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Comparing women's and men's sexual offending patterns in educational settings is a relatively recent empirical endeavor. Accordingly, gender-based examinations of schools' management of sexual allegations are lacking. We address this gap by drawing on a unique administrative dataset from an Australian jurisdiction that captures alleged improper sexual conduct by educational employees. We compare 809 female- and male-perpetrated cases reported between 2015 and 2019 with respect to event, location, victim, and perpetrator characteristics, as well as the ensuing risk management strategies and sanctions. Compared to men, reported women were younger, employed on more secure employment arrangements, and less often had a relevant discipline history. Most alleged event characteristics did not significantly differ based on perpetrator gender. Women's alleged perpetration, however, more often occurred in places external to school and involved more serious sexual victimization of comparatively older male students. After controlling for event, victim, perpetrator, and allegation characteristics there was nearly no support for a gender bias in institutional responses. However, a lack of any action was more often observed in female-perpetrated cases under very specific and limited conditions. Resultant implications for the management and oversight of employee-related allegations are discussed.

Crime prevention is typically presented in a tripartite model that includes primary, secondary, and tertiary domains. Almost every criminal justice intervention constitutes tertiary prevention and occurs reactively, in the aftermath of an offence. Child sexual abuse is no exception, and prevention science has long recommended we focus our intervention efforts further upstream. Such an approach would include earlier detection and disclosure (secondary prevention), or-even better-reducing the risks of early exposure to the environmental forces which facilitate sexual abuse in the first place (primary prevention). What is missing from the field, however, is a coherent framework through which to critique the unintended consequences of our well-intentioned responses to child sexual abuse. Such consequences include secondary trauma for victim survivors and vicarious trauma for families and practitioners. In this article, we reflect on prevention from a critical perspective that centres the principle of "first, do no harm." In doing so, we introduce the notion of 'quaternary prevention' for child sexual abuse. Public health has long recognised the risks of medicalisation, overdiagnosis, and unnecessary intervention. We encourage our field to engage within a framework of quaternary prevention to consider the iatrogenic effects of many contemporary practices and to take seriously the "do no harm" principle to improve practice across all levels of prevention., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Coadministering COVID-19 and influenza vaccines is recommended by public health authorities and intended to improve uptake and convenience; however, the extent of vaccine coadministration is largely unknown. Investigations into COVID-19 and influenza vaccine coadministration are needed to describe compliance with newer recommendations and to identify potential gaps in the implementation of coadministration., Methods: A descriptive, repeated cross-sectional study between September 1, 2021 to November 30, 2021 (Period 1) and September 1, 2022 to November 30, 2022 (Period 2) was conducted. This study included community-dwelling Medicare beneficiaries ≥ 66 years who received an mRNA COVID-19 booster vaccine in Periods 1 and 2. The outcome was an influenza vaccine administered on the same day as the COVID-19 vaccine. Adjusted ORs and 99% CIs were estimated using logistic regression to describe the association between beneficiaries' characteristics and vaccine coadministration. Statistical analysis was performed in 2023., Results: Among beneficiaries who received a COVID-19 vaccine, 78.8% in Period 1 (N=6,292,777) and 89.1% in Period 2 (N=4,757,501), received an influenza vaccine at some point during the study period (i.e., before, after, or on the same day as their COVID-19 vaccine), though rates were lower in non-White and rural individuals. Vaccine coadministration increased from 11.1% to 36.5% between periods. Beneficiaries with dementia (aOR Period 2 =1.31; 99%CI=1.29-1.32) and in rural counties (aOR Period 2 =1.19; 99%CI=1.17-1.20) were more likely to receive coadministered vaccines, while those with cancer (aOR Period 2 =0.90; 99%CI=0.89-0.91) were less likely., Conclusions: Among Medicare beneficiaries vaccinated against COVID-19, influenza vaccination was high, but coadministration of the 2 vaccines was low. Future work should explore which factors explain variation in the decision to receive coadministered vaccines., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no effective treatment options. Previous work from our laboratory identified phenethylpiperidines as a novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel antiprion compounds based on their known ability to bind to the sigma receptors, σ 1 R and σ 2 R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding σ 1 R and σ 2 R ( Sigmar1 and Tmem97 ) in prion-infected N2a cells did not alter the antiprion activity of these compounds, demonstrating that these receptors are not the direct targets responsible for the antiprion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remain to be determined, the present work forms the basis for further investigation of these compounds in preclinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer's disease, respectively, this work has immediate implications for the treatment of human prion disease.

Most child sex offending is unreported and undetected. Despite this, most research relies on the characteristics of those frequently detected and arrested. This study aims to address this disparity by examining a group of men convicted of child sexual abuse (CSA) offences with multiple victims and who evaded detection for long periods of time ( n  = 170). This sample was compared to a group of men caught quickly for CSA offences against multiple victims ( n  = 170). The two groups were compared on demographic, lifestyle, sexual deviancy, and criminogenic measures. Individuals with long detection lags had more child victims, including more pre-pubescent and male victims and commenced their sexual offending at a comparatively earlier age. Additionally, individuals with long detection lags were more likely to be non- Indigenous and to show specialization in their sexual offending. These findings have implications for identifying and managing high harm child sexual offenders who evade detection for long periods., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We investigated county-level variation in mRNA COVID-19 vaccine use among Medicare beneficiaries throughout the United States. There was greater use of Pfizer-BioNTech vaccines than Moderna vaccines in urban areas for first and booster doses.

The current study explored the association between psychopathic traits and release suitability decisions and examined the role of Psychopathy Checklist-Revised (PCL-R) and Static-99 in predicting general and sexual recidivism. The sample included 207 adult male sex offenders involved in the long-term follow-up at the Massachusetts Treatment Center for Sexually Dangerous Persons (MTC) in Bridgewater, Massachusetts. Contrary to our expectations, PCL-R Factor 2 (Lifestyle/Antisocial) scores were positively associated with being selected for gradual release, whereas PCL-R Factor 1 (Interpersonal/Affective) scores were not related to parole boards' decisions. Additionally, the interaction between the two factors was a significant predictor, suggesting that the individuals with more pronounced Factor 1 traits were less likely to be released when their Factor 2 scores were high as well. Although Static-99 scores predicted both contact and non-contact sexual recidivism, psychopathy was not related to reoffending, possibly because offenders with child victims were over-represented in the sample., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E-17 and 1.78E-11) and WBFFM (p = 2.88E-08 and 8.24E-12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass., (© 2024. The Author(s).)

