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Abstract Background Comprehensive stroke centres across England have developed investment proposals, showing the estimated increases in mechanical thrombectomy (MT) treatment volume that would justify extending the standard hours to a 24/7 service provision. These investment proposals have been developed taking a financial accounting perspective, that is by considering the financial revenues from tariff income. However, given the pressure put on local health authorities to provide value for money services, an affordability question emerges. That is, at what additional MT treatment volume the additional treatment costs are offset by the additional health economic benefits, that is quality-adjusted life years (QALYs) and societal cost savings, generated by administering MT compared to standard care. Methods A break-even analysis was conducted to identify the additional MT treatment volume required. The incremental hospital-related costs associated with the 24/7 MT extension were estimated using information and parameters from four relevant business cases. The additional societal cost savings and health benefits were estimated by adapting a previously developed Markov chain-based model. Results The additional hospital-related annual costs for extending MT to a 24/7 service were estimated at a mean of £3,756,818 (range £1,847,387 to £5,092,788). On average, 750 (range 246 to 1,571) additional eligible stroke patients are required to be treated with MT yearly for the proposed 24/7 service extension to be affordable from a health economic perspective. Overall, the additional facility and equipment costs associated with the 24/7 extension would affect this estimate by 20%. Conclusions These findings support the ongoing debate regarding the optimal levels of MT treatment required for a 24/7 extension and respective changes in hospital organisational activities. They also highlight a need for a regional-level coordination between local authorities and hospital administrations to ensure equity provision in that stroke patients can benefit from MT and that the optimal MT treatment volume is reached. Future studies should contemplate reproducing the presented analysis for different health service provision settings and decision making contexts.

Background The Gender, Age and Physiology (GAP) model is a simple mortality prediction tool in patients with idiopathic pulmonary fibrosis that uses demographic and physiological variables available at initial evaluation. White blood cell variables may have associations with idiopathic pulmonary fibrosis outcomes. We evaluated whether incorporating blood cell counts in modified GAP (cGAP) models would improve outcome prediction in patients with idiopathic pulmonary fibrosis. Patients and methods This retrospective analysis included pooled data from phase 3 randomised trials of pirfenidone in idiopathic pulmonary fibrosis (ASCEND, CAPACITY 004, CAPACITY 006). Study outcomes (disease progression, all-cause mortality, all-cause hospitalisation, respiratory-related hospitalisation) were evaluated during the initial 1-year period. Shared frailty models were used to evaluate associations between continuous and categorical baseline white and red blood cell parameters and study outcomes in a bivariate context, and to evaluate the impact of adding continuous monocyte count (cGAP1) or white and red blood cell parameters (cGAP2) to traditional GAP variables in a multivariable context based on C-statistics changes. Results Data were pooled from 1247 patients (pirfenidone, n=623; placebo, n=624). Significant associations (bivariate analyses) were idiopathic pulmonary fibrosis progression with neutrophil and eosinophil counts; all-cause mortality with monocyte and neutrophil counts; all-cause hospitalisation with monocyte count, neutrophil count and haemoglobin level; and respiratory-related hospitalisation with monocyte count, neutrophil count and haemoglobin level. In multivariate analyses, C-statistics were highest for the cGAP2 model for each of the outcomes. Conclusion Modified GAP models incorporating monocyte counts alone or plus other white and red blood cell variables may be useful to improve prediction of outcomes in patients with idiopathic pulmonary fibrosis.

Abstract This study investigates correlates of anti-S1 antibody response following COVID-19 vaccination in a U.S. population-based meta-cohort of adults participating in longstanding NIH-funded cohort studies. Anti-S1 antibodies were measured from dried blood spots collected between February 2021-August 2022 using Luminex-based microsphere immunoassays. Of 6245 participants, mean age was 73 years (range, 21-100), 58% were female, and 76% were non-Hispanic White. Nearly 52% of participants received the BNT162b2 vaccine and 48% received the mRNA-1273 vaccine. Lower anti-S1 antibody levels are associated with age of 65 years or older, male sex, higher body mass index, smoking, diabetes, COPD and receipt of BNT16b2 vaccine (vs mRNA-1273). Participants with a prior infection, particularly those with a history of hospitalized illness, have higher anti-S1 antibody levels. These results suggest that adults with certain socio-demographic and clinical characteristics may have less robust antibody responses to COVID-19 vaccination and could be prioritized for more frequent re-vaccination.

Background: Education to improve medication adherence is one of the core components of cardiac rehabilitation (CR) programs. However, the evidence on the effectiveness of CR programs on medication adherence is conflicting. Therefore, we aimed to summarize the effectiveness of CR programs versus standard care on medication adherence in patients with cardiovascular disease. Methods: A systematic review and meta-analysis was conducted. Seven databases and clinical trial registries were searched for published and unpublished articles from database inception to 09 Feb 2022. Only randomised controlled trials and quasi-experimental studies were included. Two independent reviewers conducted the screening, extraction, and appraisal. The JBI methodology for effectiveness reviews and PRISMA 2020 guidelines were followed. A statistical meta-analysis of included studies was pooled using RevMan version 5.4.1. Results: In total 33 studies were included with 16,677 participants. CR programs increased medication adherence by 14 % (RR = 1.14; 95 % CI: 1.07 to 1.22; p = 0.0002) with low degree of evidence certainty. CR also lowered the risk of dying by 17 % (RR = 0.83; 95 % CI: 0.69 to 1.00; p = 0.05); primary care and emergency department visit by mean difference of 0.19 (SMD = −0.19; 95 % CI: −0.30 to −0.08; p = 0.0008); and improved quality of life by 0.93 (SMD = 0.93; 95 % CI: 0.38 to 1.49; p = 0.0010). But no significant difference was observed in lipid profiles, except with total cholesterol (SMD = −0.26; 95 % CI: −0.44 to −0.07; p = 0.006) and blood pressure levels. Conclusions: CR improves medication adherence with a low degree of evidence certainty and non-significant changes in lipid and blood pressure levels. This result requires further investigation.

