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.

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.

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).

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.

Dynamics of a national Omicron SARS-CoV-2 epidemic during January 2022 in England.

Rapid transmission of the SARS-CoV-2 Omicron variant has led to record-breaking case incidence rates around the world. Since May 2020, the REal-time Assessment of Community Transmission-1 (REACT-1) study tracked the spread of SARS-CoV-2 infection in England through RT-PCR of self-administered throat and nose swabs from randomly-selected participants aged 5 years and over. In January 2022, we found an overall weighted prevalence of 4.41% (n = 102,174), three-fold higher than in November to December 2021; we sequenced 2,374 (99.2%) Omicron infections (19 BA.2), and only 19 (0.79%) Delta, with a growth rate advantage for BA.2 compared to BA.1 or BA.1.1. Prevalence was decreasing overall (reproduction number R = 0.95, 95% credible interval [CrI], 0.93, 0.97), but increasing in children aged 5 to 17 years (R = 1.13, 95% CrI, 1.09, 1.18). In England during January 2022, we observed unprecedented levels of SARS-CoV-2 infection, especially among children, driven by almost complete replacement of Delta by Omicron.

Omicron SARS-CoV-2 epidemic in England during February 2022: A series of cross-sectional community surveys.

Background: The Omicron wave of COVID-19 in England peaked in January 2022 resulting from the rapid transmission of the Omicron BA.1 variant. We investigate the spread and dynamics of the SARS-CoV-2 epidemic in the population of England during February 2022, by region, age and main SARS-CoV-2 sub-lineage. Methods: In the REal-time Assessment of Community Transmission-1 (REACT-1) study we obtained data from a random sample of 94,950 participants with valid throat and nose swab results by RT-PCR during round 18 (8 February to 1 March 2022). Findings: We estimated a weighted mean SARS-CoV-2 prevalence of 2.88% (95% credible interval [CrI] 2.76-3.00), with a within-round effective reproduction number (R) overall of 0.94 (0·91-0.96). While within-round weighted prevalence fell among children (aged 5 to 17 years) and adults aged 18 to 54 years, we observed a level or increasing weighted prevalence among those aged 55 years and older with an R of 1.04 (1.00-1.09). Among 1,616 positive samples with sublineages determined, one (0.1% [0.0-0.3]) corresponded to XE BA.1/BA.2 recombinant and the remainder were Omicron: N=1047, 64.8% (62.4-67.2) were BA.1; N=568, 35.2% (32.8-37.6) were BA.2. We estimated an R additive advantage for BA.2 (vs BA.1) of 0.38 (0.34-0.41). The highest proportion of BA.2 among positives was found in London. Interpretation: In February 2022, infection prevalence in England remained high with level or increasing rates of infection in older people and an uptick in hospitalisations. Ongoing surveillance of both survey and hospitalisations data is required. Funding: Department of Health and Social Care, England.

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'.

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.

Rapid increase in Omicron infections in England during December 2021: REACT-1 study.

The unprecedented rise in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections during December 2021 was concurrent with rapid spread of the Omicron variant in England and globally. We analyzed the prevalence of SARS-CoV-2 and its dynamics in England from the end of November to mid-December 2021 among almost 100,000 participants in the REACT-1 study. Prevalence was high with rapid growth nationally and particularly in London during December 2021, with an increasing proportion of infections due to Omicron. We observed large decreases in swab positivity among mostly vaccinated older children (12 to 17 years) relative to unvaccinated younger children (5 to 11 years), and in adults who received a third (booster) vaccine dose versus two doses. Our results reinforce the importance of vaccination and booster campaigns, although additional measures have been needed to control the rapid growth of the Omicron variant.

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.

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.

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 .

The Role of Senior Resident Clinics in Plastic Surgery Education in Canada.

BACKGROUND: Senior resident clinics are a means to encourage independent practice and problem solving and enhance surgical skills. The objective of this study is to investigate senior resident clinics across Canada and their utility in providing comprehensive plastic surgery training. METHODS: A web-based survey was sent to all plastic surgery program directors (PDs) and senior residents (SRs; postgraduate years 3, 4, and 5) across Canada. The surveys focused on demographics, clinic structure, procedures commonly performed, perceived autonomy, educational benefit, competency-based design considerations, and areas for improvement. Chi-square tests were used to compare responses between PDs and SRs. RESULTS: A total of 10 PDs (100% response rate) and 26 SRs (41% response rate) responded. Half of the training programs across Canada currently have senior clinics, and the format varies between institutions. Clinics generally focus on hand trauma and aesthetics. Both PDs and SRs felt that there is considerable autonomy for resident care in both the pre/post-operative and operative setting. Common barriers to implementing a senior clinic include not enough staff, not enough time, and the medicolegal risk. Most core competencies are felt to be addressed through the use of senior clinics. Methods to improve senior clinics could include more regular and higher volume clinics, enhanced equipment, and separation of hand and aesthetics clinics. CONCLUSIONS: Senior clinics are a useful method to improve plastic surgery education and address many core aspects of plastic surgery training. Implementation of supported clinics focused on hand and aesthetics surgery separately may be useful for training programs that currently lack a senior clinic.

Cross-Reactive SARS-CoV-2 Neutralizing Antibodies From Deep Mining of Early Patient Responses.

Passive immunization using monoclonal antibodies will play a vital role in the fight against COVID-19. The recent emergence of viral variants with reduced sensitivity to some current antibodies and vaccines highlights the importance of broad cross-reactivity. This study describes deep-mining of the antibody repertoires of hospitalized COVID-19 patients using phage display technology and B cell receptor (BCR) repertoire sequencing to isolate neutralizing antibodies and gain insights into the early antibody response. This comprehensive discovery approach has yielded a panel of potent neutralizing antibodies which bind distinct viral epitopes including epitopes conserved in SARS-CoV-1. Structural determination of a non-ACE2 receptor blocking antibody reveals a previously undescribed binding epitope, which is unlikely to be affected by the mutations in any of the recently reported major viral variants including B.1.1.7 (from the UK), B.1.351 (from South Africa) and B.1.1.28 (from Brazil). Finally, by combining sequences of the RBD binding and neutralizing antibodies with the B cell receptor repertoire sequencing, we also describe a highly convergent early antibody response. Similar IgM-derived sequences occur within this study group and also within patient responses described by multiple independent studies published previously.

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.

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.

Current status in decision making to treat acute type A dissection: limited versus extended repair.

Acute type A aortic dissection remains one of the most challenging conditions in aortic surgery. Despite the advancements in the field, the mortality rate still remains high. Though there is a general consensus that the ascending aorta should be replaced, the distal extension of the surgery still remains a controversy. Few surgeons argue for a conservative approach to reduce operative and postoperative morbidity while others considering the problems associated with "downstream problems" support an aggressive approach including a frozen elephant trunk. The cohort in the Indian subcontinent and APAC is far different from the western world. Many factors determine the decision for surgery apart from the pathology of the disease. Economy, availability of the suitable prosthesis, the experience of the surgeon, ease of access to the medical facility all contribute to the decision making to treat acute type A dissection.