SARS-CoV-2 variant replacement constrains vaccine-specific viral diversification.

Coronavirus disease 2019 (COVID-19) vaccine breakthrough infections have been important for all circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant periods, but the contribution of vaccine-specific SARS-CoV-2 viral diversification to vaccine failure remains unclear. This study analyzed 595 SARS-CoV-2 sequences collected from the Military Health System beneficiaries between December 2020 and April 2022 to investigate the impact of vaccination on viral diversity. By comparing sequences based on the vaccination status of the participant, we found limited evidence indicating that vaccination was associated with increased viral diversity in the SARS-CoV-2 spike, and we show little to no evidence of a substantial sieve effect within major variants; rather, we show that rapid variant replacement constrained intragenotype COVID-19 vaccine strain immune escape. These data suggest that, during past and perhaps future periods of rapid SARS-CoV-2 variant replacement, vaccine-mediated effects were subsumed with other drivers of viral diversity due to the massive scale of infections and vaccinations that occurred in a short time frame. However, our results also highlight some limitations of using sieve analysis methods outside of placebo-controlled clinical trials.

Brief Educational Workshops in Secondary Schools Trial (BESST): a cluster randomised controlled trial. Secondary analysis in those with elevated symptoms of depression.

BACKGROUND: Depression and anxiety are increasingly prevalent in adolescents. The Brief Educational Workshops in Secondary Schools Trial investigated the effectiveness of a brief self-referral stress workshop programme for sixth-form students aged 16-18 years old. OBJECTIVE: This study conducted a secondary analysis on the outcomes of participants with elevated depressive symptoms at baseline. METHODS: This is an England-wide, multicentre, cluster randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of a brief cognitive-behavioural therapy workshop (DISCOVER) compared with treatment-as-usual (TAU) (1:1). The primary outcome was depression symptoms (Mood and Feelings Questionnaire (MFQ)) at 6-month follow-up, using the intention-to-treat (ITT) population and analysed with a multilevel linear regression estimating a between-group adjusted mean difference (aMD). Cost-effectiveness, taking a National Health Service (NHS) and personal social services perspective, was explored using quality-adjusted life years (QALYs). FINDINGS: Between 4 October 2021 and 10 November 2022, 900 adolescents at 57 schools were enrolled. 314 students were identified as having elevated symptoms of depression at baseline (>27 on MFQ). In this prespecified subgroup, the DISCOVER arm included 142 participants and TAU included 172. ITT analysis included 298 participants. Primary analysis at 6 months found aMD to be -3.88 (95% CI -6.48, -1.29; Cohen's d=-0.52; p=0.003), with a similar reduction at 3 months (aMD=-4.00; 95% CI -6.58, -1.42; Cohen's d=0.53; p=0.002), indicating a moderate, clinically meaningful effect in the DISCOVER arm. We found an incremental cost-effectiveness ratio of £5255 per QALY, with a probability of DISCOVER being cost-effective at between 89% and 95% compared with TAU. CONCLUSIONS AND CLINICAL IMPLICATIONS: DISCOVER is clinically effective and cost-effective in those with elevated depressive symptoms. This intervention could be used as an early school-based intervention by the NHS. TRIAL REGISTRATION NUMBER: ISRCTN90912799.

The Impact of the COVID-19 Pandemic on Staffing Levels in Philadelphia Nursing Homes: Disparities Based on the Racial Composition of Geographical Areas.

Research to assess and inform health policy is an essential component of the policymaking process to advance equity in public health practice. This study investigated health disparities during the COVID-19 pandemic (2020-2022) in older adult institutional settings in Philadelphia, PA, to inform policy initiatives, interventions, and infrastructure development. We first explored the changing patterns of nursing staffing levels (total direct care staff and registered nurses [RNs]) measured by hours per resident per day (HPRD) before and after COVID-19. Our findings revealed that HPRD levels consistently fell below the Centers for Medicare and Medicaid Services recommended standards from 2018 to 2022, with notable declines observed starting from 2021. Results from multilevel modeling showed significant declines in HPRD for total direct care nursing staff in nursing homes located in zip codes with a high proportion of Black residents (≥40%). In contrast, HPRD for RNs significantly declined in nursing homes located in zip codes with a lower proportion of Black residents (<40%). Moreover, higher reported direct care HPRD and RN HPRD were associated with any reported COVID-19 cases only within zip codes with a low proportion of Black residents. These findings indicate the need for additional policies to address these observed patterns in staffing levels. Our study provides a foundation for future policy reviews utilizing a conceptual framework that is health equity-centric for local and state health departments program and units intended for institutional care settings for older adults.

