Factorizing polygenic epistasis improves prediction and uncovers biological pathways in complex traits.

Epistasis is central in many domains of biology, but it has not yet been proven useful for understanding the etiology of complex traits. This is partly because complex-trait epistasis involves polygenic interactions that are poorly captured in current models. To address this gap, we developed a model called Epistasis Factor Analysis (EFA). EFA assumes that polygenic epistasis can be factorized into interactions between a few epistasis factors (EFs), which represent latent polygenic components of the observed complex trait. The statistical goals of EFA are to improve polygenic prediction and to increase power to detect epistasis, while the biological goal is to unravel genetic effects into more-homogeneous units. We mathematically characterize EFA and use simulations to show that EFA outperforms current epistasis models when its assumptions approximately hold. Applied to predicting yeast growth rates, EFA outperforms the additive model for several traits with large epistasis heritability and uniformly outperforms the standard epistasis model. We replicate these prediction improvements in a second dataset. We then apply EFA to four previously characterized traits in the UK Biobank and find statistically significant epistasis in all four, including two that are robust to scale transformation. Moreover, we find that the inferred EFs partly recover pre-defined biological pathways for two of the traits. Our results demonstrate that more realistic models can identify biologically and statistically meaningful epistasis in complex traits, indicating that epistasis has potential for precision medicine and characterizing the biology underlying GWAS results.

Design and Implementation of a National SARS-CoV-2 Monitoring Program in England: REACT-1 Study.

Data System. The REal-time Assessment of Community Transmission-1 (REACT-1) Study was funded by the Department of Health and Social Care in England to provide reliable and timely estimates of prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection over time, by person and place. Data Collection/Processing. The study team (researchers from Imperial College London and its logistics partner Ipsos) wrote to named individuals aged 5 years and older in random cross-sections of the population of England, using the National Health Service list of patients registered with a general practitioner (near-universal coverage) as a sampling frame. We collected data over 2 to 3 weeks approximately every month across 19 rounds of data collection from May 1, 2020, to March 31, 2022. Data Analysis/Dissemination. We have disseminated the data and study materials widely via the study Web site, preprints, publications in peer-reviewed journals, and the media. We make available data tabulations, suitably anonymized to protect participant confidentiality, on request to the study's data access committee. Public Health Implications. The study provided inter alia real-time data on SARS-CoV-2 prevalence over time, by area, and by sociodemographic variables; estimates of vaccine effectiveness; and symptom profiles, and detected emergence of new variants based on viral genome sequencing. (Am J Public Health. 2023;113(5):545-554. https://doi.org/10.2105/AJPH.2023.307230).

Hand Rejuvenation: A Systematic Review of Techniques, Outcomes, and Complications.

BACKGROUND: Hand rejuvenation is an increasingly popular cosmetic procedure for hand atrophy and aging. The objective of this study is to systematically evaluate the techniques, outcomes, and complications of surgical hand rejuvenation. METHODS: A systematic review was undertaken using a computerized search. Publication descriptors, methodological details, techniques, outcomes, and complications were extracted. Articles were assessed using the MINORS and Cochrane instruments. RESULTS: Thirty-one studies were included. Most studies were published in the last five years (51.6 percent) and were prospective case series (35.5 percent). The mean age of patients was 56 (range 21-82), while the mean sample size was 47 (range 10-220). The most commonly examined interventions were Radiesse (32.2 percent) and fat grafting (32.2 percent). Major complications were not observed in any study, while minor complications such as edema and pain were temporary. Injection techniques varied, however, the proximal to distal fanning technique and using a cannula was associated with a lower risk of complications. Both Radiesse and fat grafting had robust long-term esthetic outcomes. CONCLUSIONS: Hand rejuvenation is a safe and efficacious surgical intervention to reduce dorsal hand atrophy. Further studies are needed to compare the long-term outcomes of common interventions. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Minding the gap in HIV host genetics: opportunities and challenges.

Genome-wide association studies (GWAS) have been successful in identifying and confirming novel genetic variants that are associated with diverse HIV phenotypes. However, these studies have predominantly focused on European cohorts. HLA molecules have been consistently associated with HIV outcomes, some of which have been found to be population specific, underscoring the need for diversity in GWAS. Recently, there has been a concerted effort to address this gap that leads to health care (disease prevention, diagnosis, treatment) disparities with marginal improvement. As precision medicine becomes more utilized, non-European individuals will be more and more disadvantaged, as the genetic variants identified in genomic research based on European populations may not accurately reflect that of non-European individuals. Leveraging pre-existing, large, multiethnic cohorts, such as the UK Biobank, 23andMe, and the National Institute of Health's All of Us Research Program, can contribute in raising genomic research in non-European populations and ultimately lead to better health outcomes.