Abstract Due to waning immunity following primary immunization with COVID-19 vaccines, booster doses may be required. The present study assessed a heterologous booster of SII-NVX-CoV2373 (spike protein vaccine) in adults primed with viral vector and inactivated vaccines. In this Phase 3, observer-blind, randomized, active controlled study, a total of 372 adults primed with two doses of ChAdOx1 nCoV-19 (n = 186) or BBV152 (n = 186) at least six months ago, were randomized to receive a booster of SII-NVX-CoV2373 or control vaccine (homologous booster of ChAdOx1 nCoV-19 or BBV152). Anti-S IgG and neutralizing antibodies (nAbs) were assessed at days 1, 29, and 181. Non-inferiority (NI) of SII-NVX-CoV2373 to the control vaccine was assessed based on the ratio of geometric mean ELISA units (GMEU) of anti-S IgG and geometric mean titers (GMT) of nAbs (NI margin > 0.67) as well as seroresponse (≥ 2 fold-rise in titers) (NI margin −10%) at day 29. Safety was assessed throughout the study period. In both the ChAdOx1 nCoV-19 prime and BBV152 prime cohorts, 186 participants each received the study vaccines. In the ChAdOx1 nCoV-19 prime cohort, the GMEU ratio was 2.05 (95% CI 1.73, 2.43) and the GMT ratio was 1.89 (95% CI 1.55, 2.32) whereas the difference in the proportion of seroresponse was 49.32% (95% CI 36.49, 60.45) for anti-S IgG and 15% (95% CI 5.65, 25.05) for nAbs on day 29. In the BBV152 prime cohort, the GMEU ratio was 5.12 (95% CI 4.20, 6.24) and the GMT ratio was 4.80 (95% CI 3.76, 6.12) whereas the difference in the proportion of seroresponse was 74.08% (95% CI 63.24, 82.17) for anti-S IgG and 24.71% (95% CI 16.26, 34.62) for nAbs on day 29. The non-inferiority of SII-NVX-CoV2373 booster to the control vaccine for each prime cohort was met. SII-NVX-CoV2373 booster showed significantly higher immune responses than BBV152 homologous booster. On day 181, seroresponse rates were ≥ 70% in all the groups for both nAbs and anti-S IgG. Solicited adverse events reported were transient and mostly mild in severity in all the groups. No causally related SAE was reported. SII-NVX-CoV2373 as a heterologous booster induced non-inferior immune responses as compared to homologous boosters in adults primed with ChAdOx1 nCoV-19 and BBV152. SII-NVX-CoV2373 showed a numerically higher boosting effect than homologous boosters. The vaccine was also safe and well tolerated.

The evaluation of coronavirus disease 2019 (COVID-19) vaccine immunogenicity remains essential as the severe acute respiratory syncytial virus 2 (SARS-CoV-2) pandemic continues to evolve and as additional variants emerge. Neutralizing antibodies are a known correlate of protection for SARS-CoV-2 vaccines. A pseudovirus neutralization (PNT) assay was developed and validated at Novavax Clinical Immunology Laboratories to allow for the detection of neutralizing antibodies in vaccine clinical trial sera. The PNT assay was precise, accurate, linear, and specific in measuring SARS-CoV-2 neutralization titers in human serum for ancestral strain and the Omicron subvariants BA.5 and XBB.1.5, with an overall geometric coefficient of variation of ≤43.4%, a percent relative bias within the expected range of −60% to 150%, and a linearity value of R2 > 0.98 for all three strains. This pseudovirus assay will be useful for the analysis of vaccine clinical trial samples to assess vaccine immunogenicity. Future work will focus on modifying the assay for emerging variants, including XBB.1.16, EG.5.1, BA.2.86, and any other variants that emerge in the ongoing pandemic.

Abstract Respiratory viral infection can lead to activation of sensory afferent nerves as indicated by the consequential sore throat, sneezing, coughing, and reflex secretions. In addition to causing troubling symptoms, sensory nerve activation likely accelerates viral spreading. The mechanism how viruses activate sensory nerve terminals during infection is unknown. In this study, we investigate whether coronavirus spike protein activates sensory nerves terminating in the airways. We used isolated vagally‐innervated mouse trachea‐lung preparation for two‐photon microscopy and extracellular electrophysiological recordings. Using two‐photon Ca2+ imaging, we evaluated a total number of 786 vagal bronchopulmonary nerves in six experiments. Approximately 49% of the sensory fibers were activated by S1 protein (4 μg/mL intratracheally). Extracellular nerve recording showed the S1 protein evoked action potential discharge in sensory C‐fibers; of 39 airway C‐fibers (one fiber per mouse), 17 were activated. Additionally, Fura‐2 Ca2+ imaging was performed on neurons dissociated from vagal sensory ganglia (n = 254 from 22 mice). The result showed that 63% of neurons responded to S1 protein. SARS‐CoV‐2 S1 protein can lead to direct activation of sensory C‐fiber nerve terminals in the bronchopulmonary tract. Direct activation of C‐fibers may contribute to coronavirus symptoms, and amplify viral spreading in a population.

A genomic analysis of 147 pediatric acute myeloid leukemia patients identifies extensive gene fusion events and mutations that expand our understanding of the genetic complexities of this cancer.

Senile gluteal dermatosis (SGD) is a common but seldom recognized condition. It is characterized clinically by unilateral or bilateral hyperkeratotic, lichenified plaques on the gluteal area, being attributed to prolonged sitting, particularly in the elderly. SGD also encompasses the recently proposed entity of prurigiform angiomatosis. Histologically, there are features of lichenification, such as epidermal hyperplasia and a preserved granular layer, with prominent dermal angioproliferation. We report 4 cases of this condition as well as novel findings of variably increased mast cells and superficial lymphatic vessels in addition to the proliferation of dermal blood vessels. We propose a unifying name for Reactive Epidermal hyperplasia and Angiogenesis of the Rear (REAR) to encapsulate the characteristic clinical and histological features of this distinct entity.

