Missense mutations in PIEZO1, which encodes the Piezo1 mechanosensor protein, define Er red blood cell antigens.

Despite the identification of the high-incidence red cell antigen Era nearly 40 years ago, the molecular background of this antigen, together with the other 2 members of the Er blood group collection, has yet to be elucidated. Whole exome and Sanger sequencing of individuals with serologically defined Er alloantibodies identified several missense mutations within the PIEZO1 gene, encoding amino acid substitutions within the extracellular domain of the Piezo1 mechanosensor ion channel. Confirmation of Piezo1 as the carrier molecule for the Er blood group antigens was demonstrated using immunoprecipitation, CRISPR/Cas9-mediated gene knockout, and expression studies in an erythroblast cell line. We report the molecular bases of 5 Er blood group antigens: the recognized Era, Erb, and Er3 antigens and 2 novel high-incidence Er antigens, described here as Er4 and Er5, establishing a new blood group system. Anti-Er4 and anti-Er5 are implicated in severe hemolytic disease of the fetus and newborn. Demonstration of Piezo1, present at just a few hundred copies on the surface of the red blood cell, as the site of a new blood group system highlights the potential antigenicity of even low-abundance membrane proteins and contributes to our understanding of the in vivo characteristics of this important and widely studied protein in transfusion biology and beyond.

Post-diagnosis physical activity and sedentary behaviour and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

Low physical activity and high sedentary behaviour have been clearly linked with colorectal cancer development, yet data on their potential role in colorectal cancer survival is limited. Better characterisation of these relationships is needed for the development of post-diagnosis physical activity and sedentary behaviour guidance for colorectal cancer survivors. We searched PubMed and Embase through 28 February 2022 for studies assessing post-diagnosis physical activity, and/or sedentary behaviour in relation to all-cause and cause-specific mortality and recurrence after colorectal cancer diagnosis. Total and recreational physical activity were assessed overall and by frequency, duration, intensity, and volume using categorical, linear, and non-linear dose-response random-effects meta-analyses. The Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel interpreted and graded the likelihood of causality. We identified 16 observational studies on 82,220 non-overlapping patients from six countries. Physical activity was consistently inversely associated with colorectal cancer morbidity and mortality outcomes, with 13%-60% estimated reductions in risk. Sedentary behaviour was positively associated with all-cause mortality. The evidence had methodological limitations including potential confounding, selection bias and reverse causation, coupled with a limited number of studies for most associations. The CUP Global Expert panel concluded limited-suggestive evidence for recreational physical activity with all-cause mortality and cancer recurrence. Total physical activity and its specific domains and dimensions, and sedentary behaviour were all graded as limited-no conclusion for all outcomes. Future research should focus on randomised trials, while observational studies should obtain objective and repeated physical activity measures and better adjustment for confounders.

Post-diagnosis adiposity and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The adiposity influence on colorectal cancer prognosis remains poorly characterised. We performed a systematic review and meta-analysis on post-diagnosis adiposity measures (body mass index [BMI], waist circumference, waist-to-hip ratio, weight) or their changes and colorectal cancer outcomes. PubMed and Embase were searched through 28 February 2022. Random-effects meta-analyses were conducted when at least three studies had sufficient information. The quality of evidence was interpreted and graded by the Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel. We reviewed 124 observational studies (85 publications). Meta-analyses were possible for BMI and all-cause mortality, colorectal cancer-specific mortality, and cancer recurrence/disease-free survival. Non-linear meta-analysis indicated a reverse J-shaped association between BMI and colorectal cancer outcomes (nadir at BMI 28 kg/m2). The highest risk, relative to the nadir, was observed at both ends of the BMI distribution (18 and 38 kg/m2), namely 60% and 23% higher risk for all-cause mortality; 95% and 26% for colorectal cancer-specific mortality; and 37% and 24% for cancer recurrence/disease-free survival, respectively. The higher risk with low BMI was attenuated in secondary analyses of RCTs (compared to cohort studies), among studies with longer follow-up, and in women suggesting potential methodological limitations and/or altered physiological state. Descriptively synthesised studies on other adiposity-outcome associations of interest were limited in number and methodological quality. All the associations were graded as limited (likelihood of causality: no conclusion) due to potential methodological limitations (reverse causation, confounding, selection bias). Additional well-designed observational studies and interventional trials are needed to provide further clarification.

Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.

Based on the World Cancer Research Fund Global Cancer Update Programme, we performed systematic reviews and meta-analyses to investigate the association of post-diagnosis adiposity, physical activity, sedentary behaviour, and dietary factors with colorectal cancer prognosis. We searched PubMed and Embase until 28th February, 2022. An independent expert committee and expert panel graded the quality of evidence. A total of 167 unique publications were reviewed, and all but five were observational studies. The quality of the evidence was graded conservatively due to the high risk of several biases. There was evidence of non-linearity in the associations between body mass index and colorectal cancer prognosis. The associations appeared reverse J-shaped, and the quality of this evidence was graded as limited (likelihood of causality: limited-no conclusion). The evidence on recreational physical activity and lower risk of all-cause mortality (relative risk [RR] highest vs. lowest: 0.69, 95% confidence interval [CI]: 0.62-0.77) and recurrence/disease-free survival (RR: 0.80, 95% CI: 0.70-0.92) was graded as limited-suggestive. There was limited-suggestive evidence for the associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), intake of whole grains and coffee with lower risk of all-cause mortality, and between unhealthy dietary patterns and intake of sugary drinks with higher risk of all-cause mortality. The evidence for other exposures on colorectal cancer outcomes was sparse and graded as limited-no conclusion. Analyses were conducted excluding cancer patients with metastases without substantial changes in the findings. Well-designed intervention and cohort studies are needed to support the development of lifestyle recommendations for colorectal cancer patients.

Post-diagnosis dietary factors, supplement use and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The role of diet in colorectal cancer prognosis is not well understood and specific lifestyle recommendations are lacking. We searched for randomised controlled trials (RCTs) and longitudinal observational studies on post-diagnosis dietary factors, supplement use and colorectal cancer survival outcomes in PubMed and Embase from inception until 28th February 2022. Random-effects dose-response meta-analyses were conducted when at least three studies had sufficient information. The evidence was interpreted and graded by the CUP Global independent Expert Committee on Cancer Survivorship and Expert Panel. Five RCTs and 35 observational studies were included (30,242 cases, over 8700 all-cause and 2100 colorectal cancer deaths, 3700 progression, recurrence, or disease-free events). Meta-analyses, including 3-10 observational studies each, were conducted for: whole grains, nuts/peanuts, red and processed meat, dairy products, sugary drinks, artificially sweetened beverages, coffee, alcohol, dietary glycaemic load/index, insulin load/index, marine omega-3 polyunsaturated fatty acids, supplemental calcium, circulating 25-hydroxyvitamin D (25[OH]D) and all-cause mortality; for alcohol, supplemental calcium, circulating 25(OH)D and colorectal cancer-specific mortality; and for circulating 25(OH)D and recurrence/disease-free survival. The overall evidence was graded as 'limited'. The inverse associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), whole grains, total, caffeinated, or decaffeinated coffee and all-cause mortality and the positive associations between unhealthy dietary patterns, sugary drinks and all-cause mortality provided 'limited-suggestive' evidence. All other exposure-outcome associations provided 'limited-no conclusion' evidence. Additional, well-conducted cohort studies and carefully designed RCTs are needed to develop specific lifestyle recommendations for colorectal cancer survivors.

Uptake and 4-week quit rates from an opt-out co-located smoking cessation service delivered alongside community-based low-dose computed tomography screening within the Yorkshire Lung Screening Trial.