Impact of the COVID-19 pandemic on hyperacute stroke treatment: experience from a comprehensive stroke centre in Singapore.

The Coronavirus disease 2019 (COVID-19) pandemic is rapidly evolving and affecting healthcare systems across the world. Singapore has escalated its alert level to Disease Outbreak Response System Condition (DORSCON) Orange, signifying severe disease with community spread. We aimed to study the overall volume of AIS cases and the delivery of hyperacute stroke services during DORSCON Orange. This was a single-centre, observational cohort study performed at a comprehensive stroke centre responsible for AIS cases in the western region of Singapore, as well as providing care for COVID-19 patients. All AIS patients reviewed as an acute stroke activation in the Emergency Department (ED) from November 2019 to April 2020 were included. System processes timings, treatment and clinical outcome variables were collected. We studied 350 AIS activation patients admitted through the ED, 206 (58.9%) pre- and 144 during DORSCON Orange. Across the study period, number of stroke activations showed significant decline (p = 0.004, 95% CI 6.513 to - 2.287), as the number of COVID-19 cases increased exponentially, whilst proportion of activations receiving acute recanalization therapy remained stable (p = 0.519, 95% CI - 1.605 to 2.702). Amongst AIS patients that received acute recanalization therapy, early neurological outcomes in terms of change in median NIHSS at 24 h (-4 versus -4, p = 0.685) were largely similar between the pre- and during DORSCON orange periods. The number of stroke activations decreased while the proportion receiving acute recanalization therapy remained stable in the current COVID-19 pandemic in Singapore.

Night Orthosis After Surgical Correction of Dupuytren Contractures: A Systematic Review.

PURPOSE: To determine the role of night orthosis use after surgical correction of Dupuytren contracture. METHODS: We searched MEDLINE, EMBASE, CINAHL, AMED, OTSeeker, and CENTRAL for articles published from inception of the databases to August 2015. Assessment was undertaken by 2 independent reviewers (O.A.S. and S.A.). Methodological quality of randomized controlled trials was assessed using the Cochrane risk of bias tool and the Newcastle-Ottawa instrument. RESULTS: Seven studies met the standard for inclusion in this review. A total of 659 patients across these 7 studies were included in the analysis, with follow-up ranging from 3 to 72 months. None of the included studies assessed recurrence. The analysis revealed no significant improvement in range of motion of hand joints for patients who received a static night orthosis after Dupuytren surgery compared with patients without an orthosis. Similarly, no differences were found in patient-reported functional status across the 2 groups. CONCLUSIONS: The current literature does not appear to support the use of static night orthosis in addition to hand therapy after surgical correction of Dupuytren contracture. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Structured simulation improves learning of the Fundamental Use of Surgical Energy™ curriculum: a multicenter randomized controlled trial.

BACKGROUND: Energy devices can result in devastating complications to patients. Yet, they remain poorly understood by trainees and surgeons. A single-institution pilot study suggested that structured simulation improves knowledge of the safe use of electrosurgery (ES) among trainees (Madani et al. in Surg Endosc 28(10):2772-2782, 2014). The purpose of this study was to estimate the extent to which the addition of this structured bench-top simulation improves ES knowledge across multiple surgical training programs. METHODS: Trainees from 11 residency programs in Canada, the USA and UK participated in a 1-h didactic ES course, based on SAGES' Fundamental Use of Surgical Energy™ (FUSE) curriculum. They were then randomized to one of two groups: an unstructured hands-on session where trainees used ES devices (control group) or a goal-directed hands-on training session (Sim group). Pre- and post-curriculum (immediately and 3 months after) knowledge of the safe use of ES was assessed using separate examinations. Data are expressed as mean (SD) and N (%), *p < 0.05. RESULTS: A total of 289 (145 control; 144 Sim) trainees participated, with 186 (96 control; 90 Sim) completing the 3-month assessment. Baseline characteristics were similar between the two groups. Total score on the examination improved from 46% (10) to 84% (10)* for the entire cohort, with higher post-curriculum scores in the Sim group compared with controls [86% (9) vs. 83% (10)*]. All scores declined after 3 months, but remained higher in the Sim group [72% (18) vs. 64% (15)*]. Independent predictors of 3-month score included pre-curriculum score and participation in a goal-directed simulation. CONCLUSIONS: This multi-institutional study confirms that a 2-h curriculum based on the FUSE program improves surgical trainees' knowledge in the safe use of ES devices across training programs with various geographic locations and resident volumes. The addition of a structured interactive bench-top simulation component further improved learning.

