-exposure to both dose levels of flubendiamide and thiodicarb. Some S. frugiperda larvae surviving on Cry1Ac and non-Bt soybean sprayed with a 50% dose of either insecticide developed into adults. However, L1 larvae developing on Cry1Ac soybean leaves sprayed with flubendiamide and L2 larvae on this soybean sprayed with thiodicarb had a prolonged immature stage, and females lower fecundity, which are likely to impact its population growth on soybean.

Flotation of small particles is one of the global challenges facing the mineral raw materials processing industry. Large amounts of non-ferrous and rare metals are lost in the flotation tailings in the form of mineral particles below 15 µm in size as a result of the low effectiveness of their capture by coarse bubbles generated in conventional flotation machines. The method of combined microflotation, which is being developed in recent years, uses not only coarse but also microbubbles (MB) produced in the stand-alone generator of air-in-water microdispersion, which serves as the flotation carriers. Depending on the dose of MB, the effect of their application may be both positive, but also negative. The theoretical analysis of various mechanisms of particle transfer onto the surface of coarse bubbles and further into the froth layer allowed to obtain the formula for the optimal MB dose f=2dddpρp, where dd is MB size; dp and ρp respectively are the size and the density of particles. Experiments performed on the copper ore flotation tailings at the Atalaya Mining (Spain) and Chaarat Kapan (Armenia) concentrators showed that, besides the optimal MB dose in the range of 1-3 ml/g, there is another optimal MB dose in the range of 10-20 ml/g, where the copper recovery increases by several percent compared to the reference test (f= 0). In the area between the optimal MB doses, the deep minimum in copper recovery is observed, which value is by several percent lower compared to the value in the reference test.

The present study aimed to examine the stereoselective pharmacokinetics of racemic ketamine in dogs at low dose. Secondary aims were to identify associated behavioural side effects and propose a ketamine infusion rate. The study was conducted on nine intact male beagles, with each dog undergoing two treatments (BOL and INF). For treatment BOL, a single intravenous bolus of 1 mg/kg racemic ketamine was administered over 2 minutes. The treatment INF involved an initial bolus of 0.5 mg/kg given over 1 minute, followed by an infusion at 0.01 mg/kg/min for 1 hour. Blood samples were collected from the left cephalic vein for pharmacokinetic analysis. The median R/S enantiomer ratio of ketamine remained close to 1 throughout the study. However, levels of S-norketamine were significantly higher than those of R-norketamine across all time points. Based on the collected data, the infusion rate predicted to achieve a steady state racemic ketamine plasma concentration of 150 ng/mL was 1.7 mg/kg/h. Furthermore, employing ROC curve analysis, a racemic ketamine plasma concentration of 102 ng/mL was defined as the cut-off value, correlating with the occurrence of undesirable behavioural patterns.

The total ionizing dose (TID) effect significantly impacts the electrical parameters of fully depleted silicon on insulator (FDSOI) devices and even invalidates the on-off function of devices. At present, most of the irradiation research on the circuit level is focused on the single event effect, and the research on the total ionizing dose effect is very little. Therefore, this study mainly analyzes the influence of TID effects on a CMOS inverter circuit based on 22 nm FDSOI transistors. First, we constructed and calibrated an N-type FDSOI metal-oxide semiconductor (NMOS) structure and P-type FDSOI metal-oxide semiconductor (PMOS) structure. The transfer characteristics and trapped charge distribution of these devices were studied under different irradiation doses. Next, we studied the TID effect on an inverter circuit composed of these two MOS transistors. The simulation results show that when the radiation dose is 400 krad (Si), the logic threshold drift of the inverter is approximately 0.052 V. These results help further investigate the impact on integrated circuits in the irradiation environment.

Background: In Transcranial Direct Current Stimulation (tDCS) the injected current gets distributed across the brain areas. The motive is to stimulate the target region-of-interest (ROI), while minimizing the current in non-target ROIs. For this purpose, determining the appropriate current-dose for an individual is difficult. Aim: To introduce Dose-Target-Determination-Index (DTDI) to quantify the focality of tDCS and examine the dose-focality relationship in three different populations. Method: Here, we extended our previous toolbox i-SATA to the MNI reference space. After a tDCS montage is simulated for a current-dose, the i-SATA(MNI) computes the average (over voxels) current density for every region in the brain. DTDI is the ratio of average current density at target ROI to the ROI with maximum value (peak region). Ideally target ROI should be the peak region, so DTDI shall range from 0 to 1. Higher the value, the better the dose. We estimated the variation of DTDI within and across individuals using T1-weighted brain images of 45 males and females distributed equally across three age groups- (a) Young adults (20 ≥ x ˂ 40 years), (b) Mid adults (40 ≥ x ˂ 60 years), and (c) Older adults (60 ≥ x ˂ 80 years). DTDI’s were evaluated for the frontal montage with electrodes at F3 and right supra-orbital for three current doses 1mA, 2mA, and 3mA with the target ROI at left middle frontal gyrus. Result: As the dose is incremented, DTDI may show (a) increase, (b) decrease, and (c) no change across the individuals. The focality decreases with age and the decline is stronger in males. Higher current dose at older age can enhance the focality of stimulation. Conclusion: DTDI provides information on which tDCS current dose will optimize the focality of stimulation. DTDI recommended dose should be prioritised based on the age (> 40 years) and sex (especially males) of an individual. The toolbox i-SATA(MNI) is freely available.

Synergy of radiation and immune system is currently receiving significant attention in oncology as numerous studies have shown that cancer irradiation can induce strong antitumor immune responses. It remains unclear, however, what are the best radiation fractionation protocols to maximize the therapeutic benefits of this synergy. Here, we present a novel mathematical model that can be used to predict and dissect the complexity of the immune-mediated response at multiple tumor sites after applying focal irradiation and systemic immunotherapy. We successfully calibrate the proposed framework with published experimental data, in which two tumors were grown in mice at two spatially separated sites from which only one was irradiated using various radiation fractionation protocols with and without concurrent systemic immunotherapy. The proposed model is calibrated to fit the temporal dynamics of tumor volume at both sites and can predict changes in immune infiltration in the non-irradiated tumors. The model was then used to investigate additional radiation fractionation protocols. Model simulations suggest that the optimal radiation doses per fraction to maximize antitumor immunity are between 10-13 Gy, at least for the experimental setting used for model calibration. This work provides the framework for evaluating radiation fractionation protocols for radiation-induced immune-mediated systemic antitumor responses.

Deep learning image reconstruction (DLIR) algorithms employs convolutional neural networks (CNNs) for CT image reconstruction to produce CT images with a very low noise level, even at low radiation dose. The aim of this study was to assess whether the DLIR algorithm reduces the CT effective dose (ED) and im-proves CT image quality in comparison with filtered back projection (FBP) and iterative reconstruction (IR) algorithms in intensive care unit (ICU) patients. We identified all consecutive patients referred to the ICU of a single hospital who underwent at least two consecutive chest and/or abdominal contrast-enhanced CT scans within a time period of 30 days using DLIR and subsequently FBP or IR algorithm (Advanced Mod-eled Iterative Reconstruction model-based algorithm [ADMIRE], or Adaptive Iterative Dose Reduction 3D [AIDR 3D]) for CT image reconstruction. The radiation ED, noise level, and signal-to-noise ratio (SNR) were compared between the different CT scanners. The non-parametric Wilcoxon test was used for statistical comparison. Statistical significance was set at p < 0.05. A total of 83 patients (mean age, 59 ± 15 years [standard deviation]; 56 men) were included. DLIR vs FBP reduced ED (18.45 ± 13.16 mSv vs 22.06 ± 9.55 mSv, P < 0.05), while DLIR vs FBP and vs ADMIRE and AIDR 3D IR algorithms reduced image noise (8.45 ± 3.24 vs 14.85 ± 2.73 vs 14.77 ± 32.77 and 11.17 ± 32.77\, P < 0.05) and increased SNR (11.53 ± 9.28 vs 3.99 ± 1.23 vs 5.84 ± 2.74 and 3.58 ± 2.74, P < 0.05). CT scanners employing DLIR reduced radiation ED and im-proved SNR compared to CT scanners using FBP, whereas CT scanners using DLIR improved SNR com-pared to CT scanners using FBP or IR algorithms in ICU patients.

Glioblastoma multiforme (GBM), the most prevalent primary malignant brain tumor in adults, exhibits a dismal 6.9% five-year survival rate post-diagnosis. Thymoquinone (TQ), the most abundant bioactive compound in Nigella Sativa, has been extensively researched for its anti-cancer properties across various human cancers. Yet, its specific anticancer mechanisms and pathways in glioblastoma remain to be elucidated. In this study, we assessed the impact of different TQ concentrations on the viability of A172 cells using WST-8 and Toluidine blue assays, followed by RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs). We confirmed their expression levels through quantitative RT-PCR and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for these DEGs. RNA-seq revealed no significant gene expression changes at 2.5 µM and 5 µM TQ concentrations. However, at 25 µM and 50 µM, TQ significantly reduced cell viability in a dose-dependent manner. We identified 1548 DEGs at 25 µM TQ (684 upregulated, 864 downregulated) and 2797 DEGs at 50 µM TQ (1528 upregulated, 1269 downregulated), with 1202 DEGs common to both concentrations. TQ inhibited key pathways such as PI3K-Akt signaling, calcium signaling, focal adhesion, and ECM-receptor interaction in A172 cells. It downregulated several potential oncogenes (e.g., AEBP1, MIAT) and genes linked to GBM proliferation and migration (e.g., SOCS2, HCP5), while modulating Wnt signaling and upregulating tumor suppressor genes (e.g., SPRY4, BEX2). TQ also affected p53 downstream targets, maintaining p53 levels. This study elucidates the anticancer mechanisms of TQ in A172 GBM cells, underscoring its effects on multiple signaling pathways and positioning TQ as a promising candidate for innovative glioblastoma treatment strategies.

