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Background Ethnicity can influence susceptibility to infection, as COVID-19 has shown. Few countries have systematically investigated ethnic variations in infection. Methods We linked the Scotland 2001 Census, including ethnic group, to national databases of hospitalizations/deaths and serological diagnoses of bloodborne viruses for 2001–2013. We calculated age-adjusted rate ratios (RRs) in 12 ethnic groups for all infections combined, 15 infection categories, and human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) viruses. Results We analysed over 1.65 million infection-related hospitalisations/deaths. Compared with White Scottish, RRs for all infections combined were 0.8 or lower for Other White British, Other White and Chinese males and females, and 1.2–1.4 for Pakistani and African males and females. Adjustment for socioeconomic status or birthplace had little effect. RRs for specific infection categories followed similar patterns with striking exceptions. For HIV, RRs were 136 in African females and 14 in males; for HBV, 125 in Chinese females and 59 in males, 55 in African females and 24 in males; and for HCV, 2.3–3.1 in Pakistanis and Africans. Conclusions Ethnic differences were found in overall rates and many infection categories, suggesting multiple causative pathways. We recommend census linkage as a powerful method for studying the disproportionate impact of COVID-19. [ABSTRACT FROM AUTHOR]

Stanford Neuromodulation Therapy (SNT), has recently shown rapid efficacy in difficult to treat (DTT) depression. We conducted an exploratory analysis of individual symptom improvements during treatment, correlated with fMRI, to investigate this rapid improvement in 23 DTT participants from an SNT RCT (12 active, 11 sham). Montgomery-Åsberg Depression Rating Scale item 7 (Lassitude) was the earliest to show improvements between active and sham, as early as treatment day 2. Lassitude score at treatment day 3 was predictive of response at 4 weeks post-treatment and response immediately after treatment. Participants with lower lassitude scores at treatment day 3 had different patterns of sgACC functional connectivity compared to participants with higher scores in both baseline and post-treatment minus baseline analyses. Further work will aim to first replicate these preliminary findings, and then to extend these findings and examine how SNT may affect lassitude and behavioral activation early in treatment., (© 2024. The Author(s).)

Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset 1 . Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals 2-4 , but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time., (© 2024. The Author(s).)

Background: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC., Patients and Methods: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR., Results: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk., Conclusions: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Low phospholipid associated cholelithiasis (LPAC) is associated with variants of the adenosine triphosphate-binding cassette subfamily B, member 4 (ABCB4) gene and is characterized by reduced phosphatidylcholine secretion into bile, impairing the formation of micelles and thus exposing bile ducts to toxic bile acids and increasing cholesterol saturation. LPAC is present in 1% of patients with gallstones and post-cholecystectomy pain is common in this group. LPAC is an under-appreciated cause of post-cholecystectomy pain. The aim of this study is to assess a cohort of patients with post-cholecystectomy pain to identify those with clinical features suggesting that further investigations for LPAC would be beneficial., Methods: A retrospective chart review was performed of the first 2 years of post-operative follow-up for all patients under 40 years of age undergoing cholecystectomy for symptomatic gallstones at a tertiary centre between January 2016 and December 2017., Results: 258 patients under the age of 40 underwent a cholecystectomy. 50 patients (19.4%) reported abdominal pain post-cholecystectomy. Five patients (1.9%) fulfilled the criteria for suspected LPAC. Family history of gallstones was documented in 33 of 258 (12.8%) of cases. Obstetric history was obtained in 69 of 197 (35%) female patients. None of the five patients identified above who satisfied the criteria of LPAC had the diagnosis of LPAC considered by their treating clinicians., Conclusion: LPAC is an under-recognized cause of post-cholecystectomy pain. Treatment can avoid long-term symptoms and complications. Clinicians should take a family history and obstetric history to alert them to the diagnosis of LPAC., (© 2024 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers., (© 2024 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC.)

Background: Transgender people may avoid seeking medical care due to previous negative experiences and fear of discrimination. Clinical laboratories can contribute to a poor patient experience and clinical outcome when the design and functionality of laboratory information management systems (LIMS) do not consider the needs of transgender patients. This survey aimed to capture current practices in United Kingdom and Republic of Ireland clinical laboratories concerning how transgender patient data and test requests are managed throughout the total testing process., Methods: An anonymous survey was distributed to clinical laboratory professionals in November 2021. Thirty-three questions covered how gender variables are recorded for transgender patients and used to inform gender-specific calculations, test access, and reference intervals (RIs)., Results: Of the 66 respondents, 70% were based in laboratories in England, with a majority of laboratories having ISO 15189 accreditation and processing 1000-10,000 blood samples daily. Eighty-five percent stated that their LIMS had a single field recording sex or gender information. Forty-three percent did not limit test access based on gender, but 68% did not append RIs for patients with unknown or indeterminate gender., Conclusions: This survey was the first to quantify how clinical laboratories manage sex and gender information and report results for transgender and non-binary patients, and details several key recommendations based on the survey responses., 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.

