EMQN best practice guidelines for genetic testing in hereditary breast and ovarian cancer.

Hereditary Breast and Ovarian Cancer (HBOC) is a genetic condition associated with increased risk of cancers. The past decade has brought about significant changes to hereditary breast and ovarian cancer (HBOC) diagnostic testing with new treatments, testing methods and strategies, and evolving information on genetic associations. These best practice guidelines have been produced to assist clinical laboratories in effectively addressing the complexities of HBOC testing, while taking into account advancements since the last guidelines were published in 2007. These guidelines summarise cancer risk data from recent studies for the most commonly tested high and moderate risk HBOC genes for laboratories to refer to as a guide. Furthermore, recommendations are provided for somatic and germline testing services with regards to clinical referral, laboratory analyses, variant interpretation, and reporting. The guidelines present recommendations where 'must' is assigned to advocate that the recommendation is essential; and 'should' is assigned to advocate that the recommendation is highly advised but may not be universally applicable. Recommendations are presented in the form of shaded italicised statements throughout the document, and in the form of a table in supplementary materials (Table S4). Finally, for the purposes of encouraging standardisation and aiding implementation of recommendations, example report wording covering the essential points to be included is provided for the most common HBOC referral and reporting scenarios. These guidelines are aimed primarily at genomic scientists working in diagnostic testing laboratories.

Rapid nursing redeployment from a specialist ward to a COVID-19 high-dependency setting.

BACKGROUND: Redeployment in health care can have a negative impact on the mental wellbeing of staff. Advanced planning and provisions for wellbeing support for health professionals has been recommended following previous pandemics. At the authors' institution nurses were redeployed overnight from a specialist cystic fibrosis ward to a COVID-19 high-dependency unit. AIM: To evaluate nurses' wellbeing following this redeployment during the first wave of the COVID-19 pandemic. METHOD: A mixed online survey, consisting of both open and closed questions, based on literature, preliminary results of the Impact of COVID-19 on the Nursing and Midwifery Workforce (ICON) study and staff feedback. This was sent to 28 nurses to explore their feelings and experiences of redeployment to a COVID-19 environment. Purposive sampling was used to select study participants while thematic analysis and descriptive statistics were used to analyse the data. FINDINGS: The survey had an 86% response rate. Using thematic analysis three key themes emerged: redeployment anxiety, lack of organisational preparedness and newfound teamworking. More than half (57%) of respondents expressed anxiety and concern when told of their redeployment; 52% reported that they did not receive adequate support from senior staff and management. However, 74% reported that they felt their nursing was positively influenced by support and teamwork from those in patient-facing roles. Twenty-five percent reported that they were looking for a new job or leaving their current role. CONCLUSION: This study examines the effects that redeployment to a COVID-19 environment has had on nurses. It highlights the need for further improvement to ensure redeployed staff are supported to safeguard their mental wellbeing.

Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey.

BACKGROUND: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. METHODS: In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). RESULTS: Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. CONCLUSION: The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.

Erratum: A method to computationally screen for tunable properties of crystalline alloys.

[This corrects the article DOI: 10.1016/j.patter.2023.100723.].

Ascorbic Acid for Methemoglobinemia Treatment: A Case Report and Literature Review.

PURPOSE: Ascorbic acid has been proposed as an alternative treatment for methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, its efficacy has never been compared to that of methylene blue given the inability of patients with G6PD deficiency to receive methylene blue. We present a case of methemoglobinemia treated with ascorbic acid in a patient without G6PD deficiency who had previously received methylene blue. SUMMARY: A 66-year-old male was treated for methemoglobinemia deemed to be secondary to benzocaine throat spray. He received intravenous (IV) methylene blue but had a severe reaction: diaphoresis, lightheadedness, and hypotension. The infusion was stopped prior to completion. Approximately 6 days later he presented with methemoglobinemia following an additional overconsumption of benzocaine and was treated with ascorbic acid. In both instances his methemoglobin levels were >30% on arterial blood gas on admission and decreased to 6.5% and 7.8%, respectively, after administration of methylene blue and ascorbic acid. CONCLUSION: Ascorbic acid had a similar effect on decreasing the concentration of methemoglobin compared to methylene blue. Further research into use of ascorbic acid as a recommended agent for treatment of methemoglobinemia is warranted.

Hepmarc: A 96 week randomised controlled feasibility trial of add-on maraviroc in people with HIV and non-alcoholic fatty liver disease.

OBJECTIVES: Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further exploration. METHODS: We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores. RESULTS: Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6-7.8) kPa, 325 (IQR 279-351) dB/m and 9.1 (IQR 8.6-9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores. CONCLUSIONS: This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis. TRIAL REGISTRATION: Clinical trial registry: ISCRTN, registration number 31461655.

Oil contamination of sediments by freeze-drying versus air-drying for organic geochemical analysis.