Introduction: Metastatic anal squamous cell carcinoma (SCC) carries a poor prognosis and the evidence base for surgical resection of metastases remains limited. The aim of this study was to establish the survival outcomes for patients undergoing metastasectomy for anal SCC., Methods: A systematic review was performed using the MEDLINE ® , Embase ® , Cochrane and PubMed ® databases. Studies were considered for inclusion in the review if they involved patients aged >18 years with a diagnosis of stage IV anal SCC who underwent metastasectomy for liver and/or lung metastases. The primary outcome measure was overall survival. Secondary outcome measures were disease free survival, early morbidity according to the Clavien-Dindo classification and quality of life, measured using a validated scoring tool. Risk of bias was assessed with the ROBINS-I (Risk Of Bias In Non-randomised Studies - of Interventions) tool., Results: There were 10 studies with a total of 98 patients. There was heterogeneity in results reporting, with recurrence free survival the most reported outcome. For all studies reporting on liver metastasectomy, the one-year overall survival rate was 87%. In studies with adequate follow-up reported, the three and five-year overall survival rates were 53% and 38% respectively. Only one study reported on lung metastasectomy patients; the overall median survival was 24 months. None of the studies reported on quality of life measures. The ROBINS-I tool identified a critical risk of bias in six studies, a serious risk in one study and a moderate risk in three studies., Conclusions: The evidence base for metastasectomy in metastatic anal SCC is limited. Further information is required to inform future treatment methods and use of a standardised outcomes reporting method is needed to support this.

Background: The WHO strategy for cervical cancer elimination strives to achieve 70% coverage with high-performance cervical screening. While few low- and middle-income countries have achieved this, high-risk human papillomavirus (hrHPV) self-testing creates the possibility to rapidly upscale access to high-performance cervical screening across resource settings. However, effective hrHPV screening requires linkage to follow-up, which has been variable in prior studies. This study developed and tested an implementation strategy aimed at improving screening and linkage to follow-up care in South East District in Botswana., Methods: This study performed primary hrHPV self-testing; those with positive results were referred for a triage visit. Withdrawals for any reason, loss-to follow-up between hrHPV test and triage visit, and number of call attempts to give hrHPV results were also documented. Acceptability of the program to patients was measured as the proportion of patients who completed a triage visit when indicated, meeting the  a priori  threshold of 80%. Feasibility was defined as the proportion of participants receiving the results and attending follow-up. To assess the associations between participant characteristics and loss-to-follow-up we used log-binomial regressions to estimate risk ratios and 95% confidence intervals (CI)., Results: Enrollment of 3,000 women occurred from February 2021 to August 2022. In total, 10 participants withdrew and an additional 33 were determined ineligible after consent, leaving a final cohort of 2,957 participants who underwent self-swab hrHPV testing. Half (50%) of participants tested positive for hrHPV and nearly all (98%) of participants received their hrHPV results, primarily via telephone.  Few calls to participants were required to communicate results: 2,397 (82%) required one call, 386 (13%) required 2 calls, and only 151 (5%) required 3-5 calls. The median time from specimen collection to participant receiving results was 44 days (IQR, 27-65). Of all hrHPV positive participants, 1,328 (90%) attended a triage visit., Discussion: In a large cohort we had low loss-to-follow-up of 10%, indicating that the strategy is acceptable. Telephonic results reporting was associated with high screening completion, required few calls to participants, and supports the feasibility of hrHPV self-testing in primary care followed by interval triage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer TD declared a shared affiliation with the author DR-M to the handling editor at the time of review., (© 2024 Luckett, Ramogola-Masire, Harris, Gompers, Gaborone, Mochoba, Ntshese, Mathoma, Kula, Shapiro and Larson.)

This study used innovative transdisciplinary methods to describe the nature and extent of early childhood memories recalled by 84 adults convicted of sexual offences. The timing of the memories, level of detail recalled and way memories were recollected were largely consistent with extant memory research. One important finding, however, was that more than 30% of our participants recalled particularly traumatic and distressing childhood experiences - a much higher proportion than previously observed in nonoffending samples. The extent to which these memories laid the foundation for subsequent emotional content and feature in the evolution of cognitive schemata is not yet well understood. With that in mind, we consider the implications of our findings for the event centrality in self-narratives. We recommend the inclusion of treatment modalities that maximise as yet unrecognised and undervalued narrative inclinations and story-telling abilities of a complicated population of individuals with rich lived experience that stands to benefit greatly from such approaches.

Objectives: To explore the perceptions of patients and healthcare professionals on Raman-faecal immunochemical test (FIT) as an alternative test for colorectal cancer exclusion in primary care., Design: Semi-structured interviews within a feasibility study., Setting: Patients presenting to primary care with colorectal symptoms and healthcare professionals working in primary and secondary care., Participants: A total of 23 patients and 12 healthcare professionals., Methods: Patient participants were asked to complete a novel combined Raman-FIT test before being seen in secondary care. This study sought their opinions about the test. We also sought the views of healthcare professionals., Findings: Patients and healthcare professionals agreed that Raman-FIT was a suitable test to be given in primary care. It aligned with routine practice and was a simple test for most patients to complete., Conclusions: Patients are willing and able to complete the Raman-FIT test in primary care. Raman-FIT may accelerate access to diagnosis with the potential to improve cancer outcomes., Patient and Public Involvement: Lay members (J. H. and I. H.) with experience and knowledge of colorectal cancer and screening contributed to developing, undertaking, and disseminating all aspects of the research. They were supported to collaborate as equal members of the research team. They were involved in developing the study as coapplicants, using personal experience to ensure that the research and its methods were relevant to the patient and public needs. Both prepared participant information sheets, coanalysed data, and contributed to study reporting and dissemination through papers, conference presentations and a lay summary., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