Neutralizing antibody responses from COVID-19 vaccines are pivotal in conferring protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Effective COVID-19 vaccines and assays measuring neutralizing antibodies against emerging variants (i.e., XBB.1.5, XBB.1.16, and XBB.2.3) are needed. The use of biosafety level (BSL)-3 laboratories for live virus assays results in higher costs and a longer turnaround time; therefore, a BSL-2–based pseudovirus neutralization assay (PNT) was developed. The pseudoviruses were produced by cotransfecting cells with plasmids encoding a lentiviral backbone-expressing luciferase reporter; non-surface proteins for lentiviral production; and ancestral or Omicron (BA.1 and BA.5) SARS-CoV-2 spike (S) proteins. The PNT was developed and optimized in dose and kinetics experiments. The representative serum samples (COVID-19–convalescent or NVX-CoV2373–vaccinated participants enrolled in the 2019nCoV-101 trial) demonstrated a wide dynamic range. The neutralization data showed robust correlation with validated anti-recombinant spike IgG levels and angiotensin-converting enzyme 2 inhibition titers (ancestral). This assay is suitable for measurement of the neutralization ability in clinical samples from individuals infected with SARS-CoV-2 or immunized with a COVID-19 vaccine. The results suggest that this PNT provides a lower cost, high-throughput, rapid turnaround alternative to BSL-3–based microneutralization assays and enables the discovery and development of effective vaccines against emerging variants.

Some of the key pests of tomatoes are virus vectors, such as whiteflies, green peach aphids, and thrips, mainly because there is a lack of full resistance to the transmitted viruses. Alternatives to reduce this problem include the use of a push-and-pull strategy. Hence, this work assessed the association between Solanum habrochaites PI 1344117, used as a companion plant, and commercial tomato varieties over tomato virus vectors and the yield quality and quantity. Field and greenhouse trials were run during the 2015, 2016, 2018, and 2019 seasons. The treatments were BRS Tospodoro and BRS Tyão cultivated as monocrops and associated with PI-134417. The number of these insects was assessed by directly counting ten plants per plot and using captures on yellow sticky traps settled in the center of the plots. The yield and the number of irregularly ripening fruits (a symptom caused by whiteflies) were also measured. Both commercial cultivars gained from the protective effect of PI 134417, expressed by the significant reduction in the virus vectors on the plants. It was also noticed that there was a reduction in the number of irregularly ripening fruits, improving the fruit quality. These results encourage the use of wild and commercial tomato genotypes in association with implementing strategies to control tomato virus vectors, reducing the need to rely only on a chemical control.

Summary: Background: NVX-CoV2373, a Covid-19 vaccine was developed in the USA with ∼90% efficacy. The same vaccine is manufactured in India after technology transfer (called as SII-NVX-CoV2373), was evaluated in this phase 2/3 immuno-bridging study. Methods: This was an observer-blind, randomised, phase 2/3 study in 1600 adults. In phase 2, 200 participants were randomized 3:1 to SII-NVX-CoV2373 or placebo. In phase 3, 1400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (940 safety cohort and 460 immunogenicity cohort). Two doses of study products (SII-NVX-CoV2373, NVX-CoV2373 or placebo) were given 3 weeks apart. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 to NVX-CoV2373 in terms of geometric mean ELISA units (GMEU) ratio of anti-S IgG antibodies 14 days after the second dose (day 36) and to determine the incidence of causally related serious adverse events (SAEs) through 180 days after the first dose. Anti-S IgG response was assessed using an Enzyme-Linked Immunosorbent Assay (ELISA) and neutralizing antibodies (nAb) were assessed by a microneutralization assay using wild type SARS CoV-2 in participants from the immunogenicity cohort at baseline, day 22, day 36 and day 180. Cell mediated immune (CMI) response was assessed in a subset of 28 participants from immunogenicity cohort by ELISpot assay at baseline, day 36 and day 180. The total follow-up was for 6 months. Trial registration: CTRI/2021/02/031554. Findings: Total 1596 participants (200 in Phase 2 and 1396 in Phase 3) received the first dose. SII-NVX-CoV2373 was found non-inferior to NVX-CoV2373 (anti-S IgG antibodies GMEU ratio 0.91; 95% CI: 0.79, 1.06). At day 36, there was more than 58-fold rise in anti-S IgG and nAb titers compared to baseline in both the groups. On day 180 visit, these antibody titers declined to levels slightly lower than those after the first dose (13–22 fold-rise above baseline). Incidence of unsolicited and solicited AEs was similar between the SII-NVX-CoV2373 and NVX-CoV2373 groups. No adverse event of special interest (AESI) was reported. No causally related SAE was reported. Interpretation: SII-NVX-CoV2373 induced a non-inferior immune response compared to NVX-CoV2373 and has acceptable safety profile. Funding: SIIPL, Indian Council of Medical Research, Novavax.

Abstract Prefibrotic primary myelofibrosis (Pre‐PMF) has been classified as a separate entity of myeloproliferative neoplasms (MPNs). Pre‐PMF is clinically heterogeneous but a specific prognostic model is lacking. Gene mutations have emerged as useful tools for stratification of myelofibrosis patients. However, there have been limited studies comprehensively investigating the mutational spectrum and its clinicopathological significance in pre‐PMF subjects. In this study, we addressed these issues by profiling the mutation status of 141 genes in 172 Chinese MPN patients including 72 pre‐PMF cases. Our findings corroborated the clinical/molecular distinctiveness of pre‐PMF and suggested a refined risk classification strategy for this entity.

