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The global outbreak of mpox virus constituted an international public health emergency. Reports have highlighted (1) a temporal association between sexual activity and mpox, (2) an association between specific sexual practices and location of lesion development, (3) a high frequency of sexual practices conferring risk for other sexually transmitted infections among cases of mpox, (4) that mpox virus can be isolated from sexual fluids, (4) that isolated virus is infectious, and (5) a high frequency of anogenital lesions prior to disease dissemination suggesting direct inoculation during sexual activities. Finally, a growing body of evidence suggests that sexual transmission is the predominant mode of transmission for mpox virus. We therefore conclude that mpox is a sexually transmitted disease. Labeling it as such will help focus public health interventions, such as vaccinations, testing, and treatment, as well as facilitate focused awareness and education programs toward behavioral modifications to reduce exposures.

Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.

BackgroundNeisseria gonorrhoeae is a major public health problem due to increasing incidence and antimicrobial resistance. Genetic markers of reduced susceptibility have been identified; the extent to which those are representative of global antimicrobial resistance is unknown. We evaluated the performance of whole-genome sequencing (WGS) used to predict susceptibility to ciprofloxacin and other antimicrobials using a global collection of N. gonorrhoeae isolates.MethodsSusceptibility testing of common antimicrobials and the recently developed zolifodacin was performed using agar dilution to determine minimum inhibitory concentrations (MICs). We identified resistance alleles at loci known to contribute to antimicrobial resistance in N. gonorrhoeae from WGS data. We tested the ability of each locus to predict antimicrobial susceptibility.ResultsA total of 481 N. gonorrhoeae isolates, collected between 2004 and 2019 and making up 457 unique genomes, were sourced from 5 countries. All isolates with demonstrated susceptibility to ciprofloxacin (MIC ≤0.06 μg/mL) had a wild-type gyrA codon 91. Multilocus approaches were needed to predict susceptibility to other antimicrobials. All isolates were susceptible to zoliflodacin, defined by an MIC ≤0.25 μg/mL.ConclusionsSingle marker prediction can be used to inform ciprofloxacin treatment of N. gonorrhoeae infection. A combination of molecular markers may be needed to determine susceptibility for other antimicrobials.

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta-Analysis Military-Relevant Brain Injury working group, we conducted a mega-analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment-related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI.

The dominant sensory phenotype in patients with diabetic polyneuropathy and neuropathic pain is a loss of function. This raises questions as to which mechanisms underlie pain generation in the face of potentially reduced afferent input. One potential mechanism is spinal disinhibition, whereby a loss of spinal inhibition leads to increased ascending nociceptive drive due to amplification of, or a failure to suppress, incoming signals from the periphery. We aimed to explore whether a putative biomarker of spinal disinhibition, impaired rate-dependent depression of the Hoffmann reflex, is associated with a mechanistically appropriate and distinct pain phenotype in patients with painful diabetic neuropathy. In this cross-sectional study, 93 patients with diabetic neuropathy underwent testing of Hoffmann reflex rate-dependent depression and detailed clinical and sensory phenotyping, including quantitative sensory testing. Compared to neuropathic patients without pain, patients with painful diabetic neuropathy had impaired Hoffmann reflex rate-dependent depression at 1, 2 and 3 Hz (P ≤ 0.001). Patients with painful diabetic neuropathy exhibited an overall loss of function profile on quantitative sensory testing. However, within the painful diabetic neuropathy group, cluster analysis showed evidence of greater spinal disinhibition associated with greater mechanical pain sensitivity, relative heat hyperalgesia and higher ratings of spontaneous burning pain. These findings support spinal disinhibition as an important centrally mediated pain amplification mechanism in painful diabetic neuropathy. Furthermore, our analysis indicates an association between spinal disinhibition and a distinct phenotype, arguably akin to hyperpathia, with combined loss and relative gain of function leading to increasing nociceptive drive.