The last two decades have seen global public recognition of the scale and impact of adult-perpetrated institutional child sexual abuse. A sizeable body of knowledge about generalized safeguarding measures has since been generated to inform organizations' prevention efforts. Apparent in the extant literature, however, is a notable lack of evidence-based and context-specific prevention strategies targeting perpetration in distinct institutional environments. This absence extends to educational settings where most reported contemporary cases occur or originate. The recommendations outlined in this article contribute to this gap. Derived from empirical findings establishing the role of context-specific rather than person-specific factors, a range of prevention strategies framed by Situational Crime Prevention are proposed for secondary educational settings. These recommendations are supplemented by the unique insights of interviewed experts with specialist professional knowledge. Recommendations center around targeting features of the environment such as high-risk locations, available guardians, and intimacy-promoting situations available in educational contexts. Taken together, this robust prevention and control agenda can create conditions for safer educational environments., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: To improve the assessment of COVID-19 vaccine use, safety, and effectiveness in older adults and persons with complex multimorbidity, the COVid VAXines Effects on the Aged (COVVAXAGE) database was established by linking CVS Health and Walgreens pharmacy customers to Medicare claims., Methods: We deterministically linked CVS Health and Walgreens customers who had a pharmacy dispensation/encounter paid for by Medicare to Medicare enrollment and claims records. Linked data include U.S. Medicare claims, Medicare enrollment files, and community pharmacy records. The data currently span 01/01/2016 to 08/31/2022. "Research-ready" files were created, with weekly indicators for vaccinations, censoring, death, enrollment, demographics, and comorbidities. Data are updated quarterly., Results: As of November 2022, records for 27,086,723 CVS Health and 23,510,025 Walgreens unique customer IDs were identified for potential linkage. Approximately 91% of customers were matched to a Medicare beneficiary ID (95% for those aged 65 years or older). In the final linked cohort, there were 38,250,873 unique beneficiaries representing ~60% of the Medicare population. Among those alive and enrolled in Medicare as of January 1, 2020 (n = 33,721,568; average age = 73 years, 74% White, 51% Medicare Fee-for-Service, and 11% dual-eligible for Medicaid), the average follow-up time was 130 weeks. The cohort contains 16,021,055 beneficiaries with evidence a first COVID-19 vaccine dose. Data are stored on the secure Medicare & Medicaid Resource Information Center Health & Aging Data Enclave., Data Access: Investigators with funded or in-progress funding applications to the National Institute on Aging who are interested in learning more about the database should contact Dr Vincent Mor [Vincent_mor@brown.edu] and Dr Kaleen Hayes [kaley_hayes@brown.edu]. A data dictionary can be provided under reasonable request., Conclusions: The COVVAXAGE cohort is a large and diverse cohort that can be used for the ongoing evaluation of COVID-19 vaccine use and other research questions relevant to the Medicare population., Competing Interests: Conflict of interest: Kaleen Hayes has received grant funding paid directly to Brown University for collaborative research from Insight Therapeutics and Sanofi Pasteur for research on complex insulin regimens. Kaleen Hayes also serves as a consultant for the Canadian Agency for Drugs and Technologies in Health. Andrew Zullo has received grant funding paid directly to Brown University by Sanofi for collaborative research on the epidemiology of infections and vaccinations among nursing home residents and infants. Stefan Gravenstein is a recipient of support from the U.S. Department of Veterans Affairs and investigator-initiated grants to Brown University and Lifespan from the National Institute of Allergy and Infectious Diseases (NIAID) to study influenza vaccine and COVID-19 in the nursing home, Pfizer to study pneumococcal vaccines, and from Sanofi Pasteur and Seqirus to study influenza vaccines. Stefan Gravenstein also performs consulting work for Icosavax, Janssen, Merck, Moderna, Novavax, Pfizer, Sanofi, Seqirus, and Vaxart; has served on the speaker’s bureaus for Seqirus, Janssen and Sanofi; and was paid to chair data safety monitoring boards from Longeveron and SciClone. Acumen, LLC (Sean McCurdy, Kristina Baird, Daniel Moran, Derek Fenson) has received federal funding from the National Institutes of Health, the Centers for Medicare & Medicaid Services, and the U.S. Food and Drug Administration to study vaccine safety and to provide vaccination surveillance support. Renae Smith-Ray, Michael Taitel, and Tanya Singh are employees of Walgreens and have received funding from Moderna and Pfizer to study vaccine uptake and effectiveness. Djeneba Audrey Djibo and Cheryl McMahill-Walraven are full-time employees of CVS Health and conduct work for government, public, and private organizations, including pharmaceutical companies, as part of their employment. All other authors have no COI to report.

The C-terminal domain of the cellular prion protein (PrP C ) contains two N-linked glycosylation sites, the occupancy of which impacts disease pathology. In this study, we demonstrate that glycans at these sites are required to maintain an intramolecular interaction with the N-terminal domain, mediated through a previously identified copper-histidine tether, which suppresses the neurotoxic activity of PrP C . NMR and electron paramagnetic resonance spectroscopy demonstrate that the glycans refine the structure of the protein's interdomain interaction. Using whole-cell patch-clamp electrophysiology, we further show that cultured cells expressing PrP molecules with mutated glycosylation sites display large, spontaneous inward currents, a correlate of PrP-induced neurotoxicity. Our findings establish a structural basis for the role of N-linked glycans in maintaining a nontoxic, physiological fold of PrP C ., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: COVID-19 booster vaccines are highly effective at reducing severe illness and death from COVID-19. Research is needed to identify whether racial and ethnic disparities observed for the primary series of the COVID-19 vaccines persist for booster vaccinations and how those disparities may vary by other characteristics. We aimed to measure racial and ethnic differences in booster vaccine receipt among U.S. Medicare beneficiaries and characterize potential variation by demographic characteristics., Methods: We conducted a cohort study using CVS Health and Walgreens pharmacy data linked to Medicare claims. We included community-dwelling Medicare beneficiaries aged ≥66 years who received two mRNA vaccine doses (BNT162b2 and mRNA-1273) as of 8/1/2021. We followed beneficiaries from 8/1/2021 until booster vaccine receipt, death, Medicare disenrollment, or end of follow-up (12/31/2021). Adjusted Poisson regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) comparing vaccine uptake between groups., Results: We identified 11,339,103 eligible beneficiaries (mean age 76 years, 60% female, 78% White). Overall, 67% received a booster vaccine (White = 68.5%; Asian = 67.0%; Black = 57.0%; Hispanic = 53.3%). Compared to White individuals, Black (RR = 0.78 [95%CI = 0.78-0.78]) and Hispanic individuals (RR = 0.72 [95% = CI 0.72-0.72]) had lower rates of booster vaccination. Disparities varied by geographic region, urbanicity, and Medicare plan/Medicaid eligibility. The relative magnitude of disparities was lesser in areas where vaccine uptake was lower in White individuals., Discussion: Racial and ethnic disparities in COVID-19 vaccination have persisted for booster vaccines. These findings highlight that interventions to improve vaccine uptake should be designed at the intersection of race and ethnicity and geographic location., Competing Interests: KH has received grant funding paid directly to Brown University for collaborative research from Insight Therapeutics and Sanofi for research on complex insulin regimens. KH also serves as a consultant for the Canadian Agency for Drugs and Technologies in Health. AZ has received grant funding paid directly to Brown University by Sanofi for collaborative research on the epidemiology of infections and vaccinations among nursing home residents and infants. SG is a recipient of support from the Pfizer to study pneumococcal vaccines and from Sanofi and Seqirus to study influenza vaccines. SG also performs consulting work for Icosavax, Janssen, Merck, Moderna, Novavax, Pfizer, Sanofi, Seqirus, and Vaxart; has served on the speaker’s bureaus for Seqirus, Janssen and Sanofi; and was paid to chair data safety monitoring boards from Longeveron and SciClone. RS-R, MT, and TS are employees of Walgreens and have received funding from Moderna and Pfizer to study vaccine uptake and effectiveness. DD and CM-W are full-time employees of CVS Health and conduct work for government, public, and private organizations, including pharmaceutical companies, as part of their employment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hayes, Harris, Zullo, Chachlani, Wen, Smith-Ray, Djibo, McCarthy, Pralea, Singh, McMahill-Walraven, Taitel, Deng, Gravenstein and Mor.)

