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There is an ongoing debate as to whether autism spectrum disorder (ASD) is expressed differently in women than men. It is unclear whether differences found are specific to autism or merely reflecting normative development. In this study, we compared sex differences in developmental trajectories of autistic and co-occurring psychopathological symptoms in adolescents with milder forms of autism to those in a normative group matched for intelligence quotient (IQ) and socioeconomic status. Data of five assessment waves from ages 11 to 22 years were analyzed using linear mixed modeling. We found that in adolescence, sex differences in developmental trajectories of psychopathological symptoms specific for autism are confined to the repetitive stereotyped domain (males had higher scores on the sensory/stereotypic and resistance to change domains, the latter difference disappeared during adolescence due to an increase of these problems in females with ASD). Other sex differences, among which an increase over time in affective and anxiety problems in females was the most outstanding, were also observed in typically developing females. These sex-specific differences have relevance in the clinical care of men and women with autism, although they are subtle compared to differences between individuals with and without autism, which are broadly present in internalizing and externalizing problem domains.

The local binding and migration behavior of the proton defect in cubic yttria-stabilized zirconia (YSZ) is studied by first-principles calculations and muon-spin spectroscopy (μSR) measurements. The calculations are based on density-functional theory (DFT) supplemented with a hybrid-functional approach with the proton defect embedded in quasi-random supercells of 10.3 mol% yttria content, where the yttrium–zirconium substitutional defects are charge compensated by oxygen vacancies. Representative migration pathways for the proton comprising both transfer and bond reorientation modes are analysed and linked to the underlying microstructure of the YSZ lattice. The μSR data show the evolution of the diamagnetic fraction corresponding to the muon-isotope analogue with an activation energy of diffusion equal to 0.17 eV. Comparisons between the calculations and the experiment allow an assessment of the character of the short-range migration of the proton particle in cubic YSZ.

Abstract Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small proportion of the heritability for NSOFCs. Rare variants have been implicated in the missing heritability. Thus, our study aimed to identify genes enriched with nonsynonymous rare coding variants associated with NSOFCs. Our sample included 814 non-syndromic cleft lip with or without palate (NSCL/P), 205 non-syndromic cleft palate only (NSCPO), and 2150 unrelated control children from Nigeria, Ghana, and Ethiopia. We conducted a gene-based analysis separately for each phenotype using three rare-variants collapsing models: (1) protein-altering (PA), (2) missense variants only (MO); and (3) loss of function variants only (LOFO). Subsequently, we utilized relevant transcriptomics data to evaluate associated gene expression and examined their mutation constraint using the gnomeAD database. In total, 13 genes showed suggestive associations (p = E−04). Among them, eight genes (ABCB1, ALKBH8, CENPF, CSAD, EXPH5, PDZD8, SLC16A9, and TTC28) were consistently expressed in relevant mouse and human craniofacial tissues during the formation of the face, and three genes (ABCB1, TTC28, and PDZD8) showed statistically significant mutation constraint. These findings underscore the role of rare variants in identifying candidate genes for NSOFCs.

Abstract Type IV pili are filamentous appendages found in most bacteria and archaea, where they can support functions such as surface adhesion, DNA uptake, aggregation, and motility. In most bacteria, PilT-family ATPases disassemble adhesion pili, causing them to rapidly retract and produce twitching motility, important for surface colonization. As archaea do not possess PilT homologs, it was thought that archaeal pili cannot retract and that archaea do not exhibit twitching motility. Here, we use live-cell imaging, automated cell tracking, fluorescence imaging, and genetic manipulation to show that the hyperthermophilic archaeon Sulfolobus acidocaldarius exhibits twitching motility, driven by retractable adhesion (Aap) pili, under physiologically relevant conditions (75 °C, pH 2). Aap pili are thus capable of retraction in the absence of a PilT homolog, suggesting that the ancestral type IV pili in the last universal common ancestor (LUCA) were capable of retraction.

