Search

Background Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term ’Lynch-like syndrome’ (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR. Methods This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance. Results We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term ’unexplained dMMR’ was recommended over LLS. Conclusion Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Vaccination decreases the risk of severe COVID-19 but its impact on postacute sequelae of COVID-19 (PASC) is unclear among patients with systemic autoimmune rheumatic diseases (SARDs) who may have blunted vaccine immunogenicity and be vulnerable to PASC.Methods: We prospectively enrolled patients with SARD from a large healthcare system who survived acute infection to complete surveys. The symptom-free duration and the odds of PASC (any symptom lasting ≥28 or 90 days) were evaluated using restricted mean survival time and multivariable logistic regression, respectively, among those with and without breakthrough infection (≥14 days after initial vaccine series).Results: Among 280 patients (11% unvaccinated; 48% partially vaccinated; 41% fully vaccinated), the mean age was 53 years, 80% were female and 82% were white. The most common SARDs were inflammatory arthritis (59%) and connective tissue disease (24%). Those with breakthrough infection had more upper respiratory symptoms, and those with non-breakthrough infection had more anosmia, dysgeusia and joint pain. Compared with those with non-breakthrough COVID-19 infection (n=164), those with breakthrough infection (n=116) had significantly more symptom-free days over the follow-up period (+21.4 days, 95% CI 0.95 to 41.91; p=0.04) and lower odds of PASC at 28 and 90 days (adjusted OR, aOR 0.49, 95% CI 0.29 to 0.83 and aOR 0.10, 95% CI 0.04 to 0.22, respectively).Conclusion: Vaccinated patients with SARDs were less likely to experience PASC compared with those not fully vaccinated. While we cannot rule out the possibility that findings may be due to intrinsic differences in PASC risk from different SARS-CoV-2 variants, these findings support the benefits of vaccination for patients with SARDs and suggest that the immune response to acute infection is important in the pathogenesis of PASC in patients with SARDs. [ABSTRACT FROM AUTHOR]

Purpose Universal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management. Methods We prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes. Results The prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years. Conclusion Universal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks. [ABSTRACT FROM AUTHOR]

Objectives: Natriuretic peptides are an important prognostic marker in patients with heart failure (HF). However, little is known regarding their prognostic significance in patients with atrial fibrillation (AF) without HF and natriuretic peptides levels are underused in these patients in daily practice.Methods: The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We investigated patients with AF without HF (defined as prior HF hospitalisation, New York Heart Association functional class≥2 or left ventricular ejection fraction<40%) using the data of B-type natriuretic peptide (BNP, n=388) or N-terminal pro-B-type natriuretic peptide (NT-proBNP, n=771) at enrolment. BNPs were converted to NT-proBNP using a conversion formula. We divided the patients according to quartiles of NT-proBNP levels and compared the backgrounds and outcomes.Results: Of 1159 patients (mean age: 72.1±10.2 years, median CHA2DS2-VASc score: 3 and oral anticoagulant (OAC) prescription: 671 (56%)), the median NT-proBNP level was 488 (IQR 169-1015) ng/L. Patients with high NT-proBNP levels were older, had higher CHA2DS2-VASc scores and had more OAC prescription (all p<0.001). Kaplan-Meier curves demonstrated that NT-proBNP levels were significantly associated with higher incidences of stroke/systemic embolism, all-cause death and HF hospitalisation during a median follow-up period of 5.0 years (log rank, all p<0.001). Multivariable Cox regression analyses revealed that NT-proBNP levels were an independent predictor of adverse outcomes even after adjustment by various confounders.Conclusion: NT-proBNP levels are a significant prognostic marker for adverse outcomes in patients with AF without HF and may have clinical value.Trial Registration Number: UMIN000005834. [ABSTRACT FROM AUTHOR]