Background and Aims: Inflammatory bowel disease (IBD), inclusive of ulcerative colitis and Crohn’s disease, are chronic inflammatory conditions that impact women of childbearing age. It has been previously shown that IBD is associated with altered metabolomic profiles, but whether metabolomic changes also affect pregnant patients with IBD is completely unknown. Methods: This was a prospective cohort study comprised of 48 pregnant women with IBD who were followed throughout preconception and pregnancy. IBD disease activity was measured using biochemical markers C-reactive protein or fecal calprotectin using enzyme-linked immunosorbent assay and clinical disease activity using Harvey-Bradshaw Index or partial Mayo scores. Serum and urine samples were collected from preconception, trimester 1, and trimester 2 and analyzed using nuclear magnetic resonance spectroscopy combined with metabolomics set enrichment analysis. Results: We identified a total of 24 urine metabolites and 17 serum metabolites which were altered by active disease across pregnancy. First trimester (T1) active disease-associated metabolites were enriched in “amino acid metabolism” and “fatty-acid β-oxidation.” The leading urine metabolites at T1 were trimethyl-N-oxide (TMAO), succinic acid, and 3-hydroxy-2-methylbutyric acid, and leading serum metabolites were TMAO, glucose, and acetic acid. Multivariate modeling using serum TMAO, glucose, and acetic acid predicts T1 disease activity and correlated with mode of delivery and infant weights at delivery. Moreover, cross–time point modeling using metabolomes predicted future disease flare-up during pregnancy. Conclusion: These results suggest select host metabolites may be able to discriminate and predict disease activity and are correlated with pregnancy outcomes at delivery. This warrants further validation of metabolomics to monitor IBD in pregnancy.

This paper builds on prior work exploring the use of risk-associated alternative healthcare (RAAH) in Canada. RAAH uptake was surveyed to explore the characteristics of adult RAAH users and the value of established psychometric instruments previously used in alternative healthcare studies in predicting RAAH behaviours: the Control Beliefs Inventory (CBI), the Reward Responsiveness Behavioural Activation System (RBAS) scale, the Positive Attitudes to Science (PAS) scale, the Satisfaction with Orthodox Medicine (SOM) scale, and the brief version of the Susceptibility to Persuasion-II (StP-II-B) scale. Findings suggest RAAH is influenced by gender, age, income, education, employment, chronic illness status, and ethnicity. Engagement in some form of RAAH was common (around 40%) and the most common types of RAAH use reported were physical manipulation and herbal/nutritional supplement use. Other higher-risk AH activities (such as use of toxins and physically invasive procedures) were also reported by about 5% of respondents. The StP-II-B and PAS instruments were predictive of the likelihood of engagement in RAAH behaviours, as illustrated by higher risk tolerance, desire for novelty, positive attitude to advertising and social influence, and positive beliefs about science. The CBI, RBAS, and SOM instruments were not predictive overall. However, the CBI and SOM instruments were predictive of engagement with physical manipulative RAAH activities, while the RBAS was predictive of herbal/nutritional RAAH engagement. These findings can help inform health professionals' understanding of public health-seeking behaviours with respect to risk.

BackgroundPeople with neurological disorders (ND) are less physically active than the general population due to physical, sensory, and/or cognitive impairments. These individuals often feel intimidated to join mainstream health and wellness centers due to lack of specialized support for people with ND. The Brain and Body Fitness Studio (BBFS) is one of the first Accredited Exercise Physiologist-led interprofessional services in Adelaide South Australia to provide individualized evidence-based multimodal exercise prescription and social support for this population. This comprehensive retrospective study evaluated the impact of BBFS on functional capacity (FC) determined as the 6-min walk distance (6 MWD) achieved during a 6-min walk test (6 MWT), of its members with ND.MethodsSixty-two BBFS members (age, 66 ± 10 years; 60% male) with ND (85% Parkinson's Disease; average time since diagnosis, 4 years [IQR, 2 to 12 years]) and complete pre- and post-6-month clinical assessment of the primary outcome of the study, the 6 MWD, were included in this retrospective analysis. A series of sub-analyses were also performed to investigate the effects of adherence to the recommended prescription of at least twice a week in the program (≥80 vs. < 80% adherence), and disease stage (time since diagnosis; ≥6 vs. < 6 years) on FC.ResultsAlthough there was no statistically significant change in 6 MWD from pre- to post-6-month BBFS program (+15 ± 90 m, p = 0.19), a clinically meaningful improvement of >14 m was evident. Improvement in 6 MWD was significantly greater in members who attended at least 80% of the recommended visits (≥80% visits, +37 ± 58 m; ≤ 80% visits,−1 ± 105 m, p = 0.046). We also found a 6 MWD improvement from pre- to post-6 months in those in the early years of their ND (< 6 years since diagnosis, +39 ± 76 m), but not in those in the later years of their ND (≥6 years since diagnosis, −36 ± 123 m, between group difference, p = 0.029).ConclusionA clinically meaningful 6 MWD improvement may be elicited by services provided by BBFS in people with ND. Overall, the benefits appear to be more evident in members who attended the BBFS for at least 80% of the recommended visits and those who were in the early stage of their ND diagnosis.

Abstract Cutaneous manifestations are variable in patients with eosinophilic granulomatosis with polyangiitis (EGPA). We report a case where bullous eruption was a presenting manifestation of EGPA. A 55‐year‐old Chinese man with a background of adult‐onset asthma and chronic sinusitis was admitted for a 3‐week history of lower limb weakness and a large bulla on his right calf with surrounding erythema. Skin biopsy showed a subepidermal blister with significant dermal eosinophilia, without vasculitis. The patient was diagnosed with EGPA with systemic involvement on the basis of a thorough medical history, eosinophilia, cardiac magnetic resonance imaging showing acute myocarditis, and nerve biopsy with eosinophilic vasculitic neuropathy. He responded well to corticosteroids and rituximab. Nonvasculitic bullous eruptions are rarely described as manifestations of EGPA. Prompt recognition of this entity is crucial for its early diagnosis.