Plerixafor for pathogen-agnostic treatment in murine thigh infection and zebrafish sepsis.

Plerixafor is a CXCR4 antagonist approved in 2008 by the FDA for hematopoietic stem cell collection. Subsequently, plerixafor has shown promise as a potential pathogen-agnostic immunomodulator in a variety of preclinical animal models. Additionally, investigator-led studies demonstrated plerixafor prevents viral and bacterial infections in patients with WHIM syndrome, a rare immunodeficiency with aberrant CXCR4 signaling. Here, we investigated whether plerixafor could be repurposed to treat sepsis or severe wound infections, either alone or as an adjunct therapy. In a Pseudomonas aeruginosa lipopolysaccharide (LPS)-induced zebrafish sepsis model, plerixafor reduced sepsis mortality and morbidity assessed by tail edema. There was a U-shaped response curve with the greatest effect seen at 0.1 µM concentration. We used Acinetobacter baumannii infection in a neutropenic murine thigh infection model. Plerixafor did not show reduced bacterial growth at 24 h in the mouse thigh model, nor did it amplify the effects of a rifampin antibiotic therapy, in varying regimens. While plerixafor did not mitigate or treat bacterial wound infections in mice, it did reduce sepsis mortality in zebra fish. The observed mortality reduction in our LPS model of zebrafish was consistent with prior research demonstrating a mortality benefit in a murine model of sepsis. However, based on our results, plerixafor is unlikely to be successful as an adjunct therapy for wound infections. Further research is needed to better define the scope of plerixafor as a pathogen-agnostic therapy. Future directions may include the use of longer acting CXCR4 antagonists, biased CXCR4 signaling, and optimization of animal models.

Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.

BACKGROUND: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints. METHODS: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms. RESULTS: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms. CONCLUSIONS: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.

Clinical effectiveness and cost-effectiveness of a brief accessible cognitive behavioural therapy programme for stress in school-aged adolescents (BESST): a cluster randomised controlled trial in the UK.

BACKGROUND: Depression and anxiety are increasingly prevalent in adolescents. The Brief Educational Workshops in Secondary Schools Trial investigated the effectiveness of a brief accessible stress workshop programme for 16-18-year-olds. We aimed to investigate the clinical effectiveness and cost-effectiveness of the DISCOVER cognitive behavioural therapy (CBT) workshop on symptoms of depression in 16-18-year-olds at 6 months compared with treatment-as-usual. METHODS: We conducted a multicentre, cluster randomised controlled trial in UK schools or colleges with sixth forms to evaluate clinical effectiveness and cost-effectiveness of a brief CBT workshop (DISCOVER) compared with treatment-as-usual. We planned to enrol 60 schools and 900 adolescents, using a self-referral system to recruit participants. Schools were randomised in a 1:1 ratio for participants to receive either the DISCOVER workshop or treatment-as-usual, stratified by site and balanced on school size and index of multiple deprivation. Participants were included if they were 16-18 years old, attending for the full school year, seeking help for stress, and fluent in English and able to provide written informed consent. The outcome assessors, senior health economist, senior statistician, and chief investigator were masked. People with lived experience were involved in the study. The primary outcome was depression symptoms measured with the Mood and Feelings Questionnaire (MFQ) at 6-month follow-up, in the intention-to-treat population of all participants with full covariate data. The trial was registered with the ISRCTN registry (ISRCTN90912799). FINDINGS: 111 schools were invited to participate in the study, seven were deemed ineligible, and 47 did not provide consent. Between Oct 4, 2021, and Nov 10, 2022, 933 students at 57 schools were screened for eligibility, seven were not eligible for inclusion, and 26 did not attend the baseline meeting and assessment, resulting in 900 adolescents participating in the study. The DISCOVER group included 443 participants (295 [67%] female and 136 [31%] male) and the treatment-as-usual group included 457 participants (346 [76%] female and 92 [20%] male). 468 (52%) of the 900 participants were White, and the overall age of the participants was 17·2 years (SD 0·6). 873 (97%) adolescents were followed up in the intention-to-treat population. The primary intention-to-treat analysis (n=854) found an adjusted mean difference in MFQ of -2·06 (95% CI -3·35 to -0·76; Cohen's d=-0·17; p=0·0019) at the 6-month follow-up, indicating a clinical improvement in the DISCOVER group. The probability that DISCOVER is cost- effective compared with treatment-as-usual ranged from 61% to 78% at a £20 000 to £30 000 per quality-adjusted life-year threshold. Nine adverse events (two of which were classified as serious) were reported in the DISCOVER group and 14 (two of which were classified as serious) were reported in the treatment-as-usual group. INTERPRETATION: Our findings indicate that the DISCOVER intervention is modestly clinically effective and economically viable and could be a promising early intervention in schools. Given the importance of addressing mental health needs early in this adolescent population, additional research is warranted to explore this intervention. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Brief Educational Workshops in Secondary Schools Trial (BESST trial), a school-based cluster randomised controlled trial of the DISCOVER workshop for 16-18-year-olds: recruitment and baseline characteristics.