Background: We compared the quality of ethnicity coding within the Public Health Scotland Ethnicity Look-up (PHS-EL) dataset, and other National Health Service datasets, with the 2011 Scottish Census., Methods: Measures of quality included the level of missingness and misclassification. We examined the impact of misclassification using Cox proportional hazards to compare the risk of severe coronavirus disease (COVID-19) (hospitalization & death) by ethnic group., Results: Misclassification within PHS-EL was higher for all minority ethnic groups [12.5 to 69.1%] compared with the White Scottish majority [5.1%] and highest in the White Gypsy/Traveller group [69.1%]. Missingness in PHS-EL was highest among the White Other British group [39%] and lowest among the Pakistani group [17%]. PHS-EL data often underestimated severe COVID-19 risk compared with Census data. e.g. in the White Gypsy/Traveller group the Hazard Ratio (HR) was 1.68 [95% Confidence Intervals (CI): 1.03, 2.74] compared with the White Scottish majority using Census ethnicity data and 0.73 [95% CI: 0.10, 5.15] using PHS-EL data; and HR was 2.03 [95% CI: 1.20, 3.44] in the Census for the Bangladeshi group versus 1.45 [95% CI: 0.75, 2.78] in PHS-EL., Conclusions: Poor quality ethnicity coding in health records can bias estimates, thereby threatening monitoring and understanding ethnic inequalities in health., (© The Author(s) 2023. Published by Oxford University Press on behalf of Faculty of Public Health.)

Objective: Characterize the distribution of healthcare utilization associated with pre-operative frailty in the year following evaluation by a surgeon., Summary Background Data: Frailty is associated with increased morbidity, mortality, and costs for surgical patients. However, the total financial burden for frail patients beyond the index surgery and inpatient stay remains unknown., Methods: Prospective cohort assembled from February 2016 to December 2020 within a multi-hospital integrated healthcare delivery and finance system (IDFS), from patients evaluated with the Risk Analysis Index (RAI) of frailty. Inclusion criteria: age greater than 18, valid RAI, membership in the IDFS Health Plan. Data were stratified by frailty and surgical status., Results: The mean (SD) age was 54.7 (16.1) and 58.2% female of the cohort (n=86,572). For all patients with reimbursement for surgery (n=53,856), frail and very frail patients incurred respective increases of 8% ( P =0.027) and 29% ( P <0.001) on utilization relative to the normal group. Robust patients saw a 52% ( P <0.001) decrease. This pattern was more pronounced in the cohort without surgery (n=32,716). The increase over normal utilization for frail and very frail patients increased to 23% ( P =0.004) and 68% ( P <0.001), respectively. Utilization among robust patients decreased 62% ( P <0.001). Increases among the frail were primarily due to increased inpatient medical and post-acute care services (all P <0.001)., Conclusions: Patient frailty is associated with increased total healthcare utilization, primarily via increased inpatient medical and post-acute care following surgery. Quantifying these frailty-related financial burdens may inform clinical decision making as well as the design of value-based reimbursement strategies., Competing Interests: Conflict of Interest Disclosures : Dr Hall reports an unpaid consulting relationship with Future Assure, LLC., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: In order to deliver appropriate and timely care planning and minimise avoidable late diagnoses, clinicians need to be aware of which patients are at higher risk of receiving a late cancer diagnosis. We aimed to determine which demographic and clinical factors are associated with receiving a 'late' cancer diagnosis (within the last 12 weeks of life)., Method: Retrospective cohort study of 2,443 people who died from cancer ('cancer decedents') in 2013-2015. Demographic and cancer registry datasets linked using patient-identifying Community Health Index numbers. Analysis used binary logistic regression, with univariate and adjusted odds ratios (SPSS v25)., Results: One third (n = 831,34.0%) received a late diagnosis. Age and cancer type were significantly associated with late cancer diagnosis (p < 0.001). Other demographic factors were not associated with receiving a late diagnosis. Cancer decedents with lung cancer (Odds Ratios presented in abstract are the inverse of those presented in the main text, where lung cancer is the reference category. Presented as 1/(OR multivariate)) were more likely to have late diagnosis than those with bowel (95% Confidence Interval [95%CI] Odds Ratio (OR)1.52 (OR1.12 to 2.04)), breast or ovarian (95%CI OR3.33 (OR2.27 to 5.0) or prostate (95%CI OR9.09 (OR4.0 to 20.0)) cancers. Cancer decedents aged > 85 years had higher odds of late diagnosis (95%CI OR3.45 (OR2.63 to 4.55)), compared to those aged < 65 years., Conclusions: Cancer decedents who were older and those with lung cancer were significantly more likely to receive late cancer diagnoses than those who were younger or who had other cancer types., (© 2023. The Author(s).)

Alkaloids found in multiple species, known as 'driver species', are more likely to be included in early-stage drug development due to their high biodiversity compared to rare alkaloids. Many synthetic approaches have been employed to hybridize the natural alkaloids in drug development. Click chemistry is a highly efficient and versatile reaction targeting specific areas, making it a valuable tool for creating complex natural products and diverse molecular structures. It has been used to create hybrid alkaloids that address their limitations and serve as potential drugs that mimic natural products. In this review, we highlight the recent advancements made in modifying alkaloids using click chemistry and their potential medicinal applications. We discuss the significance, current trends, and prospects of click chemistry in natural product-based medicine. Furthermore, we have employed computational methods to evaluate the ADMET properties and drug-like qualities of hybrid molecules.