MINERvA has measured the ν&#95;{μ}-induced coherent π^{+} cross section simultaneously in hydrocarbon (CH), graphite (C), iron (Fe), and lead (Pb) targets using neutrinos from 2 to 20 GeV. The measurements exceed the predictions of the Rein-Sehgal and Berger-Sehgal PCAC based models at multi-GeV ν&#95;{μ} energies and at produced π^{+} energies and angles, E&#95;{π}>1  GeV and θ&#95;{π}<10°. Measurements of the cross-section ratios of Fe and Pb relative to CH reveal the effective A scaling to increase from an approximate A^{1/3} scaling at few GeV to an A^{2/3} scaling for E&#95;{ν}>10  GeV.

Objective: Elevated body mass index (BMI) is a risk factor for endometrioid endometrial cancer and its precursor, endometrial intraepithelial neoplasia (EIN). Our objective was to describe the association between BMI and age at EIN diagnosis., Methods: We conducted a retrospective study of patients diagnosed with EIN from 2010 to 2020 at a large academic medical center. Patient characteristics were stratified by menopausal status and compared using a chi-square or t-test. We used linear regression to determine the parameter estimate (β) and 95% confidence interval for the association between BMI and age at diagnosis., Results: We identified 513 patients with EIN; 503 (98%) had complete medical records. Premenopausal patients were more likely to be nulliparous and to have polycystic ovary syndrome than postmenopausal patients (both p ≤ 0.001). Postmenopausal patients were more likely to have hypertension, type 2 diabetes, and hyperlipidemia (all p ≤ 0.02). There was a significant linear association between BMI and age at diagnosis in premenopausal patients (β = -0.19 (95% CI: -0.27, -0.10). In premenopausal patients, for every 1-unit increase in BMI, age at diagnosis decreased by 0.19 years. No association was observed in postmenopausal patients., Conclusions: In a large cohort of patients with EIN, increasing BMI was associated with an earlier age at diagnosis in premenopausal patients. This data suggests consideration of endometrial sampling in younger patients with known risk factors for excess estrogen exposure., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Published by Elsevier Inc.)

Aims and Objectives: The overall aim of this paper is to provide practical insight into the way that professionals caring for a person with motor neurone disease (MND) can recognise, respect and respond to that person's temporality; that is, the person that they have been, that they are now and that they will be in the future., Background: MND is an umbrella term for a group of four rare, devastating neurodegenerative terminal diseases of middle/later life. Previously, we have acknowledged the importance of different time periods in the trajectory of MND as an illness, for example, during the diagnosis stage through to end of life and decision-making at that time. Living with MND can cause anxiety at all stages of the disease trajectory especially as it can be difficult for people living with MND to communicate their desires and concerns to professionals and carers. It is important that professionals continue to provide holistic care throughout the illness trajectory and the aim of this paper is to explore past research about caring for someone with MND in relation to the concept of person-centred care., Method: The paper is based on the concatenated exploration of the findings of a hermeneutic phenomenological project. Thus, this discursive paper links elements/studies which have been published previously to develop a model of person-centred care for people with MND which recognises and respects their temporality., Conclusions: We suggest MND has a significant impact on a person's lifeworld. The proposed person-centred care model focuses on understanding (interpreting) a person in a wider temporal frame and beyond the context of their illness. The expected collaborative outcomes are that: a person is acknowledged as more than a 'patient with MND' and that a professional is providing person-centred care based on individuality of the person, through a temporal lens. This requires a collaborative approach between the person, others and professionals. Such person-centred care, focused on individuality, may prevent a person experiencing life in crisis and suffering towards the end of life., (© 2023 The Authors. Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

Importance: Head-to-head safety comparisons of the mRNA vaccines for SARS-CoV-2 are needed for decision making; however, current evidence generalizes poorly to older adults, lacks sufficient adjustment, and inadequately captures events shortly after vaccination. Additionally, no studies to date have explored potential variation in comparative vaccine safety across subgroups with frailty or an increased risk of adverse events, information that would be useful for tailoring clinical decisions., Objective: To compare the risk of adverse events between mRNA vaccines for COVID-19 (mRNA-1273 and BNT162b2) overall, by frailty level, and by prior history of the adverse events of interest., Design, Setting, and Participants: This retrospective cohort study was conducted between December 11, 2020, and July 11, 2021, with 28 days of follow-up following the week of vaccination. A novel linked database of community pharmacy and Medicare claims data was used, representing more than 50% of the US Medicare population. Community-dwelling, fee-for-service beneficiaries aged 66 years or older who received mRNA-1273 vs BNT162b2 as their first COVID-19 vaccine were identified. Data analysis began on October 18, 2022., Exposure: Dose 1 of mRNA-1273 vs BNT162b2 vaccine., Main Outcomes and Measures: Twelve potential adverse events (eg, pulmonary embolism, thrombocytopenia purpura, and myocarditis) were assessed individually. Frailty was measured using a claims-based frailty index, with beneficiaries being categorized as nonfrail, prefrail, and frail. The risk of diagnosed COVID-19 was assessed as a secondary outcome. Generalized linear models estimated covariate-adjusted risk ratios (RRs) and risk differences (RDs) with 95% CIs., Results: This study included 6 388 196 eligible individuals who received the mRNA-1273 or BNT162b2 vaccine. Their mean (SD) age was 76.3 (7.5) years, 59.4% were women, and 86.5% were White. A total of 38.1% of individuals were categorized as prefrail and 6.0% as frail. The risk of all outcomes was low in both vaccine groups. In adjusted models, the mRNA-1273 vaccine was associated with a lower risk of pulmonary embolism (RR, 0.96 [95% CI, 0.93-1.00]; RD, 9 [95% CI, 1-16] events per 100 000 persons) and other adverse events in subgroup analyses (eg, 11.0% lower risk of thrombocytopenia purpura among individuals categorized as nonfrail). The mRNA-1273 vaccine was also associated with a lower risk of diagnosed COVID-19 (RR, 0.86 [95% CI, 0.83-0.87]), a benefit that was attenuated by frailty level (frail: RR, 0.94 [95% CI, 0.89-0.99])., Conclusions and Relevance: In this cohort study of older US adults, the mRNA-1273 vaccine was associated with a slightly lower risk of several adverse events compared with BNT162b2, possibly due to greater protection against COVID-19. Future research should seek to formally disentangle differences in vaccine safety and effectiveness and consider the role of frailty in assessments of COVID-19 vaccine performance.