Inferior thyroid artery pseudoaneurysm associated with internal jugular vein puncture: a case report.

BACKGROUND: Central venous catheter placement is an important aspect of patient care for the administration of fluids and medications and for monitoring purposes. However, it is still associated with significant morbidity and mortality. CASE PRESENTATION: We report a case of iatrogenic inferior thyroid artery pseudoaneurysm during the central line placement due to internal jugular vein puncture. This is a rare complication of central venous cannulation. Fortunately the pseudoaneurysm was monitored closely, diagnosed promptly and obliterated by using radiological intervention. We discuss the risk factors and management of the unintended artery puncture. CONCLUSION: The pathway of the management post arterial puncture depends on the size of the needle or catheter, which is direct related to the consequence of arterial injuries. Identifying risk factors is very important to avoid the complications. However, the use of ultrasound guided venipuncture is the most important method to avoid mechanical complications.

Stopping anger and anxiety: evidence that inhibitory ability predicts negative emotional responding.

Research has begun to suggest that cognitive ability contributes to emotional processes and responses. The present study sought novel evidence for this hypothesis by examining the relationship between individual differences in the capacity for inhibitory control and responses to a common emotion-induction procedure involving autobiographical memories. Participants first completed a stop-signal task to measure inhibitory control and then underwent an anger, anxiety, or neutral emotion induction. Performance on the stop-signal task predicted emotional responses such that participants with poorer inhibitory control reported larger increases in anger following the anger induction and larger increases in anxiety across emotion induction conditions, relative to better inhibitors. These results suggest that individual differences in cognitive ability may influence the intensity of emotional states induced by common laboratory methods of emotion induction.

Mortality salience biases attention to positive versus negative images among individuals higher in trait self-control.

Death is inevitable. One way people cope with awareness of death is to focus on the positive things in life. Consistent with this idea, reminders of personal mortality have been found to increase optimism and tune attention towards positive information. The current research tested the hypothesis that persons higher in trait self-control are especially likely to attend to positive (versus negative) stimuli under mortality salience (MS). Participants completed a measure of trait self-control, contemplated their own mortality or a control topic, and then viewed positive and negative affective images while their gaze patterns were recorded. MS increased the attention to positive (versus negative) images among participants higher in trait self-control, whereas those lower in trait self-control exhibited a non-significant trend in the opposite direction. Thus, participants higher in trait self-control showed a positivity bias after contemplating death, which may help explain why they tend to enjoy more positive outcomes in life.

Biological age estimation using circulating blood biomarkers.

Biological age captures physiological deterioration better than chronological age and is amenable to interventions. Blood-based biomarkers have been identified as suitable candidates for biological age estimation. This study aims to improve biological age estimation using machine learning models and a feature-set of 60 circulating biomarkers available from the UK Biobank (n = 306,116). We implement an Elastic-Net derived Cox model with 25 selected biomarkers to predict mortality risk (C-Index = 0.778; 95% CI [0.767-0.788]), which outperforms the well-known blood-biomarker based PhenoAge model (C-Index = 0.750; 95% CI [0.739-0.761]), providing a C-Index lift of 0.028 representing an 11% relative increase in predictive value. Importantly, we then show that using common clinical assay panels, with few biomarkers, alongside imputation and the model derived on the full set of biomarkers, does not substantially degrade predictive accuracy from the theoretical maximum achievable for the available biomarkers. Biological age is estimated as the equivalent age within the same-sex population which corresponds to an individual's mortality risk. Values ranged between 20-years younger and 20-years older than individuals' chronological age, exposing the magnitude of ageing signals contained in blood markers. Thus, we demonstrate a practical and cost-efficient method of estimating an improved measure of Biological Age, available to the general population.

Co-crystallisation and humanisation of an anti-HER2 single-domain antibody as a theranostic tool.