Abstract: In this study, we sought to determine the effect of implementing a large-scale discharge follow-up phone call program on hospital readmission rates. Previous work has shown that patients with unaddressed concerns during discharge have significantly higher rates of care complications and hospital readmissions. This study is an observational quality improvement project completed from April 17, 2020 to January 31, 2022 at 22 hospitals in a large, integrated academic health system. A nurse-led scripted discharge follow-up phone call program was implemented to contact all patients discharged from inpatient care within 72 hours of discharge. Readmission rates were tracked before and after project implementation. Over a 21-month span, 137,515 phone calls were placed, and 57.92% of patients were successfully contacted within 7 days of discharge. The 7-day readmission rate for contacted patients was 2.91% compared with 4.73% for noncontacted patients. The 30-day readmission rate for contacted patients was 11.00% compared with 12.17% for noncontacted patients. We have found that discharge follow-up phone calls targeting patients decreases risk of readmission, which improves overall patient outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 National Association for Healthcare Quality.)

Among adults with inflammatory bowel disease (IBD), self-reported sleep disturbances are associated with active symptoms, but the association between sleep measures and endoscopic disease activity is unknown. This study aimed to (1) compare sleep-wake behaviors among IBD patients based on endoscopic and clinical disease activity and (2) describe associations between actigraphy, self-reported sleep measures, and symptoms of fatigue, anxiety, and depression. Participants wore a wrist actigraph for 10 consecutive days and completed self-reported sleep questionnaires (Pittsburgh Sleep Quality Index [PSQI] and Patient-Reported Outcome Measures System [PROMIS] Sleep Disturbance and Sleep Interference questionnaires). Clinical and endoscopic disease activity were assessed. Based on actigraphic recordings ( n = 26), average total nighttime sleep was 437 minutes and sleep efficiency was 84%. Objective sleep measures did not differ based on endoscopic or clinical disease activity. Individuals with active clinical disease had higher PROMIS Sleep Disturbance (57.3 vs. 49.7, d = 1.28) and PROMIS Sleep-Related Impairment (58.1 vs. 52.8, d = 0.51) compared with those with inactive clinical disease. Self-reported sleep was significantly associated with anxiety, depression, and fatigue. Further research is needed to better characterize the relationship between sleep and endoscopic disease activity, and determine underlying mechanisms related to poor sleep in the IBD population., Competing Interests: Kindra Clark-Snustad serves on advisory boards for Takeda, BMS, Pfizer, and AbbVie. Scott Lee has received research support from AbbVie, Janssen, Takeda, Celgene, and Pfizer and serves on advisory boards for Cornerstones Health, Janssen, Eli Lilly, Bristol-Myers Squibb, and Pfizer. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Society of Gastroenterology Nurses and Associates.)

Background: Effective symptom management is crucial to enhancing the quality of life for individuals with chronic diseases. Health care has changed markedly over the past decade as immersive, stand-alone, and wearable technologies including virtual reality have become available. One chronic pain population that could benefit from such an intervention is individuals with rheumatoid arthritis (RA). Recent pharmacologic advances in the management of RA have led to a decrease in inflammatory symptoms (eg, chronic pain) or even disease remission, yet up to 70% of patients with RA still suffer from fatigue. While VR-delivered behavior, meditation, and biofeedback programs show promise for pain and anxiety management, there is little information on the use of virtual reality meditation (VRM) for fatigue management among individuals with RA., Objective: This study aims to (1) examine the feasibility of implementing a study protocol that uses VRM, (2) determine the acceptability of using VRM for fatigue management in an outpatient population, and (3) identify barriers and contextual factors that might impact VRM use for fatigue management in outpatients with RA., Methods: We used a convergent, mixed methods design and enrolled adults aged 18 years or older with a clinical diagnosis of RA. Patient-Reported Outcome Measure Information System (PROMIS) measures of fatigue, depression, anxiety, pain behavior, and physical function were assessed alongside the brief mood introspection scale at baseline and weekly for 4 weeks. VRM use across the 4-week study period was automatically stored on headsets and later extracted for analysis. Semistructured interview questions focused on feedback regarding the participant's experience with RA, previous experience of fatigue, strategies participants use for fatigue management, and the participant's experience using VRM and recommendations for future use., Results: A total of 13 participants completed this study. Most participants completed all study surveys and measures (11/13, 84% and 13/13, 100%, respectively) and were active participants in interviews at the beginning and end of the program. Participants used VRM an average of 8.9 (SD 8.5) times over the course of the 4-week program. Most participants enjoyed VRM, found it relaxing, or recommended its use (12/13, 92%), but 8 (62%) noted barriers and conceptual factors that impacted VRM use. On average, participants saw decreases in PROMIS fatigue (-6.4, SD 5.1), depression (-5.6, SD 5.7), anxiety (-4.5, SD 6), and pain behavior (-3.9, SD 5.3), and improvements in PROMIS physical function (1.5, SD 2.7) and Brief Mood Introspection Scale mood (5.3, SD 6.7) over the course of this 4-week study., Conclusions: While this study's implementation was feasible, VRM's acceptability as an adjunctive modality for symptom management in RA is contingent on effectively overcoming barriers to use and thoughtfully addressing the contextual factors of those with RA to ensure successful intervention deployment., Trial Registration: ClinicalTrials.gov NCT04804462; https://classic.clinicaltrials.gov/ct2/show/NCT04804462., (©Nathan J Dreesmann, Diana Buchanan, Hsin-Yi Jean Tang, Thomas Furness III, Hilaire Thompson. Originally published in JMIR Formative Research (https://formative.jmir.org), 17.10.2023.)