BACKGROUND: The Brief Educational Workshops in Secondary Schools Trial (BESST) is an England-wide school-based cluster randomised controlled trial assessing the clinical and cost-effectiveness of an open-access psychological workshop programme (DISCOVER) for 16-18-year-olds. This baseline paper describes the self-referral and other recruitment processes used in this study and the baseline characteristics of the enrolled schools and participants. METHOD: We enrolled 900 participants from 57 Secondary schools across England from 4th October 2021 to 10th November 2022. Schools were randomised to receive either the DISCOVER day-long Stress workshop or treatment as usual which included signposting information. Participants will be followed up for 6 months with outcome data collection at baseline, 3-month, and 6-month post randomisation. RESULTS: Schools were recruited from a geographically and ethnically diverse sample across England. To reduce stigma, students were invited to self-refer into the study if they wanted help for stress. Their mean age was 17.2 (SD = 0.6), 641 (71%) were female and 411 (45.6%) were from ethnic minority groups. The general wellbeing of our sample measured using the Mood and Feelings Questionnaire (MFQ) found 314 (35%) of students exhibited symptoms of depression at baseline. Eighty percent of students reported low wellbeing on the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) suggesting that although the overall sample mean is below the cut-off for depression, the self-referral approach used in this study supports distressed students in coming forward. CONCLUSION: The BESST study will continue to follow up participants to collect outcome data and results will be analysed once all the data have been collected. TRIAL REGISTRATION: ISRCTN registry ISRCTN90912799. Registered on 28 May 2020.

N-acetylcysteine as a treatment for substance use cravings: A meta-analysis.

N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, and ClinicalTrials.gov were conducted in June and July of 2023 to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.

Immune and behavioral correlates of protection against symptomatic post-vaccination SARS-CoV-2 infection.

Introduction: We sought to determine pre-infection correlates of protection against SARS-CoV-2 post-vaccine inzfections (PVI) acquired during the first Omicron wave in the United States. Methods: Serum and saliva samples from 176 vaccinated adults were collected from October to December of 2021, immediately before the Omicron wave, and assessed for SARS-CoV-2 Spike-specific IgG and IgA binding antibodies (bAb). Sera were also assessed for bAb using commercial assays, and for neutralization activity against several SARS-CoV-2 variants. PVI duration and severity, as well as risk and precautionary behaviors, were assessed by questionnaires. Results: Serum anti-Spike IgG levels assessed by research assay, neutralization titers against Omicron subvariants, and low home risk scores correlated with protection against PVIs after multivariable regression analysis. Commercial assays did not perform as well as research assay, likely due to their lower dynamic range. Discussion: In the 32 participants that developed PVI, anti-Spike IgG bAbs correlated with lower disease severity and shorter duration of illness.