Objective: Pulmonary congestion is the main cause of hospital admission in patients with heart failure (HF). Lung ultrasound (LUS) is a useful tool to identify subclinical pulmonary congestion. We evaluated the usefulness of LUS in addition to physical examination (PE) in the management of outpatients with HF.Methods: In this randomised multicentre unblinded study, patients with chronic HF and optimised medical therapy were randomised in two groups: 'PE+LUS' group undergoing PE and LUS and 'PE only' group. Diuretic therapy was modified according to LUS findings and PE, respectively. The primary endpoint was the reduction in hospitalisation rate for acute decompensated heart failure (ADHF) at 90-day follow-up. Secondary endpoints were reduction in NT-proBNP, quality-of-life test (QLT) and cardiac mortality at 90-day follow-up.Results: A total of 244 patients with chronic HF and optimised medical therapy were enrolled and randomised in 'PE+LUS' group undergoing PE and LUS, and in 'PE only' group. Thirty-seven primary outcome events occurred. The hospitalisation for ADHF at 90 day was significantly reduced in 'PE+LUS' group (9.4% vs 21.4% in 'PE only' group; relative risk=0.44; 95% CI 0.23 to 0.84; p=0.01), with a reduction of risk for hospitalisation for ADHF by 56% (p=0.01) and a number needed to treat of 8.4 patients (95% CI 4.8 to 34.3). At day 90, NT-proBNP and QLT score were significantly reduced in 'PE+LUS' group, whereas in 'PE only' group both were increased. There were no differences in mortality between the two groups.Conclusions: LUS-guided management reduces hospitalisation for ADHF at mid-term follow-up in outpatients with chronic HF. [ABSTRACT FROM AUTHOR]

Objectives This study explored the prognostic factors and developed a prediction model for Chinese-American (CA) cervical cancer (CC) patients. We compared two alternative models (the restricted mean survival time (RMST) model and the proportional baselines landmark supermodel (PBLS model, producing dynamic prediction)) versus the Cox proportional hazards model in the context of time-varying effects. Setting and data sources A total of 713 CA women with CC and available covariates (age at diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis and radiation) from the Surveillance, Epidemiology and End Results database were included. Design We applied the Cox proportional hazards model to analyse the all-cause mortality with the proportional hazards assumption. Additionally, we applied two alternative models to analyse covariates with time-varying effects. The performances of the models were compared using the C-index for discrimination and the shrinkage slope for calibration. Results Older patients had a worse survival rate than younger patients. Advanced FIGO stage patients showed a relatively poor survival rate and low life expectancy. Lymph node metastasis was an unfavourable prognostic factor in our models. Age at diagnosis, FIGO stage and lymph node metastasis represented time-varying effects from the PBLS model. Additionally, radiation showed no impact on survival in any model. Dynamic prediction presented a better performance for 5-year dynamic death rates than did the Cox proportional hazards model. Conclusions With the time-varying effects, the RMST model was suggested to explore diagnosis factors, and the PBLS model was recommended to predict a patient’s w-year dynamic death rate. [ABSTRACT FROM AUTHOR]