After 2010, the source model of the microSelectron HDR Afterloader System was slightly modified from the previous model. Granero et al. named the modified source model “mHDR-v2r (revised model mHDR-v2)” and the previous model “mHDR-v2”. They concluded that the dosimetric differences arising from the dimensional changes between the mHDR-v2 and mHDR-v2r designs were negligible at almost all locations (within 0.5 % for r ≥ 0.25 cm), the two-dimensional anisotropy function difference between the two sources is found 2.1 % at r = 1.0 cm when compared with the results of the other experimental group. To confirm this difference, we performed a full Monte Carlo simulation without the energy fluence approximation. This is useful near the radiation source where charged-particle equilibrium does not hold. The two-dimensional anisotropy function of the TG-43U1 dataset showed a few percent difference between the mHDR-v2r and mHDR-v2 sources. There was no agreement in the immediate vicinity from the source (0.10 cm and 0.25 cm), when compared to Granero et al. in mHDR-v2r sources. The differences in these two-dimensional anisotropy functions were identified.

The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults (aged 60-75 years) received a single administration of 100, 150 or 200 mg/kg body weight of tyrosine. For comparison, 17 young adults (aged 18-35 years) received a dose of 150 mg/kg body weight of tyrosine. Tyrosine plasma concentrations were determined before and 90, 120, 150, 180, 210 and 240 minutes after tyrosine intake. Working memory was assessed using the N-back task at 90 minutes after tyrosine administration. Older adults showed a dose-dependent increase in plasma tyrosine concentrations (p<.001), and the plasma response was higher than for young adults with the same dose (p<.001). Load-dependent working memory performance decreased with higher doses of tyrosine (p=.048), especially in older adults with greater dose-dependent plasma tyrosine responses (p=.035). Our results show an age-related increase in plasma tyrosine response, which was associated with a dose-dependent decline in cognitive functioning in older adults.

The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection, and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley Rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and were killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis and evaluation of biological effects was performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function and cancer and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples are needed for validation.

Introduction The outcome of radiotherapy (RT) for prostate cancer (PCA) depends on the delivered dose. While the evidence for dose-escalated RT up to 80 Gy is well established, there have been only few studies examining dose escalation above 80 Gy. We initiated the presented study to assess the safety of dose escalation up to 84 Gy. Patients and methods In our retrospective analysis, we included patients who received dose-escalated RT for PCA at our institution between 2016 and 2021. We evaluated acute genitourinary (GU) and gastrointestinal (GI) toxicity as well as late GU and GI toxicity. Results A total of 86 patients could be evaluated, of whom 24 patients had received 80 Gy and 62 patients had received 84 Gy (35 without pelvis- and 27 with pelvis-radiotherapy). Regarding acute toxicities, no adverse events > grade 2 occurred. 12.5% of patients treated with 80Gy, in 25.7% of patients treated with 84 Gy excluding pelvis, and in 51.9% of patients treated with 84Gy including pelvis suffered from Grade 2 GU acute toxicity (80 Gy versus 84 Gy: p=0.186; with pelvis versus without pelvis: p=0.032). Grade 2 GI toxicity occurred in 12.5% of patients irradiated with 80Gy, in 14.3% of patients treated with 84 Gy excluding pelvis, and in 12.9% of patients treated with 84Gy including pelvis (80 Gy versus 84 Gy: p=0.582; with pelvis versus without pelvis: p=0.510).GU late toxicity of grade ≥ 2 occurred in 4.2% of patients treated with 80 Gy, in 7.1% of patients treated with 84 Gy excluding pelvic RT, and in 18.2% of patients treated with 84 Gy including pelvic RT (logrank-test p=0.237). 8.3% of patients treated with 80 Gy, in 3.6% of patients treated with Gy excluding pelvic RT, and in 0% of patients treated with 84 Gy including pelvic RT suffered from GI late toxicity of grade ≥ 2(logrank-test p=0.358). Conclusion We were able to show that dose-escalated RT in PCA up to 84 Gy is feasible and safe without asubstantial increase in toxicity. Further follow up is needed to assess survival.

A greenhouse dose-response study was conducted to determine the tolerance of three wild tomato accessions (TOM199, TOM198, TOM300) in comparison to a commercial cultivar (Better Boy) against the dicamba application at five rates (0, 70, 140, 210, and 280 g ae ha-1) at 14 and 28 days after treatment (DAT). Several physiological traits were evaluated at 0, 1, 3, 5, and 7 DAT. Wild accessions and cultivar were killed at all rates above 70 g ae ha-1 at 14 and 28 DAT, which is why differences between accessions and cultivar were only evident at 70 g ae ha-1. The GR50 (the herbicide rate that causes 50% reduction in dry weight) of Better Boy was 4.4 g ae ha-1 at 28 DAT, and this cultivar was approximately 11-fold more sensitive than wild accessions. At 7 DAT, the levels of H2O2 for wild accessions were lower than Better Boy up to 5 at 70 g ae ha-1 of dicamba. Furthermore, wild accessions showed lower herbicide absorption than Better Boy at all dicamba doses at 1, 3, and 7 DAT. All the three wild accessions expressed tolerance to the dicamba application at the dose of 70 g ae ha-1. At the same time, Better Boy and wild accessions were susceptible to dicamba application at rates of 140, 210, and 280 g ae ha-1.

Over a century ago, low-dose-rate (LDR) brachytherapy was introduced to treat prostate cancer (PCa). Since then, it has been widely applied worldwide, including in East Asia. LDR brachythera-py has been performed in 88 institutes in Japan. Beneficial clinical outcomes of LDR brachytherapy for intermediate-to-high-risk PCa have been demonstrated in large clinical trials. These clinical outcomes were achieved through advances in methods, such as urological precise needle puncture and seed placement, and the quantitative decision-making regarding radiological parameters by radiation oncologists. Combined use of LDR brachytherapy with other therapeutical modalities, such as external beam radiation and androgen deprivation therapy, for clinical risk classification of PCa has led to better anticancer treatment efficacy. In this study, we summarized basic LDR brachytherapy findings that should remain unchanged and be passed down in urology depart-ments. We also discussed the applications of LDR brachytherapy for PCa in various clinical settings, including focal and salvage therapies. In addition, we highlighted technologies associated with brachytherapy that are under development.

The severe acquired respiratory coronavirus–2 (SARS–CoV-2) infection has initiated both acute and chronic COVID–19 disease between 2020 and 2022, currently evolving with other homologous prior coronavirus strains of the Nidoviridae order, which encompasses other prevalent alpha/ beta coronaviruses, but also the Middle East Respiratory Syndrome (MERS-CoV) and SARS-CoV-1, with recent SARS–CoV–2 variants, increasing demands for effective immunogens and therapeutic approaches that will reduce global disease burden and further infection from SARS–CoV-2 affected individuals that may experience post acute sequelae (PASC) or “Long COVID”. Following a worldwide programme of prophylactic vaccination, there is still a dilemma in the efforts to find prophylactic and early therapeutic approaches that would treat novel SARS-CoV-2 variants and prevent future epidemics or pandemics within host human and animal populations, where zoonotic or cross species transfer naturally occurs. Concerns about viral immune escape intersect at a specific point; a gained evolutionary ability of several viruses to co–infect and compete against previous scientific advances since 1796 that remain undetected or asymptomatic during the early stages of infection progressing to symptomatic and severe disease through capping of the 5' end of DNA and RNA genomes respectively, which is performed by the activated viral 2’ - O - Methyltransferase (MTase) enzyme, which is a complex of two viral non-structural proteins (NSPs) joined together through an activation process (NSP10/16). Moreover, it was discovered that certain polymorphic viruses translate NSP1, which prevents the activation of various Pattern Recognition Receptors (PRRs), directly silences important interferon-stimulated genes (ISGs), is signalled in a paracrine manner to neighbouring cells, and that induces the apoptosis of host cells, inducing an effect of “trace erase” effect and making the viral infection as immunologically “invisible” as possible during the initial, key stages of viral replication and distribution, all such mechanisms occurring independently of the viruses in cause. Other viral NSPs share a role with NSP1 in directly suppressing the activation of PRRs and ISGs, and all such viral proteins help the virus in its process of self-camouflaging against first- and second-line immunity, thereby often severely impacting the quality of the produced adaptive immune responses. The outcome of all such phenomena is the sharp decrease in the host Type I and Type III interferons' (IFNs) rate of synthesis by the host cells, that would usually occur and affect homeostatic cellular pathways, resulting in further viral replication and induced apoptosis. Nonetheless, effects of microbial immune evasion during the development of other viral or carcinogenic pathologies are not widely known. In short, polymorphic viruses developed a proportionate evolutionary response against developed adaptive immune responses, by currently relying on gaps mostly situated in the natural immune system in their process of molecular self-camouflaging. Scientists developed numerous approaches of early treatment that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration whilst filtering for the most appropriate solutions. For example, the administration of recombinant human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can simulate intracellular infection and stimulate cellular activity in a timely manner, training the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Another example could involve the treatment of natural and adaptive lymphocytes with a low dose of IFNs I and possibly III, prior to their insertion into the host lymphatic system, possibly alongside additional recruitment of plasmacytoid dendritic cells (pDCs) as further interferon “factories”, all with the purpose of early infection management. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. It is until the scientific community realises this potentially crucial aspect that large proportions of the world population will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently, monkeypox and possibly avian flu. Of note, it has been indicated that IFN I and / or III display significant immunising, early therapeutic and clinical disease onset-attenuating effects for many other microbial evoked diseases, as well as for a number of oncological diseases.

