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BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimers disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Despite well-documented health benefits from exercise, a study on national trends in achieving the recommended minutes of physical activity guidelines has not improved since the guidelines were published in 2008. Peer interactions have been identified as a critical factor for increasing a population's physical activity. The objective of this study is for establishing criteria for social influences on physical activity for establishing criteria that lead to exercise persistence. A system of differential equations was developed that projects exercise trends over time. The system includes both social and non-social influences that impact changes in physical activity habits and establishes quantitative conditions that delineate population-wide persistence habits from domination of sedentary behavior. The model was generally designed with parameter values that can be estimated to data. Complete absence of social or peer influences resulted in long-term dominance of sedentary behavior and a decline of physically active populations. Social interactions between sedentary and moderately active populations were the most important social parameter that influenced low active populations to become and remain physically active. On the other hand, social interactions encouraging moderately active individuals to become sedentary drove exercise persistence to extinction. Communities should focus on increasing social interactions between sedentary and moderately active individuals to draw sedentary populations to become more active. Additionally, reducing opportunities for moderately active individuals to engage with sedentary individuals through sedentary social activities should be addressed.

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

The 2019 novel coronavirus infectious disease (COVID-19) pandemic has resulted in an unsustainable need for diagnostic tests. Currently, molecular tests are the accepted standard for the detection of SARS-CoV-2. Mass spectrometry (MS) enhanced by machine learning (ML) has recently been postulated to serve as a rapid, high-throughput, and low-cost alternative to molecular methods. Automated ML is a novel approach that could move mass spectrometry techniques beyond the confines of traditional laboratory settings. However, it remains unknown how different automated ML platforms perform for COVID-19 MS analysis. To this end, the goal of our study is to compare algorithms produced by two commercial automated ML platforms (Platforms A and B). Our study consisted of MS data derived from 361 subjects with molecular confirmation of COVID-19 status including SARS-CoV-2 variants. The top optimized ML model with respect to positive percent agreement (PPA) within Platforms A and B exhibited an accuracy of 94.9%, PPA of 100%, negative percent agreement (NPA) of 93%, and an accuracy of 91.8%, PPA of 100%, and NPA of 89%, respectively. These results illustrate the MS method's robustness against SARS-CoV-2 variants and highlight similarities and differences in automated ML platforms in producing optimal predictive algorithms for a given dataset.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

BackgroundBenfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches.ObjectiveTo conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD.MethodsThis is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA.ConclusionThe BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose.Trial registrationClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

IntroductionChemical contamination and pollution are an ongoing threat to human health and the environment. The concern over the consequences of chemical exposures at the global level continues to grow. Because resources are constrained, there is a need to prioritize interventions focused on the greatest health impact. Data, especially related to chemical exposures, are rarely available for most substances of concern, and alternate methods to evaluate their impact are needed.Structured expert judgment (sej) processA Structured Expert Judgment (Research Outreach, 2021) process was performed to provide plausible estimates of health impacts for 16 commonly found pollutants: asbestos, arsenic, benzene, chromium, cadmium, dioxins, fluoride, highly hazardous pesticides (HHPs), lead, mercury, polycyclic-aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), Per- and Polyfluorinated Substances (PFAs), phthalates, endocrine disrupting chemicals (EDCs), and brominated flame retardants (BRFs). This process, undertaken by sector experts, weighed individual estimations of the probable global health scale health impacts of each pollutant using objective estimates of the expert opinions' statistical accuracy and informativeness.Main findingsThe foremost substances, in terms of mean projected annual total deaths, were lead, asbestos, arsenic, and HHPs. Lead surpasses the others by a large margin, with an estimated median value of 1.7 million deaths annually. The three other substances averaged between 136,000 and 274,000 deaths per year. Of the 12 other chemicals evaluated, none reached an estimated annual death count exceeding 100,000. These findings underscore the importance of prioritizing available resources on reducing and remediating the impacts of these key pollutants.Range of health impactsBased on the evidence available, experts concluded some of the more notorious chemical pollutants, such as PCBs and dioxin, do not result in high levels of human health impact from a global scale perspective. However, the chemical toxicity of some compounds released in recent decades, such as Endocrine Disrupters and PFAs, cannot be ignored, even if current impacts are limited. Moreover, the impact of some chemicals may be disproportionately large in some geographic areas. Continued research and monitoring are essential; and a preventative approach is needed for chemicals.Future directionsThese results, and potential similar analyses of other chemicals, are provided as inputs to ongoing discussions about priority setting for global chemicals and pollution management. Furthermore, we suggest that this SEJ process be repeated periodically as new information becomes available.

PurposePathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration (wAMD). Many receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptors (VEGFRs) contribute to angiogenesis, whereas the RTK TIE2 is important for vascular stability. Pan-VEGFR tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib are of therapeutic interest over current antibody treatments that target only one or two ligands. This study compared the anti-angiogenic potential of these TKIs.MethodsA kinase HotSpot™ assay was conducted to identify TKIs inhibiting RTKs associated with angiogenesis and vascular stability. Half-maximal inhibitory concentration (IC50) for VEGFRs and TIE2 was determined for each TKI. In vitro angiogenesis inhibition was investigated using a human umbilical vein endothelial cell sprouting assay, and in vivo angiogenesis was studied using the chorioallantoic membrane assay. Melanin binding was assessed using a melanin-binding assay. Computer modeling was conducted to understand the TIE2-axitinib complex as well as interactions between vorolanib and VEGFRs.ResultsVorolanib, sunitinib, and axitinib inhibited RTKs of interest in angiogenesis and exhibited pan-VEGFR inhibition. HotSpot™ assay and TIE2 IC50 values showed that only axitinib potently inhibited TIE2 (up to 89%). All three TKIs effectively inhibited angiogenesis in vitro. In vivo, TKIs were more effective at inhibiting VEGF-induced angiogenesis than the anti-VEGF antibody bevacizumab. Of the three TKIs, only sunitinib bound melanin. TKIs differ in their classification and binding to VEGFRs, which is important because type II inhibitors have greater selectivity than type I TKIs.ConclusionsVorolanib, sunitinib, and axitinib exhibited pan-VEGFR inhibition and inhibited RTKs associated with pathological angiogenesis. Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability. The findings support the use of vorolanib for therapeutic inhibition of angiogenesis observed in DR, DME, and wAMD.

