Structure-independent machine-learning predictions of the CDK12 interactome.

Cyclin-dependent kinase 12 (CDK12) is a critical regulatory protein involved in transcription and DNA repair processes. Dysregulation of CDK12 has been implicated in various diseases, including cancer. Understanding the CDK12 interactome is pivotal for elucidating its functional roles and potential therapeutic targets. Traditional methods for interactome prediction often rely on protein structure information, limiting applicability to CDK12 characterized by partly disordered terminal C region. In this study, we present a structure-independent machine-learning model that utilizes proteins' sequence and functional data to predict the CDK12 interactome. This approach is motivated by the disordered character of the CDK12 C-terminal region mitigating a structure-driven search for binding partners. Our approach incorporates multiple data sources, including protein-protein interaction networks, functional annotations, and sequence-based features, to construct a comprehensive CDK12 interactome prediction model. The ability to predict CDK12 interactions without relying on structural information is a significant advancement, as many potential interaction partners may lack crystallographic data. In conclusion, our structure-independent machine-learning model presents a powerful tool for predicting the CDK12 interactome and holds promise in advancing our understanding of CDK12 biology, identifying potential therapeutic targets, and facilitating precision-medicine approaches for CDK12-associated diseases.

Pathogenic Roles for RNASET2 in Clear Cell Renal Cell Carcinoma.

A specific splicing isoform of RNASET2 is associated with worse oncologic outcomes in clear cell renal cell carcinoma (ccRCC). However, the interplay between wild-type RNASET2 and its splice variant and how this might contribute to the pathogenesis of ccRCC remains poorly understood. We sought to better understand the relationship of RNASET2 in the pathogenesis of ccRCC and the interplay with a pathogenic splicing isoform (RNASET2-SV) and the tumor immune microenvironment. Using data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium, we correlated clinical variables to RNASET2 expression and the presence of a specific RNASET2-SV. Immunohistochemical staining with matched RNA sequencing of ccRCC patients was then utilized to understand the spatial relationships of RNASET2 with immune cells. Finally, in vitro studies were performed to demonstrate the oncogenic role of RNASET2 and highlight its potential mechanisms. RNASET2 gene expression is associated with higher grade tumors and worse overall survival in The Cancer Genome Atlas cohort. The presence of the RNASET2-SV was associated with increased expression of the wild-type RNASET2 protein and epigenetic modifications of the gene. Immunohistochemical staining revealed increased intracellular accumulation of RNASET2 in patients with increased RNA expression of RNASET2-SV. In vitro experiments reveal that this accumulation results in increased cell proliferation, potentially from altered metabolic pathways. RNASET2 exhibits a tumor-promoting role in the pathogenesis of ccRCC that is increased in the presence of a specific RNASET2-SV and associated with changes in the cellular localization of the protein.

A comparative Proteomics Analysis Identified Differentially Expressed Proteins in Pancreatic Cancer-Associated Stellate Cell Small Extracellular Vesicles.

Human pancreatic stellate cells (HPSCs) are an essential stromal component and mediators of pancreatic ductal adenocarcinoma (PDAC) progression. Small extracellular vesicles (sEVs) are membrane-enclosed nanoparticles involved in cell-to-cell communications and are released from stromal cells within PDAC. A detailed comparison of sEVs from normal pancreatic stellate cells (HPaStec) and from PDAC-associated stellate cells (HPSCs) remains a gap in our current knowledge regarding stellate cells and PDAC. We hypothesized there would be differences in sEVs secretion and protein expression that might contribute to PDAC biology. To test this hypothesis, we isolated sEVs using ultracentrifugation followed by characterization by electron microscopy and Nanoparticle Tracking Analysis. We report here our initial observations. First, HPSC cells derived from PDAC tumors secrete a higher volume of sEVs when compared to normal pancreatic stellate cells (HPaStec). Although our data revealed that both normal and tumor-derived sEVs demonstrated no significant biological effect on cancer cells, we observed efficient uptake of sEVs by both normal and cancer epithelial cells. Additionally, intact membrane-associated proteins on sEVs were essential for efficient uptake. We then compared sEV proteins isolated from HPSCs and HPaStecs cells using liquid chromatography-tandem mass spectrometry. Most of the 1481 protein groups identified were shared with the exosome database, ExoCarta. Eighty-seven protein groups were differentially expressed (selected by 2-fold difference and adjusted p value ≤0.05) between HPSC and HPaStec sEVs. Of note, HPSC sEVs contained dramatically more CSE1L (chromosome segregation 1-like protein), a described marker of poor prognosis in patients with pancreatic cancer. Based on our results, we have demonstrated unique populations of sEVs originating from stromal cells with PDAC and suggest that these are significant to cancer biology. Further studies should be undertaken to gain a deeper understanding that could drive novel therapy.