Introduction Patients with autosomal dominant polycystic kidney disease (ADPKD) reach end-stage renal disease in their fifth decade on average. For effective treatment and early intervention, identifying subgroups with rapid disease progression is important in ADPKD. However, there are no epidemiological data on the clinical manifestations and disease progression of patients with ADPKD from the Asia-Pacific region. Methods and analysis The RAPID-ADPKD (Retrospective epidemiological study of Asia-Pacific patients with rapId Disease progression of Autosomal Dominant Polycystic Kidney Disease) study is a multinational, retrospective, observational cohort study of patients with ADPKD in the Asia-Pacific region (Australia, China, Hong Kong, South Korea, Taipei and Turkey). This study was designed to identify the clinical characteristics of patients with ADPKD with rapid disease progression. Adult patients with ADPKD diagnosed according to the unified ultrasound criteria and with an estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m² at baseline will be included. The cohort will include patients with ≥2 records of eGFR and at least 24 months of follow-up data. Demographic information, clinical characteristics, comorbidities, medications, eGFR, radiological findings that allow calculation of height-adjusted total kidney volume, ADPKD-related complications and the Predicting Renal Outcomes in autosomal dominant Polycystic Kidney Disease (PRO-PKD) score will be collected. Rapid progression will be defined based on the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) guideline. All other patients without any of these criteria will be classified to be of slow progression. Clinical characteristics will be compared between patients with rapid progression and those with slow progression. The incidence of complications and the effects of race and water intake on renal progression will also be analysed. The planned sample size of the cohort is 1000 patients, and data from 600 patients have been collected as of 30 May 2019. Ethics and dissemination This study was approved or is in the process of approval by the institutional review boards at each participating centre. The results will be presented in conferences and published in a journal, presenting data on the clinical characteristics, risk factors for disease progression and patterns of complications of ADPKD in Asian populations. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to develop and validate a prediction model for the duration of sickness absence (SA) spells due to back pain (International Statistical Classification of Diseases and Related Health Problems 10th Revision: M54), using Swedish nationwide register microdata.Methods: Information on all new SA spells >14 days from 1 January 2010 to 30 June 2012 and on possible predictors were obtained. The duration of SA was predicted by using piecewise constant hazard models. Nine predictors were selected for the final model based on a priori decision and log-likelihood loss. The final model was estimated in a random sample of 70% of the SA spells and later validated in the remaining 30%.Results: Overall, 64 048 SA spells due to back pain were identified during the 2.5 years; 74% lasted ≤90 days, and 9% >365 days. The predictors included in the final model were age, sex, geographical region, employment status, multimorbidity, SA extent at the start of the spell, initiation of SA spell in primary healthcare and number of SA days and specialised outpatient healthcare visits from the preceding year. The overall c-statistic (0.547, 95% CI 0.542 to 0.552) suggested a low discriminatory capacity at the individual level. The c-statistic was 0.643 (95% CI 0.634 to 0.652) to predict >90 days spells, 0.686 (95% CI 0.676 to 0.697) to predict >180 spells and 0.753 (95% CI 0.740 to 0.766) to predict >365 days spells.Conclusions: The model discriminates SA spells >365 days from shorter SA spells with good discriminatory accuracy. [ABSTRACT FROM AUTHOR]

Objective: The hypertrophic cardiomyopathy (HCM) risk-sudden cardiac death (SCD) calculator endorsed by the 2014 European Society of Cardiology has not been independently validated in the Asians. We aimed to investigate whether the HCM Risk-SCD calculator effectively predicts SCD in Korean HCM population.Methods: An observational, longitudinal cohort study was performed in 730 patients with HCM from 2007 to 2017. The primary endpoint was a composite of SCD and appropriate implantable cardioverter-defibrillator (ICD) therapy.Results: During a follow-up period of 4288 person-years, 16 (2.2%) patients reached the primary endpoint. This validation study revealed a calibration slope of 0.892 and C-statistics of 0.718. The primary endpoint occurred in 1.1% (7/615), 4.6% (3/65) and 12.0% (6/50) of low-risk, intermediate-risk and high-risk groups, respectively. Although most patients (85.2%) without the primary endpoint were classified into the low-risk group, 7 of 11 SCD (63.6%) occurred in the low-risk group. In univariable and multivariable analysis, sex (woman) was significantly associated with the primary endpoint and emerged as independent predictor. The addition of sex to the HCM Risk-SCD calculator significantly improved the predictive value of the primary endpoint (net reclassification improvement 0.557, p=0.015).Conclusions: In the Korean HCM population, the HCM Risk-SCD calculator had a high negative predictive value and accuracy for predicting SCD or appropriate ICD therapy, but misclassified a few patients experiencing the primary endpoint as low-risk or intermediate-risk groups. [ABSTRACT FROM AUTHOR]