BACKGROUND: Up to 50% of those attending for low-dose computed tomography screening for lung cancer continue to smoke and co-delivery of smoking cessation services alongside screening may maximise clinical benefit. Here we present data from an opt-out co-located smoking cessation service delivered alongside the Yorkshire Lung Screening Trial (YLST). METHODS: Eligible YLST participants were offered an immediate consultation with a smoking cessation practitioner (SCP) at their screening visit with ongoing smoking cessation support over subsequent weeks. RESULTS: Of 2150 eligible participants, 1905 (89%) accepted the offer of an SCP consultation during their initial visit, with 1609 (75%) receiving ongoing smoking cessation support over subsequent weeks. Uptake of ongoing support was not associated with age, ethnicity, deprivation or educational level in multivariable analyses, although men were less likely to engage (adjusted OR (ORadj) 0.71, 95% CI 0.56-0.89). Uptake was higher in those with higher nicotine dependency, motivation to stop smoking and self-efficacy for quitting. Overall, 323 participants self-reported quitting at 4 weeks (15.0% of the eligible population); 266 were validated by exhaled carbon monoxide (12.4%). Multivariable analyses of eligible smokers suggested 4-week quitting was more likely in men (ORadj 1.43, 95% CI 1.11-1.84), those with higher motivation to quit and previous quit attempts, while those with a stronger smoking habit in terms of cigarettes per day were less likely to quit. CONCLUSIONS: There was high uptake for co-located opt-out smoking cessation support across a wide range of participant demographics. Protected funding for integrated smoking cessation services should be considered to maximise programme equity and benefit.

Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to <8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR).

OBJECTIVE: Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4-5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP-9001-103; NCT04626674) is a single-arm, open-label study to evaluate delandistrogene moxeparvovec micro-dystrophin expression, safety, and functional outcomes following administration of commercial process delandistrogene moxeparvovec. METHODS: In cohort 1 of ENDEAVOR (N = 20), eligible ambulatory males, aged ≥4 to <8 years, received a single intravenous infusion of delandistrogene moxeparvovec (1.33 × 1014 vg/kg). The primary endpoint was change from baseline (CFBL) to week 12 in delandistrogene moxeparvovec micro-dystrophin by western blot. Additional endpoints evaluated included: safety; vector genome copies; CFBL to week 12 in muscle fiber-localized micro-dystrophin by immunofluorescence; and functional assessments, including North Star Ambulatory Assessment, with comparison with a propensity score-weighted external natural history control. RESULTS: The 1-year safety profile of commercial process delandistrogene moxeparvovec in ENDEAVOR was consistent with safety data reported in other delandistrogene moxeparvovec trials (NCT03375164 and NCT03769116). Delandistrogene moxeparvovec micro-dystrophin expression was robust, with sarcolemmal localization at week 12; mean (SD) CFBL in western blot, 54.2% (42.6); p < 0.0001. At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores; mean (SD) CFBL, +4.0 (3.5). Treatment versus a propensity score-weighted external natural history control demonstrated a statistically significant difference in least squares mean (standard error) CFBL in North Star Ambulatory Assessment, +3.2 (0.6) points; p < 0.0001. INTERPRETATION: Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One-year post-treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit for patients with Duchenne muscular dystrophy. ANN NEUROL 2023;94:955-968.

Functional Magnetic Resonance Imaging of the Amygdala and Subregions at 3 Tesla: A Scoping Review.

The amygdalae are a pair of small brain structures, each of which is composed of three main subregions and whose function is implicated in neuropsychiatric conditions. Functional Magnetic Resonance Imaging (fMRI) has been utilized extensively in investigation of amygdala activation and functional connectivity (FC) with most clinical research sites now utilizing 3 Tesla (3T) MR systems. However, accurate imaging and analysis remains challenging not just due to the small size of the amygdala, but also its location deep in the temporal lobe. Selection of imaging parameters can significantly impact data quality with implications for the accuracy of study results and validity of conclusions. Wide variation exists in acquisition protocols with spatial resolution of some protocols suboptimal for accurate assessment of the amygdala as a whole, and for measuring activation and FC of the three main subregions, each of which contains multiple nuclei with specialized roles. The primary objective of this scoping review is to provide a broad overview of 3T fMRI protocols in use to image the activation and FC of the amygdala with particular reference to spatial resolution. The secondary objective is to provide context for a discussion culminating in recommendations for a standardized protocol for imaging activation of the amygdala and its subregions. As the advantages of big data and protocol harmonization in imaging become more apparent so, too, do the disadvantages of data heterogeneity. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Long-term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial.

INTRODUCTION/AIMS: Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long-term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild-type protein) expression may positively alter disease progression in patients with DMD. We evaluated long-term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD. METHODS: An open-label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 1014 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests. RESULTS: Four patients (mean age, 5.1 years) were enrolled. There were 18 treatment-related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9-point difference in NSAA score, relative to a propensity-score-weighted external control cohort (least-squares mean [standard error] = 9.4 [3.4]; P = .0125). DISCUSSION: Gene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression.