Neutrino-induced charged-current single π^{+} production in the Δ(1232) resonance region is of considerable interest to accelerator-based neutrino oscillation experiments. In this Letter, high statistic differential cross sections are reported for the semiexclusive reaction ν&#95;{μ}A→μ^{-}π^{+}+ nucleon(s) on scintillator, carbon, water, iron, and lead targets recorded by MINERvA using a wideband ν&#95;{μ} beam with ⟨E&#95;{ν}⟩≈6  GeV. Suppression of the cross section at low Q^{2} and enhancement of low T&#95;{π} are observed in both light and heavy nuclear targets compared with phenomenological models used in current neutrino interaction generators. The cross sections per nucleon for iron and lead compared with CH across the kinematic variables probed are 0.8 and 0.5 respectively, a scaling which is also not predicted by current generators.

Background: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care., Methods: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites., Findings: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer., Interpretation: This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms., Funding: GRAIL Bio UK., Competing Interests: Declaration of interests BDN and MRM receive institutional research funding from GRAIL. MRM reports grants from Roche, Astrazeneca, BMS, Infinitopes, Immunocore, and study fees from BMS, Pfizer, MSD, Regeneron, BiolineRx, Replimune and Novartis outside of the submitted work. HK, KNK, SH, KR, YL, and HN are employees of GRAIL. HK, KNK, SH, KR, and YL hold stock in Illumina. HK reports a leadership position with GRAIL. DH reports a leadership role with CanSense, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To investigate whether trazodone is being initiated in lieu of antipsychotics following antipsychotic reduction efforts, this study described changes in medication initiation over time., Methods: We conducted a retrospective cohort study of new admissions to nursing homes in Ontario, Canada between April 2010 and December 2019 using health administrative data (N = 61,068). The initiation of antipsychotic and trazodone use was compared by year of admission using discrete time survival analysis and stratified by history of dementia., Results: Relative to residents admitted in 2014, antipsychotic initiation significantly decreased in later years (e.g., 2017 admission year hazard odds ratio [HOR 2017 ]=0.72 [95% confidence interval (95%CI)=0.62-0.82]) while trazodone initiation modestly increased (e.g., HOR 2017 =1.09 [95%CI=0.98-1.21]). The relative increase in trazodone initiation was larger among residents with dementia (e.g., HOR 2017Dem =1.22 [95%CI=1.07-1.39])., Conclusions: Differences in which medications were started following nursing home admission were observed and suggest trazodone may be initiated in lieu of antipsychotics., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

This Letter presents the first simultaneous measurement of the quasielasticlike neutrino-nucleus cross sections on C, water, Fe, Pb, and scintillator (hydrocarbon or CH) as a function of longitudinal and transverse muon momentum. The ratio of cross sections per nucleon between Pb and CH is always above unity and has a characteristic shape as a function of transverse muon momentum that evolves slowly as a function of longitudinal muon momentum. The ratio is constant versus longitudinal momentum within uncertainties above a longitudinal momentum of 4.5  GeV/c. The cross section ratios to CH for C, water, and Fe remain roughly constant with increasing longitudinal momentum, and the ratios between water or C to CH do not have any significant deviation from unity. Both the overall cross section level and the shape for Pb and Fe as a function of transverse muon momentum are not reproduced by current neutrino event generators. These measurements provide a direct test of nuclear effects in quasielasticlike interactions, which are major contributors to long-baseline neutrino oscillation data samples.

Purpose: To evaluate the impact of an inpatient pharmacy consult on discharge medications following bariatric surgery., Methods: A pharmacy consult for discharge medication review for bariatric surgery patients was instituted at an academic medical center. The intervention included conducting a medication history, reviewing home medications for updates post-bariatric surgery, creating and documenting a discharge medication plan, and providing patient education. The impact of the intervention was evaluated by comparing medication classes, doses, and formulations prescribed during the intervention relative to a historical control group., Results: The study included 85 patients who received pharmacist intervention and 167 patients who did not receive pharmacist intervention following bariatric surgery. The prescription of an extended-release medication at discharge in the intervention group was reduced by 19.3% (28.7% vs. 9.4%, p = 0.0005). For patients on hypertension medications, 94.0% had their regimen reduced in the intervention group compared with 37.5% of patients in the control group (p < 0.001). Of patients on insulin at baseline, 87.5% of patients in the intervention group had dose reductions at discharge vs. 66.7% of patients in the control group (p = 0.37). No patients in the intervention group were discharged with oral antihyperglycemic medications or non-insulin injectable medications vs. 33.3% (p = 0.12) and 20.0% (p = 0.47), respectively, in the control group. Readmission rates at 30 days were insignificantly lower in the intervention group (3.5% vs. 4.2%, p = 1)., Conclusions: Clinical pharmacist involvement in the discharge medication reconciliation process for bariatric surgery patients reduced prescribing of unadjusted medication classes, doses, and drug formulations.

Prion diseases are devastating neurodegenerative diseases caused by the structural conversion of the normally benign prion protein (PrP C ) to an infectious, disease-associated, conformer, PrP Sc . After decades of intense research, much is known about the self-templated prion conversion process, a phenomenon which is now understood to be operative in other more common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In this review, we provide the current state of knowledge concerning a relatively poorly understood aspect of prion diseases: mechanisms of neurotoxicity. We provide an overview of proposed functions of PrP C and its interactions with other extracellular proteins in the central nervous system, in vivo and in vitro models used to delineate signaling events downstream of prion propagation, the application of omics technologies, and the emerging appreciation of the role played by non-neuronal cell types in pathogenesis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The majority of colorectal cancers (CRCs) are detected after symptomatic presentation to primary care. Given the shared symptoms of CRC and benign disorders, it is challenging to manage the risk of missed diagnosis. Colonoscopy resources cannot keep pace with increasing demand. There is a pressing need for access to simple triage tools in primary care to help prioritise patients for referral., Aim: To evaluate the performance of a novel spectroscopy-based CRC blood test in primary care., Design & Setting: Mixed-methods pilot study of test performance and GP focus group discussions in South Wales., Method: Patients on the urgent suspected cancer (USC) pathway were recruited for the Raman spectroscopy (RS) test coupled to machine learning classification ('Raman-CRC') to identify CRC within the referred population. Qualitative focus group work evaluated the acceptability of the test in primary care by thematic analysis of focus group theorising., Results: A total of 532 patients aged ≥50 years referred on the USC pathway were recruited from 27 GP practices. Twenty-nine patients (5.0%) were diagnosed with CRC. Raman-CRC identified CRC with sensitivity 95.7%, specificity 69.3% with area under curve (AUC) of 0.80 compared with colonoscopy as the reference test (248 patients). Stage I and II cancers were detected with 78.6% sensitivity. Focus group themes underlined the convenience of a blood test for the patient and the test's value as a risk assessment tool in primary care., Conclusion: The findings support this novel, non-invasive, blood-based method to prioritise those patients most likely to have CRC. Raman-CRC may accelerate access to diagnosis with potential to improve cancer outcomes., (Copyright © 2022, The Authors.)