Objectives: Maintenance of remission has become central in the management of systemic lupus erythematosus (SLE). The importance of interferon-alpha (IFN-α) in the pathogenesis of SLE notwithstanding, its expression in remission has been poorly studied as yet. To study its expression in remission and its prognostic value in the prediction of a disease relapse, serum IFN-α levels were determined using an ultrasensitive single-molecule array digital immunoassay which enables the measurement of cytokines at physiological concentrations.Methods: A total of 254 SLE patients in remission, according to the Definition of Remission in SLE classification, were included in the study. Serum IFN-α concentrations were determined at baseline and patients were followed up for 1 year. Lupus flares were defined according to the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index Flare Index, whereas the Kaplan-Meier analysis and Cox regression analysis were used to estimate the time to relapse and to identify baseline factors associated with time to relapse, respectively.Results: Of all patients in remission, 26% displayed abnormally high IFN-α serum levels that were associated with the presence of antibodies specific for ribonucleoprotein (RNP), double stranded (ds)DNA and Ro/SSA60, as well as young age. Importantly, elevated-baseline IFN-α serum levels and remission duration were associated in an independent fashion, with shorter time to relapse, while low serum levels of complement component 3 and anti-dsDNA Abs were not.Conclusion: Direct serum IFN-α assessment with highly sensitive digital immunoassay permits clinicians to identify a subgroup of SLE patients, clinically in remission, but at higher risk of relapse. [ABSTRACT FROM AUTHOR]

Objective This study aimed to estimate the time of recurrent ischaemic stroke events among the first 3 years of follow-up after hospitalisation discharge. Study design A prospective cohort study. Setting The research was conducted in the Department of Neurology at a tertiary hospital, Chengdu of China, from January 2010 to June 2016. Outcome measures We estimated the restricted mean survival time (RMST) of ischaemic stroke recurrence for the first 3 years after discharge. Basic sociodemographic characteristics and major potential risk factors for recurrence were collected using a semistructured questionnaire. Regression analysis of RMST was used to identify risk factors of recurrent stroke. Participants Patients hospitalised with first-ever ischaemic stroke were eligible for this study. Patients with severe cognitive impairment were excluded. Results We included 641 surviving patients who were followed up for 3 years. Stroke recurrence occurred in 115 patients, including 16 patients who died of stroke recurrence. The cumulative risk of stroke recurrence rate was 11.51% (9.20%–14.35%) at 1 year, 16.76% (13.96%–20.05%) at 2 years and 20.07% (17.00%–23.61%) at 3 years. Modified Rankin Scale (mRS) score ≥3 thus resulted in the recurrence time loss, which was 0.22 months (p=0.008) at 6 months, 0.61 months (p=0.004) at 1 year, 1.49 months (p=0.007) at 2 years and 2.46 months (p=0.008) at 3 years. It is similar with the effects of drug adherence after stroke. The recurrence time of patients ≥75 years at 3 years was 2.02 months (p=0.220) less than that of those aged <55 years. Conclusion In China, the time of first recurrence varies among different patients with ischaemic stroke. The mRS and the level of drug adherence after stroke are important risk factors of stroke recurrence. [ABSTRACT FROM AUTHOR]