A new treatment option for cluster headache (CH) prevention is needed. Monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) ligands are used as a preventative treatment for migraine. Considering the CGRP’s role in the CH attack’s ignition and upkeep, fremanezumab and galcanezumab have been evaluated for CH preventative treatment. However, only high-dose (300 mg) galcanezumab was proven for episodic CH prevention. We herein report 3 cases of migraine and comorbid CH with previous failures of preventive treatments. The 2 cases were treated with fremanezumab and the one with non-high-dose galcanezumab. All 3 cases showed good results not only on migraine but also on CH attacks. Our report suggested the efficacy of CGRP-mABs for CH prevention. Our cases differed from the cases in the phase 3 trials of CGRP-mABs for CH prevention in the following 2 points. First, the patients had both migraine and comorbid CH. Second, the combined use of CGRP-mABs with preventative drugs for CH, such as verapamil and/or prednisolone, was performed. Future accumulation of real-world data may prove the efficacy of CGRP-mABs for CH prevention.

Coronavirus 2019 (COVID-19) is an infectious disease that is becoming a pandemic. Hydroxychloroquine in combination with azythromycin are among drugs currently in use to eradicate COVID-19. Despite concerns due to its potential cardiac toxicity, hydroxychloroquine is widely accepted in mild and moderate COVID-19 pneumonia. In this case report, we report a case of a young Indonesian adult male with suspected COVID-19 pneumonia who received hydroxychloroquine and azythromycin therapies and during 24 hour experienced deterioration of atrioventricular block.

A phase 1-2, prospective, multicenter, randomized, open-label clinical trial (Code RPCEC00000382, https://rpcec.sld.cu/trials/RPCEC00000382-En/), with parallel groups, involving 1161 participants was designed to assess safety and immunogenicity of two Cuban COVID-19 vaccines (Mambisa and Abdala) in boosting COVID-19 immunity of convalescent adults after receiving one dose of either vaccine. The main safety outcome was severe vaccination adverse events occurring in &lt;5% of vaccinees. Main immunogenicity success endpoints were ≥4-fold anti-RBD IgG seroconversion or ≥20% increase in ACE2-RBD inhibitory antibodies in &gt;55% of vaccinees in Phase 1 and &gt;70% in Phase 2. Neutralizing antibody titers against SARS-CoV-2 variants were evaluated. Both vaccines were safe; no deaths or severe adverse events occurred. Mild intensity adverse events were the most frequent (&gt;73%); headache predominated for both vaccines. Phase 1 responders were 83.3% (p = 0.0018) for Abdala. Mambisa showed similar results. Phase 2 responders were 88.6% for Abdala (p &lt;0.0001) and 74.2% for Mambisa (p = 0.0412). In both phases, anti-RBD IgG titers, inhibition percentages and neutralizing antibody titers increased significantly after the booster dose. Both vaccines were safe and their immunogenicity surpassed the study endpoints.

The demographic profile of patients transitioning from chronic kidney disease to renal replacement therapy is changing, with a higher prevalence of aging patients with multiple comorbidities such as diabetes mellitus and heart failure. Cardiovascular disease remains the leading cause of mortality in this population, exacerbated by the cardiovascular stress imposed by the HD procedure. The first year after transitioning to hemodialysis is associated with increased risks of hospitalization and mortality, particularly within the first 90–120 days, with greater vulnerability observed among the elderly. This review, based on data from clinics of Fresenius Medical Care Europe, Middle East, and Africa NephroCare, aims to optimize hemodialysis procedures to reduce mortality risk in stable incident and prevalent patients. It addresses critical aspects such as treatment duration, frequency, choice of dialysis membrane, dialysate composition, blood and dialysate flow rates, electrolyte composition, temperature control, target weight management, dialysis adequacy, and additional protocols, with a focus on mitigating prevalent intradialytic complications, particularly intradialytic hypotension prevention.

Inactivated SARS-CoV-2 vaccine (CoronaVac) is commonly used in national immunization programs. However, the immune response significantly declined within a few months. Our study assessed the immune response against SARS-CoV-2 after receiving booster shots of BNT162b2 or ChAdOx1 among health care workers who previously received CoronaVac as their primary immunization. Fifty-six participants received ChAdOx1 and forty-two participants received BNT162b2 were enrolled into this study which evaluated the immune responses including anti-SARS-CoV-2 spike total antibodies (Elecsys®), surrogated viral neutralization test (sVNT) to ancestral strain (cPass™; GenScript) and five variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) (Luminex; multiplex sVNT) and the ELISpot with spike (S1 and S2) peptide pool against the ancestral SARS-CoV-2 strain. The samples were analyzed at baseline, 4, and 12 weeks after primary immunization as well as 4 and 12 weeks after receiving the booster. This study showed a significantly higher B-cell response among the BNT162b2 than the ChAdOx1 booster group, particularly against the Omicron variant, as well as a trend of good T-cell immune response in the BNT162b2 group. Moreover, the immune response rapidly declined at 12 weeks after the booster. A fourth dose or a second booster should be recommended, especially for reducing Omicron severity.

This study addresses the challenge of assessing the carcinogenic potential of hazardous chemical mixtures, such as PFAS, which are known to contribute significantly to cancer development. Here, we propose a novel framework called HNNMixCancer that utilizes a Hybrid Neural Network (HNN) integrated into a machine-learning framework. This framework incorporates a mathematical model to simulate chemical mixtures and enables the creation of classification models for binary and multiclass classification and regression. Through extensive experimentation, we demonstrate that our HNN model outperforms other methodologies, including Random Forest, Bootstrap Aggregating, Adaptive Boosting, Support Vector Regressor, Gradient Boosting, Kernel Ridge, Decision Tree with AdaBoost, and KNeighbors, achieving a superior accuracy of 92.7% in binary classification. To address the limited availability of experimental data and enrich the training data, we generate an assumption-based virtual library of chemical mixtures using a known carcinogenic and non-carcinogenic single chemical for all the classification models. Remarkably, in this case, all methods achieve accuracies exceeding 98% for binary classification. In external validation tests, our HNN method achieves the highest accuracy of 80.5%. Furthermore, in multiclass classification, the HNN demonstrates an overall accuracy of 96.3%, outperforming RF, Bagging, and AdaBoost, which achieved 91.4%, 91.7%, and 80.2%, respectively. In regression models, HNN, RF, SVR, GB, KR, DT with AdaBoost, and KN achieve average R2 values of 0.96, 0.90, 0.77, 0.94, 0.96, 0.96, and 0.97, respectively, showcasing their effectiveness in predicting the concentration at which a chemical mixture becomes carcinogenic. Our method exhibits exceptional predictive power in prioritizing carcinogenic chemical mixtures, even when relying on assumption-based mixtures. This capability is particularly valuable for toxicology studies that lack experimental data on the carcinogenicity and toxicity of chemical mixtures. To our knowledge, this study introduces the first method for predicting the carcinogenic potential of chemical mixtures. The HNNMixCancer framework offers a novel alternative for dose-dependent carcinogen prediction. Ongoing efforts involve implementing the HNN method to predict mixture toxicity and expanding the application of HNNMixCancer to include multi-mixtures.

The major stress-inducible Hsp70 (HSPA1A) is overexpressed in the cytosol of many highly aggressive tumor cells including glioblastoma multiforme and presented on their plasma membrane. Depending on its intracellular or membrane localization, Hsp70 either promotes tumor growth or serves as a target for NK cells. The kinetics of the membrane Hsp70 (mHsp70) density on human glioma cells (U87) was studied after different irradiation doses to define the optimal therapeutic window for Hsp70-targeting NK cells. To maintain the cells in the exponential growth phase during a cultivation period of 7 days different initial cell counts were seeded. Although cytosolic Hsp70 levels remained unchanged on days 4 and 7 after a sublethal irradiation with 2 Gy, 4 Gy and 6 Gy, a dose of 2 Gy resulted in an upregulated mHsp70 density in U87 cells which peaks on day 4 and starts to decline on day 7. Higher radiation doses (4 Gy, 6 Gy) resulted in an earlier and more rapid onset of the mHsp70 expression on days 2 and 1, respectively, followed by a decline on day 5. Membrane Hsp70 levels are higher in G2/M than in G1, however, an irradiation-induced cell cycle arrest on days 4 and 7, was not associated with an increase in the mHsp70 density. Extracellular Hsp70 concentrations increased significantly compared to sham (0 Gy) irradiated cells on days 4 and 7 but not on day 1. Functionally, elevated mHsp70 densities were associated with a significantly better lysis by Hsp70-targeting NK cells. In summary, the kinetics of changes in the mHsp70 density upon irradiation on tumor cells is time- and dose-dependent.

Dermal penetration is considered to mainly occur via passive diffusion. Therefore, a high concentration gradient of dissolved active ingredient between formulation and skin is needed to achieve an effective dermal penetration. The concentration gradient between formulation and skin can be changed by changing the amount of dissolved active ingredient in the formulation. In case of poorly soluble active ingredients this can be achieved by using nanosized drug material instead of larger sized material. The smaller size and the resulting larger surface increase the kinetic solubility and thus increase the concentration gradient of dissolved active ingredient between formulation and skin, which then results in an increased dermal penetration. In this study we demonstrated that the concentration gradient between formulation and skin can also be influenced by the number of particles being present in the formulation and by the dose (volume of formulation) applied to the skin. Particles of undissolved active ingredient are known to act as a reservoir by releasing dissolved molecules in the liquid phase of the formulation. It could now be demonstrated that the particles - once the liquid in which they are dispersed evaporates - can connect to the skin via an aqueous meniscus. The aqueous meniscus contains dissolved active ingredient and therefore creates a small local spot with a locally high concentration gradient and improved dermal penetration. Therefore, the dermal penetration can be increased with formulations that contain high amounts of particles. This can be achieved by applying formulations with high numbers of particles and/or by applying larger volumes of particle containing formulations to the skin.

Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is significantly associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. And we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid, and mthfr-/- mutant all gave rise to early pericardial edema and cardiac defect at 3 days after fertilization(dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5dpf. The expression levels of cardiac marker genes hand2, gata4 and nppa changed in the abnormality of folate metabolism embryos and mthfr-/- mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. And our results reveal that folic acid has a dose-dependent biphasic effect on early cardiac development.

Critical care of neonates involves substantial usage of antibiotics and exposure to multidrug resistant (MDR) nosocomial pathogens. These pathogens are often exposed to sub-MIC doses of antibiotics which might result in a range of physiological effects. Therefore, to understand the outcome of sub-inhibitory dosage of antibiotics on Staphylococcus populations, nasal swab specimens were collected from 34 neonates admitted to the Sick Newborn Care Unit between 2017-2018, a total of 41 non-repetitive isolates were included in this study. Staphylococcus haemolyticus was the prevalent species (58.54%) with high non-susceptibility to cefotaxime (CTX) (79.16%), gentamicin (87.50%), and meropenem (54.17%). Biofilm forming abilities of S. haemolyticus isolates in the presence of sub-optimal CTX (30μg/mL), the predominantly prescribed β-lactam antibiotic, were then determined by crystal violet assays and extracellular DNA (eDNA) quantitation. CTX was found to significantly enhance biofilm production among the non-susceptible isolates (p-valueWilcoxin test- 0.000008) with increase in eDNA levels (p-valueWilcoxin test- 0.000004). Additionally, no changes in non-susceptibility were observed among populations of two MDR isolates, JNM56C1 and JNM60C2 after >500 generations of growth in the absence of antibiotic selection in vitro. These findings demonstrate that sub-MIC concentration of CTX induces biofilm formation and short-term non-exposure to antibiotics does not alter non-susceptibility among S. haemolyticus isolates.

A novel coronavirus strain (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first appeared in December 2019 and can cause acute respiratory distress syndrome and death. However, there are only limited therapy choices and no vaccine for SARS-CoV-2 is currently available. Here we report about a case of a SARS-CoV-2 caused pneumonia successfully treated with thalidomide. Thalidomide is an immunomodulatory and anti-inflammatory agent and was combined with a low-dose glucocorticoid. We suggest, that the effects of thalidomide might be related to regulating immunity, inhibiting the inflammatory cytokine surge, alleviating anxiety to reduce oxygen consumption, relieving vomit and lung exudation.

We aimed to directly compare the cost-effectiveness of the NELSON and NLST screening protocols, two trials influencing lung cancer screening implementation internationally. A decision-analytic model analyzing the cost-effectiveness of the NELSON protocols was manipulated to reflect the protocols of the NLST, while maintaining features specific to the Hungarian healthcare setting. In the NELSON protocol, there are three possible outcomes to the initial round of screening: positive, negative, or indeterminate, indicating an uncertain degree of suspicion for lung cancer. This pro-tocol differs from the NLST protocol, in which the only possible screening outcomes are positive or negative, with no indeterminate option. The NLST pathway for smokers aged 55-74 resulted in a 43 € increase in total average lifetime costs compared to the Hungarian screening pathway and re-sulted in a lifetime gain of 0.006 QALYs. The incremental costs and QALYs yield an ICER of 7875 €/QALY. Our results demonstrate that assigning any suspicious LDCT screen as a positive result (NLST protocol) rather than indeterminate (NELSON protocol) can yield a slight QALY gain that is worth the additional use of resources according to Hungary’s willingness to pay threshold. Our study provides insight on the cost-effectiveness, advantages, and disadvantages of various LDCT screening protocols for lung cancer and can assist other countries as they implement their screening programs.

This mini-review explores the comparative efficacy, safety, and clinical outcomes of high-dose proton pump inhibitor (PPI) intravenous infusion versus oral acid pump inhibitor therapy following endoscopic treatment for bleeding peptic ulcers. Recent evidence suggests that intravenous PPIs can significantly reduce the rebleeding rates within the critical first 72 hours post-intervention, with a noted rebleeding rate of 6% compared to 14% in patients receiving oral Vonoprazan (VPZ) therapy. Additionally, the rapid onset of action associated with intravenous administration leads to faster stabilization of vital signs and a reduced need for subsequent blood transfusions. Safety profiles for both intravenous and oral VPZ were favourable, with minimal adverse effects, the most common being transient headaches.However, the findings from our single-centre study with a moderate sample size prompt consideration of more extensive, multicentre trials to enhance the generalizability of the results. Current limitations include potential biases, short-term focus, missing data issues, and a need for long-term outcome data, necessitating further research. Future studies should also explore the cost-effectiveness of intravenous versus oral VPZ and the impact on patient quality of life and long-term mortality rates.This review underscores the importance of tailored PPI therapy in managing bleeding peptic ulcers post-endoscopy. It suggests a potentially pivotal role for intravenous PPIs in high-risk patient groups, advocating for a shift towards more aggressive and immediate care protocols in specific clinical settings.

This study assessed the performance of low-dose CT lung scans across various acquisition parameters and examined the impact of iterative reconstruction (IR) algorithms on image quality for lung cancer screening. The performance of multi-slice CT scanners was assessed by using a Catphan 600 phantom, specifically within the CTP404 test module that contains materials like Teflon, Delrin, Acrylic, Polystyrene, LDPE, PMP, Air, and water. Three protocols were selected and categorized into standard, low dose, and ultra-low dose. The standard protocol featured a tube voltage of 100 kVp for single-detector CT, a pitch of 0.75, detector collimation of 0.60 mm, and a gantry rotation time of 0.33 seconds, with 5 mm slice thickness. Images were reconstructed using standard kernels like B80f and 170f, combined with either FBP or various IR algorithms. Findings indicated that the noise power spectrum (NPS) peak value (HU2mm2) increased with higher IR levels, with FBP showing the highest peak. Additionally, NPS spatial frequency diminished as IR levels rose. Optimizing contrast and spatial resolution for both background and regions of interest involved adjusting the target transfer function (TTF) and contrast-to-noise ratio (CNR), crucial for protocol optimization. Proper adjustment of IR levels is vital, as higher levels can alter image texture and affect NPS spatial frequency. The results of this study showed that the use of IR algorithms in low-dose CT lung scans significantly improved image quality, particularly in terms of noise reduction and spatial resolution. However, the choice of acquisition parameters also played a crucial

Our hypothesis that controlled ozone applications interfere into the redox balance of the biological organism (first published in 1998 with a preclinical trial on protecting the liver from CCl4 intoxication), has been verified over the last 2 decades in reactive oxygen species (ROS)-induced mitochondrial pathologies, such as rheumatoid arthritis, osteoarthritis, aging processes, diabetes-2 and in prevention of intoxications. Low-dose ozone acts as a redox bioregulator: The restoration of the disturbed redox balance is comprehensible in a number of preclinical and clinical studies by a remarkable increase of the antioxidant repair markers, here mainly shown as glutathione increase and a reduction in oxidative stress markers, mainly malondialdehyde. The mechanism of action is shown, relevant data are displayed, evaluated and comprehensively discussed: The repair side of the equilibrium increases by 21% up to 140% compared to the non-ozone treated groups and depending on the indication; the stress markers are simultaneously reduced, the redox system regains its balance.

This retrospective study aimed to evaluate the impact of radiation dose on the outcomes of stereotactic radiosurgery (SRS) for benign meningiomas and determine an optimal dosing strategy for balancing tumor control and treatment-related toxicity. Clinical data of 147 patients with 164 lesions treated between 2014 and 2022 were reviewed. Primary outcomes included progression-free survival (PFS), local control rate (LCR), and radiation-induced toxicity, with secondary outcomes focusing on LCR and radiation-induced peritumoral edema (PTE) in two dose groups (≥14 Gy and &lt;14 Gy). Results revealed a median follow-up duration of 47 months, with 1-year, 2-year, and 5-year PFS rates of 99.3%, 96.7%, and 93.8% respectively, and an overall LCR of 95.1%. Radiation-induced toxicity was observed in 24.5% of patients, primarily presenting mild symptoms. Notably, no significant difference in LCR was found between the two dose groups (P = 0.628), while Group 2 (&lt;14 Gy) exhibited significantly lower PTE (P = 0.039). The study concludes that SRS with a radiation dose &lt;14 Gy demonstrates comparable tumor control with reduced toxicity, advocating for consideration of such dosing to achieve a balance between therapeutic efficacy and safety.

Background: Computed tomography examinations have produced high radiation doses to patients, especially the CT brain. This study aimed to optimize the radiation dose and image quality in adult CT brain protocol. Materials and Methods: Images were acquired by Catphan 700 phantom. Radiation doses were recorded as CTDIvol and dose length product (DLP). CT brain protocols were optimized by varying parameters such as kVp, mAs, signal-to-noise ratio (SNR) level, and Clearview iterative reconstruction (IR). Image quality were also evaluataion by The AutoQA Plus software. Results: CT Number accuracy and linearity had a robust positive correlation with the linear attenuation coefficient (µ) and showed more inaccurate CT numbers when using 80 kVp. MTF showed a higher value in 100 and 120 kVp protocols, while high contrast spatial resolution showed a higher value in 80 and 100 kVp protocols. Low contrast detectability and CNR tended to increase when using high mAs, SNR and Clearview IR protocol. Noise decreased when using a high radiation dose and a high percentage of Clearview IR. CTDIvol and DLP were increased with increasing kVp, mAs, and SNR levels, while the increasing percentage of Clearview did not affect the radiation dose. Conclusion: Optimized protocols, including radiation dose and image quality, should be evaluated to preserve diagnostic capability. The recommended parameter settings include kVp set between 100-120 kVp, mAs ranging from 200-300 mAs, SNR level within the range of 0.7-1.0, and an iterative reconstruction value of 30% Clearview to 60% or higher.