Seasonal pattern of questing ticks and prevalence of pathogenic Rickettsia and Anaplasmataceae in Khao Yai national park, Thailand.

BACKGROUND: Tick-borne diseases (TBD) are considered neglected diseases in Thailand with disease burden likely underestimated. To assess risk for emerging TBD in Thailand, the seasonality of questing tick and pathogen prevalence were studied in Khao Yai National Park, a top tourist destination. METHODS: During 2019, questing ticks around tourist attractions were systematically collected bimonthly and analyzed for Rickettsia and Anaplasmataceae bacterial species by polymerase chain reaction and DNA sequencing. RESULTS: Larvae and nymphs of questing ticks peaked in Khao Yai National Park during the late rainy-winter season, though no specific trends were observed in adult ticks. Winter (November to February) was the highest risk for human tick-bites due to higher numbers of both ticks and visitors. Of the total 5916 ticks analyzed (651 pools), Anaplasma phagocytophilum, Neoehrlichia mikurensis, Ehrlichia ewingii, and Ehrlichia chaffeensis were detected at low rates (≤0.05%). There was a higher prevalence of human rickettsioses (0.2-7%) in ticks surveyed with Rickettsia tamurae, Rickettsia raoultii, and Rickettsia montana the major species. Amblyomma ticks had the highest prevalence of Rickettsia (85%, 35/44 Amblyomma adults), in which only R. tamurae and R. raoultii were found in Amblyomma with mixed species infections common. We report the first detection of R. africae-like and N. mikurensis in Ixodes granulatus adults in Thailand, suggesting I. granulatus as a potential vector for these pathogens. CONCLUSION: This study demonstrated the risk of emerging TBD in Thailand and underscores the need for tick-bite prevention among tourists in Thailand.

Assessing Clinical Utility of Pharmacogenetic Testing in the Military Health System.

INTRODUCTION: Response to medications can differ widely among individual patients. Adverse drug reactions can lead to serious morbidity and mortality. Pharmacogenetic (PGx) testing can predict responses to medications and increased risks of adverse events where the genetic basis is understood. Several published manuscripts suggest positive impacts of systematic preemptive PGx testing. However, few studies have been conducted on PGx implementation in the Military Health System (MHS). MATERIAL AND METHODS: A cross-sectional study of adult beneficiaries in a primary care clinic at a large military treatment facility was conducted in 2022. Participants underwent PGx genotyping of CYP2C19 and CYP2D6 genes at the Defense Health Agency Genetics Reference Laboratory. Participant medication lists were compared to the current Clinical Pharmacogenetic Implementation Consortium (CPIC) PGx gene-drug guidelines to assess potential actionability of these results. RESULTS: Genotyping of CYP2C19 and CYP2D6 in 165 MHS beneficiaries (mean age: 65 years) revealed that 81.2% of participants had at least one abnormal PGx finding. Among those with an abnormal PGx result, 65% were taking a medication listed on the CPIC website with an association with the particular gene in which the finding was identified. In addition, 78% of all of the participants in the study were taking at least one medication that is metabolized by CYP2C19 or CYP2D6 with associated CPIC guidelines. CONCLUSIONS: Pharmacogenetic testing for CYP2C19 and CYP2D6 identified a substantial proportion of MHS patients at a single center who could benefit from evaluation of current medication regimens based on the CPIC guidelines. Individualized medical management may be warranted to a greater degree than previously recognized based on the findings given possible differences in medication metabolism. Many MHS beneficiaries already take medications metabolized by CYP2C19 and CYP2D6, and a substantial proportion may be at risk for preventable adverse events for medications metabolized by these enzymes. While preliminary, a large number of actionable polymorphisms among a relatively small set of individuals taking at-risk medications suggest that implementing PGx testing in clinical practice may be beneficial in the MHS with appropriate clinical infrastructure.

Sociocultural Risk and Resilience in the Context of Adverse Childhood Experiences.