BackgroundThe Women's Health Needs Study (WHNS) collected information on the health characteristics, needs, and experiences, including female genital mutilation (FGM) experiences, attitudes, and beliefs, of women aged 18 to 49 years who were born, or whose mothers were born, in a country where FGM is prevalent living in the US. The purpose of this paper is to describe the WHNS design, methods, strengths and limitations, as well as select demographic and health-related characteristics of participants.MethodsWe conducted a cross-sectional survey from November 2020 -June 2021 in four US metropolitan areas, using a hybrid venue-based sampling (VBS) and respondent-driven sampling (RDS) approach to identify women for recruitment.ResultsOf 1,132 participants, 395 were recruited via VBS and 737 RDS. Most were born, or their mothers were born, in either a West African country (Burkina Faso, Guinea, Mali, Mauritania, Sierra Leone, The Gambia) (39.0%) or Ethiopia (30.7%). More than a third were aged 30-39 years (37.5%) with a majority who immigrated at ages ≥13 years (86.6%) and had lived in the United States for ≥5 years (68.9%). Medicaid was the top health insurer (52.5%), followed by private health insurance (30.5%); 17% of participants had no insurance. Nearly half of women reported 1-2 healthcare visits within the past 12 months (47.7%). One in seven did not get needed health care due to cost (14.8%). Over half have ever used contraception (52.1%) to delay or avoid pregnancy and 76.9% had their last pelvic and/or Papanicolaou (pap) exam within the past 3 years. More than half experienced FGM (55.0%). Nearly all women believed that FGM should be stopped (92.0%).ConclusionThe VBS/RDS approach enabled recruitment of a diverse study population. WHNS advances research related to the health characteristics, needs, and experiences of women living in the US from countries where FGM is prevalent.

Environmental exposures during the perinatal period are known to have a long-term effect on adult physical and mental health. One such influential environmental exposure is the time of year of birth which affects the amount of daylight, nutrients, and viral load that an individual is exposed to within this key developmental period. Here, we investigate associations between season of birth (seasonality), four mental health traits (n = 137,588) and multi-modal neuroimaging measures (n = 33,212) within the UK Biobank. Summer births were associated with probable recurrent Major Depressive Disorder (β = 0.026, pcorr = 0.028) and greater mean cortical thickness in temporal and occipital lobes (β = 0.013 to 0.014, pcorr

The gut microbiome may affect overall cardiometabolic health. Enterolactone is an enterolignan reflective of dietary lignan intake and gut microbiota composition and diversity that can be measured in the urine. The purpose of this study was to examine the association between urinary enterolactone concentration as a reflection of gut health and blood pressure/risk of hypertension in a large representative sample from the US population. This analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) collected from January 1999 through December 2010. Variables of interest included participant characteristics (including demographic, anthropometric and social/environmental factors), resting blood pressure and hypertension history, and urinary enterolactone concentration. 10,637 participants (45 years (SE = 0.3), 51.7% (SE = 0.6%) were female) were included in analyses. In multivariable models adjusted for demographic, socioeconomic and behavioral/environmental covariates, each one-unit change in log-transformed increase in enterolactone was associated with a 0.738 point (95% CI: -0.946, -0.529; p

The human genome is pervasively transcribed and produces a wide variety of long non-coding RNAs (lncRNAs), constituting the majority of transcripts across human cell types. Some specific nuclear lncRNAs have been shown to be important regulatory components acting locally. As RNA-chromatin interaction and Hi-C chromatin conformation data showed that chromatin interactions of nuclear lncRNAs are determined by the local chromatin 3D conformation, we used Hi-C data to identify potential target genes of lncRNAs. RNA-protein interaction data suggested that nuclear lncRNAs act as scaffolds to recruit regulatory proteins to target promoters and enhancers. Nuclear lncRNAs may therefore play a role in directing regulatory factors to locations spatially close to the lncRNA gene. We provide the analysis results through an interactive visualization web portal at https://fantom.gsc.riken.jp/zenbu/reports/#F6_3D_lncRNA.

To mitigate the risk of radioactive isotope dissemination, the development of preventative and curative measures is of particular interest. For mass treatment, the developed solution must be easily administered, preferably orally, with effective, nontoxic decorporating properties against a wide range of radioactive isotopes. Currently, most orally administered chelation therapy products are quickly absorbed into the blood circulation, where chelation of the radioactive isotope is a race against time due to the short circulation half-life of the therapeutic. This report presents an alternative therapeutic approach by using a functionalized chitosan (chitosan@DOTAGA) with chelating properties that remains within the gastrointestinal tract and is eliminated in feces, that can protect against ingested radioactive isotopes. The polymer shows important in vitro chelation properties towards different metallic cations of importance, including (Cs(I), Ir(III), Th(IV), Tl(I), Sr(II), U(VI) and Co(II)), at different pH (from 1 to 7) representing the different environments in the gastrointestinal tract. An in vivo proof of concept is presented on a rodent model of uranium contamination following an oral administration of Chitosan@DOTAGA. The polymer partially prevents the accumulation of uranium within the kidneys (providing a protective effect) and completely prevents its uptake by the spleen.

BackgroundDescribing correlates of physical activity (PA) and sedentary behavior (SB) among postmenopausal cancer survivors can help identify risk profiles and can be used to support development of targeted interventions to improve PA and reduce SB in this population.ObjectiveTo describe PA/SB and identify correlates of PA/SB among cancer and cancer-free post-menopausal women.MethodsWomen from the Women's Health Study (N = 16,629) and Women's Health Initiative/Objective Physical Activity and Cardiovascular Health Study (N = 6,079) were asked to wear an accelerometer on the hip for 7 days. Multiple mixed-effects linear regression models were used to identify sociodemographic-, health-, and chronic condition-related correlates (independent variables) associated with PA and SB (dependent variables) among women with (n = 2,554) and without (n = 20,154) a history of cancer. All correlates were mutually adjusted for each other.ResultsIn unadjusted analyses, women with a history of cancer took fewer mean daily steps (4,572 (standard deviation 2557) vs 5,029 (2679) steps/day) and had lower mean moderate-to-vigorous PA (74.9 (45.0) vs. 81.6 (46.7) minutes/day) than cancer-free women. In adjusted analyses, for cancer and cancer-free women, age, diabetes, overweight, and obesity were inversely associated with all metrics of PA (average vector magnitude, time in moderate-to-vigorous PA, step volume, time at ≥40 steps/minutes, and peak 30-minute step cadence). In unadjusted analyses, mean SB was similar for those with and without cancer (529.7 (98.1) vs. 521.7 (101.2) minutes/day). In adjusted analyses, for cancer and cancer-free women, age, diabetes, cardiovascular disease, current smoking, overweight, and obesity were positive correlates of SB, while Black or Hispanic race/ethnicity, weekly/daily alcohol intake, and excellent/very good/good self-rated health were inverse correlates of SB.ConclusionSeveral sociodemographic, health, and chronic conditions were correlates of PA/SB for postmenopausal women with and without cancer. Future studies should examine longitudinal relationships to gain insight into potential determinants of PA/SB.