Background: Potentially inappropriate antipsychotic use has declined in nursing homes over the past decade; however, increases in the documentation of relevant clinical indications (eg, delusions) and the use of other psychotropic medications have raised concerns about diagnosis upcoding and medication substitution. Few studies have examined how these trends over time vary across and within nursing homes, information that may help to support antipsychotic reduction efforts., Objective: To jointly model facility-level time trends in potentially inappropriate antipsychotic use, antidepressant use, and the indications used to define appropriate antipsychotic use., Research Design: We conducted a repeated cross-sectional study of all nursing homes in Ontario, Canada between April 1, 2010 and December 31, 2019 using linked health administrative data (N=649). Each nursing home's quarterly prevalence of potentially inappropriate antipsychotic use, antidepressant use, and relevant indications were measured as outcome variables. With time as the independent variable, multivariate random effects models jointly estimated time trends for each outcome across nursing homes and the correlations between time trends within nursing homes., Results: We observed notable variations in the time trends for each outcome across nursing homes, especially for the relevant indications. Within facilities, we found no correlation between time trends for potentially inappropriate antipsychotic and antidepressant use ( r =-0.0160), but a strong negative correlation between time trends for potentially inappropriate antipsychotic use and relevant indications ( r =-0.5036)., Conclusions: Nursing homes with greater reductions in potentially inappropriate antipsychotics tended to show greater increases in the indications used to define appropriate antipsychotic use-possibly leading to unmonitored use of antipsychotics., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Scattering of high energy particles from nucleons probes their structure, as was done in the experiments that established the non-zero size of the proton using electron beams 1 . The use of charged leptons as scattering probes enables measuring the distribution of electric charges, which is encoded in the vector form factors of the nucleon 2 . Scattering weakly interacting neutrinos gives the opportunity to measure both vector and axial vector form factors of the nucleon, providing an additional, complementary probe of their structure. The nucleon transition axial form factor, F A , can be measured from neutrino scattering from free nucleons, ν μ n → μ - p and [Formula: see text], as a function of the negative four-momentum transfer squared (Q 2 ). Up to now, F A (Q 2 ) has been extracted from the bound nucleons in neutrino-deuterium scattering 3-9 , which requires uncertain nuclear corrections 10 . Here we report the first high-statistics measurement, to our knowledge, of the [Formula: see text] cross-section from the hydrogen atom, using the plastic scintillator target of the MINERvA 11 experiment, extracting F A from free proton targets and measuring the nucleon axial charge radius, r A , to be 0.73 ± 0.17 fm. The antineutrino-hydrogen scattering presented here can access the axial form factor without the need for nuclear theory corrections, and enables direct comparisons with the increasingly precise lattice quantum chromodynamics computations 12-15 . Finally, the tools developed for this analysis and the result presented are substantial advancements in our capabilities to understand the nucleon structure in the weak sector, and also help the current and future neutrino oscillation experiments 16-20 to better constrain neutrino interaction models., (© 2023. The Author(s).)

Dementia and mild cognitive impairment can be underrecognized in primary care practice and research. Free-text fields in electronic medical records (EMRs) are a rich source of information which might support increased detection and enable a better understanding of populations at risk of dementia. We used natural language processing (NLP) to identify dementia-related features in EMRs and compared the performance of supervised machine learning models to classify patients with dementia. We assembled a cohort of primary care patients aged 66 + years in Ontario, Canada, from EMR notes collected until December 2016: 526 with dementia and 44,148 without dementia. We identified dementia-related features by applying published lists, clinician input, and NLP with word embeddings to free-text progress and consult notes and organized features into thematic groups. Using machine learning models, we compared the performance of features to detect dementia, overall and during time periods relative to dementia case ascertainment in health administrative databases. Over 900 dementia-related features were identified and grouped into eight themes (including symptoms, social, function, cognition). Using notes from all time periods, LASSO had the best performance (F1 score: 77.2%, sensitivity: 71.5%, specificity: 99.8%). Model performance was poor when notes written before case ascertainment were included (F1 score: 14.4%, sensitivity: 8.3%, specificity 99.9%) but improved as later notes were added. While similar models may eventually improve recognition of cognitive issues and dementia in primary care EMRs, our findings suggest that further research is needed to identify which additional EMR components might be useful to promote early detection of dementia., Supplementary Information: The online version contains supplementary material available at 10.1007/s41666-023-00125-6., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The T2K experiment presents new measurements of neutrino oscillation parameters using 19.7 ( 16.3 ) × 10 20 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional 4.7 × 10 20 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on sin 2 θ 13 and the impact of priors on the δ CP measurement. Both analyses prefer the normal mass ordering and upper octant of sin 2 θ 23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on sin 2 θ 13 from reactors, sin 2 θ 23 = 0 . 561 - 0.032 + 0.021 using Feldman-Cousins corrected intervals, and Δ m 32 2 = 2 . 494 - 0.058 + 0.041 × 10 - 3 eV 2 using constant Δ χ 2 intervals. The CP-violating phase is constrained to δ CP = - 1 . 97 - 0.70 + 0.97 using Feldman-Cousins corrected intervals, and δ CP = 0 , π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than 2 σ credible level using a flat prior in δ CP , and just below 2 σ using a flat prior in sin δ CP . When the external constraint on sin 2 θ 13 is removed, sin 2 θ 13 = 28 . 0 - 6.5 + 2.8 × 10 - 3 , in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses., (© The Author(s) 2023.)

Background: To review whether online decision aids are available for patients contemplating pelvic exenteration (PE) for locally advanced and recurrent rectal cancer (LARC and LRRC)., Methods: A grey literature review was carried out using the Google Search™ engine undertaken using a predefined search strategy (PROSPERO database CRD42019122933). Written health information was assessed using the DISCERN criteria and International Patient Decision Aids Standards (IPDAS) with readability content assessed using the Flesch-Kincaid reading ease test and Flesch-Kincaid grade level score., Results: Google search yielded 27, 782, 200 results for the predefined search criteria. 131 sources were screened resulting in the analysis of 6 sources. No sources were identified as a decision aid according to the IPDAS criteria. All sources provided an acceptable quality of written health information, scoring a global score of 3 for the DISCERN written assessment. The median Flesch-Kincaid reading ease was 50.85 (32.5-80.8) equating to a reading age of 15-18 years and the median Flesch-Kincaid grade level score was 7.65 (range 3-9.7), which equates to a reading age of 13-14., Conclusions: This study has found that there is a paucity of online information for patients contemplating PE. Sources that are available are aimed at a high health literate patient. Given the considerable morbidity associated with PE surgery there is a need for high quality relevant information in this area. A PDA should be developed to improve decision making and ultimately improve patient experience., Competing Interests: Declaration of competing interest The authors deny any conflict of interest or competing interests., (Copyright © 2021 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population., (© 2022. The Author(s).)

