ABSTRACT
Background: Outcomes after oesophagogastric cancer surgery remain poor. Cardiopulmonary exercise testing (CPET) used for risk stratification before oesophagogastric cancer surgery is based on conflicting evidence. This study explores the relationship between CPET and postoperative outcomes, specifically for patients undergoing neoadjuvant treatment. Methods: Patients undergoing oesophagogastric cancer resection and CPET (pre- or post-neoadjuvant treatment, or both) were retrospectively enrolled into a multicentre pooled cohort study. Oxygen uptake at peak exercise (VO2 peak) was compared with 1-yr postoperative survival. Secondary analyses explored relationships between patient characteristics, tumour pathology characteristics, CPET variables (absolute, relative to weight, ideal body weight, and body surface area), and postoperative outcomes (morbidity, 1-yr and 3-yr survival) were assessed using logistic regression analyses. Results: Seven UK centres recruited 611 patients completing a 3-yr postoperative follow-up period. Oesophagectomy was undertaken in 475 patients (78%). Major complications occurred in 25%, with 18% 1-yr and 43% 3-yr mortality. No association between VO2 peak or other selected CPET variables and 1-yr survival was observed in the overall cohort. In the overall cohort, the anaerobic threshold relative to ideal body weight was associated with 3-yr survival (P=0.013). Tumour characteristics (ypT/ypN/tumour regression/lymphovascular invasion/resection margin; P<0.001) and Clavien-Dindo ≥3a (P<0.001) were associated with 1-yr and 3-yr survival. On subgroup analyses, pre-neoadjuvant treatment CPET; anaerobic threshold (absolute; P=0.024, relative to ideal body weight; P=0.001, body surface area; P=0.009) and VE/VCO2 at anaerobic threshold (P=0.026) were associated with 3-yr survival. No other CPET variables (pre- or post-neoadjuvant treatment) were associated with survival. Conclusions: VO2 peak was not associated with 1-yr survival after oesophagogastric cancer resection. Tumour characteristics and major complications were associated with survival; however, only some selected pre-neoadjuvant treatment CPET variables were associated with 3-yr survival. CPET in this cohort of patients demonstrates limited outcome predictive precision. Clinical trial registration: NCT03637647.
ABSTRACT
Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p < 0.0001), DunedinPACE (p < 0.0001), or Hannum (p = 0.01) epigenetic clocks, with no difference using the Horvath clock. Analysis of the IMM-Age score indicated a prematurely aged immune phenotype in CLD patients that was 2-fold greater than that observed in age-matched healthy controls (p < 0.0001). These findings suggested that accelerated cellular aging may contribute to a phenotype associated with advanced age in CLD patients. Therefore, therapeutic interventions to reduce biological aging in CLD patients may improve health outcomes.
Subject(s)
Aging , Epigenesis, Genetic , Muscle, Skeletal , Humans , Muscle, Skeletal/metabolism , Muscle, Skeletal/immunology , Muscle, Skeletal/pathology , Male , Female , Middle Aged , Aging/immunology , Immune System/metabolism , Immune System/immunology , Transcriptome , Adult , Aged , Chronic Disease , Liver Diseases/immunology , Liver Diseases/pathology , Case-Control Studies , Gene Expression ProfilingABSTRACT
BACKGROUND: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. METHODS: In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). RESULTS: Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. CONCLUSION: The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.