Human epidermal growth factor receptor-2 (HER2) is a well-recognised biomarker associated with 25% of breast cancers. In most cases, early detection and/or treatment correlates with an increased chance of survival. This study, has identified and characterised a highly specific anti-HER2 single-domain antibody (sdAb), NM-02, as a potential theranostic tool. Complete structural description by X-ray crystallography has revealed a non-overlapping epitope with current anti-HER2 antibodies. To reduce the immunogenicity risk, NM-02 underwent a humanisation process and retained wild type-like binding properties. To further de-risk the progression towards chemistry, manufacturing and control (CMC) we performed full developability profiling revealing favourable thermal and physical biochemical 'drug-like' properties. Finally, the application of the lead humanised NM-02 candidate (variant K) for HER2-specific imaging purposes was demonstrated using breast cancer HER2+/BT474 xenograft mice.

Enhanced external counter pulsation therapy in patients with symptomatic and severe intracranial steno-occlusive disease: a randomized clinical trial protocol.

Intracranial stenosis is prevalent among Asians and constitutes a common cause of cerebral ischemia. While the best medical therapy carries stroke recurrence rates in excess of 10% per year, trials with intracranial stenting have been associated with unacceptable peri-procedural ischemic events. Cerebral ischemic events are strongly related to the severity of intracranial stenosis, which is high in patients with severe intracranial stenosis with poor vasodilatory reserve. Enhanced External Counter Pulsation (EECP) therapy is known to improve myocardial perfusion by facilitating the development of collateral blood vessels in the heart. In this randomized clinical trial, we evaluate whether EECP therapy may be useful in patients with severe stenosis of intracranial internal carotid (ICA) or middle cerebral artery (MCA). The review of literature, methods of evaluation, status of currently used therapeutic approaches, and trial protocol have been presented. Clinical trial registration: ClinicalTrials.gov, Identifier: NCT03921827.

A comparative study using electromyography to assess hand exercises for rehabilitation after ulnar nerve decompression.

Ulnar nerve (UN) entrapment is a common peripheral neuropathy and can lead to dysfunction of both sensory and motor function of the hand. Surgical release is the mainstay of treatment, but post-operative rehabilitation of UN innervated intrinsic muscles is lacking evidence. This cohort study utilized surface electromyography (EMG) and assessed the activation of UN innervated intrinsic and extrinsic hand muscles during four exercises in healthy participants. Exercises included rotating baoding balls, squeezing a stress ball or grip device every second, and repetitive finger abduction against a rubber band. Normalized percent activation of each muscle was calculated for each exercise. It was demonstrated that rubber band resistance (RBR) finger abduction showed significantly increased activation in both intrinsic muscles tested, while minimizing activation of the one tested UN innervated extrinsic muscle. Thus, to best target the intrinsic hand muscles without fatiguing extrinsic muscles, the inexpensive and practical RBR exercise is beneficial in post-UN release rehabilitation.

Autoimmune glial fibrillary acidic protein astrocytopathy masquerading as tuberculosis of the central nervous system: a case series.

We describe the case history of three patients with meningoencephalitis who were initially treated for presumed tuberculous meningoencephalitis before being diagnosed with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. We highlight the overlapping clinical features between autoimmune GFAP astrocytopathy and tuberculous meningoencephalitis and the challenges in early diagnosis, as both entities respond to an initial course of steroids accompanying antituberculous medications. Early evaluation of GFAP-immunoglobulin G in the cerebrospinal fluid of patients who present with aseptic meningoencephalitis could reveal autoimmune GFAP astrocytopathy, which responds favorably to immunotherapy.

Prospective Multicenter Randomized Controlled Trial Comparing Early Protected Movement and Splinting for Fifth Metacarpal Neck Fracture.

BACKGROUND: Fifth metacarpal neck fractures account for 20% of all hand fractures, yet there remains debate with respect to management, particularly when conservative treatment is initiated. The objective of this study is to compare functional and patient-reported outcomes (PROs) in patients treated with early protected movement or splint immobilization. METHODS: This national multicenter prospective randomized controlled trial compared 2 groups; elastic bandage with early protected movement versus immobilization with splinting. Demographic characteristics were collected at baseline. Functional outcomes (grip strength testing) and PROs (Brief Michigan Hand Questionnaire [bMHQ]) were collected at 4, 8, and 12 weeks post-intervention. Grip strength values of the injured hand were normalized to both the non-injured hand (at baseline), and the Canadian reference values. RESULTS: Thirty-seven participants from 5 Canadian centers were randomized into the splint (n = 21) or elastic bandage group (n = 16). There were no significant differences in the bMHQ score between the splint (52.1 ± 27.2) or the elastic bandage (46.6 ± 20.4) groups (P = .51). There were no differences in baseline grip strength between the splint (15.3 ± 8.9 kg) and elastic bandage (19.9 ± 7.5 kg) groups. At 8 weeks, the elastic bandage group had a significantly higher grip strength than the splint group (93% vs 64%, respectively: P < .05), when standardized as a percentage of the Canadian reference values. CONCLUSION: Patients with Boxer's fractures treated with early protected movement had better functional outcomes by 8 weeks post-treatment as compared to the Canadian reference values of those treated with immobilization and splinting. Providers should manage Boxer's fractures with early protected movement.