Key characteristics of effective yoga interventions for managing osteoarthritis: a systematic review and meta-analysis.

This systematic review aimed to synthesise the content, structure, and delivery characteristics of effective yoga interventions for managing osteoarthritis symptoms, including joint pain and joint function. JBI guidelines were followed. 17 databases were searched for randomised controlled trials (RCTs) assessing yoga's effectiveness on osteoarthritis symptoms. Meta-analyses and a narrative synthesis were conducted to address the objective. The systematic review and meta-analysis included 18 and 16 articles (representing 16 and 14 RCTs), respectively. Overall, the included studies had low methodological quality scores. 10 of 14 yoga interventions effectively reduced pain (standardised mean difference (SMD) - 0.70; 95% confidence interval (CI) - 1.08, - 0.32) and/or improved function (- 0.40; - 0.75, - 0.04). Notably, 8 effective interventions had centre-based (supervised, group) sessions, and 6 included additional home-based (unsupervised, individual) sessions. Effective interventions included 34 yogic poses (12 sitting, 10 standing, 8 supine, 4 prone), 8 breathing practices, and 3 meditation and relaxation practices. 8 interventions included yogic poses, and 7 also incorporated breathing practices and/or meditation and relaxation practices. 4 interventions included yogic pose modifications for osteoarthritis. The median duration of centre-based sessions was 8 weeks and each session was around 53 min, mostly delivered once a week. The median duration of home-based sessions was 10 weeks and each session was 30 min, usually instructed to practice 4 times a week. Given previous studies' limitations, a high-quality long-term RCT should be conducted using synthesised findings of previous effective yoga interventions.

Examining the Effectiveness of Social Media for the Dissemination of Research Evidence for Health and Social Care Practitioners: Systematic Review and Meta-Analysis.

BACKGROUND: Social media use has potential to facilitate the rapid dissemination of research evidence to busy health and social care practitioners. OBJECTIVE: This study aims to quantitatively synthesize evidence of the between- and within-group effectiveness of social media for dissemination of research evidence to health and social care practitioners. It also compared effectiveness between different social media platforms, formats, and strategies. METHODS: We searched electronic databases for articles in English that were published between January 1, 2010, and January 10, 2023, and that evaluated social media interventions for disseminating research evidence to qualified, postregistration health and social care practitioners in measures of reach, engagement, direct dissemination, or impact. Screening, data extraction, and risk of bias assessments were carried out by at least 2 independent reviewers. Meta-analyses of standardized pooled effects were carried out for between- and within-group effectiveness of social media and comparisons between platforms, formats, and strategies. Certainty of evidence for outcomes was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework. RESULTS: In total, 50 mixed-quality articles that were heterogeneous in design and outcome were included (n=9, 18% were randomized controlled trials [RCTs]). Reach (measured in number of practitioners, impressions, or post views) was reported in 26 studies. Engagement (measured in likes or post interactions) was evaluated in 21 studies. Direct dissemination (measured in link clicks, article views, downloads, or altmetric attention score) was analyzed in 23 studies (8 RCTs). Impact (measured in citations or measures of thinking and practice) was reported in 13 studies. Included studies almost universally indicated effects in favor of social media interventions, although effect sizes varied. Cumulative evidence indicated moderate certainty of large and moderate between-group effects of social media interventions on direct dissemination (standardized mean difference [SMD] 0.88; P=.02) and impact (SMD 0.76; P<.001). After social media interventions, cumulative evidence showed moderate certainty of large within-group effects on reach (SMD 1.99; P<.001), engagement (SMD 3.74; P<.001), and direct dissemination (SMD 0.82; P=.004) and low certainty of a small within-group effect on impacting thinking or practice (SMD 0.45; P=.02). There was also evidence for the effectiveness of using multiple social media platforms (including Twitter, subsequently rebranded X; and Facebook), images (particularly infographics), and intensive social media strategies with frequent, daily posts and involving influential others. No included studies tested the dissemination of research evidence to social care practitioners. CONCLUSIONS: Social media was effective for disseminating research evidence to health care practitioners. More intense social media campaigns using specific platforms, formats, and strategies may be more effective than less intense interventions. Implications include recommendations for effective dissemination of research evidence to health care practitioners and further RCTs in this field, particularly investigating the dissemination of social care research. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42022378793; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=378793. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/45684.