Freeze-drying is widely used in geochemical laboratories for preparing wet solid environmental samples such as sediments and soils before being analyzed for their contents and states of various metal elements and labile organic components that may be temperature- and/or redox-sensitive. Screening bulk geochemical analysis of two Artic lake sediment samples prepared by freeze-drying displayed unexpectedly high contents of labile organic matter (OM) represented by the Rock-Eval S1 peaks (e.g., 8.12 and 4.84 mg HC/g sediment). The amount of labile OM was reduced greatly for the freeze-dried sediment samples after a thorough cleaning of the freeze-drier sample chamber (e.g., 2.75 and 1.46 mg HC/g sediment), but was still significantly higher than that of the equivalent air-dried samples (e.g., 0.76 and 0.23 mg HC/g sediment). Compositional analysis of the labile OM fractions by gas chromatography (GC) of both freeze-dried and air-dried aliquots of the same sediments indicates the presence of unresolved complex mixture (UCM) humps of C10-C23 hydrocarbons in the freeze-dried samples. In contrast, air-dried samples, either real sediments or blank laboratory materials represented by clean sand and thermally spent shale, do not show the C10-C23 hydrocarbon UCM humps on their GC traces. The hydrocarbon UCM humps persist in the freeze-dried samples even they further went through air-drying at ambient conditions. Both bulk and compositional analytical results in this work appear to indicate the potential risk of introduction of external hydrocarbons to the prepared materials during freeze-drying process, especially if an aged freeze-drier was used without being thoroughly cleaned and if pump oil and cooling fluids were components of the device.

A method to computationally screen for tunable properties of crystalline alloys.

Conventionally, high-throughput computational materials searches start from an input set of bulk compounds extracted from material databases, but, in contrast, many real functional materials are heavily engineered mixtures of compounds rather than single bulk compounds. We present a framework and open-source code to automatically construct and analyze possible alloys and solid solutions from a set of existing experimental or calculated ordered compounds, without requiring additional metadata except crystal structure. As a demonstration, we apply this framework to all compounds in the Materials Project to create a new, publicly available database of >600,000 unique "alloy pair" entries that can be used to search for materials with tunable properties. We exemplify this approach by searching for transparent conductors and reveal candidates that might have been excluded in a traditional screening. This work lays a foundation from which materials databases can go beyond stoichiometric compounds and approach a more realistic description of compositionally tunable materials.

Everyday emotional functioning in COVID-19 lockdowns.

Throughout the COVID-19 pandemic, policy makers have tried to balance the effectiveness of lockdowns (i.e., stay-at-home orders) with their potential mental health costs. Yet, several years into the pandemic, policy makers lack solid evidence about the toll of lockdowns on daily emotional functioning. Using data from two intensive longitudinal studies conducted in Australia in 2021, we compared the intensity, persistence, and regulation of emotions on days in and out of lockdown. Participants (N = 441, observations = 14,511) completed a 7-day study either entirely in lockdown, entirely out of lockdown, or both in and out of lockdown. We assessed emotions in general (Dataset 1) and in the context of social interactions (Dataset 2). Lockdowns took an emotional toll, but this toll was relatively mild: In lockdown, people experienced slightly more negative and less positive emotion; returned to a mildly negative emotional state more quickly; and used low-effort emotion-regulation strategies (i.e., distraction). There are three interpretations for our findings, which are not mutually exclusive. First, people may be relatively resilient to the emotional challenges posed by repeated lockdowns. Second, lockdowns may not compound the emotional challenges of the pandemic. Third, because we found effects even in a mostly childless and well-educated sample, lockdowns may take a greater emotional toll in samples with less pandemic privilege. Indeed, the high level of pandemic privilege of our sample limits the generalizability of our findings (e.g., to people with caregiving roles). (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Nagging Pain and Foot Ulcers Can be Treated into Remission.

Lower extremity ulcerations are very common in patients with diabetes. These wounds lead to amputation in a surprisingly large percentage of patients with diabetes. The mortality rate following amputation in a patient with diabetes is alarmingly high. Preventive treatment is pivotal to avoid the numerous complications associated with diabetic ulcerations. However, at the onset of ulceration, early treatment under the supervision and guidance of a specialist can result in remission. Diabetic peripheral neuropathy is also a life-altering and debilitating disease. Although some patients experience numbness, some experience pain that can be sharp, shooting, and tingling. Although treatment is challenging and often requires medication, newer modalities, such as stimulation and physical therapy, have shown promise in reversing the devastating effects of peripheral neuropathy.

Gait asymmetry and running-related injury in female collegiate cross-country runners.