Current tools for estimating the substitution distance between two related sequences struggle to remain accurate at a high divergence. Difficulties at distant homologies, such as false seeding and over-alignment, create a high barrier for the development of a stable estimator. This is especially true for viral genomes, which carry a high rate of mutation, small size, and sparse taxonomy. Developing an accurate substitution distance measure would help to elucidate the relationship between highly divergent sequences, interrogate their evolutionary history, and better facilitate the discovery of new viral genomes. To tackle these problems, we propose an approach that uses short-read mappers to create whole-genome maps, and gradient descent to isolate the homologous fraction and calculate the final distance value. We implement this approach as Mottle. With the use of simulated and biological sequences, Mottle was able to remain stable to 0.66-0.96 substitutions per base pair and identify viral outgroup genomes with 95% accuracy at the family-order level. Our results indicate that Mottle performs as well as existing programs in identifying taxonomic relationships, with more accurate numerical estimation of genomic distance over greater divergences. By contrast, one limitation is a reduced numerical accuracy at low divergences, and on genomes where insertions and deletions are uncommon, when compared to alternative approaches. We propose that Mottle may therefore be of particular interest in the study of viruses, viral relationships, and notably for viral discovery platforms, helping in benchmarking of homology search tools and defining the limits of taxonomic classification methods. The code for Mottle is available at https://github.com/tphoward/Mottle_Repo.

BackgroundLatent class analysis (LCA) identifies distinct groups within a heterogeneous population, but its application to accelerometry-assessed physical activity and sedentary behavior has not been systematically explored. We conducted a systematic scoping review to describe the application of LCA to accelerometry.MethodsComprehensive searches in PubMed, Web of Science, CINHAL, SPORTDiscus, and Embase identified studies published through December 31, 2021. Using Covidence, two researchers independently evaluated inclusion criteria and discrepancies were resolved by consensus. Studies with LCA applied to accelerometry or combined accelerometry/self-reported measures were selected. Data extracted included study characteristics and both accelerometry and LCA methods.ResultsOf 2555 papers found, 66 full-text papers were screened, and 12 papers (11 cross-sectional, 1 cohort) from 8 unique studies were included. Study sample sizes ranged from 217-7931 (mean 2249, standard deviation 2780). Across 8 unique studies, latent class variables included measures of physical activity (100%) and sedentary behavior (75%). About two-thirds (63%) of the studies used accelerometry only and 38% combined accelerometry and self-report to derive latent classes. The accelerometer-based variables in the LCA model included measures by day of the week (38%), weekday vs. weekend (13%), weekly average (13%), dichotomized minutes/day (13%), sex specific z-scores (13%), and hour-by-hour (13%). The criteria to guide the selection of the final number of classes and model fit varied across studies, including Bayesian Information Criterion (63%), substantive knowledge (63%), entropy (50%), Akaike information criterion (50%), sample size (50%), Bootstrap likelihood ratio test (38%), and visual inspection (38%). The studies explored up to 5 (25%), 6 (38%), or 7+ (38%) classes, ending with 3 (50%), 4 (13%), or 5 (38%) final classes.ConclusionsThis review explored the application of LCA to physical activity and sedentary behavior and identified areas of improvement for future studies leveraging LCA. LCA was used to identify unique groupings as a data reduction tool, to combine self-report and accelerometry, and to combine different physical activity intensities and sedentary behavior in one LCA model or separate models.

Adolescents and youth living with HIV (AYLHIV) experience worse health outcomes compared to adults. We aimed to understand the experiences of AYLHIV in care in the youth-focused Red-Carpet program in Kenya to assess the quality of service provision and identify programmatic areas for optimization. We conducted focus group discussions among 39 AYLHIV (15-24 years) and structured analysis into four thematic areas. Within the HIV testing theme, participants cited fear of positive results, confidentiality and stigma concerns, and suggested engaging the community and youth in HIV testing opportunities. Within the HIV treatment adherence theme, participants cited forgetfulness, stigma, adverse side effects, lack of family support, and treatment illiteracy as barriers to adherence. Most participants reported positive experiences with healthcare providers and peer support. In terms of the HIV status disclosure theme, AYLHIV cited concerns about their future capacity to conceive children and start families and discussed challenges with understanding HIV health implications and sharing their status with friends and partners. Youth voices informing service implementation are essential in strengthening our capacity to optimize the support for AYLHIV within the community, at schools and healthcare facilities.

BackgroundThere is an increasing awareness that sleep disturbances are a risk factor for dementia. Prior case-control studies suggested that brain grey matter (GM) changes involving cortical (i.e, prefrontal areas) and subcortical structures (i.e, putamen, thalamus) could be associated with insomnia status. However, it remains unclear whether there is a gradient association between these regions and the severity of insomnia in older adults who could be at risk for dementia. Since depressive symptoms and sleep apnea can both feature insomnia-related factors, can impact brain health and are frequently present in older populations, it is important to include them when studying insomnia. Therefore, our goal was to investigate GM changes associated with insomnia severity in a cohort of healthy older adults, taking into account the potential effect of depression and sleep apnea as well. We hypothesized that insomnia severity is correlated with 1) cortical regions responsible for regulation of sleep and emotion, such as the orbitofrontal cortex and, 2) subcortical regions, such as the putamen.Methods120 healthy subjects (age 74.8±5.7 years old, 55.7% female) were recruited from the Hillblom Healthy Aging Network at the Memory and Aging Center, UCSF. All participants were determined to be cognitively healthy following a neurological evaluation, neuropsychological assessment and informant interview. Participants had a 3T brain MRI and completed the Insomnia Severity Index (ISI), Geriatric Depression Scale (GDS) and Berlin Sleep Questionnaire (BA) to assess sleep apnea. Cortical thickness (CTh) and subcortical volumes were obtained by the CAT12 toolbox within SPM12. We studied the correlation of CTh and subcortical volumes with ISI using multiple regressions adjusted by age, sex, handedness and MRI scan type. Additional models adjusting by GDS and BA were also performed.ResultsISI and GDS were predominantly mild (4.9±4.2 and 2.5±2.9, respectively) and BA was mostly low risk (80%). Higher ISI correlated with lower CTh of the right orbitofrontal, right superior and caudal middle frontal areas, right temporo-parietal junction and left anterior cingulate cortex (p

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.