Importance: Knowledge about childhood resilience factors relevant in circumstances of marginalization and high numbers of adverse childhood experiences (ACEs) can improve interventions. Objective: To identify sociocultural resilience factors in childhood that are associated with better young adult mental health in the context of ACEs. Design, Setting, and Participants: This cohort study examined 4 waves of data from the Boricua Youth Study, which included Puerto Rican children from the South Bronx, New York, and San Juan, Puerto Rico. Participants were aged 5 to 17 years at waves 1 through 3 (2000-2003) and aged 15 to 29 years at wave 4 (2013-2017). Linear and logistic regression models tested the associations of 7 childhood resilience factors and their interaction with ACEs on young adult mental health outcomes. Data were analyzed from June 2021 to October 2023. Main Outcomes and Measures: Perceived stress, major depressive disorder and/or generalized anxiety disorder (MDD/GAD), and substance use disorder (SUD) in young adulthood. Results: Among a total 2004 participants, the mean (SD) age at wave 4 was 22.4 (2.9) years; 1024 participants (51.1%) were female, and 980 (48.9%) were male. Positive parent-child relationships and nonparental adult support during childhood were associated with both lower perceived stress (ß = -0.14; SE = 0.02; P < .001; ß = -0.08; SE = 0.03; P = .003, respectively) and lower odds of MDD/GAD (adjusted odds ratio [aOR], 0.84; 95% CI, 0.73 to 0.97; aOR = 0.81; 95% CI, 0.69 to 0.95, respectively) in young adulthood. Maternal warmth reported during childhood was also associated with lower young adult perceived stress (ß = -0.11; SE = 0.02; P < .001). None of the resilience factors were associated with SUD. The resilience factors familism, friendships, and family religiosity were not associated with any of the mental health outcomes. ACEs were associated with poorer mental health outcomes; however, none of the resilience factors exhibited interactions consistent with being protective for ACEs. Unexpectedly, higher family religiosity was associated with more perceived stress in the presence of higher ACEs. Conclusions and Relevance: The results of this study suggest that promoting positive relationships with adults during childhood may reduce later young adulthood stress and MDD/GAD. However, there is still a need to identify sociocultural childhood protective factors for ACEs. Caution should be taken in assuming what resilience factors are relevant for a given group, as higher family religiosity (one postulated resilience factor) was unexpectedly associated with a stronger, rather than a weaker, association between ACEs and perceived stress in young adulthood.

Decreased Self-reported Physical Fitness Following SARS-CoV-2 Infection and the Impact of Vaccine Boosters in a Cohort Study.

Background: The long-term effects of coronavirus disease 2019 (COVID-19) on physical fitness are unclear, and the impact of vaccination on that relationship is uncertain. Methods: We compared survey responses in a 1-year study of US military service members with (n = 1923) and without (n = 1591) a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We fit Poisson regression models to estimate the association between history of SARS-CoV-2 infection and fitness impairment, adjusting for time since infection, demographics, and baseline health. Results: The participants in this analysis were primarily young adults aged 18-39 years (75%), and 71.5% were male. Participants with a history of SARS-CoV-2 infection were more likely to report difficulty exercising (38.7% vs 18.4%; P < .01), difficulty performing daily activities (30.4% vs 12.7%; P < .01), and decreased fitness test (FT) scores (42.7% vs 26.2%; P < .01) than those without a history of infection. SARS-CoV-2-infected participants were at higher risk of these outcomes after adjusting for other factors (unvaccinated: exercising: adjusted risk ratio [aRR], 3.99; 95% CI, 3.36-4.73; activities: aRR, 5.02; 95% CI, 4.09-6.16; FT affected: aRR, 2.55; 95% CI, 2.19-2.98). Among SARS-CoV-2-positive participants, full vaccination before infection was associated with a lower risk of post-COVID-19 fitness impairment (fully vaccinated: exercise: aRR, 0.81; 95% CI, 0.70-0.95; activities: aRR, 0.76; 95% CI, 0.64-0.91; FT: aRR, 0.87; 95% CI, 0.76-1.00; boosted: exercise: aRR, 0.62; 95% CI, 0.51-0.74; activities: aRR, 0.52; 95% CI, 0.41-0.65; FT: aRR, 0.59; 95% CI, 0.49-0.70). Conclusions: In this study of generally young, healthy military service members, SARS-CoV-2 infection was associated with lower self-reported fitness and exercise capacity; vaccination and boosting were associated with lower risk of self-reported fitness loss.