Subject(s)
Laboratories , Neoplasms , Humans , Workflow , State Medicine , Genomics , United KingdomABSTRACT
NEW FINDINGS: What is the central question of this study? To what extent does musculoskeletal impairment occur (i.e., muscle mass, quality and function) in patients with end stage liver disease (ESLD) by comparison to a healthy age/sex-matched control group? What is the main finding and its importance? Muscle mass, quality and function are impaired in patients with ESLD (compared to age/sex matched controls). Importantly, greater impairments were seen in lower limb compared to arm and trunk muscle groups. These findings may suggest that there should be greater consideration of muscle health in functionally relevant lower limb muscle groups. ABSTRACT: Sarcopenia is associated with reduced quality of life and increased mortality in patients with end stage liver disease (ESLD). Historically, sarcopenia identification in ESLD utilised L3 skeletal muscle index (SMI). There are few data on muscle quality and function within lower limb muscle groups with high functional relevance. The aim of this prospective case-control study was to evaluate the quadriceps muscle in patients with ESLD. Muscle mass and quality were evaluated using MRI (quadriceps anatomical cross sectional area (ACSA), quadriceps volume index, L3 SMI, quadriceps intermuscular adipose tissue (IMAT)), mid-arm muscle circumference (MAMC) and ultrasonography (vastus lateralis (VL) thickness and quadriceps ACSA). Muscle strength/function was assessed by handgrip strength, peak quadriceps isokinetic torque and chair rise time. Thirty-nine patients with ESLD (55 years, 61% male, 48% alcoholic related liver disease (ArLD), 71% Child-Pugh B/C) and 18 age/sex-matched healthy control participants (HC) were studied. Quadriceps mass was significantly reduced in ESLD versus HC (-17%), but L3 SMI and MAMC were unchanged. Quadriceps IMAT percentage was increased in ESLD (+103%). Handgrip strength (-15%), peak isokinetic torque (-29%), and chair rise time (+56%) were impaired in ESLD. Ultrasound measures of VL thickness (r = 0.56, r = 0.57, r = 0.42) and quadriceps ACSA (r = 0.98, r = 0.86, r = 0.67) correlated to MRI quadriceps ACSA, quadriceps volume and L3 SMI, respectively. Quadriceps muscle mass, quality, and function were impaired in patients with ESLD, whereas conventional assessments of muscle (L3 SMI and MAMC) highlighted no differences between ESLD and HC. Full evaluation of lower limb muscle health is essential in ESLD in order to accurately assess sarcopenia and target future interventions.
Subject(s)
End Stage Liver Disease , Sarcopenia , Humans , Male , Female , Cross-Sectional Studies , Hand Strength , Quality of Life , Case-Control Studies , Lower Extremity , Muscle, Skeletal/physiology , Quadriceps Muscle/physiology , Muscle Strength/physiologyABSTRACT
In vitro models provide an important platform for the investigation of cellular growth and atrophy to inform, or extend mechanistic insights from, logistically challenging in vivo trials. Although these models allow for the identification of candidate mechanistic pathways, many models involve supraphysiological dosages, nonphysiological conditions, or experimental changes relating to individual proteins or receptors, all of which limit translation to human trials. To overcome these drawbacks, the use of ex vivo human plasma and serum has been used in cellular models to investigate changes in myotube hypertrophy, cellular protein synthesis, anabolic and catabolic markers in response to differing age, disease states, and nutrient status. However, there are currently no concurrent guidelines outlining the optimal methodology for this model. This review discusses the key methodological considerations surrounding the use of ex vivo plasma and serum with a focus in application to skeletal muscle cell lines (i.e., C2C12, L6, and LHCN-M2) and human primary skeletal muscle cells (HSMCs) as a means to investigate molecular signaling in models of atrophy and hypertrophy, alongside future directions.
Subject(s)
Cell Culture Techniques , Muscle Fibers, Skeletal , Humans , Cell Line , Coculture Techniques , Cell Culture Techniques/methods , Muscle Fibers, Skeletal/metabolism , Atrophy/metabolism , Atrophy/pathology , Hypertrophy/metabolism , Muscle, Skeletal/metabolism , Muscular Atrophy/pathologyABSTRACT
OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.
Subject(s)
Neoplasms , State Medicine , Humans , DNA Mismatch Repair/genetics , Laboratories , GenomicsABSTRACT
Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.