Background: This study aims to estimate ethnic inequalities in risk for positive SARS-CoV-2 tests, COVID-19 hospitalisations and deaths over time in Scotland., Methods: We conducted a population-based cohort study where the 2011 Scottish Census was linked to health records. We included all individuals ≥ 16 years living in Scotland on 1 March 2020. The study period was from 1 March 2020 to 17 April 2022. Self-reported ethnic group was taken from the census and Cox proportional hazard models estimated HRs for positive SARS-CoV-2 tests, hospitalisations and deaths, adjusted for age, sex and health board. We also conducted separate analyses for each of the four waves of COVID-19 to assess changes in risk over time., Findings: Of the 4 358 339 individuals analysed, 1 093 234 positive SARS-CoV-2 tests, 37 437 hospitalisations and 14 158 deaths occurred. The risk of COVID-19 hospitalisation or death among ethnic minority groups was often higher for White Gypsy/Traveller (HR 2.21, 95% CI (1.61 to 3.06)) and Pakistani 2.09 (1.90 to 2.29) groups compared with the white Scottish group. The risk of COVID-19 hospitalisation or death following confirmed positive SARS-CoV-2 test was particularly higher for White Gypsy/Traveller 2.55 (1.81-3.58), Pakistani 1.75 (1.59-1.73) and African 1.61 (1.28-2.03) individuals relative to white Scottish individuals. However, the risk of COVID-19-related death following hospitalisation did not differ. The risk of COVID-19 outcomes for ethnic minority groups was higher in the first three waves compared with the fourth wave., Interpretation: Most ethnic minority groups were at increased risk of adverse COVID-19 outcomes in Scotland, especially White Gypsy/Traveller and Pakistani groups. Ethnic inequalities persisted following community infection but not following hospitalisation, suggesting differences in hospital treatment did not substantially contribute to ethnic inequalities., Competing Interests: Competing interests: SVK was cochair of the Scottish Government’s Expert Reference Group on Ethnicity and COVID-19 and a member of the Scientific Advisory Group on Emergencies subgroup on ethnicity., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: The purpose of VIKING II is to create an observational cohort of volunteers with ancestry from the Northern Isles of Scotland, primarily for identifying genetic variants influencing disease. The new online protocol is separate to, but follows on from, earlier genetic epidemiological clinic-based studies in the isolated populations of Orkney and Shetland. These populations are favourable for the study of rarer genetic variants due to genetic drift, the large number of relatives, and availability of pedigree information. They are known to be genetically distinct from mainland British populations., Methods and Analysis: Online methods are being used to recruit ~4,000 people who have Northern Isles ancestry, living anywhere in the world. The option for participants to have actionable genetic results returned is offered. Consent will be taken electronically. Data will be collected at baseline through an online questionnaire and longitudinally through linkage to NHS data in the electronic health record. The questionnaire collects a variety of phenotypes including personal and family health. DNA will be extracted from saliva samples then genome-wide genotyped and exome sequenced. VIKING II aims to capitalise on the special features of the Northern Isles populations to create a research cohort that will facilitate the analysis of genetic variants associated with a broad range of traits and disease endpoints, including otherwise rare variants that have drifted to high frequency in these populations., Ethics and Dissemination: The South East Scotland Research Ethics Committee gave the study a favourable opinion. VIKING II is sponsored by the University of Edinburgh and NHS Lothian. Summary research findings will be disseminated to participants and funding bodies, presented at conferences and reported in peer-reviewed publications., Article Summary: Strengths and limitations of this studyDetailed data and biological sample collection of research volunteers with unique ancestry.Consent for access to routinely collected clinical EHR data and for future re-contact, providing a longitudinal component.Optional consent for return of actionable genetic results.~4,000 participants is a relatively small number for certain types of genetic analyses, so the cohort is underpowered on its own, in some study designs.Resources to maintain the cohort, and to store data and DNA samples, are significant, with sustainability dependent on infrastructure support and funding., Competing Interests: Conflicts of interests: All authors have completed the ICMJE uniform disclosure form and declare: no support from any organisation (other than the MRC as listed under funding above) for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Importance: Patient frailty is a known risk factor for adverse outcomes following surgery, but data are limited regarding whether systemwide interventions related to frailty are associated with improved patient outcomes., Objective: To evaluate whether a frailty screening initiative (FSI) is associated with reduced late-term mortality after elective surgery., Design, Setting, and Participants: This quality improvement study with an interrupted time series analysis used data from a longitudinal cohort of patients in a multihospital, integrated health care system in the US. Beginning in July 2016, surgeons were incentivized to measure frailty with the Risk Analysis Index (RAI) for all patients considering elective surgery. Implementation of the BPA occurred in February 2018. The cutoff for data collection was May 31, 2019. Analyses were conducted between January and September 2022., Exposures: The exposure of interest was an Epic Best Practice Alert (BPA) used to identify patients with frailty (RAI ≥42) and prompt surgeons to document a frailty-informed shared decision-making process and consider additional evaluation by a multidisciplinary presurgical care clinic or the primary care physician., Main Outcomes and Measures: The primary outcome was 365-day mortality after the elective surgical procedure. Secondary outcomes included 30-day and 180-day mortality as well as the proportion of patients referred for additional evaluation based on documented frailty., Results: A total of 50 463 patients with at least 1 year of postsurgical follow-up (22 722 before intervention implementation and 27 741 after) were included (mean [SD] age, 56.7 [16.0] y; 57.6% women). Demographic characteristics, RAI score, and operative case mix, as defined by Operative Stress Score, were similar between time periods. After BPA implementation, the proportion of frail patients referred to a primary care physician and presurgical care clinic increased significantly (9.8% vs 24.6% and 1.3% vs 11.4%, respectively; both P < .001). Multivariable regression analysis demonstrated an 18% reduction in the odds of 1-year mortality (0.82; 95% CI, 0.72-0.92; P < .001). Interrupted time series models demonstrated a significant slope change in the rate of 365-day mortality from 0.12% in the preintervention period to -0.04% in the postintervention period. Among patients triggering the BPA, estimated 1-year mortality changed by -4.2% (95% CI, -6.0% to -2.4%)., Conclusions and Relevance: This quality improvement study found that implementation of an RAI-based FSI was associated with increased referrals of frail patients for enhanced presurgical evaluation. These referrals translated to a survival advantage among frail patients of similar magnitude to those observed in a Veterans Affairs health care setting, providing further evidence for both the effectiveness and generalizability of FSIs incorporating the RAI.