BackgroundFew cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada.Materials and methodsWe evaluated screening observations on women who participated between 2001-2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles. We defined ID using a stringent criterion: combined transferrin saturation

IntroductionThe rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy.AimThis study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs.MethodsTwo hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted.ResultsThere was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days.ConclusionThe increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B.

ObjectivesTherapeutic virtual reality (VR) has emerged as an effective, drug-free tool for pain management, but there is a lack of randomized, controlled data evaluating its effectiveness in hospitalized patients. We sought to measure the impact of on-demand VR versus "health and wellness" television programming for pain in hospitalized patients.MethodsWe performed a prospective, randomized, comparative effectiveness trial in hospitalized patients with an average pain score of ≥3 out of 10 points. Patients in the experimental group received a library of 21 VR experiences administered using the Samsung Gear Oculus headset; control patients viewed specialized television programming to promote health and wellness. Clinical staff followed usual care; study interventions were not protocolized. The primary outcome was patient-reported pain using a numeric rating scale, as recorded by nursing staff during usual care. Pre- and post-intervention pain scores were compared immediately after initial treatment and after 48- and 72-hours.ResultsThere were 120 subjects (61 VR; 59 control). The mean within-subject difference in immediate pre- and post-intervention pain scores was larger in the VR group (-1.72 points; SD 3.56) than in the control group (-0.46 points; SD 3.01); this difference was significant in favor of VR (P < .04). When limited to the subgroup of patients with severe baseline pain (≥7 points), the effect of VR was more pronounced vs. control (-3.04, SD 3.75 vs. -0.93, SD 2.16 points; P = .02). In regression analyses adjusting for pre-intervention pain, time, age, gender, and type of pain, VR yielded a .59 (P = .03) and .56 (P = .04) point incremental reduction in pain versus control during the 48- and 72-hour post-intervention periods, respectively.ConclusionsVR significantly reduces pain versus an active control condition in hospitalized patients. VR is most effective for severe pain. Future trials should evaluate standardized order sets that interpose VR as an early non-drug option for analgesia.

In July 2011, renovations to Yale-New Haven Hospital inadvertently exposed the cemetery of Christ Church, New Haven, Connecticut's first Catholic cemetery. While this cemetery was active between 1833 and 1851, both the church and its cemetery disappeared from public records, making the discovery serendipitous. Four relatively well-preserved adult skeletons were recovered with few artifacts. All four individuals show indicators of manual labor, health and disease stressors, and dental health issues. Two show indicators of trauma, with the possibility of judicial hanging in one individual. Musculoskeletal markings are consistent with physical stress, and two individuals have arthritic indicators of repetitive movement/specialized activities. Radiographic analyses show osteopenia, healed trauma, and other pathologies in several individuals. Dental calculus analysis did not identify any tuberculosis indicators, despite osteological markers. Isotopic analyses of teeth indicate that all four were likely recent immigrants to the Northeastern United States. Nuclear and mitochondrial DNA were recovered from three individuals, and these analyses identified ancestry, hair/eye color, and relatedness. Genetic and isotopic results upended our initial ancestry assessment based on burial context alone. These individuals provide biocultural evidence of New Haven's Industrial Revolution and the plasticity of ethnic and religious identity in the immigrant experience. Their recovery and the multifaceted analyses described here illuminate a previously undescribed part of the city's rich history. The collective expertise of biological, geochemical, archaeological, and historical researchers interprets socioeconomic and cultural identity better than any one could alone. Our combined efforts changed our initial assumptions of a poor urban Catholic cemetery's membership, and provide a template for future discoveries and analyses.

Canines are used by both government agencies and industries for their keen olfactory capability as well as selectivity, reliability, versatility, and speed. Within the last decade, canines have been used for the detection of on-shore crude oil. They were previously shown to find these deposits with high accuracy, providing increased confidence with little risk to oil spill response survey teams. In order to efficiently train canines, it is important to understand the odorants or groups of odorants that such canines use when locating subsurface crude oil deposits, as well as track how the odorant profile changes as the crude oil undergoes degradation. In this study, headspace solid phase microextraction (HS-SPME) was used in combination with gas chromatography-mass spectrometry (GC-MS) to extract and separate odorants from the headspace of various crude oils. After, eluent fractions of the crude oil odor profile were separated and collected onto sorbent materials, which were then used as canine testing probes in a series of trials. These probes, along with negative and positive controls were presented to three previously-trained and operational crude oil detection canines. Three eluent fractions of both fresh and weathered samples were presented, resulting in a 100% response rate from the canines on all three fractions from both the fresh and weathered samples. These results indicated that canines are capable of detecting crude oil from any fraction of the odor profile demonstrating the potential of the canines to generalize across a variety of crude oils and stages of weathering. [ABSTRACT FROM AUTHOR]

IntroductionPregnant people have a higher risk of severe COVID-19 disease. They have been disproportionately impacted by COVID-19 infection control policies, which exacerbated conditions resulting in intimate partner violence, healthcare access, and mental health distress. This project examines the impact of accumulated individual health decisions and describes how perinatal care and health outcomes changed during the COVID-19 pandemic.ObjectivesQuantitative strand: Describe differences between 2019, 2021, and 2022 birth groups related to maternal vaccination, perinatal care, and mental health care. Examine the differential impacts on racialized and low-income pregnant people.Qualitative strand: Understand how pregnant people's perceptions of COVID-19 risk influenced their decision-making about vaccination, perinatal care, social support, and mental health.Methods and analysisThis is a Canadian convergent parallel mixed-methods study. The quantitative strand uses a retrospective cohort design to assess birth group differences in rates of Tdap and COVID-19 vaccination, gestational diabetes screening, length of post-partum hospital stay, and onset of depression, anxiety, and adjustment disorder, using administrative data from ICES, formerly the Institute for Clinical Evaluative Sciences (Ontario) and PopulationData BC (PopData) (British Columbia). Differences by socioeconomic and ethnocultural status will also be examined. The qualitative strand employs qualitative description to interview people who gave birth between May 2020- December 2021 about their COVID-19 risk perception and health decision-making process. Data integration will occur during design and interpretation.Ethics and disseminationThis study received ethical approval from McMaster University and the University of British Columbia. Findings will be disseminated via manuscripts, presentations, and patient-facing infographics.Trial registrationRegistration: Clinicaltrials.gov registration number: NCT05663762.