Selective nerve transfers to restore shoulder abduction and flexion in acute flaccid myelitis: A case report.

Acute flaccid myelitis (AFM) is a polio-like condition predominantly affecting children that is characterized by acute-onset, asymmetric flaccid paralysis, often preceded by a prodromal fever or viral illness. With prompt diagnosis and early surgical referral, nerve transfers may be performed to improve function. Highly selective nerve transfers are ideal to preserve existing functions while targeting specific deficits. In this report, we present a case of a double fascicular nerve transfer of median and ulnar nerve fascicles to the axillary nerve, combined with selective transfer of the spinal accessory nerve to the supraspinatus branch of the suprascapular nerve, performed for a 5-year-old girl who developed AFM after an upper respiratory infection. Six months after the onset of the patient's symptoms, the patient had continued weakness of shoulder flexion and abduction, atrophy of the deltoid, and supraspinatus muscles, though needle electromyography revealed a functioning infraspinatus muscle. The patient had no post-operative complications and at 2 years of postoperative follow up achieved shoulder abduction and flexion Active Movement Scale scores of 7/7 compared to preoperative scores of 2/7, with no loss of function in the donor nerve domains. The patient showed active shoulder abduction against gravity to 90° from 30° preoperatively and shoulder flexion to 180° from 15° preoperatively. This case report shows that highly selective nerve transfers may preserve existing functions while targeting specific deficits. A double fascicular transfer from the median and ulnar nerves to axillary nerve may provide abundant axons for functional recovery.

Influence of a single oral dose of trazodone on intradermal histamine reactivity in clinically healthy dogs.

BACKGROUND: Drug interactions are significant considerations for intradermal testing (IDT). Trazodone (TRZ) is an anxiolytic and selective histaminergic (H1 ) antagonist with no interaction in human prick tests; however, interaction in canine IDT is unknown. HYPOTHESIS/OBJECTIVES: Trazodone will not adversely affect intradermal histamine reactions in dogs. ANIMALS: Fourteen nonanxious, nonatopic, healthy client-owned dogs were enrolled in this randomised, blinded, cross-over study. MATERIALS AND METHODS: Dogs were randomised to receive low-dose TRZ (4 mg/kg) (Teva Pharmaceuticals), high-dose TRZ (8 mg/kg) or no TRZ per os two hours before intravenous sedation with dexmedetomidine (5 mcg/kg) (Dexdomitor; Zoetis). Intradermal testing was performed with five quadrupling dilutions of histamine (1:100,000 to 1:25,600,000 w/v; Greer) and 0.9% saline (Hospira), observing a minimum two weeks washout period between treatments. Two observers, who were blinded to treatment and the identity of the injections, evaluated each test using previously established subjective and objective methods. RESULTS: The mean wheal diameter of histamine 1:1,600,000 w/v was significantly smaller with low-dose TRZ (4 mg/kg) compared to the control group (p = 0.048; repeated measures ANOVA with post hoc Tukey's test). For all other histamine dilutions and saline, mean wheal diameter was not significantly different among groups. There were no significant differences in the subjective scores of all histamine dilutions and saline (p > 0.05; Friedman test). CONCLUSION AND CLINICAL RELEVANCE: A single oral dose of TRZ does not adversely affect intradermal histamine reactions in dogs.

Prevalence and Factors Associated with Behavioral Problems in 5-Year-Old Children Born with Cleft Lip and/or Palate from the Cleft Collective.