Subject(s)
Breast Neoplasms , DNA-Binding Proteins , Fanconi Anemia Complementation Group N Protein , Genetic Predisposition to Disease , Ovarian Neoplasms , Female , Humans , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Consensus , DNA-Binding Proteins/genetics , Fanconi Anemia Complementation Group N Protein/genetics , Genetic Predisposition to Disease/genetics , Germ Cells/pathology , Germ-Line Mutation/genetics , MutS Homolog 2 Protein/genetics , Ovarian Neoplasms/genetics , United KingdomABSTRACT
BACKGROUND: Wait times are significant in child mental health services but may offer opportunity to promote growth mindsets in young people with physical and mental health needs. A digital growth mindset single-session intervention is effective in young people, but its use in paediatric settings has not been examined. This mixed methods pilot aimed to assess the intervention's feasibility, acceptability, and impact in this population. METHOD: Patients aged 8-18 on waiting lists in a paediatric hospital's specialist mental health service were offered the intervention remotely. Treatment completion and retention rates, symptoms of depression and anxiety, perceived control, and personality mindset were assessed at baseline, post-treatment, and follow-ups. Semi-structured interviews to explore the intervention's acceptability were conducted post-treatment. RESULTS: Twenty-five patients completed the intervention and 17 patients and three carers/parents were interviewed. Outcomes showed small to large improvements across time-points. Most patients reported finding the intervention enjoyable, accessible, and instilled a hope for change. They valued elements of the intervention but made suggestions for improvement. CONCLUSIONS: The digital growth mindset single-session intervention is feasible, acceptable, and potentially beneficial for young people with physical and mental health needs on waiting lists. Further research is warranted to examine its effectiveness and mechanism of change.
Subject(s)
Anxiety , Mental Health Services , Humans , Child , Adolescent , Anxiety/therapy , Anxiety Disorders , Personality , Mental Health , Feasibility StudiesABSTRACT
Background and Hypothesis: This systematic review and meta-analysis review the literature regarding the prevalence of visual hallucinations in patients with first-episode psychosis. Previous reviews have focused on the prevalence of visual hallucinations in a general psychosis population, highlighting a weighted prevalence of 27%. However, no reviews have focused specifically on the experiences of those with a first episode of psychosis. Understanding "first-episode" experiences is crucial, as intervention during this "critical period" is thought to define long-term outcome. Therefore, it is important that the prevalence of different symptoms during this period is accurately represented. Study Design: Systematic searches yielded 15 studies to be meta-analyzed. Information to calculate event rates was extracted. Studies were rated for their methodological quality using a risk of bias tool. The quality of included studies varied; generalizability bias was the domain with the most risk of bias. Study Results: Prevalence rates were synthesized from the 15 papers included in the final analysis, which generated a weighted prevalence estimate of 33% of people with first-episode psychosis experiencing visual hallucinations. Subgroup analyses were carried out and did not demonstrate significant associations. Conclusions: This meta-analysis provides a robust estimate of 33% for the prevalence of visual hallucinations in first-episode psychosis; highlighting that visual hallucinations are relatively common experiences.
ABSTRACT
Gastrostomy fed children traditionally have a Formulae diet (FD), which fulfills nutritional requirements; however, many families are adopting Blended diets (BD), which are what the whole family would eat. We undertook an observational investigation of the colonic microbiota and metabonome in a small group of gastrostomy fed children, who were either on an FD or BD, and compared, where possible to their siblings (17 FD, 28 BD, 19 HS). There was no increase in complications in tube blockage or infection rates, but a significant improvement in the prevalence of bowel problems, a reduction in medication and an increase in quality of life. Metataxonomic analysis showed that the FD group was significantly different to the Sibling group, and that families did not cluster together. Whole sample metabonomics showed no differences between groups; however, univariate analysis of biologically important metabolites did differ. Changing to a BD resulted in no increase in complications or risks, but improved the overall quality of life for the children and families.
Subject(s)
Gastrointestinal Microbiome , Microbiota , Child , Humans , Gastrostomy/methods , Enteral Nutrition/methods , Quality of Life , DietABSTRACT
[This corrects the article DOI: 10.3389/fpubh.2022.854343.].