In this philological study we establish and reckon with the fact that the name Carpocrates was exceedingly rare and strange in antiquity. The rarity, we argue, was due to the name being a variant spelling or (purposeful) misspelling of the Greco-Egyptian deity Harpokrates. We also show how bizarre and even comical the name would have sounded to Hellenephone audiences. Greek parents, so far as the evidence suggests, were not naming their sons Carpocrates. We further explain how both the rarity and strangeness of the name functioned as a polemical weapon in the hands of some early Christian writers., Though evidence about Carpocrates ([phrase omitted]) remains scant, this second-century 'gnostic' teacher, associated with the alleged Secret Gospel of Mark, continues to receive attention by modern scholars. (1) Missing among [...]

Abstract Background In primary care, identifying pneumonia events in people with chronic obstructive pulmonary disease (COPD) may be challenging due to similarities in symptoms with COPD exacerbations and lack of diagnostic testing. This study explored the accuracy of pneumonia diagnosis coded in primary care by comparing diagnosis in primary care with diagnosis in hospital. Methods A study population of people with COPD in England was created using the Clinical Practice Research Datalink Aurum database linked with Hospital Episode Statistics inpatient data. Pneumonia codes only, and pneumonia code with associated clinical and/or treatment codes (chest x-ray, symptoms, antibiotics, sputum and blood culture) were used to determine pneumonia events in primary care. Events that were followed by hospitalisation within 7 days were used to estimate the positive predictive value (PPV) of pneumonia coding in primary care, using primary diagnosis of pneumonia in secondary care as the gold standard. The PPV of primary care recording of hospitalised pneumonia was also calculated. Results Two hundred seventy-four thousand one hundred fifty-six COPD patients were eligible for inclusion, of whom 7,560 had an eligible pneumonia event in primary care diagnosed between 2015–2019 which was not ‘hospital-acquired’ and was diagnosed and entered on the same day. Of the 2,094 events which were followed by hospitalisation within 7 days, 1,208 had a primary diagnosis of pneumonia in hospital, representing a PPV of pneumonia coding in primary care of 57.7% (95% CI 55.6%-59.8%). Another 284 (13.6%) were diagnosed as a COPD exacerbation and 114 (5.4%) were diagnosed as another respiratory disease. Use of additional pneumonia clinical and treatment codes had a modest effect on the PPV but substantially lowered the number of events. Of the 33,603 eligible pneumonia events identified in secondary care, only 11,445 were recorded in primary care within 42 days, representing a sensitivity of 34.1% (95% CI 33.6%-34.6%). Conclusions Use of primary care pneumonia codes and associated clinical and treatment codes to determine pneumonia is not recommended due to significant levels of misdiagnosis and many hospitalised events failing to be recorded in primary care.

Abstract Background Primary health care (PHC) has historically led and implemented successful immunization programs, driven by strong relationships with patients and communities. During the COVID-19 pandemic, Canada began its vaccination strategy with mass immunizations that later included local efforts with PHC providers. This study seeks to understand how PHC contributed to the different phases of the COVID-19 vaccination rollouts in Ontario, Canada’s most populous province. Methods We conducted a descriptive qualitative study with focus groups consisting of PHC providers, administrators, and staff in Ontario. Eight focus groups were held with 39 participants representing geographic diversity across the six Ontario Health regions. Participants reflected a diverse range of clinical, administrative, and leadership roles. Each focus group was audio-recorded and transcribed with transcriptions analyzed using thematic analysis. Results With respect to understanding PHC teams’ participation in the different phases of the COVID-19 vaccination rollouts, we identified five themes: (i) supporting long-term care, (ii) providing leadership in mass vaccinations, (iii) integrating vaccinations in PHC practice sites, (iv) reaching those in need through outreach activities; and (v) PHC’s contributions being under-recognized. Conclusions PHC was instrumental in supporting COVID-19 vaccinations in Ontario, Canada across all phases of the rollout. The flexibility and adaptability of PHC allowed teams to participate in both large-scale and small-scale vaccination efforts.

Abstract Immune checkpoint blockade has yet to produce robust anti-cancer responses for prostate cancer. Sialyltransferases have been shown across several solid tumours, including breast, melanoma, colorectal and prostate to promote immune suppression by synthesising sialoglycans, which act as ligands for Siglec receptors. We report that ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) levels negatively correlate with androgen signalling in prostate tumours. We demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion through the synthesises of sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. Here, we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. These interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.