The harsh microenvironment in early breast cancer selects for a Warburg phenotype.

The harsh microenvironment of ductal carcinoma in situ (DCIS) exerts strong evolutionary selection pressures on cancer cells. We hypothesize that the poor metabolic conditions near the ductal center foment the emergence of a Warburg Effect (WE) phenotype, wherein cells rapidly ferment glucose to lactic acid, even in normoxia. To test this hypothesis, we subjected low-glycolytic breast cancer cells to different microenvironmental selection pressures using combinations of hypoxia, acidosis, low glucose, and starvation for many months and isolated single clones for metabolic and transcriptomic profiling. The two harshest conditions selected for constitutively expressed WE phenotypes. RNA sequencing analysis of WE clones identified the transcription factor KLF4 as potential inducer of the WE phenotype. In stained DCIS samples, KLF4 expression was enriched in the area with the harshest microenvironmental conditions. We simulated in vivo DCIS phenotypic evolution using a mathematical model calibrated from the in vitro results. The WE phenotype emerged in the poor metabolic conditions near the necrotic core. We propose that harsh microenvironments within DCIS select for a WE phenotype through constitutive transcriptional reprogramming, thus conferring a survival advantage and facilitating further growth and invasion.

Sparse clusterability: testing for cluster structure in high dimensions.

BACKGROUND: Cluster analysis is utilized frequently in scientific theory and applications to separate data into groups. A key assumption in many clustering algorithms is that the data was generated from a population consisting of multiple distinct clusters. Clusterability testing allows users to question the inherent assumption of latent cluster structure, a theoretical requirement for meaningful results in cluster analysis. RESULTS: This paper proposes methods for clusterability testing designed for high-dimensional data by utilizing sparse principal component analysis. Type I error and power of the clusterability tests are evaluated using simulated data with different types of cluster structure in high dimensions. Empirical performance of the new methods is evaluated and compared with prior methods on gene expression, microarray, and shotgun proteomics data. Our methods had reasonably low Type I error and maintained power for many datasets with a variety of structures and dimensions. Cluster structure was not detectable in other datasets with spatially close clusters. CONCLUSION: This is the first analysis of clusterability testing on both simulated and real-world high-dimensional data.

Cortical plasticity in central vision loss: Cortical thickness and neurite structure.

Late-stage macular degeneration (MD) often causes retinal lesions depriving an individual of central vision, forcing them to learn to use peripheral vision for daily tasks. To compensate, many patients develop a preferred retinal locus (PRL), an area of peripheral vision used more often than equivalent regions of spared vision. Thus, associated portions of cortex experience increased use, while portions of cortex associated with the lesion are deprived of sensory input. Prior research has not well examined the degree to which structural plasticity depends on the amount of use across the visual field. Cortical thickness, neurite density, and orientation dispersion were measured at portions of cortex associated with the PRL, the retinal lesion, and a control region in participants with MD as well as age-matched, gender-matched, and education-matched controls. MD participants had significantly thinner cortex in both the cortical representation of the PRL (cPRL) and the control region, compared with controls, but no significant differences in thickness, neurite density, or orientation dispersion were found between the cPRL and the control region as functions of disease or onset. This decrease in thickness is driven by a subset of early-onset participants whose patterns of thickness, neurite density, and neurite orientation dispersion are distinct from matched control participants. These results suggest that people who develop MD earlier in adulthood may undergo more structural plasticity than those who develop it late in life.

COVID-19-related adrenal haemorrhage: Multicentre UK experience and systematic review of the literature.

OBJECTIVE: Adrenal haemorrhage (AH) is an uncommon, usually incidental imaging finding in acutely unwell patients. AH has been reported during coronavirus disease 2019 (COVID-19) infection and following ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccination. The Society for Endocrinology (SfE) established a task force to describe the UK experience of COVID-19-related AH. DESIGN: A systematic literature review was undertaken. A survey was conducted through the SfE clinical membership to identify patients with COVID-19-related AH using a standardized data collection tool. RESULTS: The literature search yielded 25 cases of COVID-19-related AH (19 bilateral; 13 infection-related, and 12 vaccine-related). Eight UK centres responded to the survey with at least one case. A total of 18 cases were included in the descriptive study, including 11 from the survey and 7 UK-based patients from the systematic review. Seven patients (4 males; median age 53 (range 26-70) years), had infection-related AH (four bilateral). Median time from positive COVID-19 test to AH detection was 8 (range 1-30) days. Eleven cases of vaccine-related AH (eight bilateral) were captured (3 males; median age 47 (range 23-78) years). Median time between vaccination (nine Oxford-AstraZeneca and two Pfizer-BioNTech) and AH was 9 (range 2-27) days; 9/11 AH occurred after the first vaccine dose. Acute abdominal pain was the commonest presentation (72%) in AH of any cause. All 12 patients with bilateral AH and one patient with unilateral AH required glucocorticoid replacement. CONCLUSION: Adrenal haemorrhage with consequential adrenal insufficiency can be a complication of COVID-19 infection and vaccination. Adrenal function assessment is mandatory to avoid the potentially fatal consequences of unrecognized adrenal insufficiency.

Detectable Lipidomes and Metabolomes by Different Plasma Exosome Isolation Methods in Healthy Controls and Patients with Advanced Prostate and Lung Cancer.

Circulating exosomes in the blood are promising tools for biomarker discovery in cancer. Due to their heterogeneity, different isolation methods may enrich distinct exosome cargos generating different omic profiles. In this study, we evaluated the effects of plasma exosome isolation methods on detectable multi-omic profiles in patients with non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and healthy controls, and developed an algorithm to quantify exosome enrichment. Plasma exosomes were isolated from CRPC (n = 10), NSCLC (n = 14), and healthy controls (n = 10) using three different methods: size exclusion chromatography (SEC), lectin binding, and T-cell immunoglobulin domain and mucin domain-containing protein 4 (TIM4) binding. Molecular profiles were determined by mass spectrometry of extracted exosome fractions. Enrichment analysis of uniquely detected molecules was performed for each method with MetaboAnalyst. The exosome enrichment index (EEI) scores methods based on top differential molecules between patient groups. The lipidomic analysis detected 949 lipids using exosomes from SEC, followed by 246 from lectin binding and 226 from TIM4 binding. The detectable metabolites showed SEC identifying 191 while lectin binding and TIM4 binding identified 100 and 107, respectively. When comparing uniquely detected molecules, different methods showed preferential enrichment of different sets of molecules with SEC enriching the greatest diversity. Compared to controls, SEC identified 28 lipids showing significant difference in NSCLC, while only 1 metabolite in NSCLC and 5 metabolites in CRPC were considered statistically significant (FDR < 0.1). Neither lectin-binding- nor TIM4-binding-derived exosome lipids or metabolites demonstrated significant differences between patient groups. We observed the highest EEI from SEC in lipids (NSCLC: 871.33) which was also noted in metabolites. These results support that the size exclusion method of exosome extraction implemented by SBI captures more heterogeneous exosome populations. In contrast, lectin-binding and TIM4-binding methods bind surface glycans or phosphatidylserine moieties of the exosomes. Overall, these findings suggest that specific isolation methods select subpopulations which may significantly impact cancer biomarker discovery.

Sustainable and equivalent improvements in symptoms and functional well-being following viral cure from ledipasvir/sofosbuvir versus elbasvir/grazoprevir for chronic hepatitis C infection: Findings from the randomized PRIORITIZE trial.

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.

A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study.

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

An Analysis of Frequency of Continuous Blood Pressure Variation and Haemodynamic Responses during Haemodialysis.

BACKGROUND: Higher beat-to-beat blood pressure (BP) variation during haemodialysis (HD) has been shown to be associated with elevated cardiac damage markers and white matter ischaemic changes in the brain suggesting relevance to end-organ perfusion. We aimed to characterize individual patterns of BP variation and associated haemodynamic responses to HD. METHODS: Fifty participants underwent continuous non-invasive haemodynamic monitoring during HD and BP variation were assessed using extrema point (EP) frequency analysis. Participants were divided into those with a greater proportion of low frequency (LF, n = 21) and high frequency (HF, n = 22) of BP variation. Clinical and haemodynamic data were compared between groups. RESULTS: Median EP frequencies for mean arterial pressure (MAP) of mid-week HD sessions were 0.54 Hz (interquartile range 0.18) and correlated with dialysis vintage (r = 0.32, p = 0.039), NT pro-BNP levels (r = 0.32, p = 0.038), and average real variability (ARV) of systolic BP (r = 0.33, p = 0.029), ARV of diastolic BP (r = 0.46, p = 0.002), and ARV of MAP (r = 0.57, p < 0.001). In the LF group, MAP positively correlated with cardiac power index (CPI) in each hour of dialysis, but not with total peripheral resistance index (TPRI). In contrast, in the HF group, MAP correlated with TPRI in each hour of dialysis but only with CPI in the first hour. CONCLUSIONS: EP frequency analysis of continuous BP monitoring during dialysis allows assessment of BP variation and categorization of individuals into low- or high-frequency groups, which were characterized by different haemodynamic responses to dialysis. This may assist in improved individualization of dialysis therapy.

Home visits in rural general practice: what does the future hold?

INTRODUCTION: Declining house-call rates have been documented worldwide; however, up-to-date data on current rates are lacking, particularly in rural settings. Systematic reviews in this area are inconsistent; however, other work, principally qualitative research, demonstrates benefits for both doctors and patients. The aim of this study was to establish the current rate of, and reasons for, home visits in a rural general practice setting. METHODS: This was a descriptive observational study in the north-west of Ireland. Fourteen general practice training practices with approximately 30 000 patients were recruited. Data on house calls done in each practice were collected during May and June 2019. Anonymised data were analysed using Microsoft Excel and GraphPad. RESULTS: Data were received on 547 house calls. The rate of house calls done within normal working hours (443) was calculated at 87 house calls/1000 patients/year (raw proportion 1.44%). Using the N-1 χ2 test, this rate was compared to that calculated in a similar 2009 study (143/1000/year; raw proportion 2.43%), giving a difference of 0.991% (95% confidence interval 0.759-1.22%; p<0.001). This is a statistically significant reduction of 40% over 10 years. Most (86.2%) house calls were to patients aged over 65 years. House calls were commonly done for respiratory infection (17%), other infections (12%), palliative care (11%) and pain (11%). Most patients were managed solely within the community (88.3%), with 45.8% of those requiring a prescription, and only 11.7% of house calls being referred to hospital. CONCLUSION: There are documented benefits to home visits and yet the rate of house calls has been declining worldwide. With no recent literature on the rate or reasons for home visits in rural general practice, this research has demonstrated that the house call rate in the north-west of Ireland is falling, mirroring the decline seen in other parts of Europe, Australia and the USA. These house calls are mainly for elderly patients to address infection or palliative care, and the majority can be managed successfully by general practitioners in the community. With an ageing population with increasing multi-morbidity, planning for care delivery to these patients is important for clinicians going forward. We now need to decide if house calls are a service worth saving.

Noninvasive continuous intradialytic blood pressure monitoring: the key to improving haemodynamic stability.

PURPOSE OF REVIEW: Intradialytic hypotension (IDH) occurs in 20% of haemodialysis treatments, leading to end-organ ischaemia, increased morbidity and mortality; and contributing to poor quality of life for patients. Treatment of IDH is reactive since brachial blood pressure (BP) is recorded only intermittently during haemodialysis, making early detection and prediction of hypotension impossible. Noninvasive continuous BP monitoring would allow earlier detection of IDH and thus support the development of methods for its prediction and consequently prevention. RECENT FINDINGS: Noninvasive continuous BP monitoring is not yet part of routine practice in renal dialysis units, with a small number of devices (e.g. finger cuffs) having occasionally been used in research settings. In use, patients frequently report pain or discomfort at measurement sites. Additionally, these devices can be unreliable in patients with reduced blood flow to the digits, often manifest in dialysis patients. All existing methods are sensitive to patient movement.A new method for continuously estimating BP has been developed by monitoring arterial pressure near the arteriovenous fistula which can be achieved without any extraneous monitoring equipment attached to the patient. Additionally, artificial intelligence-based methods for real-time prediction of IDH are currently emerging. SUMMARY: Key monitoring technologies and computational methods are emerging to support the development of real-time IDH prediction.

Evaluating tertiary adrenal insufficiency in rheumatology patients on long-term systemic glucocorticoid treatment.

OBJECTIVE: Patients with rheumatic diseases are often treated with prolonged, high-dose systemic glucocorticoids which can cause hypothalamic-pituitary-adrenal (HPA) axis suppression and development of tertiary adrenal insufficiency. Adrenal insufficiency carries the risk of serious, potentially life-threatening adrenal crisis. Our study evaluated the prevalence, characteristics and recovery of patients with underlying rheumatology conditions who had received prolonged glucocorticoid treatment. DESIGN AND PATIENTS: Retrospective, cross-sectional study. We evaluated 238 patients seen in outpatient rheumatology clinic, managed in accordance with current nationally and internationally accepted clinical guidelines. MEASUREMENTS: Data collected included patient demographics, historical steroid data, 09.00 h cortisol/short synacthen test (SST) results and follow-up data on those with repeat assessments. RESULTS: Overall, 65% of our cohort had a 09.00 h cortisol <350 nmol/L. On SST, 43% of patients demonstrated evidence of possible tertiary adrenal insufficiency. Prednisolone equivalent dose at time of SST was significantly higher in the group who failed SST vs. those who passed; mean of 5.57 mg vs. 3.59mg (p = .005). 09.00 h cortisol result correlated with 30-min cortisol on SST (R2  = .20, p = .002). 0-min cortisol on SST correlated more strongly with 30-min cortisol than 09.00 h cortisol (R2  = .59, p-value < .001). Patients with 0-min cortisol >350 nmol/L, all passed their SST. Patients who remained on prednisolone were more likely to recover (71%) vs. those switched to hydrocortisone (27%), P = .02. Peak steroid dose was predictive of recovery; significantly lower in those who recovered (mean of 22.3 mg vs. 33.8 mg, P = .03). Steroid duration was not found to be a predictor of recovery [recovery (64.2 months) vs. non-recovery (55.6 months), P = .58]. There was no correlation found to outcome on SST with age, sex, peak steroid dose, steroid duration, underlying rheumatological condition, additional exogenous steroid use or serum sodium. CONCLUSIONS: Forty three percent of our patients demonstrated sub-optimal adrenal function on SST. Steroid dose at the time of SST was the only significant predictive risk factor for tertiary adrenal insufficiency. 09.00 h cortisol demonstrated good correlation with outcome on SST and could represent a valid screening test to reduce need for SST if 09.00 h >350 nmol/L. Further prospective data are required to further characterize risk factors, predictive features of recovery and establish optimal management strategy of steroids (prednisolone vs hydrocortisone) to encourage adrenal recovery.

Patient-reported outcomes 12 months after hepatitis C treatment with direct-acting antivirals: Results from the PROP UP study.

BACKGROUND & AIMS: The long-term impact of hepatitis C virus (HCV) therapy with all-oral direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) has not been well-described. We characterized changes in PROs from pre-treatment to 12 months post-treatment in a real-world cohort. METHODS: PROP UP was a multi-centre observational cohort study of 1601 patients treated with DAAs at 11 US gastroenterology/hepatology practices from 2015 to 2017. PROs were evaluated pre-treatment (T1) and 12 months post-treatment (T5). A minimally important change (MIC) threshold was prespecified as >5% change in PRO scores from T1 to T5. Multivariable analyses identified predictors of change. RESULTS: Three-quarters of patients were 55 or older; 45% were female, 60% were white, 33% were black, nearly half had cirrhosis. The most commonly-prescribed DAA regimens were sofosbuvir-based (83%) and grazoprevir/elbasvir (11%). Study retention was >95%. On average, small improvements were observed at 3 months post-treatment in all PROs and sustained at 12 months post-treatment among patients with sustained virologic response (SVR). Clinically meaningful improvements were achieved in fatigue (mean change score: -3.7 [-4.2, -3.1]), sleep (mean change score: -3.1 [-3.7, -2.5]), abdominal pain (mean change score: -2.6 [-3.3, -1.9]) and functional well-being (mean change score: -7.0 [-6.0, -8.0]). Symptom improvements were generally not sustained with no SVR (n = 52). Patients with cirrhosis and MELD ≥12 had the greatest improvements in functional well-being (-12.9 [-17.6, -8.1]). CONCLUSIONS: The improvements in patient-reported outcomes reported by patients who achieved SVR following HCV DAA therapy were durable at 12 months post-treatment.