As the COVID-19 pandemic continues, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge. Immunogenicity evaluation of vaccines and identification of correlates of protection for vaccine effectiveness is critical to aid the development of vaccines against emerging variants. Anti-recombinant spike (rS) protein immunoglobulin G (IgG) quantitation in the systemic circulation (serum/plasma) is shown to correlate with vaccine efficacy. Thus, an enzyme-linked immunosorbent assay (ELISA)-based binding assay to detect SARS-CoV-2 (ancestral and variant strains) anti-rS IgG in human serum samples was developed and validated. This assay successfully met acceptance criteria for inter/intra-assay precision, specificity, selectivity, linearity, lower/upper limits of quantitation, matrix effects, and assay robustness. The analyte in serum was stable for up to 8 freeze/thaw cycles and 2 years in −80 °C storage. Similar results were observed for the Beta, Delta, and Omicron BA.1/BA.5/XBB.1.5 variant-adapted assays. Anti-rS IgG assay results correlated significantly with neutralization and receptor binding inhibition assays. In addition, usage of international reference standards allows data extrapolation to WHO international units (BAU/mL), facilitating comparison of results with other IgG assays. This anti-rS IgG assay is a robust, high-throughput method to evaluate binding IgG responses to S protein in serum, enabling rapid development of effective vaccines against emerging COVID-19 variants.

Abstract Merck KGaA observed slight differences in the dissolution of Concor® (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro–in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations‐time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution “safe space.” A PBBM for bisoprolol was built using in vitro, in silico, and clinical data. We evaluated potential influences of variability in dissolution of bisoprolol batches on its clinical performance through PBBM and virtual bioequivalence (BE) trials. We demonstrated that in vitro dissolution was not critical for the clinical performance of bisoprolol over a wide range of tested values. Based on virtual BE trials, safe space expansion was explored using hypothetical dissolution data. A formulation with in vitro dissolution reaching 70% dissolved in 15 min and 79.5% in 30 min was shown to be BE to classical fast dissolution of bisoprolol (>85% within 15 min), as point estimates and 90% confidence intervals of the maximum plasma concentration and area under the concentration‐time curve were within the BE limits (0.8–1.25).

BackgroundMany adults do not reach the recommended exercise participation guidelines, often citing lack of time as a barrier. Reduced exertion high-intensity training (REHIT) is a mode of exercise that takes as few as 10 min and has been shown to be as effective as other modalities. The Fitness Fatness Index (FFI) is a recently developed index that is used to predict cardiovascular disease (CVD) risk. The aim of this study was to determine the efficacy of a REHIT vs. a traditional moderate-intensity continuous training (MICT) on FFI in physically inactive adults.MethodsThirty-two participants were randomized into one of two 8-week exercise intervention groups: (i) REHIT (n = 16); (ii) MICT (n = 16). The REHIT group performed 10 min of individualized cycling intervals on 2–4 days of the week. The MICT group were prescribed aerobic exercise at 50–65% of their heart rate reserve (HRR) on 3–5 days of the week. FFI was recorded at baseline and post 8-weeks, with FFI being calculated as cardiorespiratory fitness (CRF) (expressed as metabolic equivalents) divided by waist to height ratio (WtHR). A 1-unit increase in FFI was recognized as a clinically significant change in FFI.ResultsThe REHIT group showed significantly greater (+1.95, ±0.63) improvements in FFI compared to those in the MICT (+0.99, ±0.47) group (between group difference, p < 0.001). Furthermore, there was a greater proportion of participants who achieved a clinically significant change in FFI in the REHIT group (12/12, 100%) than in the MICT group (8/15, 53%) (between group difference, p = 0.01).ConclusionThis study suggests that REHIT may be a more efficacious exercise modality to increase FFI than MICT. This outcome is beneficial as the clinician can prescribe REHIT to physically inactive adults who cite lack of time as a barrier to physical activity participation and achieve significant reductions in CVD risk.

Abstract Background Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. Methods Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P

Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

Abstract Background Alcohol, substance use, and mental health disorders constitute major public health issues worldwide, including in low income and lower middle-income countries, and early initiation of use is an important predictor for developing substance use disorders in later life. This study reports on the existence of childhood alcohol abuse and dependence in a sub-study of a trial cohort in Eastern Uganda. Methods The project SeeTheChild—Mental Child Health in Uganda (STC) included a sub-study of the Ugandan site of the study PROMISE SB: Saving Brains in Uganda and Burkina Faso. PROMISE SB was a follow-up study of a trial birth cohort (PROMISE EBF) that estimated the effect that peer counselling for exclusive breast-feeding had on the children’s cognitive functioning and mental health once they reached 5–8 years of age. The STC sub-study (N = 148) used the diagnostic tool MINI-KID to assess mental health conditions in children who scored medium and high (≥ 14) on the Strengths and Difficulties Questionnaire (SDQ) in the PROMISE SB cohort N = (119/148; 80.4%). Another 29/148 (19.6%) were recruited from the PROMISE SB cohort as a comparator with low SDQ scores (

Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) show immune evasion of vaccine-derived immunity, highlighting the need for better clinical immunogenicity biomarkers. To address this need, an enzyme-linked immunosorbent assay-based, human angiotensin-converting enzyme 2 (hACE2) binding inhibition assay was developed to measure antibodies against the ancestral strain of SARS-CoV-2 and was validated for precision, specificity, linearity, and other parameters. This assay measures the inhibition of SARS-CoV-2 spike (S) protein binding to the receptor, hACE2, by serum from vaccine clinical trials. Inter- and intra-assay precision, specificity, linearity, lower limit of quantitation, and assay robustness parameters successfully met the acceptance criteria. Heme and lipid matrix effects showed minimal interference on the assay. Samples were stable for testing in the assay even with 8 freeze/thaws and up to 24 months in −80 °C storage. The assay was also adapted for variants (Delta and Omicron BA.1/BA.5), with similar validation results. The hACE2 assay showed significant correlation with anti-recombinant S immunoglobulin G levels and neutralizing antibody titers. This assay provides a rapid, high-throughput option to evaluate vaccine immunogenicity. Along with other clinical biomarkers, it can provide valuable insights into immune evasion and correlates of protection and enable vaccine development against emerging COVID-19 variants.