Research Purposes. Technological advancement and globalization increase demand for flexible work arrangements, particularly remote working, which pose limitations and challenges to auditors in maintaining audit quality. The study aims to determine which domain of work-from-home setup significantly influences the audit quality of external auditors. Research Methods The study used quantitative research design and correlational techniques to test the relationship and significance of the variables. It was participated by CPAs in public practice who experienced remote auditing and employed the random sampling technique in selecting the respondents. The data were analyzed and interpreted using the mean, standard deviation, Pearson's correlation, and regression Research Results and Findings. The results concluded that the effectiveness of work-from-home setup and audit quality have a moderately strong, positive correlation. Only the propensity to work remotely and work-life balance significantly influenced the audit quality of external auditors. The findings imply that despite the physical absence and changes in processes, working from home can be an effective work setup in attaining and maintaining high-quality audits and has the potential to address the demand for flexible work arrangements if appropriately administered. The study suggests strengthening remote audits by creating and utilizing online tools for managing audit activities, such as submission of evidence, planning, and audit preparation.

Abstract Background Organized physical activity programs have been shown to provide wide benefits to participants, though there are relatively few studies examining the impact of these programs for individuals with developmental disabilities. This pilot study was conducted to determine the feasibility and impact of an undergraduate-led dance intervention program for children and adolescents with developmental disabilities. We evaluated the impact of the dance program on motor ability and social skills. Methods The study design was a waitlist control clinical trial in which participants were randomized to active and control groups. Eligible participants included male and female children and adolescents between the ages of 4 and 17 years with neurodevelopmental disabilities. The Motor Assessment Battery for Children Checklist and the Social Responsiveness Scale were used to assess change in motor and social skills, respectively. After gathering baseline data, the active group completed 1 h of online dance classes per week for 10 weeks, while the control group entered a 10-week waiting period. All participants then returned for a follow-up visit. Pre- and post-intervention data were analyzed using linear mixed-effects modeling adjusting for age and class attendance with subject random intercept. Results We recruited and randomized 43 participants with neurodevelopmental disabilities (mean age = 8.63, SD = 2.98), of which 30 participated in dance classes. The attendance rate was 82.6% for the active group and 61.7% for the control group. The active group demonstrated a significant improvement in motor skills in an unpredictable environment, as indicated on the Motor Assessment Battery for Children Checklist (n = 21, p = 0.05). We also observed positive trends in social skills that did not reach significance. Conclusions Our results indicate that it is feasible to develop and implement a fully digital dance intervention program for individuals with developmental disabilities. Further, we find that change in motor skills can be detected after just 10 h of low-intensity participation. However, a lack of significant change in social skills coupled with limitations in study implementation suggests further research is needed to determine the full impact of this dance program. Trial Registration ClinicalTrials.gov Protocol Registration System: Protocol ID 20-001680-AM-00005, registered 17/2/2021 – Retrospectively Registered, https://clinicaltrials.gov/study/NCT04762290 .

Abstract Polycystic liver disease (PLD) is a rare condition observed in three genetic diseases, including autosomal dominant polycystic liver disease (ADPLD), autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). PLD usually does not impair liver function, and advanced PLD becomes symptomatic when the enlarged liver compresses adjacent organs or increases intra-abdominal pressure. Currently, the diagnosis of PLD is mainly based on imaging, and genetic testing is not required except for complex cases. Besides, genetic testing may help predict patients’ prognosis, classify patients for genetic intervention, and conduct early treatment. Although the underlying genetic causes and mechanisms are not fully understood, previous studies refer to primary ciliopathy or impaired ciliogenesis as the main culprit. Primarily, PLD occurs due to defective ciliogenesis and ineffective endoplasmic reticulum quality control. Specifically, loss of function mutations of genes that are directly involved in ciliogenesis, such as Pkd1 , Pkd2, Pkhd1, and Dzip1l, can lead to both hepatic and renal cystogenesis in ADPKD and ARPKD. In addition, loss of function mutations of genes that are involved in endoplasmic reticulum quality control and protein folding, trafficking, and maturation, such as PRKCSH, Sec63, ALG8, ALG9, GANAB, and SEC61B, can impair the production and function of polycystin1 (PC1) and polycystin 2 (PC2) or facilitate their degradation and indirectly promote isolated hepatic cystogenesis or concurrent hepatic and renal cystogenesis. Recently, it was shown that mutations of LRP5, which impairs canonical Wnt signaling, can lead to hepatic cystogenesis. PLD is currently treated by somatostatin analogs, percutaneous intervention, surgical fenestration, resection, and liver transplantation. In addition, based on the underlying molecular mechanisms and signaling pathways, several investigational treatments have been used in preclinical studies, some of which have shown promising results. This review discusses the clinical manifestation, complications, prevalence, genetic basis, and treatment of PLD and explains the investigational methods of treatment and future research direction, which can be beneficial for researchers and clinicians interested in PLD.