Circadian preference and physical and cognitive performance in adolescence: A scoping review.

Adolescence is a crucial period of development which coincides with changes in circadian rhythmicity. This may augment the impact of circadian preference on performance in this group. We aimed to scope the literature available on chronotypes and their effect on physical and mental aspects of performance in adolescents. Studies were identified by systematically searching bibliographical databases and grey literature. The Morningness-Eveningness Questionnaire was the most frequently reported tool for circadian preference assessment. Academic achievement was the most prevailing outcome, with evidence suggesting that morning type adolescents tend to outperform evening types, yet the results vary depending on multiple factors. Performance in tests of intelligence and executive functions was generally better at optimal times of the day (synchrony effect). Physical performance was examined in 8 studies, with very heterogeneous outcomes. Although the associations between circadian preference and performance in adolescents are evident in some areas, there are many factors that may be involved in the relationship and require further investigation. This review highlights the assessment of physical performance in relation to chronotypes, the multidimensional assessment of circadian preference, and the need for longitudinal studies as priorities for further research.Protocol: OSF Registration - Public registration, DOI: 10.17605/OSF.IO/UCA3Z.

Time measurement in insect photoperiodism: external and internal coincidence.

The identity and nature of the photoperiodic photoreceptors are now quite well known, as is the nature of the endocrine regulation of the resulting diapauses. The central problem of time measurement-how the photoperiodic clock differentiates long from short days-however, is still obscure, known only from whole-animal experiments and abstract models, although it is clearly a function of the insect circadian system. This review describes some of these experiments in terms of oscillator entrainment and two widely applicable photoperiodic clock models, external and internal coincidence, mainly using data from experiments on flesh flies (Sarcophaga spp) and the parasitic wasp, Nasonia vitripennis.

Undiagnosing St Joan: She Does Not Need a Medical or Psychiatric Diagnosis.

ABSTRACT: This article traces the history of Joan of Arc through her brief life that includes leading an army in defense of France at the age of 17 and ending with her death at the stake at the age of 19. In her activities, St Joan reported that she was guided by voices and visions in which she communicated with venerated spiritual figures such as St Michael and St Margaret. Questions have arisen about the nature of these experiences, and various medical and psychiatric diagnoses have been offered by contemporary experts. In our effort to evaluate the diagnostic proposals, we have examined the incidence of voices and visions in the Middle Ages, and we have followed that with a review of nonpathologic voice-hearing in our own era. We then move on to an analysis of some proposed medical and psychiatric diagnoses, all of which we find unconvincing. With this background, we argue that St Joan does not warrant a medical or psychiatric diagnosis. Such a conclusion, however, leaves us with another issue, that of Joan's achievements. How do we understand an adolescent being able to lead an army? Addressing this question proves more difficult than deciding whether St Joan warrants a diagnosis. In addition to her achievements in the war against Britain, Joan of Arc stands out as both the most documented person in Western civilization up until her era, and as the only person who has been both condemned and canonized by the Catholic Church.

In vitro activity of rhinacanthin analogues against drug resistant Plasmodium falciparum isolates from Northeast Thailand.