We multiply ascertained the BRCA1 pathogenic missense variant c.5207T > C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of population cohorts in clinical care, especially in isolated populations. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isle of Westray, Orkney. Further clinical cases were identified through targeted testing for V1736A in women of Orcadian ancestry attending National Health Service (NHS) genetic clinics for breast and ovarian cancer family risk assessments. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2088 volunteer participants with three or more Orcadian grandparents, in the ORCADES research cohort, was interrogated to estimate the population prevalence of V1736A in Orcadians. The effects of the variant were assessed using Electronic Health Record (EHR) linkage. Twenty out of 2088 ORCADES research volunteers (~1%) carry V1736A, with a common haplotype around the variant. This allele frequency is ~480-fold higher than in UK Biobank participants. Cost-effectiveness of population screening for BRCA1 founder pathogenic variants has been demonstrated at a carrier frequency below the ~1% observed here. Thus we suggest that Orcadian women should be offered testing for the BRCA1 V1736A founder pathogenic variant, starting with those with known Westray ancestry., (© 2023. The Author(s).)

Background: To reduce health inequalities, the creatinine-based chronic kidney disease epidemiology collaboration 2021 formula for estimated glomerular filtration rate (eGFR) is replacing the 2009 formula, which required adjustment specifically for Black individuals. We compared the 2021 and 2009 creatinine-based formulae with cystatin C-based eGFR in Black people on antiretroviral therapy (ART) with HIV RNA <200 c/ml., Methods: Cross-sectional analysis of paired serum creatinine and cystatin C measurements. Bias, imprecision, accuracy, and performance for identifying individuals with eGFR cystatin C <60 (units: ml/min per 1.73 m 2 ) were determined. The effects of ART with no, mild-moderate, or marked effect on tubular creatinine secretion on the performance of the 2021 formula was assessed., Results: We included 362 individuals (mean age 51 years, 56% female, mean eGFR-cystatin C 88.3). Overall, the 2021 (vs. the 2009 race-adjusted) formula was less biased and had improved imprecision and accuracy compared with eGFR-cystatin C but underestimated eGFR-cystatin C in those with eGFR ≥90 and overestimated eGFR-cystatin C in those with eGFR <60. The 2021 (vs. the 2009) formula had high specificity (95% vs. 97%) and negative predictive value (97% vs. 96%), but low sensitivity (56% vs. 52%) and positive predictive value (44% vs. 54%) for identifying individuals with eGFR-cystatin C <60 ( P  > 0.25). Performance at the eGFR <60 cut-off was minimally affected by ART exposure group., Conclusion: The CKD-EPI 2021 creatinine-based formula was better aligned with eGFR-cystatin C than the 2009 formula. eGFR-cystatin C may provide clinically useful information in Black people with eGFR <60 irrespective of ART regimen., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Pseudanabaena dominates cyanobacterial blooms in the First-Generation Magnox Storage Pond (FGMSP) at a UK nuclear site. The fission product Cs is a radiologically significant radionuclide in the pond, and understanding the interactions between Cs and Pseudanabaena spp. is therefore important for determining facility management strategies, as well as improving understanding of microbiological responses to this non-essential chemical analogue of K. This study evaluated the fate of Cs following interactions with Pseudanabaena catenata, a laboratory strain most closely related to that dominating FGMSP blooms. Experiments showed that Cs (1 mM) exposure did not affect the growth of P. catenata, while a high concentration of K (5 mM) caused a significant reduction in cell yield. Scanning transmission X-ray microscopy elemental mapping identified Cs accumulation to discrete cytoplasmic locations within P. catenata cells, indicating a potential bioremediation option for Cs. Proteins related to stress responses and nutrient limitation (K, P) were stimulated by Cs treatment. Furthermore, selected K + transport proteins were mis-regulated by Cs dosing, which indicates the importance of the K + transport system for Cs accumulation. These findings enhance understanding of Cs fate and biological responses within Pseudanabaena blooms, and indicate that K exposure might provide a microbial bloom control strategy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Low phospholipid-associatedcholelithiasis (LPAC) is a clinical syndrome that can be associated with variants in the adenosinetriphosphate-binding cassette subfamily B, member 4 (ABCB4) transporter gene, in a proportion of patients. The diagnosis of LPAC is defined by clinical as well as imaging criteria of intrahepatic hyperechoic foci or