Abstract Oxygen availability can have profound effects on cell fate decisions and survival, in part by regulating expression of hypoxia-inducible factors (HIFs). In the ovary, HIF expression has been characterised in granulosa cells, however, any requirement in oocytes remains relatively undefined. Here we developed a Hif2a/Epas1 germline-specific knockout mouse line in which females were fertile, however produced 40% fewer pups than controls. No defects in follicle development were detected, and quality of MII oocytes was normal, as per assessments of viability, intracellular reactive oxygen species, and spindle parameters. However, a significant diminishment of the primordial follicle pool was evident in cKO females that was attributed to accelerated follicle loss from postnatal day 6 onwards, potentially via disruption of the autophagy pathway. These data demonstrate the importance of HIF signalling in oocytes, particularly at the primordial follicle stage, and lend to the importance of controlling oxygen tension in the development of in vitro growth and maturation approaches for assisted reproduction.

Abstract Antimicrobial resistance genes (ARG), such as extended-spectrum β-lactamase (ESBL) and carbapenemase genes, are commonly carried on plasmids. Plasmids can transmit between bacteria, disseminate globally, and cause clinically important resistance. Therefore, targeting plasmids could reduce ARG prevalence, and restore the efficacy of existing antibiotics. Cobalt complexes possess diverse biological activities, including antimicrobial and anticancer properties. However, their effect on plasmid conjugation has not been explored yet. Here, we assessed the effect of four previously characterised bis(N-picolinamido)cobalt(II) complexes lacking antibacterial activity on plasmid conjugation in Escherichia coli and Klebsiella pneumoniae. Antimicrobial susceptibility testing of these cobalt complexes confirmed the lack of antibacterial activity in E. coli and K. pneumoniae. Liquid broth and solid agar conjugation assays were used to screen the activity of the complexes on four archetypical plasmids in E. coli J53. The cobalt complexes significantly reduced the conjugation of RP4, R6K, and R388 plasmids, but not pKM101, on solid agar in E. coli J53. Owing to their promising activity, the impact of cobalt complexes was tested on the conjugation of fluorescently tagged extended-spectrum β-lactamase encoding pCTgfp plasmid in E. coli and carbapenemase encoding pKpQILgfp plasmid in K. pneumoniae, using flow cytometry. The complexes significantly reduced the conjugation of pKpQILgfp in K. pneumoniae but had no impact on pCTgfp conjugation in E. coli. The cobalt complexes did not have plasmid-curing activity, suggesting that they target conjugation rather than plasmid stability. To our knowledge, this is the first study to report reduced conjugation of clinically relevant plasmids with cobalt complexes. These cobalt complexes are not cytotoxic towards mammalian cells and are not antibacterial, therefore they could be optimised and employed as inhibitors of plasmid conjugation.