The best form of prevention against human infection through bacteria, viruses and other parasites is ozone disinfection of wastewater and drinking water as a highly effective, well-known method. As a therapeutic measure, various preclinical studies showed promising results, which are being revisited and reconsidered in times of pandemics and led to interesting results in recent clinical trials and reports, as presented by the example of protective measures against covid-19 in particularly vulnerable clinical personnel. In patients with rheumatoid arthritis, repeated ozone treatments have led to new findings in the "immunomodulation" through ozone. The more effective immune response is discussed as the response of innate immune memory and opens interesting aspects for complementary treatment of autoimmune diseases.

Local anaesthetic agents suppress action potentials in excitable tissues by blocking voltage-gated sodium channels. In doing so they inhibit the depolarisation of nociceptive nerve fibres and so prevent the transmission of pain impulses. UK legislation allows HCPC-registered Podiatrists with POM-A annotation access to six local anaesthetic drugs and two of these with the addition of adrenaline. The use of local anaesthetia has transformed the treatment of nail pathology by Podiatrists. In the UK, the drug of choice in podiatric practice is 3% mepivacaine hydrochloride: it is a good choice of drug for digital anaesthesia. This paper will review the chemistry, pharmacology and dose calculation of mepivacaine, and challenge some of the orthodoxy over the rigid calculation of maximum safe dosages.

Background: Rituximab is a monoclonal antibody widely used in the treatment of inflammatory and autoimmune disorders. Despite reports of its effectiveness in the treatment of demyelinating diseases of central nervous system (DDCNS), it is not yet approved for use in these disorders. The aim of this study was to investigate the effectiveness and safety of low dose rituximab in three different subgroups of DDCNS including relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS) and neuromyelitis-optica-spectrum disorders (NMOSD).Methods: In a prospective cohort study, we monitored expanded-disability-status-scale (EDSS), relapses (new attacks) and serum-IgG levels to assess effectiveness and drug-adverse-events for safety in patients with RRMS, SPMS and NMOSD. These patients were candidates to receive rituximab according to our common practice protocol. We switched patients to rituximab if there was poor response to first line therapies. We follow a low dose protocol in our center (500 mg twice, two weeks apart, repeating every six months) and these patients treated in a 4-year period were assessed retrospectively for evaluation of our protocol’s safety and effectiveness. Results: 99 patients (42 RRMS, 43 SPMS and 14 NMOSD) received rituximab for a range of 12 to 40 months period. New attacks occurred in 8 RRMS (19%), 10 SPMS (23%) and 1 NMOSD (7%) patients. EDSS decreased in RRMS and NMOSD cases. Serum-IgG levels decremented in SPMS and NMOSD patients. Drug-adverse-events happened in two cases.Conclusion: In this study, low dose rituximab showed substantial effectiveness in preventing disease progression with a considerably good safety profile.

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n=6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n=6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.4% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in hippocampus (+9.24%) and PFC (+6.1%) whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin’s antidepressive actions are linked to increased persistent synaptogenesis and possibly also to an acute decrease in 5-HT2AR density.

Firocoxib is a non-steroidal anti-inflammatory drug specifically formulated for veterinary medicine and selectively acts on inhibiting the cyclooxygenase 2 enzyme(COX-2). This study aimed to evaluate the possible adverse effects of administering oral therapeutic firocoxib on gastric mucosa, hematological parameters, coagulation cascade, and hepatic and renal biochemistry in healthy horses. Nine clinically healthy Arabian horses, approximately nine years old, received 0.1mg/kg of oral firocoxib for 14 days. Before beginning treatment, a gastroscopic examination was conducted, and venous blood samples were obtained for laboratory tests on D0. Follow-up blood samples and gastroscopic examinations were taken on D7 and D14 after starting treatment and one week after completing treatment on D21. No changes were found in the gastroscopic and hematological tests. Additionally, coagulation and serum biochemistry levels remain between normal values for this particular species. However, the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT) indicate reduced blood coagulation capacity, which contradicts the expected effect of treatment with selective COX-2 inhibitors, as these drugs theoretically promote coagulation. Administering Firocoxib to horses is safe as it does not cause any significant adverse reactions. Therefore, it is a suitable option for managing inflammatory conditions in these animals.

Background and Objectives: The complications seen after lower impacted third molar surgery affect the quality of life of the patients. The aim of the study was to investigate the efficacy of a single preoperative dose of deflazacort on pain, swelling and trismus following impacted lower third molar surgery. Materials and Methods: This randomised, prospective, double-blind, split-mouth clinical study included 30 healthy individuals with bilaterally impacted lower third molars that was removed for orthodontic purposes between September 2017 and September 2018. Group 1 was given a placebo (single dose vitamin C tablet) and group 2 was given a single 30 mg dose of deflazacort 1 hour prior to the surgery. Pain was evaluated using the visual analog scale for 1 week postoperatively. Edema (in mm) and trismus (in mm) were evaluated preoperatively and on postoperative days 2 and 7. The Mann-Whitney U test was applied for group analysis. p values < 0.05 were considered statistically significant. Results: When postoperative pain scores were evaluated, a significant difference was found between the groups only at the 6th and 12th hours (p0.05). Even high trismus values were recorded on the 2nd day, it was observed that the trismus resolved on the 7th day. There were no significant differences in trismus between the groups at any time point (p>0.05). Evaluation of swelling showed that there was no statistically significant difference between the study and control groups at any time point (p>0.05). No side effect was detected in both the study and the control groups. Conclusions: This was the first split-mouth study evaluating the anti-inflammatory effect of deflazacort after lower impacted third molar surgery. A single dose of 30 mg deflazacort was shown to be effective in reducing pain at 6 and 12 hours postoperatively.

Kiribati is a Pacific Island nation with a widely dispersed population and one of the highest rates of leprosy worldwide. Single dose rifampicin post exposure prophylaxis (SDR-PEP) of leprosy contacts has reduced new case detection rates in controlled trials. In 2018, a SDR-PEP programme was introduced in Kiribati that included screening and chemoprophylaxis of household contacts of leprosy cases both retrospectively (2010-2017) and prospectively (2018 onwards). We conducted a retrospective audit to determine comprehensiveness, timeliness and feasibility of the SDR-PEP programme. Overall, 13,643 household contacts were identified (9,791 in the retrospective and 3,850 in the prospective cohort). In the retrospective cohort, 1,044 (11%) contacts were absent, 403 (4%) were ineligible for SDR and 42 new cases were detected (0.4%) Overall SDR coverage was 84.7%. In the prospective cohort, 164 (4%) contacts were absent, 251 (7%) were ineligible for SDR and 23 new cases were diagnosed (0.6%). Overall, SDR coverage was 88.1%. Across both cohorts, there were a total of 23 SDR refusals. The median time to SDR ad-ministration was 220 days (IQR 162-468) and 120 days (IQR 36-283) for the retrospective and prospective cohorts respectively. SDR was readily accepted in both cohorts. The new case detec-tion rate (0.5%) is consistent with that seen in other studies. Overall SDR coverage in both the retrospective and prospective phases met programmatic expectations.

Background: The UNHLM pledged to enroll 30 million in TB preventive treatment (TPT) by 2022, necessitating TPT expansion to all at TB risk. We assessed uptake and completion of a 12-dose, weekly isoniazid-rifapentine (3HP) TPT regimen. Methods: Between February 2018 - March 2019 in Dhaka, community-based TPT using 3HP targeted household contacts of 883 confirmed drug-sensitive pulmonary TB patients. Adhering to WHO guidelines, contacts underwent active TB screening before TPT initiation. Results: Of 3,193 contacts who advised health facility visits for screening, 67% (n=2,149) complied. Among these, 1,804 (84%) received chest X-rays. Active TB was diagnosed in 39 (2%) contacts; they commenced TB treatment. Over 97% of 1,216 contacts began 3HP TPT, with completion rates higher among females, those with more education and income, non-slum residents, and those without 3HP-related adverse events. Adverse events, mainly mild, occurred in 5% of participants. Conclusions: The 3HP weekly regimen, with its short duration, self-administered option, and minimal side effects, achieved satisfactory completion rates. A community-focused 3HP TPT approach is feasible, scalable nationally, and aligns with UNHLM targets.

Total-body PET/CT scanners provide increased sensitivity, enabling the adjustment of imaging parameters by reducing injected activity or shortening acquisition time. This study aimed to evaluate the limitations of reduced [18F]FDG activity doses on image quality, lesion detectabil-ity, and quantification of lesion uptake in the Biograph Vision Quadra, as well as to assess the benefits of the recently introduced ultra-high sensitivity mode in a clinical setting. A number of 26 patients who underwent [18F]FDG-PET/CT (3.0 MBq/kg, 5 min. scan time) were included in this analysis. PET raw data was rebinned for shorter frame durations to simulate 5 min. scans with lower activities in high sensitivity (HS) and ultra-high sensitivity (UHS) modes. Image quality, noise, and lesion detectability (n=82) were assessed using a 5-point Likert scale. The co-efficient of variation (CoV), signal-to-noise ratio (SNR), tumor-to-background ratio (TBR), and standardized uptake values (SUV) including SUVmean, SUVmax, and SUVpeak were evaluated. Sub-jective image ratings were generally superior in UHS compared to HS mode. At 0.5 MBq/kg, le-sion detectability decreased to 95% (HS) and 98% (UHS). SNR was comparable at 1.0 MBq/kg in HS (5.7±0.6) and 0.5 MBq/kg in UHS (5.5±0.5). With lower doses, there were negligible reductions in SUVmean and SUVpeak, whereas SUVmax increased steadily. Reducing [18F]FDG activity to 1.0 MBq/kg (HS/UHS) in a total-body PET/CT provides diagnostic image quality without statistical-ly significant changes in uptake parameters. UHS mode improves image quality, noise, and le-sion detectability compared to HS mode.