microlithiasis and biliary sludge on ultrasound. The aim of the study was to assess the role of imaging in investigating patients presenting with clinical features suggesting a diagnosis of LPAC., Methods: Imaging findings in 51 patients with clinical LPAC were retrospectively reviewed. Most patients had been referred with difficult-to-manage biliary pain postcholecystectomy and some with intrahepatic dilated ducts and stones. The diagnosis of LPAC was made on clinical features., Results: The patients were young with symptom onset at median age 24 years and were mainly female (75%). Ultrasound was performed by an expert in 48/51 and magnetic resonance cholangiopancreatography (MRCP) in 47/51 patients. Targeted liver ultrasound found small hyperechoic foci with comet tail artifacts or posterior acoustic shadowing typical of LPAC in 30/48 (63%) of examinations. However, ultrasound examinations performed before referral for investigation did not report these findings. Intrahepatic duct dilatation was seen in 26/51 (51%) of cases. MRCP did not reliably detect microlithiasis., Conclusions: Targeted liver ultrasound performed by an expert aware of the possible diagnosis is the pivotal investigation for patients with clinical features suggesting LPAC. The findings in ultrasound performed before referral suggest LPAC is under-recognized and under-diagnosed., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Older patients with acute leukemia (AL) have a high symptom burden and poor prognosis. Although integration of palliative care (PC) with oncologic care has been shown to improve quality-of-life and end-of-life care in patients with AL, the malignant hematologists at our tertiary care hospital make limited use of PC services and do so late in the disease course. Using the Plan-Do-Study-Act (PDSA) methodology, we aimed to increase early PC utilization by older patients with newly diagnosed AL., Methods: We instituted the following standardized criteria to trigger inpatient PC consultation: (1) age 70 years and older and (2) new AL diagnosis within 8 weeks. PC consultations were tracked during sequential PDSA cycles in 2021 and compared with baseline rates in 2019. We also assessed the frequency of subsequent PC encounters in patients who received a triggered inpatient PC consult., Results: The baseline PC consultation rate before our intervention was 55%. This increased to 77% and 80% during PDSA cycles 1 and 2, respectively. The median time from diagnosis to first PC consult decreased from 49 days to 7 days. Among patients who received a triggered PC consult, 43% had no subsequent inpatient or outpatient PC encounter after discharge., Conclusion: Although standardized PC consultation criteria led to earlier PC consultation in older patients with AL, it did not result in sustained PC follow-up throughout the disease trajectory. Future PDSA cycles will focus on identifying strategies to maintain the integration of PC with oncologic care over time, particularly in the ambulatory setting.

Background: People with advanced cancer frequently use the GP out-of-hours (GPOOH) service. Considerable amounts of routine GPOOH data are uncoded. Therefore, these data are omitted from existing healthcare datasets., Aim: To conduct a free-text analysis of a GPOOH dataset, to identify reasons for attendance and care delivered through GPOOH to people with advanced cancer., Design and Setting: An analysis of a GPOOH healthcare dataset was undertaken. It contained all coded and free- text information for 5749 attendances from a cohort of 2443 people who died from cancer in Tayside, Scotland, from 2013-2015., Method: Random sampling methods selected 575 consultations for free-text analysis. Each consultation was analysed by two independent reviewers to determine the following: assigned presenting complaints; key and additional palliative care symptoms recorded in free text; evidence of anticipatory care planning; and free-text recording of dispensed medications. Inter-rater reliability concordance was established through Kappa testing., Results: More than half of all coded reasons for attendance ( n = 293; 51.0%) were 'other' or 'missing'. Free-text analysis demonstrated that nearly half ( n = 284; 49.4%) of GPOOH attendances by people with advanced cancer were for pain or palliative care. More than half of GPOOH attendances ( n = 325; 56.5%) recorded at least one key or additional palliative care symptom in free text, with the commonest being breathlessness, vomiting, cough, and nausea. Anticipatory care planning was poorly recorded in both coded and uncoded records. Uncoded medications were dispensed in more than one- quarter of GPOOH consultations., Conclusion: GPOOH delivers a substantial amount of pain management and palliative care, much of which is uncoded. Therefore, it is unrecognised and under-reported in existing large healthcare data analyses., (© The Authors.)