Abstract Purpose 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in

Objectives. To describe the characteristics and outcomes of COVID-19 cases in Jamaica and to explore the risk factors associated with severe COVID-19 from 9 March to 31 December 2020. Methods. A cross-sectional analysis of national surveillance data was conducted using confirmed COVID-19 cases in Jamaica. Definitions of a confirmed case, disease severity, and death were based on World Health Organization guidelines. Chi-square and Fisher exact tests were used to determine association with outcomes. Logistic regression models were used to determine predictors of severe COVID-19. Results. This analysis included 12 169 cases of COVID-19 (median age, 36 years; 6 744 females [ 55.4%]) of which 512 cases (4.2%) presented with severe disease, and of those, 318 patients (62.1%) died (median age at death, 71.5 years). Severe disease was associated with being male (OR 1.4; 95% CI, 1.2-1.7) and 40 years or older (OR, 6.5; 95% CI, 5.1-8.2). COVID-19 death was also associated with being male (OR, 1.4; 95% CI, 1.1-1.7), age 40 years or older (OR, 17.9; 95% CI, 11.6-27.7), and in the Western versus South East Health Region (OR 1.7; 95% CI, 1.2-2.3). Conclusions. The findings of this cross-sectional analysis indicate that confirmed cases of COVID-19 in Jamaica were more likely to be female and younger individuals, whereas COVID-19 deaths occurred more frequently in males and older individuals. There is increased risk of poor COVID-19 outcomes beginning at age 40, with males disproportionately affected. COVID-19 death also varied by geographic region. This evidence could be useful to other countries with similar settings and to policymakers charged with managing outbreaks and health.

People with autism spectrum disorder (ASD) and non-spectrum developmental delays frequently exhibit maladaptive behaviors throughout the lifespan, which can have pervasive effects on quality of life. Maladaptive behaviors have been shown to change over time as a function of various individual-level factors (e.g., cognitive ability), yet research is primarily limited to parent-reported measures. To expand upon this work, the present study aimed to examine trajectories of teacher- and parent-reported maladaptive behaviors (i.e., hyperactivity, irritability, social withdrawal) and to test whether individual-level predictors (e.g., autism features, verbal intelligence quotient) and school-related predictors (e.g., teacher type, student-adult ratio, personal aide, school type) impact these trajectories among 165 individuals with ASD or non-spectrum delays from ages 9 to 18. Multilevel models revealed that, according to both teacher and parent report, participants showed the greatest improvement in hyperactivity, less but still notable improvement in irritability, and stable levels of social withdrawal over time. Higher verbal ability and fewer ASD features, in addition to mainstream school placement, emerged as important individual- and school-related differences associated with fewer maladaptive behaviors over time. The multi-informant perspective and longitudinal design provide novel insight into the manifestations of these maladaptive behaviors across different contexts and across time. Findings highlight the consistency of teacher- and parent-reported trajectories over time and further emphasize the importance of targeting maladaptive behaviors using a multisystem intervention approach in both school and home contexts.

Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co-occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four-class solution (no symptoms, apathy, depression, and combined apathy/depression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathy/depression syndrome exists, supported by the model fit test with the four-class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy R 2). Using a data-driven method, we show distinct and statistically meaningful co-occurrence of apathy and depressive symptoms. There was evidence that these classes have different clinical associations, which may help inform diagnostic categories for research studies and clinical practice.HighlightsWe found four classes: no symptoms, apathy, depression and apathy/depression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms.

Violet Jiménez Sims, Kerry Lord, Marlene Megos, and Ushawnda Mitchell describe a new approach to addressing the gap between the racial diversity of teachers and students in U.S. public schools. The Connecticut Teacher Residency program (CT-TRP) is a grow-your-own approach to teacher training, certification, and retention that combines an academic program with a residency model while centering cultural competency. The program breaks down common barriers to the teaching profession by covering the cost of tuition, paying a living wage to candidates during their one-year residency, and helping them prepare for certification exams.