Introduction Person-centered care (PCC) is considered a fundamental approach to address clients’ needs. There is a dearth of data on specific actions that HIV treatment providers identify as priorities to strengthen PCC. Objective This study team developed the Person-Centered Care Assessment Tool (PCC-AT), which measures PCC service delivery within HIV treatment settings. The PCC-AT, including subsequent group action planning, was implemented across 29 facilities in Zambia among 173 HIV treatment providers. Mixed-methods study objectives included: (1) identify types of PCC-strengthening activities prioritized based upon low and high PCC-AT scores; (2) identify common themes in PCC implementation challenges and action plan activities by low and high PCC-AT score; and (3) determine differences in priority actions by facility ART clinic volume or geographic type. Methods The study team conducted thematic analysis of action plan data and cross-tabulation queries to observe patterns across themes, PCC-AT scores, and key study variables. Results The qualitative analysis identified 39 themes across 29 action plans. A higher proportion of rural compared to urban facilities identified actions related to stigma and clients’ rights training; accessibility of educational materials and gender-based violence training. A higher proportion of urban and peri-urban compared to rural facilities identified actions related to community-led monitoring. Discussion Findings provide a basis to understand common PCC weaknesses and activities providers perceive as opportunities to strengthen experiences in care. Conclusion To effectively support clients across the care continuum, systematic assessment of PCC services, action planning, continuous quality improvement interventions and re-measurements may be an important approach.

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, in a pilot study with a retrospective cohort design, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of the BRCA1 185delAG pathogenic variant, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, tested the association of VNTRs and breast cancer risk using Cox regression models, and estimated the effect size using a retrospective likelihood approach. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR]

Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (β=0.251, P=0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (β=0.266, P=0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P

Abstract: Background: Pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention and is being scaled up globally. Patients on PrEP have high rates of bacterial STIs, like Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG), thus routine screening is recommended. However, access to screening tests for STIs are limited in many low-resource settings. The objectives of this study were to determine the prevalence of CT and NG among participants in Vietnam’s first PrEP program. Methods: From January through April 2022 participants in the PrEP program at the Sexual Health Promotion Clinic in Hanoi, Vietnam were recruited to study STI prevalence. Study participants completed a survey collecting demographic, behavioral and clinical characteristics. Participants self-collected urine, rectal, and pharyngeal specimens for nucleic-acid testing. Participants positive for NG had an additional specimen collected for culture and antibiotic susceptibility. Results: In total, 108 participants were enrolled, median age was 24 years (IQR: 22– 28). All were male and reported having sex with men in the prior 12 months. The median number of sex partners in the prior 1 month was 1 (IQR: 1 – 2). Symptoms within the prior week were reported by 41.7% (45/108) – 19.4% reported rectal, 15.7% reported urethral, and 26.9% reported pharyngeal symptoms. The overall prevalence of CT or NG infections was 31.5% (34/108). The prevalence of CT was 24.1% (26/108); by anatomic site, there were 17 (15.7%) rectal, 10 (9.3%) pharyngeal, and 6 (5.6%) urethral infections. The prevalence of NG was 13.0% (14/108); there were 12 (11.1%) pharyngeal, 9 (8.3%) rectal, and 0 urethral infections. Among participants reporting any symptoms, CT prevalence was 26.7% (12/45) and NG prevalence 13.3% (6/45). All infections were treated. Conclusion: The prevalence of CT and NG was very high among this population of young MSM in a PrEP program in Hanoi, Vietnam. A high proportion of CT infections were rectal (65%) and 86% of NG infections were pharyngeal. These findings highlight the need for expanded access to extragenital nucleic-acid testing among PrEP programs in low- and middle-income countries. Studies demonstrating the benefit of CT/NG screening and treatment within PrEP programs are urgently needed. Disclosures: Jeffrey Klausner, MD MPH, Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Cepheid: Research equipment and supplies.