Objective An increasing proportion of fetuses are exposed to antenatal corticosteroids (ACS). Despite their immediate beneficial effects, the long-term safety of ACS has been an ongoing source of concern. In the current study, we assessed the likelihood of neurodevelopmental problems among term infants exposed to ACS earlier in pregnancy compared with non-exposed term infants. Design Retrospective cohort study (2006–2011). Median duration of follow-up was 7.8 (IQR 6.4–9.2) years. Setting Population-based study, Ontario, Canada. Participants All live singleton infants born at term (≥370/7 weeks gestation) (n=529 205). Exposure ACS during pregnancy. Primary and secondary outcome measures A composite of diagnostic or billing codes reflecting proven or suspected neurodevelopmental problems during childhood including audiometry testing, visual testing or physician service claim with a diagnosis code related to a suspected neurocognitive disorder. Results At 5 years of age, the cumulative rate for the primary outcome was higher among infants exposed to ACS compared with non-exposed infants: 61.7% (3346/5423) vs 57.8% (302 520/523 782), respectively (p<0.001; number needed to harm (NNH)=25, 95% CI 19 to 38; adjusted HR (aHR) 1.12, 95% CI 1.08 to 1.16). Similar findings were observed for each of the individual components of the primary outcome: 15.3% vs 12.7% for audiometry testing (p<0.001; NNH=39, 95% CI 29 to 63; aHR 1.18, 95% CI 1.11 to 1.25); 45.4% vs 43.5% for visual testing (p=0.006; NNH=54, 95% CI 31 to 200; aHR 1.08, 95% CI 1.04 to 1.12) and 25.8% vs 21.6% for suspected neurocognitive disorder (p<0.001; NNH=24, 95% CI 19 to 33; aHR 1.16, 95% CI 1.10 to 1.21). Conclusions We found an association among term infants between exposure to ACS during pregnancy and healthcare utilisation during childhood related to suspected neurocognitive and neurosensory disorders. [ABSTRACT FROM AUTHOR]

Tumour-induced osteomalacia (TIO), or oncogenic osteomalacia, is a paraneoplastic syndrome marked by hypophosphataemia, renal phosphate wasting, bone pain, weakness, and fractures. The syndrome has been reported with both benign and malignant tumours including parotid gland basal cell tumours, thyroid carcinomas, colon adenocarcinomas, and prostate cancer. Often, the syndrome is marked by an insidious course during which patients present with generalised bony pain and weakness, which do not resolve until the underlying tumour is identified and treated. We present a case of a patient with Parkinson’s disease whose subacute weakness, lower extremity paresis, and renal phosphate wasting led to the synchronous diagnosis of metastatic prostate adenocarcinoma and TIO. [ABSTRACT FROM AUTHOR]

Background Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts. Methods We included patients with CRC from Ohio 2013-2016 and Iceland 2000-2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and MLH1 methylation testing when indicated. Germline nextgeneration sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared. Results Of the 232 and 51 patients with nonmethylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10-4) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10-6) and have multiple LS-associated tumours (OR=6.67, p=3.31×10-5). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts. Conclusions Individuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS. [ABSTRACT FROM AUTHOR]

Introduction New medications for anaemia associated with chronic kidney disease (CKD) are desirable, owing to the limitations of erythropoiesis-stimulating agents (ESAs), the current standard of care. Molidustat is a novel hypoxiainducible factor prolyl-hydroxylase inhibitor that stimulates erythropoietin production, predominately in the kidney. We report methodological details of three phase III trials, named MolIdustat once dailY improves renal Anaemia By Inducing erythropoietin (MIYABI), designed primarily to investigate the efficacy of molidustat therapy in adults with renal anaemia and dialysis-dependent CKD. Methods and analysis MIYABI Haemodialysis-Correction (HD-C) is a single-arm trial (24-week treatment duration) in approximately 25 patients on haemodialysis, currently untreated with ESAs. MIYABI Peritoneal Dialysis (PD) is a single-arm trial (36 week treatment duration) in approximately 50 patients on peritoneal dialysis, treated or untreated with ESAs. MIYABI Haemodialysis- Maintenance (HD-M) is a randomised, active-controlled, double-blinded, double-dummy trial (52-week treatment duration) comparing molidustat with darbepoetin alfa in approximately 225 patients on haemodialysis, treated with ESAs. Molidustat (starting dose 75 mg/day) will be titrated 4-weekly to maintain haemoglobin in predetermined target ranges. The primary objective is to evaluate the efficacy of molidustat, using the following measures: the rate of rise in haemoglobin (g/L/week) at the first dose change up to week 8 (MIYABI HD-C); responder rate (MIYABI HD-C and MIYABI PD); mean haemoglobin level during weeks 33-36 and non-inferiority to darbepoetin alfa shown by change in mean haemoglobin level from baseline (MIYABI HD-M). The secondary objectives are to assess safety, pharmacokinetics and pharmacodynamics. These trials will provide the first evaluations of molidustat therapy in patients receiving either peritoneal dialysis or currently untreated with ESAs on haemodialysis, and provide further evidence in patients treated with ESAs on haemodialysis. Ethics and dissemination The protocols were approved by ethics committees at all participating sites. The trials will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Results arising from these studies will be published in peer-reviewed journal(s). [ABSTRACT FROM AUTHOR]