Background In patients with coronavirus disease 2019 (COVID-19) requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) 1 year after discharge. Methods Adults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies (Post-hospitalisation COVID-19 and the International Severe Acute Respiratory and emerging Infection Consortium). HRQoL, assessed by the EuroQol-Five Dimensions–Five Levels utility index (EQ-5D-5L UI), pre-hospital and 1 year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient-reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. Findings Of the 1888 participants included in the primary analysis, 1149 received corticosteroids. There was no between-group difference in EQ-5D-5L UI at 1 year (mean difference 0.004, 95% CI −0.026–0.034). A similar reduction in EQ-5D-5L UI was seen at 1 year between corticosteroid exposed and nonexposed groups (mean±sd change −0.12±0.22 versus −0.11±0.22). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a cohort of 109 318 patients admitted to hospital with COVID-19, EQ-5D-5L UI at 1 year remained similar between the two groups. Interpretation Systemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL 1 year after hospital discharge. Treatments to address the persistent reduction in HRQoL are urgently needed.

Background Each year in England, 450,000 children and young people (CYP) under 18 years of age are transported by ambulance to emergency departments. Approximately 20% of these suffer acute pain caused by illness or injury. Pain is a highly complex sensory and emotional experience. The intersection between acute pain, unwell CYP and the unpredictable pre-hospital environment is convoluted. Studies have shown that prehospital pain management in CYP is poor, with 61% of those suffering acute pain not achieving effective pain relief (abolition or reduction of pain score by 2 or more out of 10) when attended by ambulance. Consequences of poor acute pain management include altered pain perception, post-traumatic stress disorder and the development of chronic pain. This realist review will aim to understand how ambulance clinicians can provide improved prehospital acute pain management for CYP. Methods A realist review will be conducted in accordance with the Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) guidance. A five-stage approach will be adopted; 1) Developing an Initial Programme Theory (IPT): develop an IPT with key stakeholder input and evidence from informal searching; 2) Searching and screening: conduct a thorough search of relevant research databases and other literature sources and perform screening in duplicate; 3) Relevance and rigour assessment: assess documents for relevance and rigour in duplicate; 4) Extracting and organising data: code relevant data into conceptual “buckets” using qualitative data analysis software; and 5) Synthesis and Programme Theory (PT) refinement: utilise a realist logic of analysis to generate context-mechanism-outcome configurations (CMOCs) within and across conceptual “buckets”, test and refine the IPT into a realist PT. Conclusion The realist PT will enhance our understanding of what works best to improve acute prehospital pain management in CYP, which will then be tested and refined within a realist evaluation. Registration PROSPERO Registration: CRD42024505978

ABSTRACT In 2000, Cleide Costa published a paper presenting the state of knowledge of the Neotropical Coleopte ra, with a focus on the Brazilian fauna. Twenty-four years later, thanks to the development of the Coleoptera section of the Taxonomic Catalog of the Brazilian Fauna (CTFB - Catálogo Taxonômico da Fauna do Brasil) through the collaboration of 100 coleopterists from all over the globe, we can build on Costa’s work and present an updated overview of the state of knowledge of the beetles from Brazil. There are currently 35,699 species in 4,958 genera and 116 families known to occur in the country, including representatives of all extant suborders and superfamilies. Our data show that the Brazilian beetle fauna is the richest on the planet, concentrating 9% of the world species diversity, with some estimates accounting to up to 15% of the global total. The most diverse family in numbers of genera is Cerambycidae (1,056 genera), while in number of species it is Chrysomelidae (6,079 species). Conotrachelus Dejean, 1835 (Curculionidae) is the most species-rich genus, with 570 species. The French entomologist Maurice Pic is the author who has contributed the most to the naming of species recorded from Brazil, with 1,794 valid names in 36 families, whereas the Brazilians Ubirajara R. Martins and Maria Helena M. Galileo are the only ones among the top-ten authors to have named species in the 21st century. Currently, approximately 144 new species of Brazilian beetles are described each year, and this average is projected to increase in the next decade to 180 species per year, or about one new Brazilian beetle every two days.