Supporting the development and training of paraeducators can be complex; however, that support in rural settings can be especially challenging. The unique structure of rural settings, often with limited personnel and available resources, can create challenges for recruiting and retaining quality candidates within the field of paraeducation. This study explored the perceptions and experiences of rural educators who support paraeducators and their training. Participants were interviewed about how their individual classroom and school district training models support paraeducators. Specific questions were targeted at opportunities for and quality of professional development, performance feedback, and models of support for rural paraeducators in rural areas throughout the Midwest. Overall, seven themes emerged from interviews revolving around the need for initial training to be more specific to setting and student needs, creation of cohesive meeting times with intensive training for the most challenging students, the need for structured meetings, and a clearinghouse of resources and support.

INTRODUCTION Standardized patient (SP) encounters allow medical students to practice physical examination skills and clinical reasoning. SP cases are used for learning and assessment, but recorded encounters can also be valuable curriculum evaluation tools. We aimed to review SP encounters to improve abdominal examination skills and the broader physical examination curriculum. METHODS We reviewed recorded SP encounters of third-year medical students on surgery clerkship rotation. Students examined a cisgender woman presenting with acute right lower abdominal pain. We observed abdominal examinations to determine which maneuvers were attempted and completed correctly. We then used these outcomes to develop targeted clerkship training for the subsequent student cohort. Our intervention targeted abdominal examination gaps by explaining how to integrate abdominal examination findings with a focused history for surgical patients. We evaluated the intervention's impact on abdominal examination skills with third-year medical students in comparison (2021-2022, n = 119) and intervention (2022-2023, n = 132) groups. RESULTS In both the comparison and intervention groups, nearly all students attempted at least 1 general examination maneuver like auscultation, palpation, percussion, or rebound tenderness. Only 40% of students in the comparison group attempted an advanced maneuver like the Rovsing, Psoas, or Obturator sign. After the intervention, 75% of students in the intervention group attempted an advanced maneuver (χ 2 (1, 251) = 31.0, p

ObjectivesTo determine whether life expectancy (LE) changes between 2000 and 2019 were associated with race, rural status, local economic prosperity, and changes in local economic prosperity, at the county level.MethodsBetween 12/1/22 and 2/28/23, we conducted a retrospective analysis of 2000 and 2019 data from 3,123 United States counties. For Total, White, and Black populations, we compared LE changes for counties across the rural-urban continuum, the local economic prosperity continuum, and for counties in which local economic prosperity dramatically improved or declined.ResultsIn both years, overall, across the rural-urban continuum, and for all studied populations, LE decreased with each progression from the most to least prosperous quintile (all p < 0.001); improving county prosperity between 2000–2019 was associated with greater LE gains (p < 0.001 for all).ConclusionAt the county level, race, rurality, and local economic distress were all associated with LE; improvements in local economic conditions were associated with accelerated LE. Policymakers should appreciate the health externalities of investing in areas experiencing poor economic prosperity if their goal is to improve population health.

Background Autistic women are at high risk of developing restrictive eating disorders (REDs), such as anorexia nervosa. Aims This study provides an overview of the clinical characteristics of autistic women with REDs to (i) enhance understanding of increased risk, and (ii) support the identification of autistic women in eating disorder services. Method We compared self-reported autistic and disordered eating characteristics of: autistic participants with REDs (Autism + REDs; n = 57); autistic participants without REDs (Autism; n = 69); and women with REDs who are not autistic (REDs; n = 80). We also included a group of women with high autistic traits (HATs) and REDs, but no formal autism diagnosis (HATs + REDs; n = 38). Results Autism + REDs participants scored similarly to Autism participants in terms of autistic characteristics and to REDs participants in terms of experiencing traditional disordered eating symptoms. Autism + REDs participants were distinguished from both groups by having more restricted and repetitive behaviours and autism-specific eating behaviours related to sensory processing, flexibility and social differences. HATs + REDs participants showed a similar pattern of scores to Autism + REDs participants, and both also presented with high levels of co-occurring mental health difficulties, particularly social anxiety. Conclusion The presentation of autistic women with REDs is complex, including both traditional disordered eating symptoms and autism-related needs, as well as high levels of co-occurring mental health difficulties. In eating disorder services, the REDs presentation of autistic women and those with HATs should be formulated with reference to autism-specific eating behaviours and co-occurring difficulties. Treatment adaptations should be offered to accommodate autistic characteristics and related needs.