BACKGROUND: Running biomechanics are commonly linked to injury. There is limited evidence on the effects of running speed on asymmetry and the prospective association of asymmetry and injury. The purposes of this study were to describe the degree in asymmetry in biomechanical variables commonly associated with injury, examine the effect of speed on asymmetry, and determine if there were any significant differences in pre-season measures of asymmetry between runners who went on to sustain an injury during the competitive season compared to those who remained healthy. METHODS: Three-dimensional running biomechanics were obtained from twenty-two female collegiate cross-country runners at four different running speeds prior to their season. Asymmetry was quantified using the Symmetry Angle. Participants were followed over the twelve-week season and all time-loss injuries were identified. FINDINGS: There was no significant effect of velocity on asymmetry. Additionally, there were no significant differences in symmetry between runners who sustained an injury (n = 7) and those that remained injury-free (n = 15) during the cross-country season. INTERPRETATION: Clinicians working with runners should expect a high degree of symmetry in running biomechanics when performing gait analyses across running speeds. In regards to injury, caution should be used when linking injury to asymmetry.

Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records.

OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

ADHD symptoms and diagnosis in adult preterms: systematic review, IPD meta-analysis, and register-linkage study.

BACKGROUND: This study examined differences in ADHD symptoms and diagnosis between preterm and term-born adults (≥18 years), and tested if ADHD is related to gestational age, birth weight, multiple births, or neonatal complications in preterm borns. METHODS: (1) A systematic review compared ADHD symptom self-reports and diagnosis between preterm and term-born adults published in PubMed, Web of Science, and PROQUEST until April 2021; (2) a one-stage Individual Participant Data(IPD) meta-analysis (n = 1385 preterm, n = 1633 term; born 1978-1995) examined differences in self-reported ADHD symptoms[age 18-36 years]; and (3) a population-based register-linkage study of all live births in Finland (01/01/1987-31/12/1998; n = 37538 preterm, n = 691,616 term) examined ADHD diagnosis risk in adulthood (≥18 years) until 31/12/2016. RESULTS: Systematic review results were conflicting. In the IPD meta-analysis, ADHD symptoms levels were similar across groups (mean z-score difference 0.00;95% confidence interval [95% CI] -0.07, 0.07). Whereas in the register-linkage study, adults born preterm had a higher relative risk (RR) for ADHD diagnosis compared to term controls (RR = 1.26, 95% CI 1.12, 1.41, p < 0.001). Among preterms, as gestation length (RR = 0.93, 95% CI 0.89, 0.97, p < 0.001) and SD birth weight z-score (RR = 0.88, 95% CI 0.80, 0.97, p < 0.001) increased, ADHD risk decreased. CONCLUSIONS: While preterm adults may not report higher levels of ADHD symptoms, their risk of ADHD diagnosis in adulthood is higher. IMPACT: Preterm-born adults do not self-report higher levels of ADHD symptoms, yet are more likely to receive an ADHD diagnosis in adulthood compared to term-borns. Previous evidence has consisted of limited sample sizes of adults and used different methods with inconsistent findings. This study assessed adult self-reported symptoms across 8 harmonized cohorts and contrasted the findings with diagnosed ADHD in a population-based register-linkage study. Preterm-born adults may not self-report increased ADHD symptoms. However, they have a higher risk of ADHD diagnosis, warranting preventive strategies and interventions to reduce the presentation of more severe ADHD symptomatology in adulthood.

Do People Work Hard to Maintain Social Distance?

How far away from each other people sit or stand reveals much about their social proximity, but merely sitting or standing may not test the limits of social boundaries as much as collaborating on tasks requiring physical coordination. In this study, we asked university students to walk two abreast while carrying a long pipe from one end of a workspace to another. Hurdles in the workspace forced the dyads to decide whether to walk close together without stepping over the hurdles or walk farther apart, stepping over the hurdles. The subjects often chose the latter option, stepping over 18-inch high hurdles rather than walking on level ground.

Big Data in a Nano World: A Review on Computational, Data-Driven Design of Nanomaterials Structures, Properties, and Synthesis.

The recent rise of computational, data-driven research has significant potential to accelerate materials discovery. Automated workflows and materials databases are being rapidly developed, contributing to high-throughput data of bulk materials that are growing in quantity and complexity, allowing for correlation between structural-chemical features and functional properties. In contrast, computational data-driven approaches are still relatively rare for nanomaterials discovery due to the rapid scaling of computational cost for finite systems. However, the distinct behaviors at the nanoscale as compared to the parent bulk materials and the vast tunability space with respect to dimensionality and morphology motivate the development of data sets for nanometric materials. In this review, we discuss the recent progress in data-driven research in two aspects: functional materials design and guided synthesis, including commonly used metrics and approaches for designing materials properties and predicting synthesis routes. More importantly, we discuss the distinct behaviors of materials as a result of nanosizing and the implications for data-driven research. Finally, we share our perspectives on future directions for extending the current data-driven research into the nano realm.

Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility.

The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.