Background: Almost one-third of fibrosing ILD (fILDs) have a clinical disease behavior similar to IPF, demonstrating a progressive phenotype (PF-ILD). However, there are no globally accepted criteria on the definition of a progressive phenotype in non-IPF fILD yet. Four different definitions have been used; however, no internationally accepted definition currently exists.Research Question: To compare the clinical and functional characteristics of progressive fILD according to the currently available definitions.Study design and methods: Cases of fILD were identified retrospectively from the database of the tertiary referral center for ILD in Heidelberg. Lung function, clinical signs of progression, and radiological changes were evaluated. Patients with fILD were considered to have progression according to each of the four available definitions: Cottin (CO), RELIEF (RE), INBUILD (IN), and UILD study. Lung function changes, expressed as mean absolute decline of FVC%, were reported every 3 months following diagnosis and analyzed in the context of each definition. Survival was also analyzed.Results: A total of 566 patients with non-IPF fILD were included in the analysis. Applying CO-, RE-, IN-, and UILD-definitions, 232 (41%), 183 (32%), 274 (48%), and 174 (31%) patients were defined as PF-ILD, respectively. RE- and UILD-criteria were the most stringent, with only 32 and 31% patients defined as progressive, while IN- was the most broad, with almost 50% of patients defined as progressive. CO- definition was in-between, classifying 41% as progressive. PF ILD patients with a UILD definition had worse prognosis.Interpretation: Depending on the definition used, the existing criteria identify different groups of patients with progressive fILD, and this may have important prognostic and therapeutic implications.

BackgroundNVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant.Methods and findingsThe phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-μg or 25-μg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median ConclusionsThe study confirmed the phase 1 findings that the 2-dose regimen of 5-μg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 μg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies.Trial registrationClinicalTrials.gov NCT04368988.

Abstract Background We have previously modelled that the optimal number of comprehensive stroke centres (CSC) providing endovascular thrombectomy (EVT) in England would be 30 (net 6 new centres). We now estimate the relative effectiveness and cost-effectiveness of increasing the number of centres from 24 to 30. Methods We constructed a discrete event simulation (DES) to estimate the effectiveness and lifetime cost-effectiveness (from a payer perspective) using 1 year’s incidence of stroke in England. 2000 iterations of the simulation were performed comparing baseline 24 centres to 30. Results Of 80,800 patients admitted to hospital with acute stroke/year, 21,740 would be affected by the service reconfiguration. The median time to treatment for eligible early presenters (

Abstract Background Connexin 43 (Cx43) plays a central role in the inflammatory response and wound healing. Targeting Cx43 expression reduces inflammation in a variety of injuries. The expression pattern of Cx43 has not been described for many inflammatory skin diseases. Objectives To describe the expression patterns of Cx43 in eczema, psoriasis, Steven‐Johnson syndrome/toxic epidermal necrolysis. Methods Archival skin biopsies from patients with eczema, psoriasis, and Steven‐Johnson syndrome/toxic epidermal necrosis were identified and examined, with sister sections stained for Cx43 and imaged by confocal microscopy. All samples were compared to age and site‐matched normal skin controls. Results Epidermal Cx43 is reduced in acute eczema, absent in regions of spongiosis, and is highly elevated in subacute and chronic eczema. In plaque psoriasis, Cx43 is overexpressed in areas with psoriasiform hyperplasia with a fish‐scale‐like appearance but is lost in regions surrounding neutrophil microabscesses. Cx43 staining is strong in the neutrophils within these microabscesses. In SJS/TEN, Cx43 expression is elevated in areas bordering normal tissue but is rapidly lost in areas of keratinocyte necrosis. Conclusions Dynamic changes in Cx43 levels are seen in inflammatory skin diseases and may represent future potential therapeutic targets.

Abstract Background Metabolic syndrome substantially increases risk of cardiovascular events. It is therefore imperative to develop or optimize ways to prevent or attenuate this condition. Exercise training has been long recognized as a corner-stone therapy for reducing individual cardiovascular risk factors constituting the metabolic syndrome. However, the optimal exercise dose and its feasibility in a real world setting has yet to be established. The primary objective of this randomized trial is to investigate the effects of different volumes of aerobic interval training (AIT) compared to the current exercise guideline of moderate-intensity continuous training (MICT) on the composite number of cardiovascular disease risk factors constituting the metabolic syndrome after a 16 week, 1-year, and 3-year follow-up. Methods This is a randomized international multi-center trial including men and women aged ≥30 years diagnosed with the metabolic syndrome according to the International Diabetes Federation criteria. Recruitment began in August 2012 and concluded in December 2016. This trial consists of supervised and unsupervised phases to evaluate the efficacy and feasibility of different exercise doses on the metabolic syndrome in a real world setting. This study aims to include and randomize 465 participants to 3 years of one of the following training groups: i) 3 times/week of 4 × 4 min AIT at 85–95% peak heart rate (HRpeak); ii) 3 times/week of 1 × 4 min AIT at 85–95% HRpeak; or iii) 5–7 times/week of ≥30 min MICT at 60–70% HRpeak. Clinical examinations, physical tests and questionnaires are administered to all participants during all testing time points (baseline, 16 weeks and after 1-, and 3-years). Discussion This multi-center international trial indeed aims to ease the burden in healthcare/economic cost arising from treating end-stage CVD related conditions such as stroke and myocardial infarction, that could eventually emerge from the metabolic syndrome condition. Trial registration Clinical registration number: NCT01676870, ClinicalTrials.gov (August 31, 2012).

Uridine 5′-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not well studied. This work assesses physiologically based pharmacokinetic (PBPK) modeling as a tool for predicting intestinal metabolism due to UGTs in the human gastrointestinal tract. Available data for intestinal UGT expression levels and in vitro approaches that can be used to predict intestinal metabolism of UGT substrates are reviewed. Human PBPK models for UGT substrates with varying extents of UGT-mediated intestinal metabolism (lorazepam, oxazepam, naloxone, zidovudine, cabotegravir, raltegravir, and dolutegravir) have demonstrated utility for predicting the extent of intestinal metabolism. Drug–drug interactions (DDIs) of UGT1A1 substrates dolutegravir and raltegravir with UGT1A1 inhibitor atazanavir have been simulated, and the role of intestinal metabolism in these clinical DDIs examined. Utility of an in silico tool for predicting substrate specificity for UGTs is discussed. Improved in vitro tools to study metabolism for UGT compounds, such as coculture models for low clearance compounds and better understanding of optimal conditions for in vitro studies, may provide an opportunity for improved in vitro–in vivo extrapolation (IVIVE) and prospective predictions. PBPK modeling shows promise as a useful tool for predicting intestinal metabolism for UGT substrates.