BackgroundPerson-centered care (PCC) within HIV treatment services has demonstrated potential to overcome inequities in HIV service access while improving treatment outcomes. Despite PCC being widely considered a best practice, no consensus exists on its assessment and measurement. This study in Zambia builds upon previous research that informed development of a framework for PCC and a PCC assessment tool (PCC-AT). ObjectiveThis mixed methods study aims to examine the preliminary effectiveness of the PCC-AT through assessing the association between client HIV service delivery indicators and facility PCC-AT scores. We hypothesize that facilities with higher PCC-AT scores will demonstrate more favorable HIV treatment continuity, viral load (VL) coverage, and viral suppression in comparison to those of facilities with lower PCC-AT scores. MethodsWe will implement the PCC-AT at 30 randomly selected health facilities in the Copperbelt and Central provinces of Zambia. For each study facility, data will be gathered from 3 sources: (1) PCC-AT scores, (2) PCC-AT action plans, and (3) facility characteristics, along with service delivery data. Quantitative analysis, using STATA, will include descriptive statistics on the PCC-AT results stratified by facility characteristics. Cross-tabulations and/or regression analysis will be used to determine associations between scores and treatment continuity, VL coverage, and/or viral suppression. Qualitative data will be collected via action planning, with detailed notes collected and recorded into an action plan template. Descriptive coding and emerging themes will be analyzed with NVivo software. ResultsAs of May 2024, we enrolled 29 facilities in the study and data analysis from the key informant interviews is currently underway. Results are expected to be published by September 2024. ConclusionsAssessment and measurement of PCC within HIV treatment settings is a novel approach that offers HIV treatment practitioners the opportunity to examine their services and identify actions to improve PCC performance. Study results and the PCC-AT will be broadly disseminated for use among all project sites in Zambia as well as other HIV treatment programs, in addition to making the PCC-AT publicly available to global HIV practitioners. International Registered Report Identifier (IRRID)DERR1-10.2196/54129

In this paper, we outline our qualitative protocol for the largest, independent, mixed-method, evaluation of the High Volume-Low Complexity Surgical Hubs programme in England – The MEASURE study. In addition to serving as a protocol paper, we outline the key methodological considerations and adaptations that are needed when designing big qualitative studies – complex (multi-site, multi-stakeholder), multi-method (e.g. interviews, observations, documents) qualitative research involving a large number of participations ( n = 100+). This paper expands on our previous methodological work, where we used our experience of undertaking a big qualitative study as part of a mixed-method evaluation of a national emergency care-based initiative, to outline the methodological considerations and uncertainties for designing and analysing “big” qualitative studies. In this paper, we put these considerations into practice by providing a transparent account of our qualitative study design. The methodological reflections which we present are centred around the areas where we feel there is the most uncertainty for big qualitative research: study design, sampling (of case sites and stakeholders) and analysis. Underpinning this uncertainty are broader challenges which utilising this approach incite. Namely, that striving for both breadth (national-level insights) and depth (local variation and context), challenges paradigmatic norms and expectations and forces either methodological innovation, or the adaption of existing qualitative methods. We hope this paper provides transparency and insight into an area of qualitative research which has, potentially due to a perception of “safety in numbers” been inherently trusted and rarely scrutinised. Ultimately, we hope that by providing a transparent account of our study design and the challenges we have faced that we continue to encourage discussion and innovation in this evolving area of qualitative research.