Introduction: We performed an external validation of the Brock model using the National Lung Screening Trial (NLST) data set, following strict guidelines set forth by the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis statement. We report how external validation results can be interpreted and highlight the role of recalibration and model updating.Materials and Methods: We assessed model discrimination and calibration using the NLST data set. Adhering to the inclusion/exclusion criteria reported by McWilliams et al, we identified 7879 non-calcified nodules discovered at the baseline low-dose CT screen with 2 years of follow-up. We characterised differences between Pan-Canadian Early Detection of Lung Cancer Study and NLST cohorts. We calculated the slope on the prognostic index and the intercept coefficient by fitting the original Brock model to NLST. We also assessed the impact of model recalibration and the addition of new covariates such as body mass index, smoking status, pack-years and asbestos.Results: While the area under the curve (AUC) of the model was good, 0.905 (95% CI 0.882 to 0.928), a histogram plot showed that the model poorly differentiated between benign and malignant cases. The calibration plot showed that the model overestimated the probability of cancer. In recalibrating the model, the coefficients for emphysema, spiculation and nodule count were updated. The updated model had an improved calibration and achieved an optimism-corrected AUC of 0.912 (95% CI 0.891 to 0.932). Only pack-year history was found to be significant (p<0.01) among the new covariates evaluated.Conclusion: While the Brock model achieved a high AUC when validated on the NLST data set, the model benefited from updating and recalibration. Nevertheless, covariates used in the model appear to be insufficient to adequately discriminate malignant cases. [ABSTRACT FROM AUTHOR]

Objectives To empirically assess the relation between study characteristics and prognostic model performance in external validation studies of multivariable prognostic models. Design Meta-epidemiological study. Data sources and study selection On 16 October 2018, we searched electronic databases for systematic reviews of prognostic models. Reviews from non-overlapping clinical fields were selected if they reported common performance measures (either the concordance (c)-statistic or the ratio of observed over expected number of events (OE ratio)) from 10 or more validations of the same prognostic model. Data extraction and analyses Study design features, population characteristics, methods of predictor and outcome assessment, and the aforementioned performance measures were extracted from the included external validation studies. Random effects meta-regression was used to quantify the association between the study characteristics and model performance. Results We included 10 systematic reviews, describing a total of 224 external validations, of which 221 reported c-statistics and 124 OE ratios. Associations between study characteristics and model performance were heterogeneous across systematic reviews. C-statistics were most associated with variation in population characteristics, outcome definitions and measurement and predictor substitution. For example, validations with eligibility criteria comparable to the development study were associated with higher c-statistics compared with narrower criteria (difference in logit c-statistic 0.21(95% CI 0.07 to 0.35), similar to an increase from 0.70 to 0.74). Using a case-control design was associated with higher OE ratios, compared with using data from a cohort (difference in log OE ratio 0.97(95% CI 0.38 to 1.55), similar to an increase in OE ratio from 1.00 to 2.63). Conclusions Variation in performance of prognostic models across studies is mainly associated with variation in case-mix, study designs, outcome definitions and measurement methods and predictor substitution. Researchers developing and validating prognostic models should realise the potential influence of these study characteristics on the predictive performance of prognostic models. [ABSTRACT FROM AUTHOR]