Objectives: Examination of lung function abnormalities among coal miners has historically focused on actively working miners. This likely underestimates the true burden of chronic respiratory disease. The objective of this study was to characterise patterns and severity of lung function impairment among a population of former coal miners., Methods: Cross-sectional data from 2568 former coal miners evaluated at eight US Black Lung clinics in a 12-month period were retrospectively analysed for patterns of prebronchodilator spirometric abnormality and severity of lung function impairment. Spirometry data from a subset of former miners with chest radiographs were analysed based on the presence and severity of coal workers' pneumoconiosis (CWP)., Results: Abnormal spirometry was identified in 56.6% of subjects. The age-standardised prevalence of airflow obstruction among miners aged ≥45 years was 18.9% overall and 12.2% among never smokers. Among 1624 subjects who underwent chest radiography, the prevalence and severity of abnormal spirometry increased with worsening radiographic category for pneumoconiosis. Of never-smoking former miners without radiographic CWP, 39.0% had abnormal spirometry; 25.1% had abnormally low forced expiratory volume in 1 s (FEV 1 ), and 17.1% had moderate to severe FEV 1 impairment., Conclusions: Abnormal spirometry is common among former coal miners. While ever-smoking former miners had higher rates of airflow obstruction, never-smoking former miners also demonstrated clinically significant airflow obstruction, including those without radiographic pneumoconiosis. These findings demonstrate the importance of recognising physiological as well as imaging manifestations of coal mine dust lung diseases in former miners., Competing Interests: Competing interests: LHTG, CSR, DH and RAC provided expert testimony in medicolegal cases relating to occupational lung disease. RAC provided consultation to Boehringer Ingelheim Pharmaceuticals., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Neutrino charged-current quasielastic-like scattering, a reaction category extensively used in neutrino oscillation measurements, probes nuclear effects that govern neutrino-nucleus interactions. This Letter reports the first measurement of the triple-differential cross section for ν&#95;{μ} quasielastic-like reactions using the hydrocarbon medium of the MINERvA detector exposed to a wideband beam spanning 2≤E&#95;{ν}≤20  GeV. The measurement maps the correlations among transverse and longitudinal muon momenta and summed proton kinetic energies, and compares them to predictions from a state-of-art simulation. Discrepancies are observed that likely reflect shortfalls with modeling of pion and nucleon intranuclear scattering and/or spectator nucleon ejection from struck nuclei. The separate determination of leptonic and hadronic variables can inform experimental approaches to neutrino-energy estimation.

This study examines the differential childhood adversities experienced by two samples of Australian adolescents involved in the juvenile justice system: male youth who had been adjudicated for sexual offences and their counterparts who had been adjudicated for nonsexual violence. The sample is comprised of clients referred to a service that explicitly prioritises cases identified to be high risk, high need, and living in rural or remote areas. Male youth who had committed a sexual offence were more likely than their counterparts to have experienced emotional and sexual abuse and neglect in their childhoods. Alternatively, the childhoods of the comparison group were marked by characteristics of more general household dysfunction. Potential explanations for these findings are provided. The onset of sexual offending is presented as a possible consequence of poor attachment and emotional dysregulation and the impact of vicarious violence, and a chaotic family life are considered in the development of subsequent nonsexual violence. The implications of these findings for both clinical practice and future research are discussed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pancreatic cancer claims over 460,000 victims per year. The carbohydrate antigen (CA) 19-9 test is the blood test used for pancreatic cancer's detection; however, its levels can be raised in symptomatic patients with other non-malignant diseases, or with other tumors in the surrounding area. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy has demonstrated exceptional potential in cancer diagnostics, and its clinical implementation could represent a significant step towards early detection. This proof-of-concept study, investigating the use of ATR-FTIR spectroscopy on dried blood serum, focused on the discrimination of both cancer versus healthy control samples, and cancer versus symptomatic non-malignant control samples, as a novel liquid biopsy approach for pancreatic cancer diagnosis. Machine learning algorithms were applied, achieving results of up to 92% sensitivity and 88% specificity when discriminating between cancers ( n = 100) and healthy controls ( n = 100). An area under the curve (AUC) of 0.95 was obtained through receiver operating characteristic (ROC) analysis. Balanced sensitivity and specificity over 75%, with an AUC of 0.83, were achieved with cancers ( n = 35) versus symptomatic controls ( n = 35). Herein, we present these results as demonstration that our liquid biopsy approach could become a simple, minimally invasive, and reliable diagnostic test for pancreatic cancer detection.

Background: Estimates of polypharmacy have primarily been derived from prescription claims, and less is known about the use of non-prescription medications (alone or in combination with prescription medications) across the frailty spectrum or by sex. Our objectives were to estimate the prevalence of polypharmacy (total, prescription, non-prescription, and concurrent prescription and non-prescription) overall, and by frailty, sex and broad age group., Data: Canadian Health Measures Survey, Cycle 5, 2016 to 2017., Methods: Among Canadians aged 40 to 79 years, all prescription and non-prescription medications used in the month prior to the survey were documented. Polypharmacy was defined as using five or more medications total (prescription and non-prescription), prescription only and non-prescription only. Concurrent prescription and non-prescription use was defined as two or more and three or more of each. Frailty was defined using a 31-item frailty index (FI) and categorized as non-frail (FI ≤ 0.1) and pre-frail or frail (FI > 0.1). Survey-weighted descriptive statistics were calculated overall and age standardized., Results: We analyzed 2,039 respondents, representing 16,638,026 Canadians (mean age of 56.9 years; 51% women). Overall, 52.4% (95% confidence interval [CI] = 47.3 to 57.4) were defined as pre-frail or frail. Age-standardized estimates of total polypharmacy, prescription polypharmacy and concurrent prescription and non-prescription medication use were significantly higher among pre-frail or frail versus non-frail adults (e.g., total polypharmacy: 64.1% versus 31.8%, respectively). Polypharmacy with non-prescription medications was common overall (20.5% [95% CI = 16.1 to 25.8]) and greater among women, but did not differ significantly by frailty., Interpretation: Polypharmacy and concurrent prescription and non-prescription medication use were common among Canadian adults, especially those who were pre-frail or frail. Our findings highlight the importance of considering non-prescribed medications when measuring the exposure to medications and the potential risk for adverse outcomes.