Introduction Biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionised the treatment of inflammatory arthritis (IA). However, many people with IA still require planned orthopaedic surgery to reduce pain and improve function. Currently, bDMARDs are withheld during the perioperative period due to potential infection risk. However, this predisposes patients to IA flares and loss of disease control. The question of whether to stop or continue bDMARDs in the perioperative period has not been adequately addressed in a randomised controlled trial (RCT).Methods and analysis PERISCOPE is a multicentre, superiority, pragmatic RCT investigating the stoppage or continuation of bDMARDs. Participants will be assigned 1:1 to either stop or continue their bDMARDs during the perioperative period. We aim to recruit 394 adult participants with IA. Potential participants will be identified in secondary care hospitals in the UK, screened by a delegated clinician. If eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported PROMIS-29 (Patient Reported Outcome Measurement Information System) over the first 12 weeks postsurgery. Secondary outcome measures are as follows: PROMIS - Health Assessment Questionnaire (PROMIS-HAQ), EQ-5D-5L, Disease activity: generic global Numeric Rating Scale (patient and clinician), Self-Administered Patient Satisfaction scale, Health care resource use and costs, Medication use, Surgical site infection, delayed wound healing, Adverse events (including systemic infections) and disease-specific outcomes (according to IA diagnosis). The costs associated with stopping and continuing bDMARDs will be assessed. A qualitative study will explore the patients’ and clinicians’ acceptability and experience of continuation/stoppage of bDMARDs in the perioperative period and the impact postoperatively.Ethics and dissemination Ethical approval for this study was received from the West of Scotland Research Ethics Committee on 25 April 2023 (REC Ref: 23/WS/0049). The findings from PERISCOPE will be submitted to peer-reviewed journals and feed directly into practice guidelines for the use of bDMARDs in the perioperative period.Trial registration number ISRCTN17691638.

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Antimicrobial-resistant Neisseria gonorrhoeae infections are a threat to public health. Novel strategies for combating such resistance include the development of molecular assays to facilitate real-time prediction of antimicrobial susceptibility. Resistance to ciprofloxacin is determined by the presence of a single mutation at codon 91 of the gyrase A gene; molecular assays to guide therapy are commercially available. Resistance to cefixime is conferred via 1 of 6 critical mutations in either the mosaic penA gene or specific loci in the nonmosaic region. Resistance to ceftriaxone is conferred through mutations in 1 of 4 genes: penA, ponA, penB, and mtr; however, the ability to predict reduced susceptibility based on those genes varies by geographic region. Here, we highlight the work done toward the development of 3 such assays for ciprofloxacin, cefixime, and ceftriaxone, discuss the status of our current understanding and ongoing challenges, and suggest future directions.

Surges of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among health care workers (HCWs) have led to critical staffing shortages. From January 4 to February 4, 2022, we implemented a return-to-work antigen testing program for HCWs, and 870 HCWs participated. Antigen test positivity was 60.5% for those ≤5 days from symptom onset or positive polymerase chain reaction (PCR), and 47.4% were positive at day 7. Antigen positivity was associated with receiving a booster vaccination and being ≤6 days from symptom onset or PCR test, but not age or a symptomatic infection. Rapid antigen testing can be a useful tool to guide return-to-work and isolation precautions for HCWs following infection.

We report Mycetohabitans rhizoxinica bacteremia in a 65-year-old woman in California, USA, who was undergoing chimeric antigen receptor T-cell therapy for multiple myeloma. Acute brain infarction and pneumonia developed; Rhizopus microsporus mold was isolated from tracheal suction. Whole-genome sequencing confirmed bacteria in blood as genetically identical to endofungal bacteria inside the mold.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P

Abstract Antimicrobial resistance in Neisseria gonorrhoeae is an urgent global health issue 1. Resistance to ceftriaxone, the mainstay of gonorrhea treatment, is increasing2,3. Many genotypic mutations are associated with decreased susceptibility to ceftriaxone 4,5. In this study, N. gonorrhoeae genomes from the PathogenWatch database were downloaded and used to train and test different machine learning (ML) models to predict ceftriaxone susceptibility/decreased susceptibility (S/DS). We evaluated seven different ML algorithms with 97 SNPs that are known to be associated with ceftriaxone resistance. After identifying the ML algorithm with the highest performance metrics, the impact score of individual SNPs were calculated. The algorithm was then retrained using various combinations of top scoring SNPs to measure performance. The study identified 5 SNPs that performed well to predict decreased susceptibility and might be promising targets for molecular assays to predict S/DS to ceftriaxone. The ML methods reported here might have applications for predicting AMR within other pathogens.