Objective: The objective of this multihospital study was to investigate how the intervention of coaching to bedside shift report (BSR) correlates with Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) outcomes and relates to Centers for Medicare and Medicaid Services (CMS) Hospital Value-Based Purchasing (VBP) Program points over a 4-year period (2017-2020) for an acute care hospital health system., Background: Hospital leaders' responsibilities include intertwined areas of patient experience and fiscal accountability. Coaching to BSR is reported to have numerous benefits to the patient's experience. Published studies completed with hospital systems evaluating the intervention of coaching to BSR and how it correlated to patient experience and VBP are limited., Methods: Coaching to BSR was implemented at 16 adult acute care hospitals. Patient-reported BSR rates were collected in tandem with HCAHPS for 4 years. Statistical correlations were assessed between patient-reported BSR and HCAHPS and consequential effect on VBP dimension scores., Results: Coaching to BSR had a significant impact on top- and bottom-box "rate the hospital" HCAHPS scores at a system and hospital level. Value-based purchasing points and percentages increased over 2017-2020, potentially leading to lower CMS penalty claims over the period the BSR was implemented., Conclusions: Coaching is a key factor when creating a favorable patient experience. The implementation and sustainability of coaching to BSR may result in improved patient experience ratings and increase VBP point accumulation to hospital systems., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Polygenic risk scores (PRSs) can predict the risk of colorectal cancer (CRC) and target screening more precisely than current guidelines using age and family history alone. Primary care, as a far-reaching point of healthcare and routine provider of cancer screening and risk information, may be an ideal location for their widespread implementation., Methods: This trial aims to determine whether the SCRIPT intervention results in more risk-appropriate CRC screening after 12 months in individuals attending general practice, compared with standard cancer risk reduction information. The SCRIPT intervention consists of a CRC PRS, tailored risk-specific screening recommendations and a risk report for participants and their GP, delivered in general practice. Patients aged between 45 and 70 inclusive, attending their GP, will be approached for participation. For those over 50, only those overdue for CRC screening will be eligible to participate. Two hundred and seventy-four participants will be randomised to the intervention or control arms, stratified by general practice, using a computer-generated allocation sequence. The primary outcome is risk-appropriate CRC screening after 12 months. For those in the intervention arm, risk-appropriate screening is defined using PRS-derived risk; for those in the control arm, it is defined using family history and national screening guidelines. Timing, type and results of the previous screening are considered in both arms. Objective health service data will capture screening behaviour. Secondary outcomes include cancer-specific worry, risk perception, predictors of CRC screening behaviour, screening intentions and health service use at 1, 6 and 12 months post-intervention delivery., Discussion: This trial aims to determine whether a PRS-derived personalised CRC risk estimate delivered in primary care increases risk-appropriate CRC screening. A future population risk-stratified CRC screening programme could incorporate risk assessment within primary care while encouraging adherence to targeted screening recommendations., Trial Registration: Australian and New Zealand Clinical Trial Registry ACTRN12621000092897p. Registered on 1 February 2021., (© 2022. The Author(s).)

Background: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, long-term condition characterised by post-exertional malaise, often with fatigue that is not significantly relieved by rest. ME/CFS has no confirmed diagnostic test or effective treatment and we lack knowledge of its causes. Identification of genes and cellular processes whose disruption adds to ME/CFS risk is a necessary first step towards development of effective therapy., Methods: Here we describe DecodeME, an ongoing study co-produced by people with lived experience of ME/CFS and scientists. Together we designed the study and obtained funding and are now recruiting up to 25,000 people in the UK with a clinical diagnosis of ME/CFS. Those eligible for the study are at least 16 years old, pass international study criteria, and lack any alternative diagnoses that can result in chronic fatigue. These will include 5,000 people whose ME/CFS diagnosis was a consequence of SARS-CoV-2 infection. Questionnaires are completed online or on paper. Participants' saliva DNA samples are acquired by post, which improves participation by more severely-affected individuals. Digital marketing and social media approaches resulted in 29,000 people with ME/CFS in the UK pre-registering their interest in participating. We will perform a genome-wide association study, comparing participants' genotypes with those from UK Biobank as controls. This should generate hypotheses regarding the genes, mechanisms and cell types contributing to ME/CFS disease aetiology., Discussion: The DecodeME study has been reviewed and given a favourable opinion by the North West - Liverpool Central Research Ethics Committee (21/NW/0169). Relevant documents will be available online ( www.decodeme.org.uk ). Genetic data will be disseminated as associated variants and genomic intervals, and as summary statistics. Results will be reported on the DecodeME website and via open access publications., (© 2022. The Author(s).)