OBJECTIVES: To determine the UK prevalence of behavioral problems in 5-year-old children born with isolated or syndromic cleft lip and/or palate (CL/P) compared to the general population and identify potentially associated factors. DESIGN: Observational study using questionnaire data from the Cleft Collective 5-Year-Old Cohort study and three general population samples. MAIN OUTCOME MEASURE: The Strengths and Difficulties Questionnaire (SDQ). PARTICIPANTS: Mothers of children (age: 4.9-6.8 years) born with CL/P (n = 325). UK general population cohorts for SDQ scores were: Millennium Cohort Study (MCS) (n = 12 511), Office of National Statistics (ONS) normative school-age SDQ data (n = 5855), and Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 9386). RESULTS: By maternal report, 14.2% of children born with CL/P were above clinical cut-off for behavioral problems, which was more likely than in general population samples: 7.5% of MCS (OR = 2.05 [1.49-2.82], P < 0.001), 9.8% of ONS (OR = 1.52 [1.10-2.09], P = 0.008), and 6.6% of ALSPAC (OR = 2.34 [1.70-3.24], P < 0.001). Children in the Cleft Collective had higher odds for hyperactivity, emotional and peer problems, and less prosocial behaviors. Maternal stress, lower maternal health-related quality of life and family functioning, receiving government income support, and maternal smoking showed evidence of association (OR range: 4.41-10.13) with behavioral problems, along with maternal relationship status, younger age, and lower education (OR range: 2.34-3.73). CONCLUSIONS: Findings suggest elevated levels of behavioral problems in children born with CL/P compared to the general population with several associated maternal factors similar to the general population.

Cleft lip Sidedness and the Association with Additional Congenital Malformations.

OBJECTIVE: To investigate the association between the sidedness of orofacial clefts and additional congenital malformations. DESIGN: Linkage of a national registry of cleft births to national administrative data of hospital admissions. SETTING: National Health Service, England. PARTICIPANTS: 2007 children born with cleft lip ± alveolus (CL ± A) and 2724 with cleft lip and palate (CLP) born between 2000 and 2012. MAIN OUTCOME MEASURE: The proportion of children with ICD-10 codes for additional congenital malformations by the sidedness (left, right or bilateral) of orofacial clefts. RESULTS: For CL ± A phenotypes, there was no evidence for a difference in the prevalence of additional anomalies between left (22%, reference), right (22%, aOR 1.02, 95% CI 0.80 to 1.28; P = .90) and bilateral clefts (23%, aOR 1.09, 95% CI 0.75 to 1.57; P = .66). For CLP phenotypes, there was evidence of a lower prevalence of additional malformations in left (23%, reference) compared to right (32%, aOR 1.54, 95% CI 1.25 to 1.91; P < .001) and bilateral clefts (33%, aOR 1.64, 95% CI 1.35 to 1.99; P < .001). CONCLUSIONS: The prevalence of additional congenital malformations was similar across sidedness subtypes with CL ± A phenotypes but was different for sidedness subtypes within CLP cases. These data support the hypothesis that CL ± A has a different underlying aetiology from CLP and that within the CLP phenotype, right sided CLP may lie closer in aetiology to bilateral CLP than it does to left sided CLP.

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis.

AIMS/HYPOTHESIS: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk. METHODS: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence. RESULTS: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints. CONCLUSIONS/INTERPRETATION: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis. DATA AVAILABILITY: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

Use of Statistical Process Control Methods for Early Detection of Healthcare Facility-Associated Nontuberculous Mycobacteria Outbreaks: A Single-Center Pilot Study.

BACKGROUND: Nontuberculous mycobacteria (NTM) are emerging pathogens increasingly implicated in healthcare facility-associated (HCFA) infections and outbreaks. We analyzed the performance of statistical process control (SPC) methods in detecting HCFA NTM outbreaks. METHODS: We retrospectively analyzed 3 NTM outbreaks that occurred from 2013 to 2016 at a tertiary care hospital. The outbreaks consisted of pulmonary Mycobacterium abscessus complex (MABC) acquisition, cardiac surgery-associated extrapulmonary MABC infection, and a bronchoscopy-associated pseudo-outbreak of Mycobacterium avium complex (MAC). We analyzed monthly case rates of unique patients who had positive respiratory cultures for MABC, non-respiratory cultures for MABC, and bronchoalveolar lavage cultures for MAC, respectively. For each outbreak, we used these rates to construct a pilot moving average (MA) SPC chart with a rolling baseline window. We also explored the performance of numerous alternative control charts, including exponentially weighted MA, Shewhart, and cumulative sum charts. RESULTS: The pilot MA chart detected each outbreak within 2 months of outbreak onset, preceding actual outbreak detection by an average of 6 months. Over a combined 117 months of pre-outbreak and post-outbreak surveillance, no false-positive SPC signals occurred (specificity, 100%). Prospective use of this chart for NTM surveillance could have prevented an estimated 108 cases of NTM. Six high-performing alternative charts detected all outbreaks during the month of onset, with specificities ranging from 85.7% to 94.9%. CONCLUSIONS: SPC methods have potential to substantially improve HCFA NTM surveillance, promoting early outbreak detection and prevention of NTM infections. Additional study is needed to determine the best application of SPC for prospective HCFA NTM surveillance in other settings.