Background: Vitamin D is vital for musculoskeletal health, and supplementation may lower risk of falls. Past research in residential aged care (RAC) settings on the effects of vitamin D on falls have reported inconclusive findings, partly due to study design limitations. We utilised a longitudinal study design to assess the association between the use of vitamin D and falls over 36 months in RAC. Method: A longitudinal cohort study was conducted using routinely collected electronic data spanning 9 years from 27 RAC facilities in Sydney, New South Wales, Australia. The study included 4520 permanent residents aged 65 years or older who were admitted for the first time from 1 July 2014 and stayed for a minimum of one month. We identified daily vitamin D usage over 36 months, and measured adherence using the Proportion of Days Covered (PDC) metric. A PDC value of ≥80 % signifies optimal adherence. Primary outcomes were the number of all falls and injurious falls. A rolling time-varying predictor-outcome approach and Generalized Estimating Equations (GEE) were applied to determine the longitudinal link between vitamin D supplement use and subsequent risk of falls. Results: Over two-thirds of residents (67.8 %; n = 3063) received vitamin D supplements during their stay, with a median PDC of 74.8 % among users, and 44.6 % (n = 1365) achieving optimal adherence. Increasing age, osteoporosis or fracture history, and dementia were associated with a greater likelihood of achieving optimal adherence. Crude fall incident rates were 8.05 and 2.92 incidents per 1000 resident days for all falls and injurious falls respectively. After accounting for relevant demographic and clinical factors, no significant links were observed between vitamin D supplement usage and fall outcomes: all falls (Incident Rate Ratio [IRR] 1.01; 95 % CI 1.00–1.02; P = 0.237) and injurious falls (IRR 1.01; 95 % CI 1.00–1.02; P = 0.091). Conclusion: Vitamin D supplementation was not associated with a reduced risk of falls, suggesting it is not an effective intervention for preventing falls in RAC. While clinicians should ensure adequate vitamin D intake for residents' nutritional and bone health, it should not be a standalone falls prevention intervention in RAC populations.

BackgroundIndividuals affected by the post-covid condition (PCC) show an increased fatigue and the so-called post-exertion malaise (PEM) that led health professionals to advise against exercise although accumulating evidence indicates the contrary. The goal of this study is to determine the impact of a closely monitored 8-week mixed exercise program on physical capacity, symptoms, fatigue, systemic oxidative stress and plasma proteomic profiles of PCC cases.MethodsTwenty-five women and men with PCC were assigned sequentially to exercise (n = 15) and non-exercise (n = 10) groups. Individuals with no PCC served as a control group. The exercise program included cardiovascular and resistance exercises. Physical capacity, physical activity level and the presence of common PCC symptoms were measured before and after the intervention. Fatigue was measured the day following each exercise session. Plasma and PBMC samples were collected at the beginning and end of the training program. Glutathione and deoxyguanosine levels in PBMC and plasma proteomic profiles were evaluated.ResultsBicep Curl (+15% vs 4%; p = 0.040) and Sit-to-Stand test (STS-30 (+31% vs +11%; p = 0.043)) showed improvement in the exercise group when compared to the non-exercise group. An interaction effect was also observed for the level of physical activity (p =0.007) with a positive effect of the program on their daily functioning and without any adverse effects on general or post-effort fatigue. After exercise, glutathione levels in PBMCs increased in women but remained unchanged in men. Discernable changes were observed in the plasma proteomics profile with certain proteins involved in inflammatory response decreasing in the exercise group.ConclusionsSupervised exercise adapted to the level of fatigue and ability is safe and effective in PCC patients in improving their general physical capacity and wellbeing. Systemic molecular markers that accompany physical improvement can be monitored by analyzing plasma proteomics and markers of oxidative stress. Large-scale studies will help identify promising molecular markers to objectively monitor patient improvement.