IntroductionThe career intentions of medical students can exert influence on service provision and medical staffing in the health services. It is vital for a specialty's development and sustainability that it has a constant stream of trainees into it annually. An appreciation of how a specialty is viewed by medical students can be used as an opportunity for early intervention in order to improve perception of the specialty and reduce future workforce problems, such as retention and attrition within obstetrics and gynaecology (O&G). We aimed to analyse positive and negative factors of the specialty of O&G as perceived by medical students in order to gain insight into changes that need to be made to improve recruitment and retention into the specialty.MethodsA 70-item structured questionnaire consisting of demographic information and 5-point Likert scale questions relating to O&G was administered to final year medical students in the Republic of Ireland. Data were analysed with descriptive statistics, logistic regression, and odds ratios as appropriate.ResultsOf 195 medical students approached, 134 completed the questionnaire, a response rate of 68.7%. The majority were female (55.2%, n = 74) and 76.1% of respondents (n = 102) were Direct Entry Medicine students, with the remainder Graduate Entry Medicine students. 30.8% (n = 41) of students who responded scored 6 or more on a 10-point Likert scale when asked about their likelihood of considering a career in O&G. Students' clerkship experience factored heavily into their perception of the specialty and was more likely to be positive if they experienced direct consultant engagement and the opportunity for hands-on experience. Lifestyle factors, litigation and media were found to be deterrents to considering the specialty after graduation.ConclusionsThis study demonstrates the importance of good clerkship experience in fostering an interest amongst undergraduates in O&G. Educators and those working within the specialty should showcase the strengths of the specialty during undergraduate education, and work on ameliorating deterrents to ultimately provide a structured approach to improving recruitment into O&G.

Longitudinal, community-based sampling is important for understanding prevalence and transmission of respiratory pathogens. Using a minimally invasive sampling method, the FAMILY Micro study monitored the oral, nasal and hand microbiota of families for 6 months. Here, we explore participant experiences and opinions. A mixed methods approach was utilised. A quantitative questionnaire was completed after every sampling timepoint to report levels of discomfort and pain, as well as time taken to collect samples. Participants were also invited to discuss their experiences in a qualitative structured exit interview. We received questionnaires from 36 families. Most adults and children >5y experienced no pain (94% and 70%) and little discomfort (73% and 47% no discomfort) regardless of sample type, whereas children ≤5y experienced variable levels of pain and discomfort (48% no pain but 14% hurts even more, whole lot or worst; 38% no discomfort but 33% moderate, severe, or extreme discomfort). The time taken for saliva and hand sampling decreased over the study. We conducted interviews with 24 families. Families found the sampling method straightforward, and adults and children >5y preferred nasal sampling using a synthetic absorptive matrix over nasopharyngeal swabs. It remained challenging for families to fit sampling into their busy schedules. Adequate fridge/freezer space and regular sample pick-ups were found to be important factors for feasibility. Messaging apps proved extremely effective for engaging with participants. Our findings provide key information to inform the design of future studies, specifically that self-sampling at home using minimally invasive procedures is feasible in a family context.

BackgroundSince the pandemic onset, deprivation has been seen as a significant determinant of COVID-19 incidence and mortality. This study explores outcomes of COVID-19 in the context of material deprivation across three pandemic waves in Ireland.MethodsBetween 1st March 2020 and 13th May 2021, 252,637 PCR-confirmed COVID-19 cases were notified in Ireland. Cases were notified to the national Computerised Infectious Disease Reporting (CIDR) system. Each case was geo-referenced and assigned a deprivation category according to the Haase-Pratschke (HP) Deprivation Index. Regression modelling examined three outcomes: admission to hospital; admission to an intensive care unit (ICU) and death.ResultsDeprivation increased the likelihood of contracting COVID-19 in all age groups and across all pandemic waves, except for the 20-39 age group. Deprivation, age, comorbidity and male gender carried increased risk of hospital admission. Deprivation was not a factor in predicting ICU admission or death, and diagnosis in wave 2 was associated with the lowest risk of all three outcomes.ConclusionsOur study suggests that COVID-19 spreads easily through all strata of society and particularly in the more deprived population; however this was not a consistent finding. Ireland is ethnically more homogenous than other countries reporting a larger deprivation gradient, and in such societies, structural racial differences may contribute more to poor COVID outcomes than elements of deprivation.

The current methods used for producing triploid Atlantic salmon are generally reliable but not infallible, and each batch of triploids must be validated to ensure consumer trust and licensing compliance. Microsatellites have recently been shown to offer a cheaper and more convenient alternative to traditional flow cytometry for triploidy validation in a commercial setting. However, incubating eggs to at least the eyed stage for microsatellite validation poses challenges, such as reduced quality and performance of triploids produced from later eggs in the stripping season. To address these issues, we propose another option: extracting DNA from recently fertilised eggs for use in conjunction with microsatellite validation. To achieve this, we have developed an optimized protocol for HotSHOT extraction that can rapidly and cheaply extract DNA from Atlantic salmon eggs, which can then be used for triploidy validation through microsatellites. Our approach offers a simpler and more cost-effective way to validate triploidy, without the need for skilled dissection or expensive kits.