ABSTRACT
Cocoa flavanols have been shown to improve muscle function and may offer a novel approach to protect against muscle atrophy. Hippuric acid (HA) is a colonic metabolite of (-)-epicatechin (EPI), the primary bioactive compound of cocoa, and may be responsible for the associations between cocoa supplementation and muscle metabolic alterations. Accordingly, we investigated the effects of EPI and HA upon skeletal muscle morphology and metabolism within an in vitro model of muscle atrophy. Under atrophy-like conditions (24h 100µM dexamethasone (DEX)), C2C12 myotube diameter was significantly greater following co-incubation with either 25µM HA (11.19±0.39µm) or 25µM EPI (11.01±0.21µm) compared to the vehicle control (VC; 7.61±0.16µm, both P < .001). In basal and leucine-stimulated states, there was a significant reduction in myotube protein synthesis (MPS) rates following DEX treatment in VC (P = .024). Interestingly, co-incubation with EPI or HA abrogated the DEX-induced reductions in MPS rates, whereas no significant differences versus control treated myotubes (CTL) were noted. Furthermore, co-incubation with EPI or HA partially attenuated the increase in proteolysis seen in DEX-treated cells, preserving LC3 α/ß II:I and caspase-3 protein expression in atrophy-like conditions. The protein content of PGC1α, ACC, and TFAM (regulators of mitochondrial function) were significantly lower in DEX-treated versus. CTL cells (all P < .050). However, co-incubation with EPI or HA was unable to prevent these DEX-induced alterations. For the first time we demonstrate that EPI and HA exert anti-atrophic effects on C2C12 myotubes, providing novel insight into the association between flavanol supplementation and favourable effects on muscle health.
Subject(s)
Catechin , Humans , Catechin/metabolism , Dexamethasone/adverse effects , Muscle Fibers, Skeletal , Muscular Atrophy/chemically induced , Muscular Atrophy/prevention & control , Muscle, Skeletal/metabolismABSTRACT
BACKGROUND: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing. METHODS: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway). RESULTS: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met. CONCLUSION: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses. TRIAL REGISTRATION NUMBER: ISRCTN87845055.
Subject(s)
Breast Neoplasms , Referral and Consultation , Humans , Female , State Medicine , Telephone , Genetic Testing , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , United KingdomABSTRACT
Background: Carceral facilities are high-risk settings for COVID-19 transmission. Little is known about the hidden burden of infection or practical barriers to infection control in these settings, especially in jails. There is also limited research on the mental health impacts of the pandemic among people living and working in carceral facilities. Methods: Between July 8, 2020 and April 30, 2021, we performed SARS-CoV-2 rapid antibody testing and administered a questionnaire among residents and staff of four Northern California jails. We utilized multivariable logistic regression, adjusting for demographic and carceral characteristics, to analyze factors associated with prior infection, including perceived likelihood of prior infection and access to new masks. We additionally assessed the implementation of, perceptions toward, and impacts of COVID-19 policies in practice. We engaged stakeholder representatives, including incarcerated individuals, to guide study design, procedures, and results interpretation. Results: We enrolled 788 jail residents and 380 jail staff. Nearly half of residents and two-thirds of staff who were antibody-positive had not previously tested positive for COVID-19. Among residents without a prior COVID-19 diagnosis, antibody positivity was significantly associated with perceived likelihood of prior infection (adjusted OR = 8.9; 95% CI, 3.6-22.0). Residents who had flu-like illness in jail cited inadequate responses to reported illness and deterrents to symptom reporting, including fears of medical isolation and perceptions of medical neglect. Residents also disclosed deficient access to face masks, which was associated with antibody positivity (adjusted OR = 13.8, 95% CI, 1.8-107.0). Worsened mental health was pervasive among residents, attributed not only to fear of COVID-19 and unsanitary jail conditions but also to intensified isolation and deprivation due to pandemic restrictions on in-person visitation, programs, and recreation time. Conclusion: Carceral settings present significant challenges to maintaining infection control and human rights. Custody officials should work diligently to transform the conditions of medical isolation, which could mitigate deterrents to symptom reporting. Furthermore, they should minimize use of restrictive measures like lockdowns and suspension of visitation that exacerbate the mental health harms of incarceration. Instead, custody officials should ensure comprehensive implementation of other preventive strategies like masking, testing, and vaccination, in conjunction with multisector efforts to advance decarceration.