The combination of non-steroidal anti-inflammatory drugs (NSAIDs) with non-opioid analgesics is common in clinical practice for the treatment of acute pain conditions like post-operative and post-traumatic pain. Besides that, and despite the very satisfactory results achieved by oral analgesics, parenteral analgesia is a key tool in the treatment of painful conditions when the enteral routes are not convenient. The parenteral ready-to-use fixed-dose combinations of NSAIDs with non-opioid analgesics like paracetamol or metamizole could play a central role in the treatment of painful conditions since they are able to gather into only one formulation the advantages of multimodal and parenteral analgesia. Surprisingly, only very recently a parenteral ready-to-use fixed-dose combination of Ibuprofen/Paracetamol was launched to the market. This review aims to review the current availability of NSAID-based Parenteral Fixed-dose combinations with paracetamol and metamizole in the European and American markets, and how the combination of such drugs could play a central role in a multimodal analgesia strategy. Also, it is explored how the parenteral formulations of NSAIDs, paracetamol, and metamizole could serve as starting elements for the development of new parenteral ready-to-use fixed-dose combinations. With this review, we concluded that, despite the well-recognized utility of combining NSAIDs with non-opioid analgesics, there are in the literature several randomized clinical trial studies unable to demonstrate clear advantages concerning their efficacy and safety. In the future, it is deemed necessary to perform clinical trials specifically designed to assess the efficacy and safety of these fixed-dose formulations to generate solid evidence of their clinical advantages.

The rural communities are affected by gaseous emissions from intensive livestock production. Practical mitigation technologies are needed to minimize emissions from stored manure and improve air quality inside barns. In our previous research, the one-time surficial application of biochar to swine manure significantly reduced emissions of NH3 and phenol. We observed that the mitigation effect decreased with time during the 30-day trials. In this research, we hypothe-sized that bi-weekly reapplication of biochar could improve the mitigation effect on a wider range of odorous compounds using larger scale and longer trials. The objective was to evaluate the effectiveness of biochar dose and reapplication on mitigation of targeted gases (NH3, odor-ous VOCs, odor, GHGs) from stored swine manure on a pilot-scale setup over 8-weeks. The bi-weekly reapplication of the lower biochar dose (2 kg/m2) showed much higher significant percent reductions of emissions for NH3 (33% without & 53% with reapplication) and skatole (42% without & 80% with reapplication), respectively. In addition, the reapplication resulted in the emergence of statistical significance to the mitigation effect for all other targeted VOCs. Spe-cifically, for indole, the % reduction improved from 38% (p=0.47, without reapplication) to 78% (p=0.018, with reapplication). For phenol, the % reduction improved from 28% (p=0.71, without reapplication) to 89% (p=0.005, with reapplication). For p-cresol, the % reduction improved from 31% (p=0.86, without reapplication) to 74% (p=0.028, with reapplication). For 4-ethyl phenol, the percent emissions reduction improved from 66% (p=0.44, without reapplication) to 87% (p=0.007, with reapplication). The one-time 2 kg/m2 and 4 kg/m2 treatments showed similar effectiveness in mitigating all targeted gases, and no statistical difference was found between the dosages. The one-time treatments showed significant % reductions of 33% & 42% and 25% & 48% for NH3 and skatole, respectively. The practical significance is that the higher (one-time) biochar dose may not necessarily result in improved performance over the 8-week manure storage, but the bi-weekly reapplication showed significant improvement in mitigating NH3 and odorous VOCs. The lower dosages and the frequency of reapplication on the larger-scale should be explored to optimize biochar treatment and bring it closer to on-farm trials.

Nicotine exposure may affect NSCLC is associated with lung cancer in humans. Whether nicotine exhibits carcinogenesis promoted activities in tumor growth still unknown. Nicotine is known to have dichotomous effects on cancer biology, acting like a pro- or anti-carcinogenesis agent. There are different functions between adenocarcinoma and squamous NSCLC cancer cells. Excess generation of nicotine may inhibit mitochondrial metabolism, protein modification, and DNA cleavage. Materials and Methods: We used the H520 NSCLC line obtained from human lung epithelial cells to detected nicotine growth and toxicity using MTT assay and western blotting. The concentration of nicotine stimulated cell growth to correspond to low concentration, while high concentration was cytotoxic. Results: According to MTT assay results, at 1.0 μM nicotine has significantly enhanced the H520 cell viability (%). Nicotine induced lung cancer carcinogenesis through mechanisms of α7nAchR, EGFR, HDAC2/4/5, Cyclin D/Cyclin E, Bcl-2, p-Akt, and inflammatory proteins of NF-KappaB and COX2 increases at 1.0 μM. Apoptosis proteins were decreases at 1.0 μM nicotine by p21, p27, c-jun, and p38α using western blotting. Nicotine stimulates tumor growth is mediated through α7nicotinic-acetylcholine receptors (α7nAChR), possibly involving inflammation. On the other hand, at high nicotine concentrations (> 1.0 μM) with consistent cytotoxic effects and appeared to be due to direct cell kill. Nicotine can prevent apoptosis induced by NSCLC. Conclusion: Therefore, the effects on chemotherapeutics by NSCLC malignant cell lines, nicotine in concentrations as low as 1.0 μM decreased. These mechanisms are responsible for the genotoxic effects caused by nicotine. This leads to downstream effects on decreased apoptosis, increased cell proliferation and transformation. The malignant NSCLC cells respond to the treatment with nicotine in lung cancer, the nicotine-mediated induction of growth may provide one of its links to α7nAchR or EGFR.

This study aims to evaluate the patient’s dose exposure from Computed Tomography Pulmonary Angiography (CTPA) examination and to estimates the cancer risk induced from the examinations based on the patient’s size. One hundred patients were recruited, and data information was collected retrospectively. A multi-detector (MDCT) (Philips Brilliance 128, USA) scanner were utilized for the CTPA examination, and dose data were obtained from the system. The effective diameter of each subjects’ image was measured for the Size-specific dose estimates (SSDEs). All subjects divided into Group 1 (19 – 25 cm), Group 2 (25-28 cm) and Group 3 (28-38 cm), where the association between gender were analysed. Effective dose (E), SSDE, organ dose and cancer risk of each group were evaluated and compared statistically using independent t-test and one-way ANOVA. The range of mean CTDI_vol, DLP and E values were (6.44 – 17.42 mGy), (239 – 631 mGy), (5.19 – 13.90 mSv), respectively. In respective with the patient’s effective diameter, the mean SSDE value for Group 1, Group 2 and Group 3 were 9.93 ± 3.89 mGy, 13.70 ± 9.04 mGy and 22.29 ± 7.35 mGy. The organ dose and cancer risk attained for breast, lung and liver were 17.05 ± 10.40 mGy (194 per one million procedure), 17.55 ± 10.86 mGy (192 per one million procedure) and 15.04 ± 9.75 mGy (53 per one million procedure), respectively. Lung and breast with more massive patient’s effective diameter received the highest dose exposure which increases the probability of the cancer risk. CTDI_vol was found to be underestimated, and SSDE provides more accurate in describing the radiation dose and cancer risk. Body effective diameter found to be significant on the estimation except for gender. Therefore, it is essential to apply optimised protocols in order to reduce patient’s exposure during CTPA examination.

Background: Approximately 75% of all head and neck cancer patients are treated with radiotherapy (RT). RT to the oral cavity results in acute and late adverse events which can be severe and detrimental to a patient’s quality of life and function. The purpose of this study was to explore associations between RT dose to a defined oral cavity organ at risk (OAR) avoidance structure, provider and patient reported outcomes (PROs), opioid use, and hospitalization. Methods: This was a retrospective analysis of prospectively obtained outcomes using multivariable modeling. The study included 196 patients treated with RT involving the oral cavity for a head and neck tumor. A defined oral cavity OAR avoidance structure was used in all patients for RT treatment planning. Validated PROs were collected prospectively. Opioid use and hospitalization were abstracted electronically from medical records. Results: Multivariable modeling revealed the mean dose to the oral cavity OAR was significantly associated with opioid use (p=0.0082) and hospitalization (p=0.0356) during and within 30 days of completing RT. Conclusion: The findings of this study may be valuable in RT treatment planning for patients with tumors of the head and neck region to reduce the need for opioid use and hospitalization during treatment.

This study aims to evaluate the factors influencing the adherence to the 2nd and 3rd doses during each cycle of seasonal malaria chemoprevention (SMC) in Burkina Faso, Mali, and Niger. Overall, 3,132 people were interviewed during surveys between 2019 and 2020 in 15 health districts. The median age was 30 years. In Burkina , Mali, and Niger, the proportions of non-adherence were 4.15% , 5.60%, and 13.30%, respectively (95% CI (-3.27% -0.37 %, p = 0.114 ) for the 2nd dose and 3.98%, 5.60% and 14.39% for the 3rd dose. The main cause of non-adherence to the 2nd and 3rd doses was other illnesses in 28.5% and 29.78% respectively in Burkina, 5.35% and 5.35% in Mali and 1.6% and 0.75% in Niger. It was followed by vomiting in 12.24% and 10.63% for Burkina and 2.45% and 3.78% in Niger. The last causes were refusal in 6.12% and 4.25% in Burkina , 33.9% and 15.25% in Mali and 0.8% and 1.51% in Niger. Non-adherence of doses related to parents was primary due to their absence in 28.5% and 27.65% in Burkina , 16.07% and 16.07% in Mali and 7.37 % and 6.06% in Niger. Travelling was the second cause in 12.24 % and 12.76% in Burkina , 19.64% and 19.64% in Mali and 0.81% and 0.75% in Niger. Non-adherence related to community distributors was mainly due to missing of the doses in 4.08% and 4.25% in Burkina , 23.21% and 23.21% in Mali, 77.04% and 76.51% in Niger. Our study reported very small proportions of non-adherence to 2nd and 3rd doses of SMC and identified the main causes of non-adherence.