Audit studies demonstrate that unemployed people are less likely to receive a callback when they apply for a job than employed candidates, the reason for this is unclear. Across two experiments (N = 461), we examine whether the perceived competence of unemployed candidates accounts for this disparity. In both studies, participants assessed one of two equivalent curriculum vitae’s, differing only on the current employment status. We find that unemployed applicants are less likely to be offered an interview or hired. The relationship between the employment status of the applicant and these employment-related outcomes is mediated by the perceived competence of the applicant. We conducted a mini meta-analysis, finding that the effect size for the difference in employment outcomes was d = .274 and d = .307 respectively, while the estimated indirect effect was -.151[-.241, -.062]. These results offer a mechanism for the differential outcomes of job candidates by employment status.

Background Patients presenting to the emergency department (ED) with dizziness may be imaged via CTA head and neck to detect acute vascular pathology including large vessel occlusion. We identify commonly documented clinical variables which could delineate dizzy patients with near zero risk of acute vascular abnormality on CTA. Methods We performed a cross-sectional analysis of adult ED encounters with chief complaint of dizziness and CTA head and neck imaging at three EDs between 1/1/2014-12/31/2017. A decision rule was derived to exclude acute vascular pathology tested on a separate validation cohort; sensitivity analysis was performed using dizzy “stroke code” presentations. Results Testing, validation, and sensitivity analysis cohorts were composed of 1072, 357, and 81 cases with 41, 6, and 12 instances of acute vascular pathology respectively. The decision rule had the following features: no past medical history of stroke, arterial dissection, or transient ischemic attack (including unexplained aphasia, incoordination, or ataxia); no history of coronary artery disease, diabetes, migraines, current/long-term smoker, and current/long-term anti-coagulation or anti-platelet medication use. In the derivation phase, the rule had a sensitivity of 100% (95% CI: 0.91–1.00), specificity of 59% (95% CI: 0.56–0.62), and negative predictive value of 100% (95% CI: 0.99–1.00). In the validation phase, the rule had a sensitivity of 100% (95% CI: 0.61–1.00), specificity of 53% (95% CI: 0.48–0.58), and negative predictive value of 100% (95% CI: 0.98–1.00). The rule performed similarly on dizzy stroke codes and was more sensitive/predictive than all NIHSS cut-offs. CTAs for dizziness might be avoidable in 52% (95% CI: 0.47–0.57) of cases. Conclusions A collection of clinical factors may be able to “exclude” acute vascular pathology in up to half of patients imaged by CTA for dizziness. These findings require further development and prospective validation, though could improve the evaluation of dizzy patients in the ED.

Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever and, in some cases, chronic carriage after resolution of acute disease. This study examined sequential isolates of S. Typhi from a single host with persistent asymptomatic infection. These isolates, along with another S. Typhi isolate recovered from a household contact with typhoid fever, were subjected to whole genome sequencing and analysis. In addition, direct sequencing of the bile fluid from the host with persistent infection was also performed. Comparative analysis of isolates revealed three sub-populations of S. Typhi with distinct genetic patterns. Metagenomic sequencing recognised only two of the three sub-populations within the bile fluid. The detection and investigation of insertion sequences IS10R and associated deletions complemented analysis of single nucleotide polymorphisms. These findings improve our understanding of within-host dynamics of S. Typhi in cases of persistent infection and inform epidemiological investigations of transmission events associated with chronic carriers.

The efficacy of using human volatile organic compounds (VOCs) as a form of forensic evidence has been well demonstrated with canines for crime scene response, suspect identification, and location checking. Although the use of human scent evidence in the field is well established, the laboratory evaluation of human VOC profiles has been limited. This study used Headspace-Solid Phase Microextraction-Gas Chromatography-Mass Spectrometry (HS-SPME-GC-MS) to analyze human hand odor samples collected from 60 individuals (30 Females and 30 Males). The human volatiles collected from the palm surfaces of each subject were interpreted for classification and prediction of gender. The volatile organic compound (VOC) signatures from subjects' hand odor profiles were evaluated with supervised dimensional reduction techniques: Partial Least Squares-Discriminant Analysis (PLS-DA), Orthogonal-Projections to Latent Structures Discriminant Analysis (OPLS-DA), and Linear Discriminant Analysis (LDA). The PLS-DA 2D model demonstrated clustering amongst male and female subjects. The addition of a third component to the PLS-DA model revealed clustering and minimal separation of male and female subjects in the 3D PLS-DA model. The OPLS-DA model displayed discrimination and clustering amongst gender groups with leave one out cross validation (LOOCV) and 95% confidence regions surrounding clustered groups without overlap. The LDA had a 96.67% accuracy rate for female and male subjects. The culminating knowledge establishes a working model for the prediction of donor class characteristics using human scent hand odor profiles.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.

ObjectivesThis review aims to undertake a comprehensive review of the literature and investigate associations of age and gender on 30 days post carotid endarterectomy (CEA) and up to 5 years post CEA stroke, death, and combined stroke and death.DesignA systematic review and meta-analysis.MethodsThree main electronic databases including the Cochrane Library, MEDLINE, and Embase were searched from their inception to July 2022. Studies examining operative risks (i.e., stroke, death, and combined stroke and death following CEA) linked to age or gender were included. Two independent reviewers were responsible for study selection, quality assessment, and data extraction. Odds ratio (OR) and 95% confidence interval (CI) of all outcomes were calculated.Results44609 studies were retrieved from the search. There were 127 eligible studies (80 studies of age, 72 studies of gender, 25 studies of age and gender) for pooling in the meta-analysis. With regards to stroke and death risks within 30 days post CEA; patients aged ≥75 had higher death (OR 1.38; 95% CI 1.10-1.75) than patients aged ConclusionsThis meta-analysis highlights that older people is associated with increased stroke risk, particularly asymptomatic octogenarians who had higher likelihood of death within 30 days post CEA. In addition, female especially those with asymptomatic carotid stenosis had greater likelihood of stroke within 30 days post CEA surgery.