Systemic lupus erythematosus (SLE) is a chronic, multi-organ disease that predominantly affects young women of childbearing age. It is also a disease in which epigenetic modulation is emerging as an important mechanism for understanding how the environment interacts with inherited genes to produce disease. Much of the genetic risk for SLE identified in genome-wide association studies has been shown to lie in the non-coding genome, where epigenetic modifications of DNA and histone proteins regulate and co-ordinate transcription on a genome-wide basis. Novel methodologies, including high-throughput sequencing of open chromatin, RNA sequencing, protein microarrays, and gas chromatography-mass spectrometry, have revealed intriguing insights into the pathogenesis of SLE. We review these recent data and their potential contribution to more accurate diagnoses and the development of new therapeutic agents to improve patient outcomes.

Abstract: Introduction: In some Amazonian river basins, hair mercury concentration is above the recommended levels. We evaluated the influence of birth geographical location in the hair mercury level of Amazonian riverine children. Materials and Methods: Hair mercury concentration was measured in 219 children living in four Amazonian riverine communities: Tapajós River (São Luiz do Tapajós and Barreiras villages, n = 110), Tocantins River (Limoeiro do Ajurú village, n = 61), and Caeté River (Caratateua village, n = 48). We used Poisson regression analysis to evaluate the association between native and non-native children from each village and its hair mercury concentration. Results: Higher mercury exposure was found in native children from São Luiz do Tapajós (range = 0.81-22.38 µg/g) followed by native children from Barreiras (range = 0.48-13.46 µg/g), non-native children from São Luiz do Tapajós (range = 0.26-22.18 µg/g), non-native children from Barreiras (range = 0.43-20.76 µg/g), followed by the children from Caeté and Tocantins river basins. We observed that Tapajós villages’ native children had higher prevalence of mercury exposure children than other children (p < 0.05). Conclusions: Birth geographical location has association to mercury levels in the hair of children who lived in a same community with history of mercury exposure.

There is heterogeneity in the observed O2peak response to similar exercise training, and different exercise approaches produce variable degrees of exercise response (trainability). The aim of this study was to combine data from different laboratories to compare O2peak trainability between various volumes of interval training and Moderate Intensity Continuous Training (MICT). For interval training, volumes were classified by the duration of total interval time. High-volume High Intensity Interval Training (HIIT) included studies that had participants complete more than 15 min of high intensity efforts per session. Low-volume HIIT/Sprint Interval Training (SIT) included studies using less than 15 min of high intensity efforts per session. In total, 677 participants across 18 aerobic exercise training interventions from eight different universities in five countries were included in the analysis. Participants had completed 3 weeks or more of either high-volume HIIT (n = 299), low-volume HIIT/SIT (n = 116), or MICT (n = 262) and were predominately men (n = 495) with a mix of healthy, elderly and clinical populations. Each training intervention improved mean O2peak at the group level (P < 0.001). After adjusting for covariates, high-volume HIIT had a significantly greater (P < 0.05) absolute O2peak increase (0.29 L/min) compared to MICT (0.20 L/min) and low-volume HIIT/SIT (0.18 L/min). Adjusted relative O2peak increase was also significantly greater (P < 0.01) in high-volume HIIT (3.3 ml/kg/min) than MICT (2.4 ml/kg/min) and insignificantly greater (P = 0.09) than low-volume HIIT/SIT (2.5 mL/kg/min). Based on a high threshold for a likely response (technical error of measurement plus the minimal clinically important difference), high-volume HIIT had significantly more (P < 0.01) likely responders (31%) compared to low-volume HIIT/SIT (16%) and MICT (21%). Covariates such as age, sex, the individual study, population group, sessions per week, study duration and the average between pre and post O2peak explained only 17.3% of the variance in O2peak trainability. In conclusion, high-volume HIIT had more likely responders to improvements in O2peak compared to low-volume HIIT/SIT and MICT.

Background. Increased visceral adipose tissue (VAT) is strongly associated with cardiometabolic risk factors. Accurate quantification of VAT is available through magnetic resonance imaging (MRI), which incurs a significant financial and time burden. We aimed to assess the accuracy of dual-energy X-ray absorptiometry- (DXA-) derived VAT (DXA-VAT) against a gold standard MRI protocol (MRI-VAT) in children with normal weight and obesity cross-sectionally, and over the course of a lifestyle intervention. Methodology. MRI-VAT and DXA-VAT were quantified in 61 children (30 normal weight and 31 with obesity) at baseline. Children with obesity entered a three-month exercise and/or nutrition intervention after which VAT was reassessed. MRI- and DXA-VAT cross-sectional area, volume, and mass were quantified, and associations were calculated at baseline (n = 61) and pre-post intervention (n = 28, 3 participants dropped out). Method agreement was assessed through Bland–Altman analysis, linear regression, and Passing–Bablok regression. Results. At baseline, all DXA- and MRI-VAT outcomes were strongly associated (r = 0.90, P0.05). DXA significantly overestimated VAT CSA (cross-sectional area), volume, and mass when compared with MRI (P