Blood pressure, calcium channel blockers, and the risk of prostate cancer: a Mendelian randomization study.

BACKGROUND: Observational studies have found some evidence of an association between elevated blood pressure and prostate cancer risk; however, the results are inconclusive. We tested whether systolic blood pressure (SBP) influences prostate cancer risk and evaluated the effect of calcium channel blockers (CCB) on the disease using Mendelian randomization (MR) approach. METHODS: We used 278 genetic variants associated with SBP and 16 genetic variants in CCB genes as instrumental variables. Effect estimates were obtained from the UK Biobank sample of 142,995 males and from PRACTICAL consortium (79,148 cases and 61,106 controls). RESULTS: For each 10 mm Hg increase in SBP the estimated effect was OR 0.96 (0.90-1.01) for overall prostate cancer; and OR 0.92 (0.85-0.99) for aggressive prostate cancer. The MR-estimated effect of a 10 mm Hg- SBP lowering through CCB genetic variants was OR 1.22 (1.06-1.42) for all prostate cancers and OR 1.49 (1.18-1.89) for aggressive prostate cancer. CONCLUSION: The results of our study did not support a causal relationship between SBP and prostate cancer; however, we found weak evidence of a protective effect of high SBP on aggressive prostate cancer and we found that blocking calcium channel receptors may increase prostate cancer risk.

PREFER: A New Predictive Modeling Framework for Molecular Discovery.

Machine-learning and deep-learning models have been extensively used in cheminformatics to predict molecular properties, to reduce the need for direct measurements, and to accelerate compound prioritization. However, different setups and frameworks and the large number of molecular representations make it difficult to properly evaluate, reproduce, and compare them. Here we present a new PREdictive modeling FramEwoRk for molecular discovery (PREFER), written in Python (version 3.7.7) and based on AutoSklearn (version 0.14.7), that allows comparison between different molecular representations and common machine-learning models. We provide an overview of the design of our framework and show exemplary use cases and results of several representation-model combinations on diverse data sets, both public and in-house. Finally, we discuss the use of PREFER on small data sets. The code of the framework is freely available on GitHub.

Do the research priorities identified in SAGES Delphi studies resonate with rural general surgeons: a Washington state perspective.

BACKGROUND: Rural surgeons operate in an environment significantly different from that of their colleagues, and as such they face unique challenges. We hypothesized the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) research agenda (as identified in the results of the 2014 Delphi study) will differ in its priorities from those identified by rural surgeons. We aimed to pilot a study in Washington state that could be replicated in other areas of the USA and the world. METHODS: We identified general surgeons working at rural critical access hospitals in the state of Washington. We then conducted virtual, semi-structured interviews and followed up with surveys and site visits. The survey included the 2014 SAGES Delphi-ranked research priorities. We asked rural surgeons to rank their top 5 of these 40 priorities and to detail any additional which were not on the list. RESULTS: We contacted 79 surgeons with a 30% response rate. We conducted 25 semi-structured interviews and received 18 completed follow-up surveys. These interviews were followed by site visits at 4 of the 23 sites. Of the original Delphi research priorities, those most cited by rural surgeons were #8 ("What is the best method for incorporating new techniques and technology for surgeons of variable levels of experience or training?") and #1 ("How do we best train, assess, and maintain proficiency of surgeons and surgical trainees in flexible endoscopy, laparoscopy, and open surgery?"). Four surgeons included the last SAGES priority (#40 "Is quality of life improved after ventral hernia repair?") among their top 5. CONCLUSION: This study suggests that although rural surgeons' research priorities align with the published SAGES Delphi survey, these surgeons rank the priorities differently. This may be because the predominant study population of the Delphi is SAGES membership who work in urban and academic centers. Plans for future SAGES Delphi survey could capture these unique priorities by intentional involvement of rural and community surgeons.