BACKGROUND: New anti-malarial drugs are needed urgently to address the increasing challenges of drug-resistant falciparum malaria. Two rhinacanthin analogues containing a naphthoquinone moiety resembling atovaquone showed promising in-vitro activity against a P. falciparum laboratory reference strain (K1). The anti-malarial activity of these 2 compounds was further evaluated for P. falciparum field isolates from an area of multi-drug resistance in Northeast Thailand. METHODS: Using a pLDH enzyme-linked immunosorbent assay, four P. falciparum isolates from Northeast Thailand in 2018 were tested for in vitro sensitivity to the two synthetic rhinacanthin analogues 1 and 2 as well as established anti-malarials. Mutations in the P. falciparum cytochrome b gene, a marker for atovaquone (ATQ) resistance, were genotyped in all four field isolates as well as 100 other clinical isolates from the same area using PCR-artificial Restriction Fragment Length Polymorphisms. Pfkelch13 mutations, a marker for artemisinin (ART) resistance, were also examined in all isolates. RESULTS: The 50% inhibitory concentrations (IC50) of P. falciparum field isolates for rhinacanthin analogue 1 was 321.9-791.1 nM (median = 403.1 nM). Parasites were more sensitive to analogue 2: IC50 48.6-63.3 nM (median = 52.2 nM). Similar results were obtained against P. falciparum reference laboratory strains 3D7 and W2. The ART-resistant IPC-5202 laboratory strain was more sensitive to these compounds with a median IC50 45.9 and 3.3 nM for rhinacanthin analogues 1 and 2, respectively. The ATQ-resistant C2B laboratory strain showed high-grade resistance towards both compounds (IC50 > 15,000 nM), and there was a strong positive correlation between the IC50 values for these compounds and ATQ (r = 0.83-0.97, P < 0.001). There were no P. falciparum cytochrome b mutations observed in the field isolates, indicating that P. falciparum isolates from this area remained ATQ-sensitive. Pfkelch13 mutations and the ring-stage survival assay confirmed that most isolates were resistant to ART. CONCLUSIONS: Two rhinacanthin analogues showed parasiticidal activity against multi-drug resistant P. falciparum isolates, although less potent than ATQ. Rhinacanthin analogue 2 was more potent than analogue 1, and can be a lead compound for further optimization as an anti-malarial in areas with multidrug resistance.

Development, religious affiliation, and social context: Substance use disorders in Puerto Rican transitional age youth.

Introduction: Transitional age youth (i. e., ages 16-24; TAY) use higher levels of substances than any age group in the United States. Understanding what factors increase substance use during TAY could suggest novel targets for prevention/intervention. Studies suggest that religious affiliation is inversely associated with substance use disorders (SUDs). However, the association of religious affiliation and SUD, including the role of gender and social context, has not been studied in TAY of Puerto Rican ethnicity. Methods: Using data from N = 2,004 TAY of Puerto Rican ethnicity across two social contexts-Puerto Rico (PR) and the South Bronx, NY (SBx)-we tested the association of religious identity (Catholic, Non-Catholic Christian, Other/Mixed, and no religious affiliation, or "None"), and four SUD outcomes (alcohol use disorder, tobacco use disorder, illicit SUD, and any SUD). Logistic regression models were used to examine the association between religious identity and SUDs, then we tested for interaction by social context and gender. Result: Half the sample identified as female; 30, 44, and 25% were 15-20, 21-24, and 25-29 years of age, respectively; 28% of the sample received public assistance. There was a statistically significant difference between sites for public assistance (22 and 33% in SBx/PR, respectively; p < 0.001); 29% of the sample endorsed None (38 and 21% in SBx/PR, respectively.) Compared to None, identifying as Catholic was associated with reduced risk of illicit SUD (OR = 0.51, p = 0.02), and identifying as Non-Catholic Christian with reduced risk for any SUD (OR = 0.68, p = 0.04). Additionally, in PR but not SBx, being Catholic or Non-Catholic Christian was protective for illicit SUD when compared to None (OR = 0.13 and 0.34, respectively). We found no evidence of an interaction between religious affiliation and gender. Discussion: The percentage of PR TAY who endorse no affiliation is higher than the general PR population, reflective of increasing religious non-affiliation among TAY across cultures. Critically, TAY with no religious affiliation are twice as likely as Catholics to have illicit SUD, and 1.5 times as likely as Non-Catholic Christians to have any SUD. Endorsing no affiliation is more adverse for illicit SUD in PR than the SBx, underscoring the importance of social context.

A machine learning approach identifies distinct early-symptom cluster phenotypes which correlate with hospitalization, failure to return to activities, and prolonged COVID-19 symptoms.

BACKGROUND: Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles. METHODS: 1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations. RESULTS: We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 ("Nasal cluster") is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 ("Sensory cluster") is highly correlated with loss of smell or taste, and cluster 3 ("Respiratory/Systemic cluster") is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01). CONCLUSIONS: We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk.