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Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3–COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10 −5 to 10 −3 . Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD -associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Purpose Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses. Methods Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients’ fibroblasts were used to perform mass spectrometry-based proteomics. Results UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients’ fibroblasts. Conclusion Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia.

This study aimed to explore the diagnostic accuracy of the Patient-Generated Subjective Global Assessment (PG-SGA) malnutrition risk screening tool when used to score patients based on their electronic medical records (EMR), compared to bedside screening interviews. In-patients at a rural health service were screened at the bedside (n = 50) using the PG-SGA, generating a bedside score. Clinical notes within EMRs were then independently screened by blinded researchers. The accuracy of the EMR score was assessed against the bedside score using area under the receiver operating curve (AUC), sensitivity, and specificity. Participants were 62% female and 32% had conditions associated with malnutrition, with a mean age of 70.6 years (SD 14.9). The EMR score had moderate diagnostic accuracy relative to PG-SGA bedside screen, AUC 0.74 (95% CI: 0.59–0.89). The accuracy, specificity and sensitivity of the EMR score was highest for patients with a score of 7, indicating EMR screen is more likely to detect patients at risk of malnutrition. This exploratory study showed that applying the PG-SGA screening tool to EMRs had enough sensitivity and specificity for identifying patients at risk of malnutrition to warrant further exploration in low-resource settings.

Lumbar spine MRI can help guide the choice of corticosteroid injection in pain management. We investigated whether patient-reported symptom information from a questionnaire could improve agreement in the choice of type, level, and side of injection.In this prospective observational study, 120 patients (median age 64, 70 men) were recruited from patients referred for pain management. After informed consent, they completed electronic questionnaires that obtained symptom information for later use during MRI reviews. In 3 research arms, 6 radiologists chose injections that would ideally deliver corticosteroid to the presumed sources of pain in (1) MRI studies reviewed with symptom information from questionnaires, (2) MRI studies reviewed without symptom information, and (3) MRI reports. Blinded to questionnaire results, radiologists providing clinical care and interviewing patients chose ideal therapeutic injections to establish reference standards. Injections were categorized by type, level, and side and compared using percent agreement and kappa statistics. Interreading agreement was analyzed.Compared to the reference standard, kappa agreements for injection types, levels, and sides were almost perfect when MRIs were reviewed knowing symptoms (0.85-0.93), fair without symptoms (0.23-0.35) (all P .001) and fair in MRI reports (0.24-0.36) (all P .001). Interreading kappa agreements were almost perfect knowing symptoms (0.82-0.90), but only moderate without symptoms (0.42-0.49) (all P .001).Radiologists reviewing lumbar spine MRI converged on the type, level, and side of ideal therapeutic injection whether they obtained symptom information from direct patient interview or electronic questionnaire. Observer agreement was significantly lower without symptom information.

PURPOSE: To assess the clinical effectiveness of cryoablation for palliation of painful bone metastases. MATERIALS AND METHODS: MOTION (Multicenter Study of Cryoablation for Palliation of Painful Bone Metastases) (ClinicalTrials.gov NCT 02511678) was a multicenter, prospective, single-arm study of adults with metastatic bone disease who were not candidates for or had not benefited from standard therapy, that took place from February 2016 to March 2018. At baseline, participants rated their pain using the Brief Pain Inventory-Short Form (reference range from 0 to 10 points); those with moderate to severe pain, who had at least one metastatic candidate tumor for ablation, were included. The primary effectiveness endpoint was change in pain score from baseline to week 8. Participants were followed for 24 weeks after treatment. Statistical analyses included descriptive statistics and logistic regression to evaluate changes in pain score over the postprocedure follow-up period. RESULTS: A total of 66 participants (mean age, 60.8 years ± 14.3 [standard deviation]; 35 [53.0%] men) were enrolled and received cryoablation; 65 completed follow-up. Mean change in pain score from baseline to week 8 was −2.61 points (95% CI: −3.45, −1.78). Mean pain scores improved by 2 points at week 1 and reached clinically meaningful levels (more than a 2-point decrease) after week 8; scores continued to improve throughout follow-up. Quality of life improved, opioid doses were stabilized, and functional status was maintained over 6 months. Serious adverse events occurred in three participants. CONCLUSION: Cryoablation of metastatic bone tumors provided rapid and durable pain palliation, improved quality of life, and offered an alternative to opioids for pain control. Keywords: Ablation Techniques, Metastases, Pain Management, Radiation Therapy/Oncology Supplemental material is available for this article. © RSNA, 2021

BackgroundThe effects of coronavirus disease 2019 (COVID-19) on the population's mental health and well-being are likely to be profound and long lasting.AimsTo investigate the trajectory of mental health and well-being during the first 6 weeks of lockdown in adults in the UK.MethodA quota survey design and a sampling frame that permitted recruitment of a national sample was employed. Findings for waves 1 (31 March to 9 April 2020), 2 (10 April to 27 April 2020) and 3 (28 April to 11 May 2020) are reported here. A range of mental health factors was assessed: pre-existing mental health problems, suicide attempts and self-harm, suicidal ideation, depression, anxiety, defeat, entrapment, mental well-being and loneliness.ResultsA total of 3077 adults in the UK completed the survey at wave 1. Suicidal ideation increased over time. Symptoms of anxiety, and levels of defeat and entrapment decreased across waves whereas levels of depressive symptoms did not change significantly. Positive well-being also increased. Levels of loneliness did not change significantly over waves. Subgroup analyses showed that women, young people (18–29 years), those from more socially disadvantaged backgrounds and those with pre-existing mental health problems have worse mental health outcomes during the pandemic across most factors.ConclusionsThe mental health and well-being of the UK adult population appears to have been affected in the initial phase of the COVID-19 pandemic. The increasing rates of suicidal thoughts across waves, especially among young adults, are concerning.

Background; The effects of COVID-19 on the population's mental health and wellbeing are likely to be profound and long-lasting.\ud Aims: To investigate the trajectory of mental health and wellbeing during the first six weeks of lockdown in adults in the UK.\ud Method: A quota survey design and a sampling frame that permitted recruitment of a national sample was employed. Findings for waves 1 (31st March to 9th April 2020), 2 (10th April to 27th April 2020) and 3 (28th April to 11th May 2020) are reported here. A range of mental health factors was assessed: pre-existing mental health problems, suicide attempts and self-harm, suicidal ideation, depression, anxiety, defeat, entrapment, mental well-being, and loneliness.\ud Results: A total of 3077 adults in the UK completed the survey at wave 1. Suicidal ideation increased over time. Symptoms of anxiety, levels of defeat and entrapment decreased across waves whereas levels of depressive symptoms did not change significantly. Positive wellbeing also increased. Levels of loneliness did not change significantly over waves. Sub- group analyses showed that females, young people (18-29 years), those from more socially disadvantaged backgrounds, and those with pre-existing mental health problems have worse mental health outcomes during the pandemic across most factors.\ud Conclusions: The mental health and wellbeing of the UK adult population appears to have been affected in the initial phase of the COVID-19 pandemic. The increasing rates of suicidal thoughts across waves, especially among young adults, are concerning.

Rationale and Objectives Train and apply natural language processing (NLP) algorithms for automated radiology-arthroscopy correlation of meniscal tears. Materials and Methods In this retrospective single-institution study, we trained supervised machine learning models (logistic regression, support vector machine, and random forest) to detect medial or lateral meniscus tears on free-text MRI reports. We trained and evaluated model performances with cross-validation using 3593 manually annotated knee MRI reports. To assess radiology-arthroscopy correlation, we then randomly partitioned this dataset 80:20 for training and testing, where 108 test set MRIs were followed by knee arthroscopy within 1 year. These free-text arthroscopy reports were also manually annotated. The NLP algorithms trained on the knee MRI training dataset were then evaluated on the MRI and arthroscopy report test datasets. We assessed radiology-arthroscopy agreement using the ensembled NLP-extracted findings versus manually annotated findings. Results The NLP models showed high cross-validation performance for meniscal tear detection on knee MRI reports (medial meniscus F1 scores 0.93–0.94, lateral meniscus F1 scores 0.86–0.88). When these algorithms were evaluated on arthroscopy reports, despite never training on arthroscopy reports, performance was similar, though higher with model ensembling (medial meniscus F1 score 0.97, lateral meniscus F1 score 0.99). However, ensembling did not improve performance on knee MRI reports. In the radiology-arthroscopy test set, the ensembled NLP models were able to detect mismatches between MRI and arthroscopy reports with sensitivity 79% and specificity 87%. Conclusion Radiology-arthroscopy correlation can be automated for knee meniscal tears using NLP algorithms, which shows promise for education and quality improvement.

A Man with Joint Pain and Eye Redness A 37-year-old man presented with arthralgias, rash, calf pain, and redness in both eyes. The C-reactive protein level was elevated, and the erythrocyte sedimen...

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery., Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Aims: To test the effectiveness of a theoretically based text‐message intervention to reduce binge drinking among socially disadvantaged men. Design: A multi‐centre parallel group, pragmatic, individually randomized controlled trial. Setting: Community‐based study conducted in four regions of Scotland. Participants: A total of 825 men aged 25–44 years recruited from socially disadvantaged areas who had two or more episodes of binge drinking (> 8 UK units on a single occasion) in the preceding 28 days: 411 men were randomized to the intervention and 414 to the control. Intervention and comparator: A series of 112 interactive text messages was delivered by mobile phone during a 12‐week period. The intervention was structured around the Health Action Process Approach, a comprehensive model which allows integration of a range of evidence‐based behaviour change techniques. The control group received 89 texts on general health, with no mention of alcohol or use of behaviour change techniques. Measurements: The primary outcome measure was the proportion of men consuming > 8 units on three or more occasions (in the previous 28 days) at 12 months post‐intervention. Findings: The proportion of men consuming > 8 units on three or more occasions (in the previous 28 days) was 41.5% in the intervention group and 47.8% in the control group. Formal analysis showed that there was no evidence that the intervention was effective [odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.57–1.08; absolute reduction 5.7%, 95% CI = −13.3 to 1.9]. The Bayes factor for this outcome was 1.3, confirming that the results were inconclusive. The retention was high and similar in intervention (84.9%) and control (86.5%) groups. Most men in the intervention group engaged with the text messages: almost all (92%) replied to text messages and 67% replied more than 10 times. Conclusions: A theoretically based text‐messaging intervention aimed at reducing binge drinking in disadvantaged men was not found to reduce prevalence of binge drinking at 12‐month follow‐up.