Background: Partially hydrolyzed guar gum (PHGG) is a water-soluble, prebiotic fiber that is used in foods and supplements. The effects of PHGG and its role in gut health are still being studied. The purpose of this study was to evaluate changes in the gut microbiome composition of healthy individuals in response to low-dose PHGG supplementation compared with a low fiber diet. Methods: A randomized, double-blind, placebo-controlled crossover study was performed on 33 healthy subjects (17 male, 16 female). Each subject completed three 14-day treatment periods with a 2-week washout between each period. Treatments included supplementation with 3 g PHGG, 6 g PHGG, or placebo. During all periods, the participants followed a low fiber diet (<14 g/day). Stools were collected on days 0 and 14 of each period. Gut microbiome profiling was performed using 16S rRNA sequencing. Results: Supplementation of 3 g and 6 g PHGG significantly increased Verrucomicrobia on day 14 when compared to the placebo (p=0.0066 and p= 0.0068, respectively). On the genus level, Akkermansia was significantly increased on day 14 with both the 3 g and 6 g PHGG doses (p=0.0081 and p=0.0083). Faecalibacterium was significantly decreased on day 14 with 3 g PHGG (p=0.0054). Conclusion: Supplementing with low doses of PHGG has the potential to cause shifts in gut microbiome composition. By increasing beneficial microbes, PHGG can improve the microbiome composition of healthy individuals and may play a role in the treatment of inflammatory gastrointestinal diseases.

Vitamin C status is known to be associated with several demographic and lifestyle factors. These include gender, age, ethnicity, pregnancy/lactation, body weight, smoking status and dietary habits. In the present study, our aim was to interrogate the National Health and Nutrition Examination Survey (NHANES) 2017-2018 datasets to assess the impact of these factors on vitamin C dose-concentration relationships to establish if there are higher requirements for vitamin C in certain subpopulations and the possible extent of these additional requirements. The relevant data were extracted from the NHANES 2017-2018 datasets, the final cohort of which comprised 2828 non-supplementing adult males and females (aged 18 – 80+ years) with both vitamin C serum concentrations and dietary intake data available. The data was subsequently stratified by gender, age tertiles (≤36, 37-58, ≥59 years), ethnicity (non-Hispanic white, non-Hispanic black, and total Hispanic), socioeconomic tertiles (poverty income ratios: &gt;3.0, 1.36 – 3.0, ≤1.35), weight tertiles (≤72, 72-91, ≥91 kg), BMI tertiles (≤26, 26-32, ≥32 kg/m2) and smoking status. Sigmoidal (four parameter logistic) curves with asymmetrical 95% confidence intervals were fitted to the dose-concentration data. We found that males required vitamin C intakes ~1.2-fold higher than females to reach ‘adequate’ serum concentrations of 50 µmol/L. Males had both higher body weight and a higher prevalence of smoking than females. Smokers required vitamin C intakes ~2.0-fold higher than non-smokers to reach adequate vitamin C concentrations. Relative to adults in the lighter weight tertile, adults in the heaver weight tertile required ~2.0-fold higher dietary intakes of vitamin C to reach adequate serum concentrations. We did not observe any impact of ethnicity or socioeconomic status on the vitamin C dose-concentration relationship, and although no significant difference between younger and older adults was observed at vitamin C intakes &gt; 75 mg/day, at intakes &lt; 75 mg/day, older adults had an attenuated serum response to vitamin C intake. In conclusion, certain demographic and lifestyle factors, specifically gender, smoking and body weight, have a significant impact on vitamin C requirements. Overall, the data indicate that the general population must consume ~110 mg/day of vitamin C to attain adequate serum concentrations, smokers require ~165 mg/day relative to non-smokers, and heavier people (100+ kg) require ~155 mg/day to reach the same vitamin C concentrations. These findings have important implications for global vitamin C dietary recommendations.

Brachytherapy is often applied to oral cancers, with good outcomes and minimal loss of oral function. Especially, mold brachytherapy is best suited for superficial oral cancers with little or no bone invasion, such as gingival cancer, palatal mucosal cancer, or buccal mucosal cancer because of the thin tissue thickness that needs to be irradiated. A few cases have been reported on mold brachytherapy for gingival cancers, especially with high-dose-rates (HDR), these treatments were performed during hospitalization. We report a case of lower gingival squamous cell carcinoma (SCC) treated with HDR mold brachytherapy in an outpatient setting. A 71-year-old male with lower gingival SCC had received HDR mold brachytherapy (54 Gy, 9 fractions, 5 days) as an outpatient. Eighteen months after the mold therapy, the patient had no recurrence and no metastasis. A search of the literature revealed no previous report of a case of gingival cancer treated with HDR mold brachytherapy in an outpatient.

This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses (TLD) with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the TLD of a drug divided by the volume of the receptacle it is contained within. The product density is given by the product of three terms: the packing density (the mass of powder divided by the volume of the receptacle), the drug loading (the mass of drug divided by the mass of powder), and the aerosol performance (the TLD divided by the mass of drug). This manuscript discusses strategies for maximizing each of these terms. Spray drying at low drying rates with small amounts of a shell-forming excipient (low Peclet Number) leads to formation of higher density particles with high packing densities. This enables ultrahigh TLD (>100 mg of drug) to be achieved from a single receptacle. Emptying of powder from capsules is directly proportional to the mass of powder in the receptacle, requiring an inhaled volume of about 1 L for fill masses between 40 and 50 mg and up to 3.2 L for a fill mass of 150 mg.

Objective: To describe outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low dose hydroxychloroquine, and azithromycin (the triple therapy) dependent on risk stratification. Design: Retrospective case series study. Setting: General practice. Participants: 141 COVID-19 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the year 2020. Main Outcome Measures: Risk-stratified treatment decision, rate of hospitalization and all-cause death. Results: Of 335 positively PCR-tested COVID-19 patients, 127 were treated with the triple therapy. 104 of 127 met the defined risk stratification criteria and were included in the analysis. In addition, 37 treated and eligible patients who were confirmed by IgG tests were included in the treatment group (total N=141). 208 of the 335 patients did not meet the risk stratification criteria and were not treated. After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-67; 73% male) got a prescription for the triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control. 4 of 141 treated patients (2.8%) were hospitalized, which was significantly less (p<0.001) compared with 58 of 377 untreated patients (15.4%) (odds ratio 0.16, 95% CI 0.06-0.5). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated group. One patient (0.7%) died in the treatment group versus 13 patients (3.5%) in the untreated group (odds ratio 0.2, 95% CI 0.03-1.5; p=0.16). There were no cardiac side effects. Conclusions: Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalizations and 5 times less all-cause deaths.

X-ray Fluorescence Computed Tomography (XFCT) is an emerging non-invasive imaging technique providing molecular-level data, gaining attention for high-resolution imaging. However, increased sensitivity with benchtop X-ray sources raises radiation exposure. Artificial Intelligence (AI), particularly deep learning (DL), has revolutionized medical imaging by delivering high-quality images in the presence of noise. In XFCT, traditional methods rely on complex algorithms for noise reduction, but AI holds promise in addressing high-dose concerns. We present an optimized SCUNet model for noise reduction in low-concentration XRF images. Compared to higher-dose images, our method’s effectiveness is evaluated. While various denoising techniques exist for X-ray and CT, few address to XFCT. The DL model is trained and assessed using the augmented data, focusing on background noise reduction. Image quality is measured using PSNR and SSIM, comparing outcomes with 100% X-ray dose images. Results show the proposed algorithm achieves high-quality images from low-dose and low-contrast agents, with a maximum PSNR of 39.05 and SSIM of 0.86. The model outperforms BM3D, NLM, DnCNN, and SCUNet in both visual inspection and quantitative analysis, particularly in high-noise scenarios. This indicates the potential of AI, specifically the SCUNet model, in significantly improving XFCT imaging by mitigating the trade-off between sensitivity and radiation exposure.

To determine the impacts of metabolizable energy levels on the performance indices of geese and to forecast the ideal range of dietary metabolizable energy levels, this study was carried out. Literature on the effects of dietary metabolized energy level on the performance of geese was searched from CNKI, Wanfang, VIP, PubMed, Web of Science, and ScienceDirect databases from January 1, 2000, to December 31, 2022. A dose-response meta-analysis was performed by STATA (14.0), data were calculated by the robust error meta-regression model (REMR), and nonlinear dose-effect curves were plotted by the restricted cubic spline method (RCS). 29 papers were chosen from the 1,475 literatures that fit the criteria and were included in the dose-response meta-analysis. There were 6,079 geese included in the sample. The following production performance indices included average daily gain (ADG), average daily feed intake (ADFI), feed-to-gain ratio (F/G), dressed percentage, percentage of half-eviscerated yield, percentage of eviscerated yield, percentage of breast muscle, percentage of leg muscle and percentage of abdominal fat. The Egger test assessed publication bias, while sensitivity analysis was used to examine the heterogeneity. The verified results are consistent and reliable. The results indicated that for each group, the optimal dietary metabolizable energy level was about 13 to 13.5MJ/kg for medium-sized geese aged 0 to 4 weeks, 12 to 13MJ/kg for medium-sized geese aged above 5 weeks, 12.5 to 13MJ/kg for small-sized geese aged 0 to 4 weeks, and 13 to 13.5MJ/kg for mall-sized geese over 5 weeks of age. Future research should be conducted on related diets of large-sized geese, small-sized geese, and higher metabolizable energy levels.