Objective: High-sensitivity cardiac troponin I (hs-cTnI) is an emerging biomarker for cardiovascular risk. We examined hs-cTnI as a predictor of mortality and cardiovascular outcomes in an Australian population-based cohort and evaluated if a sex difference exists.Methods: Serum hs-cTnI was measured in the Busselton Health Study 1994/1995 Cohort (n=3939). Outcome measures were total and cardiovascular mortality, cardiovascular disease (CVD) and coronary heart disease (CHD) events, heart failure and stroke.Results: Hs-cTnI was detectable (>1.2 ng/L) in 66.1% of participants (males 81.8%, females 54.4%) at baseline. There were 886 deaths (including 361 from CVD) and 940 CVD events during 20-year follow-up. Adjusting for Framingham Risk Score variables, hs-cTnI was a significant predictor of total mortality (HR (95% CI): 1.16 (1.09 to 1.24)), CVD mortality (1.33 (1.23 to 1.44)), CVD events (1.18 (1.11 to 1.25)), CHD events (1.11 (1.03 to 1.20)), heart failure (1.44 (1.31 to 1.58)) and stroke (1.13 (1.03 to 1.24)) per doubling of hs-cTnI at baseline. HRs remained significant in CVD-free individuals at baseline (n=3215), except for CHD events. There were no significant interactions between sex and hs-cTnI as a predictor of outcomes. Compared with individuals with hs-cTnI ≤1.2 ng/L, men with hs-cTnI ≥6.0 ng/L and women with hs-cTnI ≥4.0 ng/L had an HR of 2.18 (1.42 to 3.37) and 1.84 (1.30 to 2.62), respectively, for any CVD event, which persisted in the CVD-free subgroup.Conclusions: Cardiac troponin I, measured with a high-sensitive assay, is an independent predictor of fatal and non-fatal CVD events and may help identify at-risk individuals in a general population. [ABSTRACT FROM AUTHOR]

Objectives There are limited data on mortality in patients with type 2 diabetes mellitus (T2DM) in Sub-Saharan Africa. We aimed at determining the mortality rate, and the causes and the predictors of death in patients with T2DM followed as outpatients in a reference hospital in Cameroon. Design Retrospective cohort study. Setting A reference hospital in Cameroon. Participants From December 2015 to March 2016, patients with T2DM aged 18 years and older and who consulted between January 2009 and December 2014, were contacted directly or through their next of kin, and included in this study. All participants with less than 75% of desired data in files, those who could not be reached on the phone and those who refused to provide consent were excluded from the study. Of the 940 eligible patients, 628 (352 men and 276 women) were included and completed the study, giving a response rate of 66.8%. Outcome measures Death rate, causes of death and predictors of death. Results Of the 628 patients (mean age: 56.5 years; median diabetes duration: 3.5 years) followed up for a total of 2161 person-years, 54 died, giving a mortality rate of 2.5 per 100 person-years and a cumulative mortality rate of 8.6%. Acute metabolic complications (22.2%), cardiovascular diseases (16.7%), cancers (14.8%), nephropathy (14.8%) and diabetic foot syndrome (13.0%) were the most common causes of death. Advanced age (adjusted HR (aHR) 1.06, 95% CI 1.02 to 1.10; P=0.002), raised glycated haemoglobin (HbA1c) (aHR 1.16, 95% CI 1.00 to 1.35; P=0.051), low blood haemoglobin (aHR 1.06, 95% CI 1.02 to 1.10; P=0.002) and proteinuria (aHR 2.97, 95% CI 1.40 to 6.28; P=0.004) were identified as independent predictors of death. Conclusions The mortality rate in patients with T2DM is high in our population, with acute metabolic complications as the leading cause. Patients with advanced age, raised HbA1c, anaemia or proteinuria are at higher risk of death and therefore represent the target of interest to prevent mortality in T2DM. [ABSTRACT FROM AUTHOR]