RENSEIGNEMENTS GÉNÉRAUX: Les fractures du col du cinquième métacarpien représentent 20 % de toutes les fractures de la main, mais leur prise en charge ne fait pas l'unanimité, en particulier lorsqu'un traitement classique est instauré. L'objectif de cette étude consiste à comparer les résultats fonctionnels et les résultats déclarés par le patient traité au moyen d'une protection contre le mouvement instaurée de manière précoce ou d'une attelle pourimmobilization. MÉTHODOLOGIE: Cet essai multicentrique, national, prospectif, contrôlé et mené à répartition aléatoire a comparé 2 groupes recevant les traitements suivants: un bandage élastique et une protection contre le mouvement instaurée de manière précoce, d'une part, et une attelle pourimmobilization, d'autre part. Les caractéristiques démographiques ont été recueillies au début de l'étude. Les résultats fonctionnels (épreuve de force de préhension) et les résultats déclarés par le patient (questionnaire bMHQ [Brief Michigan Hand Questionnaire], question bref de Michigan portant sur les mains) ont été recueillis 4, 8 et 12 semaines après l'intervention. Les valeurs de la force de préhension de la main blessée ont été normalisées en fonction à la fois de la main non blessée (au départ) et des valeurs de référence canadiennes. RÉSULTATS: Trente-sept participants de cinq centres canadiens ont été répartis aléatoirement dans le groupe traité au moyen d'une attelle (n = 21) ou celui traité par un bandage élastique (n = 16). Aucune différence significative sur le plan du score bMHQ n'a été observé entre les groupes traité au moyen d'une attelle (52,1 ± 27,2) ou d'un bandage élastique (46,6 ± 20,4; P = .51). Il n'y avait aucune différence au chapitre de la force de préhension initiale entre le groupe traité au moyen d'une attelle (15,3 ± 8,9 kg) et celui traité par un bandage élastique (19,9 ± 7,5 kg). Après huit semaines, le groupe traité par un bandage élastique présentait une force de préhension significativement plus élevée que celle du groupe traité au moyen d'une attelle (93 % contre 64 %, respectivement: P < .05), après la normalizationdes valeurs en pourcentage par rapport aux valeurs de référence canadiennes. CONCLUSION: Les patients subissant une « fracture du boxeur ¼ traités au moyen d'une protection contre le mouvement instaurée de manière précoce obtenaient de meilleurs résultats fonctionnels huit semaines après le traitement, vis-à-vis des valeurs de référence canadiennes, que ceux traités par une attelle pourimmobilization. Les professionnels de la santé devraient donc prendre en charge les fractures de boxeur au moyen d'une protection contre le mouvement instaurée de manière précoce.

Twin peaks: The Omicron SARS-CoV-2 BA.1 and BA.2 epidemics in England.

Rapid transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has led to record-breaking incidence rates around the world. The Real-time Assessment of Community Transmission-1 (REACT-1) study has tracked SARS-CoV-2 infection in England using reverse transcription polymerase chain reaction (RT-PCR) results from self-administered throat and nose swabs from randomly selected participants aged 5 years and older approximately monthly from May 2020 to March 2022. Weighted prevalence in March 2022 was the highest recorded in REACT-1 at 6.37% (N = 109,181), with the Omicron BA.2 variant largely replacing the BA.1 variant. Prevalence was increasing overall, with the greatest increase in those aged 65 to 74 years and 75 years and older. This was associated with increased hospitalizations and deaths, but at much lower levels than in previous waves against a backdrop of high levels of vaccination.

Dynamics of competing SARS-CoV-2 variants during the Omicron epidemic in England.

The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant (first detected in November 2021) exhibited a high degree of immune evasion, leading to increased infection rates worldwide. However, estimates of the magnitude of this Omicron wave have often relied on routine testing data, which are prone to several biases. Using data from the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys assessing prevalence of SARS-CoV-2 infection in England, we estimated the dynamics of England's Omicron wave (from 9 September 2021 to 1 March 2022). We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct variants, intermittent epidemics of similar magnitudes may become the 'new normal'.