Curating genomic disease-gene relationships with Gene2Phenotype (G2P).

Genetically determined disorders are highly heterogenous in clinical presentation and underlying molecular mechanism. The evidence underpinning these conditions in the peer-reviewed literature requires robust critical evaluation for diagnostic use. Here, we present a structured curation process for Gene2Phenotype (G2P).

Evaluation of the usability and acceptability of the P-STEP® mobile app: feasibility study protocol.

Background: The new P-STEP® (Personalised Space Technology Exercise Platform) app is designed to bring together tailored exercise guidance and up-to-date air quality information. The app allows individuals to plan outdoor exercise walking routes while minimising their exposure to air pollution. Individuals with chronic long-term conditions, particularly respiratory and cardiovascular conditions, can use the app in order to minimise the risk of their symptoms being exacerbated by pollution, while still gaining the benefits of outdoor exercise.

Private Doctors' Perspective towards "Patient First" in TB Diagnostic Cascade, Hisar, India.

TB diagnosis has been simplified in India following advances in available diagnostic tools. This facilitates private doctors' "patient first" approach toward early diagnosis; however, costs remain high. India's NTEP established a TB diagnostic network, which is free for patients and incentivizes private doctors to participate.

Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need.

Clonal CD8 T Cells Accumulate in the Leptomeninges and Communicate with Microglia in Human Neurodegeneration.

Murine studies have highlighted a crucial role for immune cells in the meninges in surveilling the central nervous system (CNS) and influencing neuroinflammation. However, how meningeal immunity is altered in human neurodegeneration and its effects on CNS inflammation is understudied. We performed the first single-cell analysis of the transcriptomes and T cell receptor (TCR) repertoire of 104,635 immune cells from 55 postmortem human brain and leptomeningeal tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease.

Simultaneous spectral differentiation of multiple fluorophores in super-resolution imaging using a glass phase plate.

By engineering the point-spread function (PSF) of single molecules, different fluorophore species can be imaged simultaneously and distinguished by their unique PSF patterns. Here, we insert a silicon-dioxide phase plate at the Fourier plane of the detection path of a wide-field fluorescence microscope to produce distinguishable PSFs (X-PSFs) at different wavelengths. We demonstrate that the resulting PSFs can be localized spatially and spectrally using a maximum-likelihood estimation algorithm and can be utilized for hyper-spectral super-resolution microscopy of biological samples.

Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration.

Recent murine studies have highlighted a crucial role for the meninges in surveilling the central nervous system (CNS) and influencing CNS inflammation. However, how meningeal immunity is altered in human neurodegeneration and its potential effects on neuroinflammation is understudied. In the present study, we performed single-cell analysis of the transcriptomes and T cell receptor repertoire of 72,576 immune cells from 36 postmortem human brain and leptomeninges tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease.

The role of high cholesterol in SARS-CoV-2 infectivity.

Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2. The virus binds to angiotensinogen converting enzyme 2 (ACE2), which mediates viral entry into mammalian cells. COVID-19 is notably severe in the elderly and in those with underlying chronic conditions.

Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.

Background: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits.

Methods: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland.

Rapid 3D-STORM imaging of diverse molecular targets in tissue.

Fine-scale molecular architecture is critical for nervous system and other biological functions. Methods to visualize these nanoscale structures would benefit from enhanced accessibility, throughput, and tissue compatibility. Here, we report RAIN-STORM, a rapid and scalable nanoscopic imaging optimization approach that improves three-dimensional visualization for subcellular targets in tissue at depth.

Very early invasive angiography versus standard of care in higher-risk non-ST elevation myocardial infarction: study protocol for the prospective multicentre randomised controlled RAPID N-STEMI trial.

Background: There are a paucity of randomised data on the optimal timing of invasive coronary angiography (ICA) in higher-risk patients with non-ST elevation myocardial infarction (N-STEMI). International guideline recommendations for early ICA are primarily based on retrospective subgroup analyses of neutral trials.

Aims: The RAPID N-STEMI trial aims to determine whether very early percutaneous revascularisation improves clinical outcomes as compared with a standard of care strategy in higher-risk N-STEMI patients.

Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory airway disease. The epithelial-derived IL-33 and its receptor ST2 have been implicated in airway inflammation and infection. We aimed to determine whether astegolimab, a selective ST2 IgG2 monoclonal antibody, reduces exacerbations in COPD.

Arthroscopic hip surgery compared with personalised hip therapy in people over 16 years old with femoroacetabular impingement syndrome: UK FASHIoN RCT.