Introduction: Approximately 5%-10% of new rectal cancers are locally advanced (locally advanced rectal cancer (LARC)) at presentation with 4%-8% recurring (locally recurrent rectal cancer (LRRC)) after initial treatment. Patients with potentially curable disease have to consider many trade-offs when considering major exenterative surgery. There are no decision tools for these patients and current resources have found to not meet minimum international standards. The overall aim of this study is to produce a validated patient decision aid (PtDA) to assist patients considering radical pelvic exenteration for LARC and LRRC created in line with international minimum standards., Methods and Analysis: This study is a national, multicentre mixed methods project and has been designed in keeping with guidance from the International Patient Decision Aids Standard.This study is in four stages. In stage 1, we will develop the PtDA and its content using agile developmental methodology. In stage 2, we will assess the content and face validity of the PtDA using mixed-methods with key stakeholders. In stage 3, we will assess the feasibility and efficacy of the PtDA. In stage 4, we will establish the barriers and facilitators to the use of a PtDA in the outpatient setting. Questionnaires including the QQ-10, EORTC PATSAT-C33, Preparation for Decision-Making Scale and the NoMAD survey will be analysed during the study. Interviews will be analysed using thematic analysis., Ethics and Dissemination: Research ethics approval from North of Scotland Research Ethics Service 19/NS/0056 (IRAS 257890) has been granted. Results will be published in open access peer-reviewed journals, presented in conferences and distributed through bowel research UK charity. External endorsement will be sought from the International Patient Decision Standards Collaboration inventory of PtDAs., Prospero Registration Number: CRD42019122933., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The prion protein is a multifunctional protein that exists in at least two different folding states. It is subject to diverse proteolytic processing steps that lead to prion protein fragments some of which are membrane-bound whereas others are soluble. A multitude of ligands bind to the prion protein and besides proteinaceous binding partners, interaction with metal ions and nucleic acids occurs. Although of great importance, information on structural and functional consequences of prion protein binding to its partners is limited. Here, we will reflect on the structure-function relationship of the prion protein and its binding partners considering the different folding states and prion protein fragments., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Antipsychotic reduction in nursing homes has been a focus of research and policy attention for several decades; however, there is evidence that these initiatives may have had unintended consequences, such as medication substitution and changes in diagnosis coding. Our objectives were to describe temporal changes in the use of antipsychotics, potential substitution medications, and diagnoses and symptoms used to establish the appropriateness of antipsychotic prescribing., Design: Repeated cross-sectional study design., Setting and Participants: Individuals, 66 to 105 years of age, living in nursing homes in Ontario, Canada between April 1, 2010 and December 31, 2019., Methods: Linked health administrative and clinical data were used to estimate the quarterly prevalence of dispensed antipsychotics, antidepressants, anticonvulsants, and benzodiazepines, as well as diagnoses and symptoms (eg, schizophrenia and delusions) applied to establish the appropriateness of antipsychotic use. Generalized linear models with generalized estimating equations, binomial distribution, and identity link function estimated the absolute changes over time among the population overall, by dementia diagnosis, and by severity of aggressive behaviors and cognitive impairment., Results: Among over 70,000 nursing home residents each quarter, we observed general declines in antipsychotic (-0.70% per year [95% confidence limit (CL) -0.74%, -0.66%]) and benzodiazepine use (-1.17% per year [95% CL -1.20%, -1.14%]), and increases in antidepressant (0.89% per year [95% CL 0.84%, 0.94%]) and anticonvulsant use (1.06% per year [95% CL 1.03%, 1.09%]). Although initially stable, the coding of delusions increased from 3.5% to 10.2% (1.18% per year [95% CL 1.12%, 1.24%]) between 2014 and 2019, whereas schizophrenia remained stable. Increases in antidepressant use and recorded delusions were more pronounced among residents with dementia and aggressive behaviors., Conclusions and Implications: Medication substitution and changes in diagnosis/symptom coding may be potential unintended consequences of initiatives to reduce inappropriate antipsychotic use. How this corresponds to resident-level prescribing and clinical outcomes warrants further investigation., (Copyright © 2022 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Spectral pre-processing is an essential step in data analysis for biomedical diagnostic applications of Raman spectroscopy, allowing the removal of undesirable spectral contributions that could mask biological information used for diagnosis. However, due to the specificity of pre-processing for a given sample type and the vast number of potential pre-processing combinations, optimisation of pre-processing via a manual "trial and error" format is often time intensive with no guarantee that the chosen method is optimal for the sample type. Here we present the use of high-performance computing (HPC) to trial over 2.4 million pre-processing permutations to demonstrate the optimisation on the pre-processing of human serum Raman spectra for colorectal cancer detection. The effect of varying pre-processing order, using extended multiplicative scatter correction, spectral smoothing, baseline correction, binning and normalization was considered. Permutations were assessed on their ability to detect patients with disease using a random forest (RF) algorithm trained with 102 patients (510 spectra) and independently tested with a set of 439 patients (1317 spectra) in a primary care patient cohort. Optimising via HPC enables improved performance in diagnostic abilities, with sensitivity increasing by 14.6%, specificity increasing by 6.9%, positive predictive value increasing by 3.4%, and negative predictive value increasing by 2.4% when compared to a standard pre-processing optimisation. Ultimate values of these metrics are very important for diagnostic adoption, and once diagnostics demonstrate good accuracy these types of optimisations can make a significant difference to roll-out of a test and demonstrating advantages over existing tests. We also provide tips/recommendations for pre-processing optimisation without the use of HPC. From the HPC permutations, recommendations for appropriate parameter constraints for conducting a more basic pre-processing optimisation are also detailed, thus helping model development for researchers not having access to HPC.

Most child sexual abuse (CSA) remains unreported and undetected. Despite this, much of what we know about perpetrators of CSA is derived from samples of convicted CSA offenders. Significant knowledge gaps remain about those who have evaded detection. This study addresses this gap with an in-depth content analysis of the case files of ten convicted child sexual offenders (CSOs) with the longest detection lag, selected from a broader group ( n = 349) of men incarcerated at the Massachusetts Treatment Center (MTC). Participants were examined on a range of offender characteristics including Adverse Childhood Experiences (ACEs), cognitive distortions, antisocial traits, indicators of pedophilia and Machiavellian or narcissistic traits, offense facilitating factors, and grooming behavior. A tentative profile emerged with the following characteristics: direct experience of childhood abuse, various cognitive distortions, specialized rather than versatile criminal history, pedophilic traits, Machiavellian traits, and engaging in a range of offense-facilitating behaviors including grooming. We provide insight into offenders who evade detection for CSA and set the foundation for further research to inform prevention strategies for law enforcement agencies and child-serving organizations.