Persistent inflammation contributes to the development of cardiovascular disease (CVD) as an HIV-associated comorbidity. Innate immune cells such as monocytes are major drivers of inflammation in men and women with HIV. The study objectives are to examine the contribution of circulating non-classical monocytes (NCM, CD14dimCD16+) and intermediate monocytes (IM, CD14+CD16+) to the host response to long-term HIV infection and HIV-associated CVD. Women with and without chronic HIV infection (H) were studied. Subclinical CVD (C) was detected as plaques imaged by B-mode carotid artery ultrasound. The study included H-C-, H+C-, H-C+, and H+C+ participants (23 of each, matched on race/ethnicity, age and smoking status), selected from among enrollees in the Women's Interagency HIV Study. We assessed transcriptomic features associated with HIV or CVD alone or comorbid HIV/CVD comparing to healthy (H-C-) participants in IM and NCM isolated from peripheral blood mononuclear cells. IM gene expression was little affected by HIV alone or CVD alone. In IM, coexisting HIV and CVD produced a measurable gene transcription signature, which was abolished by lipid-lowering treatment. In NCM, versus non-HIV controls, women with HIV had altered gene expression, irrespective of whether or not they had comorbid CVD. The largest set of differentially expressed genes was found in NCM among women with both HIV and CVD. Genes upregulated in association with HIV included several potential targets of drug therapies, including LAG3 (CD223). In conclusion, circulating monocytes from patients with well controlled HIV infection demonstrate an extensive gene expression signature which may be consistent with the ability of these cells to serve as potential viral reservoirs. Gene transcriptional changes in HIV patients were further magnified in the presence of subclinical CVD.

The interaction between human Growth Hormone (hGH) and hGH Receptor (hGHR) has basic relevance to cancer and growth disorders, and hGH is the scaffold for Pegvisomant, an anti-acromegaly therapeutic. For the latter reason, hGH has been extensively engineered by early workers to improve binding and other properties. We are particularly interested in E174 which belongs to the hGH zinc-binding triad; the substitution E174A is known to significantly increase binding, but to now no explanation has been offered. We generated this and several computationally-selected single-residue substitutions at the hGHR-binding site of hGH. We find that, while many successfully slow down dissociation of the hGH-hGHR complex once bound, they also slow down the association of hGH to hGHR. The E174A substitution induces a change in the Circular Dichroism spectrum that suggests the appearance of coiled-coiling. Here we show that E174A increases affinity of hGH against hGHR because the off-rate is slowed down more than the on-rate. For E174Y (and certain mutations at other sites) the slowdown in on-rate was greater than that of the off-rate, leading to decreased affinity. The results point to a link between structure, zinc binding, and hGHR-binding affinity in hGH.

Chemotherapy-induced impairment of autophagy is implicated in cardiac toxicity induced by anti-cancer drugs. Imperfect translation from rodent models and lack of in vitro models of toxicity has limited investigation of autophagic flux dysregulation, preventing design of novel cardioprotective strategies based on autophagy control. Development of an adult heart tissue culture technique from a translational model will improve investigation of cardiac toxicity. We aimed to optimize a canine cardiac slice culture system for exploration of cancer therapy impact on intact cardiac tissue, creating a translatable model that maintains autophagy in culture and is amenable to autophagy modulation. Canine cardiac tissue slices (350 μm) were generated from left ventricular free wall collected from euthanized client-owned dogs (n = 7) free of cardiovascular disease at the Foster Hospital for Small Animals at Tufts University. Cell viability and apoptosis were quantified with MTT assay and TUNEL staining. Cardiac slices were challenged with doxorubicin and an autophagy activator (rapamycin) or inhibitor (chloroquine). Autophagic flux components (LC3, p62) were quantified by western blot. Cardiac slices retained high cell viability for >7 days in culture and basal levels of autophagic markers remained unchanged. Doxorubicin treatment resulted in perturbation of the autophagic flux and cell death, while rapamycin co-treatment restored normal autophagic flux and maintained cell survival. We developed an adult canine cardiac slice culture system appropriate for studying the effects of autophagic flux that may be applicable to drug toxicity evaluations.

A substantial body of evidence suggests that young people, including those at the crucial transition points between 16 and 24, now face severe mental health challenges. In this article, we analyse data from 10 waves of a major UK longitudinal household cohort study, Understanding Society, to examine the relationship between income and anxiety and depression among 16- to 24-year-olds. Using random effects logistic regression (Model 1) allowing for whether the individual was depressed in the previous period as well as sex, age, ethnicity, whether the individual was born in the UK, region, rurality, highest qualification, marital status, employment status and attrition, we find a significant and inversely monotonic adjusted association between average net equivalised household income quintiles and clinical threshold levels of depressive symptoms SF-12 Mental Component Summary (MCS score ≤45.6). This means that being in a higher income group is associated with a reduced likelihood of clinically significant depressive symptoms, allowing for observable confounding variables. Using a 'within-between' model (Model 2), we find that apart from among those with the very highest incomes, increases in average net equivalised household income over the course of childhood and adolescence are significantly associated with reduced symptoms of anxiety and depression as measured by a higher SF-12 MCS score. Compared with previous reviews, the data presented here provides an estimate of the magnitude of effect that helps facilitate microsimulation modelling of impact on anxiety and depression from changes in socioeconomic circumstances. This enables a more detailed and complete understanding of the types of socioeconomic intervention that might begin to address some of the causes of youth mental health problems.

IntroductionThe exact pathogenesis of fibromyalgia (FM) syndrome is unclear. However, various infectious have been implicated with the development of FM after their acute phase. We aimed to investigate the incidence of FM syndrome among convalesced individuals following hospitalization for Acute Coronavirus Disease-2019 (COVID-19).MethodsWe performed a cross-sectional study on patients who were discharged after COVID-19 hospitalization from the Sheba Medical Center, Israel, between July 2020 to November 2020. A phone interview was performed consisting of the following questionnaires: the Fibromyalgia Survey Diagnostic Criteria Questionnaire, Sense of Coherence Questionnaire to evaluate resilience, and the Subjective Traumatic Outlook Questionnaire to assess the associated psychological aspects of the trauma. The incidence of post-COVID FM was calculated and regression models were performed to identify predictors.ResultsThe study population consisted of 198 eligible patients who completed the phone interview. The median age was 64 (52-72) and 37% were women. The median follow-up was 5.2 months (IQR 4.4-5.8). The incidence of FM was 15% (30 patients) and 87% (172 patients) had at least one FM-related symptom. Female gender was significantly associated with post-COVID FM (OR 3.65, p = 0.002). In addition, high median Subjective Traumatic Outlook scores and low median Sense of Coherence scores were both significantly associated with post-COVID FM (OR 1.19, pConclusionsFM is highly prevalent among COVID-19 convalescent patients. Our finding suggests that a significant subjective traumatic experience and a low resilience are highly associated with post-COVID FM.