Background: Advances in targeted therapy development and tumor sequencing technology are reclassifying cancers into smaller biomarker-defined diseases. Randomized controlled trials (RCTs) are often impractical in rare diseases, leading to calls for single-arm studies to be sufficient to inform clinical practice based on a strong biological rationale. However, without RCTs, favorable outcomes are often attributed to therapy but may be due to a more indolent disease course or other biases. When the clinical benefit of targeted therapy in a common cancer is established in RCTs, this benefit may extend to rarer cancers sharing the same biomarker. However, careful consideration of the appropriateness of extending the existing trial evidence beyond specific cancer types is required. A framework for extrapolating evidence for biomarker-targeted therapies to rare cancers is needed to support transparent decision-making. Objectives: To construct a framework outlining the breadth of criteria essential for extrapolating evidence for a biomarker-targeted therapy generated from RCTs in common cancers to different rare cancers sharing the same biomarker. Design: A series of questions articulating essential criteria for extrapolation. Methods: The framework was developed from the core topics for extrapolation identified from a previous scoping review of methodological guidance. Principles for extrapolation outlined in guidance documents from the European Medicines Agency, the US Food and Drug Administration, and Australia’s Medical Services Advisory Committee were incorporated. Results: We propose a framework for assessing key assumptions of similarity of the disease and treatment outcomes between the common and rare cancer for five essential components: prognosis of the biomarker-defined cancer, biomarker test analytical validity, biomarker actionability, treatment efficacy, and safety. Knowledge gaps identified can be used to prioritize future studies. Conclusion: This framework will allow systematic assessment, standardize regulatory, reimbursement and clinical decision-making, and facilitate transparent discussions between key stakeholders in drug assessment for rare biomarker-defined cancers.

Under the Trump presidency, the United States and China were embroiled in an open trade war that threatened the neoliberal world order. This paper attempts to put forward an explanation of the trade war from a world-systems perspective. Using the world-systems theory, systemic cycles accumulation theory, and the new international division of labor thesis, the paper contends that the rise of China and the protectionist stance of the United States were products of the neoliberal world economic and political order. It concludes that the trade war has not ended with the end of the Trump presidency. On the contrary, the trade war is systemic and will continue to be fought regardless of which party or persons who occupy the White House. The willingness of the American leadership to use international institutions as dispute resolution mechanisms and avoid unilateral undertakings would define the nature of the trade war and its possible outcomes.

BackgroundTsetse flies (Glossina sp.) are vectors of Trypanosoma brucei subspecies that cause human African trypanosomiasis (HAT). Capturing and screening tsetse is critical for HAT surveillance. Classically, tsetse have been microscopically analysed to identify trypanosomes, but this is increasingly replaced with molecular xenomonitoring. Nonetheless, sensitive T. brucei-detection assays, such as TBR-PCR, are vulnerable to DNA cross-contamination. This may occur at capture, when often multiple live tsetse are retained temporarily in the cage of a trap. This study set out to determine whether infected tsetse can contaminate naïve tsetse with T. brucei DNA via faeces when co-housed.Methodology/principle findingsInsectary-reared teneral G. morsitans morsitans were fed an infectious T. b. brucei-spiked bloodmeal. At 19 days post-infection, infected and naïve tsetse were caged together in the following ratios: (T1) 9:3, (T2) 6:6 (T3) 1:11 and a control (C0) 0:12 in triplicate. Following 24-hour incubation, DNA was extracted from each fly and screened for parasite DNA presence using PCR and qPCR. All insectary-reared infected flies were positive for T. brucei DNA using TBR-qPCR. However, naïve tsetse also tested positive. Even at a ratio of 1 infected to 11 naïve flies, 91% of naïve tsetse gave positive TBR-qPCR results. Furthermore, the quantity of T. brucei DNA detected in naïve tsetse was significantly correlated with cage infection ratio. With evidence of cross-contamination, field-caught tsetse from Tanzania were then assessed using the same screening protocol. End-point TBR-PCR predicted a sample population prevalence of 24.8%. Using qPCR and Cq cut-offs optimised on insectary-reared flies, we estimated that prevalence was 0.5% (95% confidence interval [0.36, 0.73]).Conclusions/significanceOur results show that infected tsetse can contaminate naïve flies with T. brucei DNA when co-caged, and that the level of contamination can be extensive. Whilst simple PCR may overestimate infection prevalence, quantitative PCR offers a means of eliminating false positives.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Dissemination of food-borne L. monocytogenes in the host relies on internalin-mediated invasion, but the underlying invasion strategies remain elusive. Here we use live-cell microscopy to follow single cell interactions between individual human cells and L. monocytogenes and elucidate mechanisms associated with internalin B (InlB)-mediated invasion. We demonstrate that whilst a replicative invasion of nonphagocytic cells is a rare event even at high multiplicities of invasion, L. monocytogenes overcomes this by utilising a strategy relaying on PrfA-mediated ActA-based aggregation. We show that L. monocytogenes forms aggregates in extracellular host cell environment, which promote approximately 5-fold more host cell adhesions than the non-aggregating actA-ΔC mutant (which lacks the C-terminus coding region), with the adhering bacteria inducing 3-fold more intracellular invasions. Aggregation is associated with robust MET tyrosine kinase receptor clustering in the host cells, a hallmark of InlB-mediated invasion, something not observed with the actA-ΔC mutant. Finally, we show via RNA-seq analyses that aggregation involves a global adaptive response to host cell environment (including iron depletion), resulting in metabolic changes in L. monocytogenes and upregulation of the PrfA virulence regulon. Overall, our analyses provide new mechanistic insights into internalin-mediated host-pathogen interactions of L. monocytogenes.