BACKGROUND: Adverse events are often misreported in clinical trials, leading to an incomplete understanding of toxicities. We aimed to test automated laboratory adverse event ascertainment and grading (via the ExtractEHR automated package) to assess its scalability and define adverse event rates for children with acute myeloid leukaemia and acute lymphoblastic leukaemia. METHODS: For this retrospective cohort study from the Childrens Oncology Group (COG), we included patients aged 0-22 years treated for acute myeloid leukaemia or acute lymphoblastic leukaemia at Childrens Healthcare of Atlanta (Atlanta, GA, USA) from Jan 1, 2010, to Nov 1, 2018, at the Childrens Hospital of Philadelphia (Philadelphia, PA, USA) from Jan 1, 2011, to Dec 31, 2014, and at the Texas Childrens Hospital (Houston, TX, USA) from Jan 1, 2011, to Dec 31, 2014. The ExtractEHR automated package acquired, cleaned, and graded laboratory data as per Common Terminology Criteria for Adverse Events (CTCAE) version 5 for 22 commonly evaluated grade 3-4 adverse events (fatal events were not evaluated) with numerically based CTCAE definitions. Descriptive statistics tabulated adverse event frequencies. Adverse events ascertained by ExtractEHR were compared to manually reported adverse events for patients enrolled in two COG trials (AAML1031, NCT01371981; AALL0932, NCT02883049). Analyses were restricted to protocol-defined chemotherapy courses (induction I, induction II, intensification I, intensification II, and intensification III for acute myeloid leukaemia; induction, consolidation, interim maintenance, delayed intensification, and maintenance for acute lymphoblastic leukaemia). FINDINGS: Laboratory adverse event data from 1077 patients (583 from Childrens Healthcare of Atlanta, 200 from the Childrens Hospital of Philadelphia, and 294 from the Texas Childrens Hospital) who underwent 4611 courses (549 for acute myeloid leukaemia and 4062 for acute lymphoblastic leukaemia) were extracted, processed, and graded. Of the 166 patients with acute myeloid leukaemia, 86 (52%) were female, 80 (48%) were male, 96 (58%) were White, and 132 (80%) were non-Hispanic. Of the 911 patients with acute lymphoblastic leukaemia, 406 (45%) were female, 505 (55%) were male, 596 (65%) were White, and 641 (70%) were non-Hispanic. Patients with acute myeloid leukaemia had the most adverse events during induction I and intensification II. Hypokalaemia (one [17%] of six to 75 [48%] of 156 courses) and alanine aminotransferase (ALT) increased (13 [10%] of 134 to 27 [17%] of 156 courses) were the most prevalent non-haematological adverse events in patients with acute myeloid leukaemia, as identified by ExtractEHR. Patients with acute lymphoblastic leukaemia had the greatest number of adverse events during induction and maintenance (eight adverse events with prevalence ≥10%; induction and maintenance: anaemia, platelet count decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, ALT increased, and hypocalcaemia; induction: hypokalaemia; maintenance: aspartate aminotransferase [AST] increased and blood bilirubin increased), as identified by ExtractEHR. 187 (85%) of 220 total comparisons in 22 adverse events in four AAML1031 and six AALL0923 courses were substantially higher with ExtractEHR than COG-reported adverse event rates for adverse events with a prevalence of at least 2%. INTERPRETATION: ExtractEHR is scalable and accurately defines laboratory adverse event rates for paediatric acute leukaemia; moreover, ExtractEHR seems to detect higher rates of laboratory adverse events than those reported in COG trials. These rates can be used for comparisons between therapies and to counsel patients treated on or off trials about the risks of chemotherapy. ExtractEHR-based adverse event ascertainment can improve reporting of laboratory adverse events in clinical trials. FUNDING: US National Institutes of Health, St Baldricks Foundation, and Alexs Lemonade Stand Foundation.