Maternal iodine status in a multi-ethnic UK birth cohort: Associations with child cognitive and educational development.

BACKGROUND: Maternal iodine requirements increase during pregnancy to supply thyroid hormones critical for fetal neurodevelopment. Iodine insufficiency may result in poorer cognitive or child educational outcomes but current evidence is sparse and inconsistent. OBJECTIVES: To quantify the association between maternal iodine status and child educational outcomes. METHODS: Urinary iodine concentrations (UIC) and iodine/creatinine ratios (I:Cr) were measured in 6971 mothers at 26-28 weeks' gestation participating in the Born in Bradford cohort. Maternal iodine status was examined in relation to child school achievement (early years foundation stage (EYFS), phonics, and Key Stage 1 (KS1)), other learning outcomes, social and behavioural difficulties, and sensorimotor control in 5745 children aged 4-7 years. RESULTS: Median (interquartile range) UIC was 76 µg/L (46, 120), and I:Cr was 83 µg/g (59, 121). Overall, there was no strong or consistent evidence to support associations between UIC or I:Cr and neurodevelopmental outcomes. For instance, predicted EYFS and phonics scores (primary outcomes) at the 25th vs 75th I:Cr percentiles (99% confidence intervals) were similar, with no evidence of associations: EYFS scores were 32 (99% CI 31, 33) and 33 (99% CI 32, 34), and phonics scores were 34 (99% CI 33, 35) and 35 (99% CI 34, 36), respectively. CONCLUSIONS: In the largest single study of its kind, there was little evidence of detrimental neurodevelopmental outcomes in children born to pregnant women with iodine insufficiency as defined by World Health Organization-outlined thresholds. Alternative functional biomarkers for iodine status in pregnancy and focused assessment of other health outcomes may provide additional insight.

Mercury in soils impacted by alluvial gold mining in the Peruvian Amazon.

Gold mining is the largest source of mercury (Hg) pollution worldwide. The discharge of mercury in the environment bears direct human health risks and is likely to increase cascading effects throughout local food chains. In the Peruvian Amazon the mining process consists of slashing and burning trees, followed by extraction of gold-bearing sediment, amalgamation with Hg and gold recovery, leading each year to the degradation of 6,000-10,000 ha and the release of 180 metric tons of Hg per year to the enviroment. The purpose of this study was to determine soil Hg levels in soils of abandoned alluvial gold mine spoils and undisturbed forest in the Madre de Dios region, the epicenter of alluvial gold mining in Peru. We selected gold mine spoils of the two most important technologies locally applied for gold extraction, i.e., Minimally Mechanized Mining (MMM) and Highly Mechanized Mining (HMM), in the native communities of Laberinto and Kotzimba, respectively. We collected 127 and 35 soil samples (0-20cm depth) from potentially contaminated sites and undisturbed forest, respectively. Physicochemical analysis and determination of Hg levels were determined for all soil samples. None of the samples had Hg concentrations above Peruvian, Canadian and British Environmental Quality Standards for Agricultural Soil (6.6mg/kg). Hg levels in MMM and HMM were not significantly different between the two areas. The main variables explaining variation of soil Hg concentrations were the vegetation cover, soil organic matter, soil pH and clay particle content, which explained up to 80% of data set variation. Surprisingly, highest Hg concentrations were found in untouched old-growth forest bordering the mine spoils, but there was also a trend of increasing Hg concentrations with the regenerating vegetation. Our findings suggest that Hg concentrations in old mine spoils are low and shouldn't stand in the way of efforts to restore soil conditions and develop sustainable land uses. However, it is urgent to end the use of Hg in mining operation to decrease human and environmental risks.