Aim was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) and to describe the sources of variability. The study included 50 patients (1-18 years) who received 3 or 5 g/m2 of HDMTX. Nonlinear mixed effects modeling approach was applied for data analysis. Parameter estimation was performed by FOCEI, whereas stepwise covariate modeling was used to assess variability factors. The final two-compartment model incorporates the effect of body weight using allometric scaling and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical 70 kg subject were: 11 L/h for clearance (CL), 46.5 L and 16.4 L for volume of central (V1) and peripheral compartment (V2), respectively, and 0.168 L/h for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 30% in MTX CL was observed among patients’ hemoglobin values reported in the study. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to HDMTX disposition.

Older adults (age ≥65) are at high risk of influenza morbidity and mortality. This study evaluated the impact of a hypothetical two-dose influenza vaccine regimen per season to reduce symptomatic flu cases by providing preseason (first dose) and mid-season (second dose) protection to offset waning vaccine effectiveness (VE). The Framework for Reconstructing Epidemiological Dynamics (FRED), an agent-based modeling platform, was used to compare typical one-dose vaccination to a two-dose vaccination strategy. Primary models incorporated waning VE of 10% per month and varied influenza season timing (December through March) to estimate cases and hospitalizations in older adults. Additional scenarios modeled reductions in uptake and VE of the second dose, and overall waning. In seasons with later peaks, two vaccine doses had the largest potential to reduce cases (14.4% with February peak, 18.7% with March peak) and hospitalizations (13.1% with February peak, 16.8% with March peak). Reductions in cases and hospitalizations still resulted but decreased when 30% of individuals failed to receive a second dose, second dose VE was reduced, or overall waning was reduced to 7% per month. Agent-based modeling indicates that two influenza vaccine doses could decrease cases and hospitalizations in older individuals. The highest impact occurred in the more frequently observed late-peak seasons. The beneficial impact of the two-dose regimen persisted despite model scenarios of reduced uptake of the second dose, decreased VE of the second dose, or overall VE waning.

Advanced paternal age at fertilization has been suggested to be a risk factor for neurodevelopmental, psychiatric and other disorders in offspring. One emerging hypothesis suggests that altered offspring phenotype is linked with age-related accumulation of epigenetic changes in the sperm of fathers. Given that paternal age is increasing in the developed world, understanding aging-related epigenetic changes in sperm is needed as well as environmental factors that modify such changes. In this study, we characterize age-dependent changes in sperm DNA methylation profiles between young pubertal (postnatal day (PNDs) 65) and mature (PND120) Wistar rats. We also analyze these changes in rats exposed perinatally to 0.2 mg/kg of ubiquitous environmental xenobiotic 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47). Reduced representation bisulfite sequencing (RRBS) libraries were prepared from caudal epididymal sperm DNA and differentially methylated regions (DMRs; ≥ 10x coverage depth, ≥ 3 CpGs per cluster, ≥ 5% methylation change, q < 0.05) were identified via MethPipe package. In control animals, 5,319 age-dependent DMRs were identified, with 99.3% DMRs hypermethylated in mature animals compared to young pubertal rats. These age-related DMRs were enriched for functional categories essential for embryonic development, such as pattern specification, forebrain and sensory organ development, Hippo and Wnt pathways. Age-related changes in sncRNA, reported in different study, target similar list of genes and biological categories.In BDE-47 exposed rats, sperm DNA methylation was higher in young pubertal and lower in mature animals when compared to controls, which resulted in a significant attenuation in the number of age-dependent DMRs (N = 189) identified in the exposed group. In conclusion, our results indicate that the natural aging process has profound effects on sperm methylation levels and this effect may be modified by environmental exposures. Moreover, our results further support the role of epigenetic mechanisms as a likely link betwen paternal age and offspring health and development.

As a result of the cancer immunotherapy revolution hundreds of clinical trials of the newly approved immunotherapies are now under way to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by blockade of co-inhibitory signals. While success stories of terminal cancer patients achieving complete remissions are accumulating, not enough research has been done into the risks of the new therapies. Since the use of immunotherapy is becoming more common, and is expected to develop into first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the nemesis of immunotherapy. Immune-related adverse events (IrAEs) could affect any tissue, their incidence may reach up to 90% of patients and toxicity is dose-dependent. While the combination of two immune checkpoint inhibitors (ICIs) increased efficacy, the incidence of severe adverse events was also increased. Apparently, ICIs cannot be restricted to the targeted anti-tumor T cell population. The long lasting objective of cancer regression can only be achieved by paying a price: tolerance to healthy self tissues is compromised. In the face of an ipilimumab induced pan-lymphocytic activation, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune suppressive treatments, but instead harnessing the autoimmune forces by an off label low-dose combined anti-CTLA-4 and anti-PD1 antibody blockade, which is supplemented with conventional interleukin-2 stimulation and hyperthermia. The proof-of-principle of the low-dose-combination therapy was demonstrated in a heavily pre-treated triple negative breast cancer (TNBC) patient with far advanced pulmonary metastases and severe shortness of breath, who had exhausted all conventional treatment. Her pulmonary metastases went into complete remission with transient WHO I-II diarrhea and skin rash. She lived for 27 months after starting the low-dose-combination therapy. She had recurrence as a sternal mass and pleural metastases up to 3 cm. Since the low-dose-combination protocol consists only of approved drugs and treatments, this exceptional response should instigate further research efforts.

Environmental chemicals, including PFAS (per- and polyfluoroalkyl substances), pesticides, industrial chemicals, and consumer products, commonly exist as mixtures. These substances are frequently exposed or co-exposed in varying concentrations, leading to potentially hazardous health effects such as cancer in humans. Thus, understanding the dose-dependent toxicity of chemical mixtures is important for assessing health risks. In this context, comprehensive methods for assessing the toxicity and identifying the mechanisms of harmful chemical mixtures are currently lacking. Here, the dose-dependent toxicity assessments of chemical mixtures are performed in three methodologically distinct phases. In the first phase, we evaluated our machine learning method (AI-HNN) and pathophysiology method (CPTM) for predicting toxicity. In the second phase, we integrated AI-HNN and CPTM to establish a comprehensive new approach method (NAM) framework called AI-CPTM, targeted at refining prediction accuracy and providing a comprehensive understanding of toxicity mechanisms. The third phase involved experimental validations of the AI-CPTM predictions. Initially, we developed binary, multiclass classification, and regression models to predict binary, categorical toxicity, and toxic potencies, using nearly a thousand experimental mixtures. This empirical dataset was expanded with virtual mixtures compensating the lack of experimental data and broadening the scope of the dataset. For comparison, we also developed additional machine learning models based on RF, Bagging, AdaBoost, SVR, GB, KR, DT, KN, and Consensus methods. The models achieved overall accuracies of over 80% with AUC values exceeding 90%. The regression models achieved an R2 >0.88. In the second phase, we innovatively integrated HNN-derived toxicity predictions with Z-scores from CPTM, resulting method called AI-CPTM. In the final phase, we demonstrated the superior performance of AI-CPTM through rigorous literature and statistical performance validations. Additionally, the predictive capability of AI-CPTM, including for PFAS mixtures and their interaction effects, was demonstrated by experimental validations using dose-response zebrafish embryo toxicity assays. Overall, the AI-CPTM approach significantly improves upon the limitations of standalone models and has shown extensive enrichments in the identification of toxic chemicals and mixtures. Further experimental studies involving human cell models, patient-derived xenografts, and investigations into the toxicity of multiple mixtures are currently underway.

The persistent burden of chronic hepatitis B among ≤5-year-old children in Africa suggests missed opportunities for controlling mother-to-child transmission (MTCT) of the hepatitis B virus (HBV). This scoping review maps the evidence base on the risk of HBV MTCT, the status of HBV MTCT mitigation strategies including hepatitis B birth-dose vaccination, and the role of systems complexity on the suboptimal adoption and performance of hepatitis B birth-dose vaccination programs in Africa. Overall, 88 peer-reviewed and grey literature sources published between 2000–2022 were included in this review. The evidence base consistently argues for a growing risk of HBV MTCT amidst the HIV co-epidemic in the region. Without universal HBV screening programs integrated within broader antenatal care services, current selective hepatitis B birth-dose vaccination is unlikely to effectively interrupt HBV MTCT. We underscore critical health systems-related barriers to universal adoption and optimal performance of hepatitis B birth-dose vaccination programs in the region. To better conceptualize the role of complexity and system-wide effects on the observed performance of the program, we propose an adapted systems-based logic model. Ultimately, exploring contextualized complex systems approaches to scaling-up universal hepatitis B birth-dose vaccination programs should form an integral part of the regional research agenda.

Diabetes mellitus leads to cardiovascular complications including impaired cardiac β-adrenoceptor (β-AR) function. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin (EMPA) improve outcomes in heart failure patients and animal models thereof. Therefore, we have investigated the effects of EMPA on in vivo cardiac function (pressure-volume loop analysis) and β-AR-mediated contractile responses (papillary strips) in streptozotocin (STZ; 40 mg/kg, i.p.)-induced diabes in male Sprague Dawley rats (control, EMPA-treated control, diabetic, EMPA-treated diabetic) in a design reflecting late-onset treatment. 13-16 weeks after STZ injection treatment with a low dose of EMPA (10 mg/kg/day, daily oral gavage) or vehicle was administered for another 8 weeks. EMPA did not change cardiac function in control rats. Diabetic rats had a reduced heart rate, cardiac output, stroke work, rate of contration and rate of relaxation and increased isovolumic relaxation, whereas in vitro responses were not markedly attenuated. Treatment with EMPA showed a trend for improvement of some but not all parameters. Our results indicate that low dose EMPA treatment had limited effects on cardiac impairment despite reducing blood glucose when initiated after diabetes is manifest. Future studies with a higher dose and greater sample sizes could help to clarify the possible benefits of EMPA on the diabetic heart.