Background: Femoroacetabular impingement syndrome is an important cause of hip pain in young adults. It can be treated by arthroscopic hip surgery or with physiotherapist-led conservative care.

Objective: To compare the clinical effectiveness and cost-effectiveness of hip arthroscopy with best conservative care.

Comparing ultrastable lasers at 7 × 10 fractional frequency instability through a 2220 km optical fibre network.

Ultrastable lasers are essential tools in optical frequency metrology enabling unprecedented measurement precision that impacts on fields such as atomic timekeeping, tests of fundamental physics, and geodesy. To characterise an ultrastable laser it needs to be compared with a laser of similar performance, but a suitable system may not be available locally. Here, we report a comparison of two geographically separated lasers, over the longest ever reported metrological optical fibre link network, measuring 2220 km in length, at a state-of-the-art fractional-frequency instability of 7 × 10 for averaging times between 30 s and 200 s.

The role of high cholesterol in age-related COVID19 lethality.

Coronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan, China in 2019. The disease is notably severe in elderly and those with underlying chronic conditions. A molecular mechanism that explains why the elderly are vulnerable and why children are resistant is largely unknown.

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice.

Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown.

Prolonged survival after disseminated Rhinocladiella infection treated with surgical excision and posaconazole.

Cerebral abscess due to pigmented molds is a rare but usually fatal infection occasionally seen in transplant recipients. A 67-year-old man of Iraqi origin underwent a deceased donation renal transplant for renal failure and 2 months later was diagnosed with an abscess in the left posterior frontal lobe of his brain. Subsequent biopsy proved this to be due to the mold Rhinocladiella mackenziei.

Cavity-enhanced non-destructive detection of atoms for an optical lattice clock.

We demonstrate a new method of cavity-enhanced non-destructive detection of atoms for a strontium optical lattice clock. The detection scheme is shown to be linear in atom number up to at least 2×10 atoms, to reject technical noise sources, to achieve signal to noise ratio close to the photon shot noise limit, to provide spatially uniform atom-cavity coupling, and to minimize inhomogeneous ac Stark shifts. These features enable detection of atoms with minimal perturbation to the atomic state, a critical step towards realizing an ultra-high-stability, quantum-enhanced optical lattice clock.

Findings and Lessons Learned From Strengthening the Provision of Voluntary Long-Acting Reversible Contraceptives With Postabortion Care in Guinea.

Integrating voluntary family planning into postabortion care (PAC) presents a critical opportunity to reduce future unintended pregnancies. Although Guinea has low contraceptive prevalence overall, acceptance of long-acting reversible contraceptives (LARCs) among PAC clients is higher than among interval LARC users and higher than the national average. In 2014, we assessed the extent of LARC provision within PAC services and the factors influencing integration.

A pyramid MOT with integrated optical cavities as a cold atom platform for an optical lattice clock.

We realize a two-stage, hexagonal pyramid magneto-optical trap (MOT) with strontium, and demonstrate loading of cold atoms into cavity-enhanced 1D and 2D optical lattice traps, all within a single compact assembly of in-vacuum optics. We show that the device is suitable for high-performance quantum technologies, focusing especially on its intended application as a strontium optical lattice clock. We prepare 2 × 10 spin-polarized atoms of Sr in the optical lattice within 500 ms; we observe a vacuum-limited lifetime of atoms in the lattice of 27 s; and we measure a background DC electric field of 12 V m from stray charges, corresponding to a fractional frequency shift of (-1.

Integrated community case management: planning for sustainability in five African countries.

Background: The World Health Organization (WHO) launched an initiative to plan for the sustainability of integrated community case management (iCCM) programmes supported by the Rapid Access Expansion (RAcE) Programme in five African countries in 2016. WHO contracted experts to facilitate sustainability planning among Ministries of Health, WHO, nongovernmental organisation grantees, and other stakeholders.

Methods: We designed an iterative and unique process for each RAcE project area which involved creating a sustainability framework to guide planning; convening meetings to identify and prioritise elements of the framework; forming technical working groups to build country ownership; and, ultimately, creating roadmaps to guide efforts to fully transfer ownership of the iCCM programmes to host countries.

A scalable arbitrary waveform generator for atomic physics experiments based on field-programmable gate array technology.

We present a field-programmable gate array (FPGA) based control system that has been implemented to control a strontium optical lattice clock at the National Physical Laboratory, UK. Bespoke printed circuit boards have been designed and manufactured, including an 8-channel, 16-bit digital to analog converter board with a 2 μs update rate and a 4-channel direct-digital synthesis board clocked at 1 GHz. Each board includes its own FPGA with 28 digital output lines available alongside the specialized analog or radio frequency outputs.