Maternal iodine status, intrauterine growth, birth outcomes and congenital anomalies in a UK birth cohort.

BACKGROUND: Severe iodine insufficiency in pregnancy has significant consequences, but there is inadequate evidence to indicate what constitutes mild or moderate insufficiency, in terms of observed detrimental effects on pregnancy or birth outcomes. A limited number of studies have examined iodine status and birth outcomes, finding inconsistent evidence for specific outcomes. METHODS: Maternal iodine status was estimated from spot urine samples collected at 26-28 weeks' gestation from 6971 mothers in the Born in Bradford birth cohort. Associations with outcomes were examined for both urinary iodine concentration (UIC) and iodine-to-creatinine ratio (I:Cr). Outcomes assessed included customised birthweight (primary outcome), birthweight, small for gestational age (SGA), low birthweight, head circumference and APGAR score. RESULTS: There was a small positive association between I:Cr and birthweight in adjusted analyses. For a typical participant, the predicted birthweight centile at the 25th percentile of I:Cr (59 µg/g) was 2.7 percentage points lower than that at the 75th percentile of I:Cr (121 µg/g) (99% confidence interval (CI) 0.8 to 4.6), birthweight was predicted to be 41 g lower (99% CI 13 to 69) and the predicted probability of SGA was 1.9 percentage points higher (99% CI 0.0 to 3.7). There was no evidence of associations using UIC or other birth outcomes, including stillbirth, preterm birth, ultrasound growth measures or congenital anomalies. CONCLUSION: Lower maternal iodine status was associated with lower birthweight and greater probability of SGA. Whilst small, the effect size for lower iodine on birthweight is comparable to environmental tobacco smoke exposure. Iodine insufficiency is avoidable, and strategies to avoid deficiency in women of reproductive age should be considered. TRIAL REGISTRATION: ClinicalTrials.gov NCT03552341. Registered on June 11, 2018.

Development and Reporting of Prediction Models: Guidance for Authors From Editors of Respiratory, Sleep, and Critical Care Journals.

Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of "modifiable risk factors", measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.

Medication Non-adherence in a Prospective, Multi-center Cohort Treated with Hepatitis C Direct-Acting Antivirals.

BACKGROUND: The prevalence and risk factors for non-adherence to direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) in clinical practice settings are under-studied. OBJECTIVES: (1) To quantify DAA non-adherence in the total cohort and among subgroups with and without mental health conditions, alcohol use, and substance use, and (2) to investigate patient- and treatment-level risk factor non-adherence. DESIGN: Prospective, observational cohort study. PARTICIPANTS: A total of 1562 patients receiving DAAs between January 2016 and October 2017 at 11 US medical centers including academic and community practices. MAIN MEASURES: Self-reported medication non-adherence, defined as any missed doses in the past 7 days, surveyed early (T2: at 4 ± 2 weeks) and late in treatment (T3: 2-3 weeks prior to end of treatment). Non-adherence to post-treatment follow-up visits was defined as absence of lab results after DAA therapy completion. KEY RESULTS: Of 1447 patients, 162 (11%) reported non-adherence at T2 or T3. Medical records indicated 262 (17%) of the 1562 participants had not returned for post-treatment visits. At baseline, 37% of patients reported mental health conditions, 15% reported alcohol use, and 23% reported using substances in the previous year. Baseline characteristics associated with DAA non-adherence included alcohol use (OR 1.96), younger age (< 35 years vs. > 55 years: OR 3.40), non-white race (OR > 2.26), and DAA treatment cohort, but not substance use or mental health condition. Non-adherence to follow-up exhibited association with younger age and a higher baseline overall symptom burden. Among 1287 patients with evaluable sustained virologic response (SVR) data, 53 patients (4%) did not achieve SVR. The bivariate correlation between adherence and SVR was negligible (r = 0.01). CONCLUSIONS: DAA non-adherence was low and SVR rates were high. Mental health conditions, substance use, and alcohol use should not disqualify patients from DAA therapy. Patients with alcohol use disorder before DAA therapy initiation may benefit from targeted on-treatment support.