Summary: Background: There is uncertainty regarding how best to support patients with anorexia nervosa following inpatient or day care treatment. This study evaluated the impact of augmenting intensive treatment with a digital, guided, self-management intervention (ECHOMANTRA) for patients with anorexia nervosa and their carers. Methods: In this pragmatic multicentre randomised controlled trial and economic evaluation, patients with a diagnosis of anorexia nervosa or atypical anorexia nervosa, aged 16+ and attending one of the 31 inpatient or day-patient services in the UK were randomised with one of their carers to receive ECHOMANTRA plus treatment as usual (TAU), or TAU alone. ECHOMANTRA was hosted on a digital platform and included a workbook, recovery-oriented video-clips and online facilitated groups (patients only, carers only, joint patient-carer). Participants were randomised on a 1:1 ratio using a minimisation algorithm to stratify by site (N = 31) and severity (defined by BMI

Speech-language pathology graduate programs do not reflect equity across racial and ethnic groups. Training programs must adopt an anti-racist stance and intentionally and strategically plan for equity and inclusion of students and professionals who are Black, Indigenous and Persons of Color (BIPOC). Retention of minoritized students must be supported by inclusion efforts. The authors review systems of support essential to the recruitment and retention of BIPOC students in graduate programs. Through funding support from a grant, the authors developed a model of training bilingual SLP students to work with dual language learners through an inclusive model of interprofessional education. Finally, the authors conclude with a discussion of questions faculty should consider to create institutional change. The authors are hopeful that this article provides SLP programs a best practice framework to build a diverse pipeline of speech-language pathologists better equipped to deliver effective culturally and linguistically responsive interventions for the clients served within our field and across our transdisciplinary work.

As more students elect to complete their doctoral studies online, faculty need to identify and implement mentorship approaches that are conducive to student understanding of the dissertation process. Faculty to mentee relationships are a prominent aspect of student retention and success in doctoral programs. Due to advances in technology, dissertation chairs have access to tools that allow for real-time feedback and support. Therefore, this study examined student dissertation and faculty mentorship experiences. Participants expressed satisfaction in their doctoral studies and dissertation process. However, students shared challenges associated with balancing multiple commitments, feeling lower levels of writing self-confidence, and understanding the dissertation process and expectations. These findings provide additional support on the importance of developing and maintaining positive online doctoral experiences.