Background: People who die from cancer ('cancer decedents') may latterly experience unpleasant and distressing symptoms. Prescribing medication for pain and symptom control is essential for good-quality palliative care; however, such provision is variable, difficult to quantify and poorly characterised in current literature. This study aims to characterise trends in prescribing analgesia, non-analgesic palliative care medication and non-palliative medications, to cancer decedents, in their last year of life, and to assess any associations with demographic or clinical factors., Methods: This descriptive study, analysed all 181,247 prescriptions issued to a study population of 2443 cancer decedents in Tayside, Scotland (2013-2015), in the last year of life, linking prescribing data to demographic, and cancer registry datasets using the unique patient-identifying Community Health Index (CHI) number. Anonymised linked data were analysed in Safe Haven using chi-squared test for trend, binary logistic regression and Poisson regression in SPSSv25., Results: In their last year of life, three in four cancer decedents were prescribed strong opioids. Two-thirds of those prescribed opioids were also prescribed laxatives and/or anti-emetics. Only four in ten cancer decedents were prescribed all medications in the 'Just in Case' medication categories and only one in ten was prescribed breakthrough analgesia in the last year of life. The number of prescriptions for analgesia and palliative care drugs increased in the last 12 weeks of life. The number of prescriptions for non-palliative care medications, including anti-hypertensives, statins and bone protection, decreased over the last year, but was still substantial. Cancer decedents who were female, younger, or had lung cancer were more likely to be prescribed strong opioids; however, male cancer decedents had higher odds of being prescribed breakthrough analgesia. Cancer decedents who had late diagnoses had lower odds of being prescribed strong opioids., Conclusions: A substantial proportion of cancer decedents were not prescribed strong opioids, breakthrough medication, or medication to alleviate common palliative care symptoms (including 'Just in Case' medication). Many patients continued to be prescribed non-palliative care medications in their last days and weeks of life. Age, gender, cancer type and timing of diagnosis affected patients' odds of being prescribed analgesic and non-analgesic palliative care medication., (© 2022. The Author(s).)

Objective: To examine the demographic, clinical, and temporal factors associated with cancer decedents being a frequent or very frequent unscheduled care (GP-general practice Out-Of-Hours (GPOOH) and Accident & Emergency (A&E)) attender, in their last year of life., Methods: Retrospective cohort study, of all 2443 cancer decedents in Tayside, Scotland, over 30- months period up to 06/2015, comparing frequent attenders (5-9 attendances/year) and very frequent attenders (≥10 attendances/year) to infrequent attenders (1-4 attendances/year) and non-attenders. Clinical and demographic datasets were linked to routinely-collected clinical data using the Community Health Index number. Anonymised linked data were analysed in SafeHaven, using binary/multinomial logistic regression, and Generalised Estimating Equations analysis., Results: Frequent attenders were more likely to be older, and have upper gastrointestinal (GI), haematological, breast and ovarian malignancies, and less likely to live in accessible areas or have a late cancer diagnosis. They were more likely to use GPOOH than A&E, less likely to have face-to-face unscheduled care attendances, and less likely to be admitted to hospital following unscheduled care attendance., Conclusions: Age, cancer type, accessibility and timing of diagnosis relative to death were associated with increased likelihood of being a frequent or very frequent attender at unscheduled care., 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.)

Little information has been compiled across studies about existing interventions to mitigate issues of medical financial hardship, despite growing interest in health care delivery. The purpose of this qualitative systematic scoping review was to examine content and outcomes of interventions to address medical financial hardship. PRISMA guidelines were applied to present results using PubMed, Scopus, and CINAHL, published between January 1980 and August 2020. Additional studies were identified through reference lists of selected papers. Included studies focused on mitigating medical financial hardship from out-of-pocket (OOP) health care expenses as an intervention strategy with at least 1 evaluation component. Screening 2412 articles identified 339 articles for full-text review, 12 of which met inclusion criteria. Variation was found regarding targets and outcome measurement of intervention. Primary outcomes were in the following categories: financial outcomes (eg, OOP expenses), behavioral outcomes, psychosocial, health care utilization, and health status. No included studies reported significant reduction in OOP expenses, perceptions of financial burden/toxicity, or health status. However, changes were observed for behavioral outcomes (adherence to treatment, patient needs addressed), some psychosocial outcomes (mental health symptoms, perceived support, patient satisfaction), and care utilization such as routine health care. No patterns were observed in the achievement of outcomes across studies based on intensity of intervention. Few rigorous studies exist in this emerging field, and studies have not shown consistent positive effects. Future research should focus on conceptual clarity of the intervention, align outcome measurement and achieve consensus around outcomes, and employ rigorous study designs, measurement, and outcome follow-up.