Bo Li,1,2 Michael Siuta,1 Vanessa Bright,1,2 Dmitry Koktysh,3,4 Brittany K Matlock,5 Megan E Dumas,1 Meiying Zhu,1 Alex Holt,1 Donald Stec,3,6 Shenglou Deng,7 Paul B Savage,7 Sebastian Joyce,8,9 Wellington Pham1,2,6,10–12 1Institute of Imaging Science, Vanderbilt University School of Medicine, 2Department of Radiology and Radiological Sciences, 3Department of Chemistry, Vanderbilt University, 4Vanderbilt Institute of Nanoscale Science and Engineering, 5Vanderbilt Flow Cytometry Shared Resource, Vanderbilt University, 6Vanderbilt Institute of Chemical Biology, 7Department of Chemistry and Biochemistry, Brigham Young University, 8Department of Pathology, Microbiology and Immunology, Vanderbilt University, 9Veterans Administration Tennessee Valley Healthcare System, 10Department of Biomedical Engineering, 11Vanderbilt Ingram Cancer Center, 12Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA Abstract: The present study investigated the immunoenhancing property of our newly designed nanovaccine, that is, its ability to induce antigen-specific immunity. This study also evaluated the synergistic effect of a novel compound PBS-44, an α-galactosylceramide analog, in boosting the immune response induced by our nanovaccine. The nanovaccine was prepared by encapsulating ovalbumin (ova) and an adjuvant within the poly(lactic-co-glycolic acid) nanoparticles. Quantitative analysis of our study data showed that the encapsulated vaccine was physically and biologically stable; the core content of our nanovaccine was found to be released steadily and slowly, and nearly 90% of the core content was slowly released over the course of 25 days. The in vivo immunization studies exhibited that the nanovaccine induced stronger and longer immune responses compared to its soluble counterpart. Similarly, intranasal inhalation of the nanovaccine induced more robust antigen-specific CD8+ T cell response than intraperitoneal injection of nanovaccine. Keywords: nanovaccine, dendritic cells, GalCer, inhalable vaccine

Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.

Organophosphorus compounds (OP) are chemicals widely used as pesticides in different applications such as agriculture and public health (vector control), and some of the highly toxic forms have been used as chemical weapons. After application of OPs in an environment, they persist for a period, suffering a degradation process where the biotic factors are considered the most relevant forms. However, to date, the biodegradation of OP compounds is not well understood. There are a plenty of structure-based biodegradation estimation methods, but none of them consider enzymatic interaction in predicting and better comprehending the differences in the fate of OPs in the environment. It is well known that enzymatic processes are the most relevant processes in biodegradation, and that hydrolysis is the main pathway in the natural elimination of OPs in soil samples. Due to this, we carried out theoretical studies in order to investigate the interactions of these OPs with a chosen enzyme—the phosphotriesterase. This one is characteristic of some soils’ microorganisms, and has been identified as a key player in many biodegradation processes, thanks to its capability for fast hydrolyzing of different OPs. In parallel, we conducted an experiment using native soil in two conditions, sterilized and not sterilized, spiked with specific amounts of two OPs with similar structure—paraoxon-ethyl (PXN) and O-(4-nitrophenyl) O-ethyl methylphosphonate (NEMP). The amount of OP present in the samples and the appearance of characteristic hydrolysis products were periodically monitored for 40 days using analytical techniques. Moreover, the number of microorganisms present was obtained with plate cell count. Our theoretical results were similar to what was achieved in experimental analysis. Parameters calculated by enzymatic hydrolysis were better for PXN than for NEMP. In soil, PXN suffered a faster hydrolysis than NEMP, and the cell count for PXN was higher than for NEMP, highlighting the higher microbiological toxicity of the latter. All these results pointed out that theoretical study can offer a better comprehension of the possible mechanisms involved in real biodegradation processes, showing potential in exploring how biodegradation of OPs relates with enzymatic interactions.

Oscillations of brain proteins in circadian rhythms are important for determining several cellular and physiological processes in anticipation of daily and seasonal environmental rhythms. In addition to the suprachiasmatic nucleus, the primary central oscillator, the cerebellum shows oscillations in gene and protein expression. The variety of local circuit rhythms that the cerebellar cortex contains influences functions such as motivational processes, regulation of feeding, food anticipation, language, and working memory. The molecular basis of the cerebellar oscillator has been demonstrated by “clock gene” expression within cells of the cerebellar layers. Genetic and epidemiological evidence suggests that disruption of circadian rhythms in humans can lead to many pathological conditions. Despite this importance, data about clock gene and protein expression in the cerebellum of diurnal (day-active) species, specifically primates, is currently poorly explored, mainly in regard to cellular identity, as well as the relationship with other molecules also involved in cerebellar functions. These studies could contribute to clarification of the possible mechanisms behind cerebellar rhythmicity. Considering that calcium binding proteins (CaBPs) play crucial roles in preserving and modulating cerebellar functions and that clock gene expression can be controlled by afferent projections or paracrine circadian signals such as the hormone melatonin, the present study aimed to describe cellular identities, distribution patterns and day/night expression changes in PER1, PER2, CaBPs, and MT1 and MT2 melatonin receptors in the cerebellar cortex of a diurnal primate using conventional fluorescence and peroxidase-antiperoxidase immunocytochemical techniques. PER1 and PER2 immunoreactive (IR) cells were observed in the Purkinje cells of the cerebellum, and MT1 and MT2 receptors were localized around Purkinje cells in the Pj layer in Bergmann cells. This identity was confirmed by the S100β-IR of these cells. The highest expression of PER seen in the daytime analysis coincided with the highest expression of melatonin receptors. CaBPs showed day/night morphological and density changes in the cerebellar cortex. The presence of the same temporal variations in the expression of PER in the Pj neurons and in MT1 and MT2 receptors in Bergmann cells indicates a possible relation between these cells during the rhythmic processing of the cerebellum, in addition to the CaBP temporal morphological and density changes.

We aimed to compare Gleason score and tumor laterality between transrectal ultrasound-guided biopsy of the prostate (TRUSBX) and radical prostatectomy (RP). Some factors that could cause a discrepancy in results between these two procedures were also evaluated. Among the 318 cases reviewed, 191 cases were selected for inclusion in this comparative study. We divided the patients into two groups using the Gleason score: an intermediate/high-grade group (≥7) and a low-grade group ( 0.05). Thus, our study showed that TRUSBX has a high likelihood of underestimating both the Gleason score and tumor laterality in prostate cancer (PCa). The size of the fragment appears to be an important factor influencing the likelihood of laterality underestimation and Gleason score overestimation via TRUSBX. Due to the high likelihood of underestimation of the Gleason score and tumor laterality by 12-core prostate biopsy, we conclude that this type of biopsy should not be used alone to guide therapy in PCa.

Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.