Subject(s)
COVID-19 , Antibodies, Viral , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Testing , Humans , Infection Control , Jails , SARS-CoV-2ABSTRACT
PURPOSE: Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely. METHODS: Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification. RESULTS: We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score. CONCLUSION: In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings.
Subject(s)
Genetic Testing , Neoplasms , Genetic Predisposition to Disease , Genetic Variation/genetics , Humans , Laboratories , Neoplasms/diagnosis , Neoplasms/geneticsABSTRACT
Sarcopenia is a common complication affecting liver disease patients, yet the underlying mechanisms remain unclear. We aimed to elucidate the cellular mechanisms that drive sarcopenia progression using an in vitro model of liver disease. C2C12 myotubes were serum and amino acid starved for 1-h and subsequently conditioned with fasted ex vivo serum from four non-cirrhotic non-alcoholic fatty liver disease patients (NAFLD), four decompensated end-stage liver disease patients (ESLD) and four age-matched healthy controls (CON) for 4- or 24-h. After 4-h C2C12 myotubes were treated with an anabolic stimulus (5 mM leucine) for 30-min. Myotube diameter was reduced following treatment with serum from ESLD compared with CON (−45%) and NAFLD (−35%; p < 0.001 for both). A reduction in maximal mitochondrial respiration (24% and 29%, respectively), coupling efficiency (~12%) and mitophagy (~13%) was identified in myotubes conditioned with NAFLD and ESLD serum compared with CON (p < 0.05 for both). Myostatin (43%, p = 0.04) and MuRF-1 (41%, p = 0.03) protein content was elevated in myotubes treated with ESLD serum compared with CON. Here we highlight a novel, experimental platform to further probe changes in circulating markers associated with liver disease that may drive sarcopenia and develop targeted therapeutic interventions.
Subject(s)
End Stage Liver Disease , Non-alcoholic Fatty Liver Disease , Sarcopenia , Humans , Muscle Fibers, Skeletal , Non-alcoholic Fatty Liver Disease/complications , Protein Biosynthesis , Sarcopenia/complicationsABSTRACT
Carceral facilities are high-risk settings for COVID-19 transmission. Factors associated with COVID-19 vaccine acceptance and hesitancy among incarcerated individuals are poorly understood, especially among jail residents. Here, we conducted a retrospective review of electronic health record (EHR) data on COVID-19 vaccine uptake in custody and additionally administered a survey to assess reasons for vaccine hesitancy, sources of COVID-19 information, and medical mistrust among residents of four Northern California jails. We performed multivariate logistic regression to determine associations with vaccine acceptance. Of 2,564 jail residents offered a COVID-19 vaccine between March 19, 2021 and June 30, 2021, 1,441 (56.2%) accepted at least one dose. Among vaccinated residents, 497 (34.5%) had initially refused. Vaccine uptake was higher among older individuals, women, those with recent flu vaccination, and those living in shared housing. Among 509 survey respondents, leading reasons for vaccine hesitancy were concerns around side effects and suboptimal efficacy, with cost and the need for an annual booster being other hypothetical deterrents to vaccination. Vaccine hesitancy was also associated with mistrust of medical personnel in and out of jail, although this association varied by race/ethnicity. Television and friends/family were the most common and most trusted sources of COVID-19 information, respectively. Overall, vaccine acceptance was much lower among jail residents than the local and national general population. Interventions to increase vaccination rates in this setting should utilize accessible and trusted sources of information to address concerns about side effects and efficacy, while working to mitigate medical and institutional mistrust among residents.
ABSTRACT
PURPOSE: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. METHODS: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. RESULTS: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. CONCLUSION: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.