Antibiotics are frequently prescribed for children in the outpatient setting. Although sometimes necessary, antibiotic use is associated with important downstream effects including the development of antimicrobial resistance among human and environmental microorganisms. Current outpatient stewardship efforts focus on guiding appropriate antibiotic prescribing practices among providers, but little is known about parents' understanding of antibiotics and appropriate disposal of leftover antibiotics. To help bridge this gap, we conducted a qualitative study to assess parental understanding of their children's antibiotics, their adherence to antibiotic instructions, and their disposal practices. We conducted a semi-structured interview with parents of 13 children diagnosed with acute respiratory illnesses and prescribed antibiotics in an urban outpatient clinic. We found that parents had limited understanding of how antibiotics work. Although they received instructions about antibiotic use during the healthcare visit, adherence to the prescription and appropriate disposal of antibiotics was suboptimal. Limited baseline understanding of antibiotics, their prior experiences with antibiotics, perceptions about their social networks' antibiotic use, and information provided to them by healthcare providers may influence these behaviors. Our findings can inform educational efforts of outpatient stewardship programs to help optimize parental understanding of how to use and dispose of their children's antibiotics.

BackgroundOpioid use disorder is a serious public health problem in Nepal. People who use opioids often experience psychological distress and poor quality of life. Opioid agonist Treatment (OAT) is central in managing opioid dependence. This study aimed to examine factors associated with quality of life and serious psychological distress among OAT service users in the Kathmandu Valley, Nepal and compare those who had injected opioids prior to OAT and those who had not.MethodsA cross-sectional study with 231 was conducted using a semi-structured questionnaire, the Nepalese versions of the Kessler 6 psychological distress scale and World Health Organization Quality of Life scale (WHOQOL-BREF). Bivariate and multivariate analyses were undertaken to examine factors associated with quality of life and serious psychological distress.ResultsMost participants were males (92%) and about half had injected opioids before initiating OAT. Serious psychological distress in the past four weeks was significantly more prevalent among participants with a history of injecting (32.2%) than those who did not inject (15.9%). In the adjusted linear regression model, those who had history of injecting were likely to have lower physical quality of life compared to non-injectors. Those self-reporting a past history of mental illness were more than seven times and those with medical comorbidity twice more likely to have serious psychological distress over last four weeks. Lower socioeconomic status and a history of self-reported mental illness in the past were found to be significantly associated with lower quality of life on all four domains.ConclusionThose who had history of injecting were younger, had frequent quit attempts, higher medical comorbidity, lower socioeconomic status and remained longer in OAT services. Alongside OAT, the complex and entangled needs of service users, especially those with a history of injecting drugs, need to be addressed to improve quality of life and lessen psychological distress.

BackgroundThe SARS-CoV-2 pandemic has caused an unprecedented strain on healthcare systems worldwide, including the United Kingdom National Health Service (NHS). We conducted an observational cohort study of SARS-CoV-2 infection in frontline healthcare workers (HCW) working in an acute NHS Trust during the first wave of the pandemic, to answer emerging questions surrounding SARS-CoV-2 infection, diagnosis, transmission and control.MethodsUsing self-collected weekly saliva and twice weekly combined oropharyngeal/nasopharyngeal (OP/NP) samples, in addition to self-assessed symptom profiles and isolation behaviours, we retrospectively compared SARS-CoV-2 detection by RT-qPCR of saliva and OP/NP samples. We report the association with contemporaneous symptoms and isolation behaviour.ResultsOver a 12-week period from 30th March 2020, 40·0% (n = 34/85, 95% confidence interval 31·3-51·8%) HCW had evidence of SARS-CoV-2 infection by surveillance OP/NP swab and/or saliva sample. Symptoms were reported by 47·1% (n = 40) and self-isolation by 25·9% (n = 22) participants. Only 44.1% (n = 15/34) participants with SARS-CoV-2 infection reported any symptoms within 14 days of a positive result and only 29·4% (n = 10/34) reported self-isolation periods. Overall agreement between paired saliva and OP/NP swabs was 93·4% (n = 211/226 pairs) but rates of positive concordance were low. In paired samples with at least one positive result, 35·0% (n = 7/20) were positive exclusively by OP/NP swab, 40·0% (n = 8/20) exclusively by saliva and in only 25·0% (n = 5/20) were the OP/NP and saliva result both positive.ConclusionsHCW are a potential source of SARS-CoV-2 transmission in hospitals and symptom screening will identify the minority of infections. Without routine asymptomatic SARS-CoV-2 screening, it is likely that HCW with SARS-CoV-2 infection would continue to attend work. Saliva, in addition to OP/NP swab testing, facilitated ascertainment of symptomatic and asymptomatic SARS-CoV-2 infections. Combined saliva and OP/NP swab sampling would improve detection of SARS-CoV-2 for surveillance and is recommended for a high sensitivity strategy.

PurposeThis prospective observational study aimed to establish the frequency of postoperative nocturnal respiratory abnormalities among patients undergoing major surgery who received ward-level care. These abnormalities may have implications for postoperative pulmonary complications (PPCs).MethodsEligible patients underwent blinded noninvasive continuous capnography with pulse oximetry using the Capnostream™ 20p monitor over the first postoperative night. All patients received oxygen supplementation and patient-controlled opioid analgesia. The primary outcome was the number of prolonged apnea events (PAEs), defined as end-tidal carbon dioxide (EtCO2) ≤5 mmHg for 30-120 seconds or EtCO2 ≤5 mmHg for >120 seconds with oxygen saturation (SpO2) ResultsAmong 125 patients who had sufficient data for analysis, a total of 1800 PAEs occurred in 67 (53.4%) patients. The highest quartile accounted for 89.1% of all events. Amongst patients who experienced any PAEs, the median (IQR) number of PAE/patient was four (2-12). As proportions of recorded time (median (IQR)), AI, ODI, and IPI were aberrant for 12.4% (0-43.2%), 19.1% (2.0-57.1%), and 11.5% (3.1-33.3%) respectively. Only age, ARISCAT, and opioid consumption/kg were associated with PPCs.ConclusionsPAE and aberrant indices were frequently detected on the first postoperative night. However, they did not correlate with PPCs. Future research should investigate the significance of detected aberrations.