The development of hand-carried, battery-powered ultrasound devices has created a new practice in ultrasound diagnostic imaging, called 'point-of-care' ultrasound (POCUS). Capitalising on device portability, POCUS is marked by brief and limited ultrasound imaging performed by the physician at the bedside to increase diagnostic accuracy and expediency. The natural evolution of POCUS techniques in general medicine, particularly with pocket-sized devices, may be in the development of a basic ultrasound examination similar to the use of the binaural stethoscope. This paper will specifically review how POCUS improves the limited sensitivity of the current practice of traditional cardiac physical examination by both cardiologists and non-cardiologists. Signs of left ventricular systolic dysfunction, left atrial enlargement, lung congestion and elevated central venous pressures are often missed by physical techniques but can be easily detected by POCUS and have prognostic and treatment implications. Creating a general set of repetitive imaging skills for these entities for application on all patients during routine examination will standardise and reduce heterogeneity in cardiac bedside ultrasound applications, simplify teaching curricula, enhance learning and recollection, and unify competency thresholds and practice. The addition of POCUS to standard physical examination techniques in cardiovascular medicine will result in an ultrasound-augmented cardiac physical examination that reaffirms the value of bedside diagnosis. [ABSTRACT FROM AUTHOR]

Background Accurate estimation of prognosis in multimorbid hospital patients could improve quality of care. This study aims to determine the relative importance and added value of a performance-based activities of daily living (ADL) measure with regard to mortality prediction. Methods 200 inpatients, aged over 60 years, were recruited at the Department of General Internal Medicine at a tertiary university hospital. Two nested survival models were built, one with established risk factors (age, sex, Charlson comorbidity index, haemoglobin, albumin, body mass index and glomerular filtration rate), and one using the same covariates with the Gottfries-Bråne-Steen (GBS)-ADL measure added. The relative importance of GBS-ADL was evaluated in the full model. The added value of GBS-ADL was determined by comparing the nested models using four approaches: difference in overall χ2, discrimination, continuous net reclassification index (NRI >0) and integrated discrimination improvement (IDI). Results In the full model, GBS-ADL was the single most important predictor of mortality (χ2-df=30, p<0.001). The likelihood ratio χ2 test showed significant added value of ADL (p<0.001). The C-statistic was 0.78 with ADL and 0.72 without (difference 0.058, 95% CI 0.022 to 0.094). The NRI >0 was 0.42 (95% CI 0.20 to 0.58) and IDI 0.15 (95% CI 0.07 to 0.22). Conclusions Compared with a set of available clinical risk factors, impairment in ADL was a stronger predictor of all-cause mortality, showing substantial added value. Implementing quantitative ADL measurements could enable more appropriate and individual care for the elderly. [ABSTRACT FROM AUTHOR]

The article presents guidelines of the British Thoracic Society for investigation and management of pulmonary nodules in Great Britain. Topics discussed include classification of adenocarcinoma in relation to nodule type, technical aspects of imaging of pulmonary nodules and a algorithm for treatment of pulmonary nodule. It also informs about the radiofrequency ablation and stereotactic ablative body radiotherapy for treatment of pulmonary nodule.

Background Global longitudinal strain (GLS) is a robust, well validated and reproducible technique for the measurement of LV longitudinal deformation. We sought to assemble evidence that GLS is an accurate marker in predicting cardiovascular outcomes, compared to LVEF. Methods We undertook a systematic review of the evidence from observational studies which compared GLS against LVEF in predicting major adverse cardiac events. The primary outcome was all-cause mortality. The secondary outcome was a composite of cardiac death, malignant arrhythmia, hospitalisation due to heart failure, urgent valve surgery or heart transplantation, and acute coronary ischaemic event. A random effects model was used to combine HR and 95% CIs. A meta-regression was undertaken to assess the impact of potential covariates. Results Data were collated from 16 published articles (n=5721 adults) comprising 15 prospective and 1 retrospective observational studies. The underlying cardiac conditions were heart failure, acute myocardial infarction, valvular heart disease, and miscellaneous cardiac diseases. Mortality was independently associated with each SD change in the absolute value of baseline GLS (HR 0.50, 95% CI 0.36 to 0.69; p<0.002) and less strongly with LVEF (HR 0.81, 95% CI 0.72 to 0.92; p=0.572). The HR per SD change in GLS was associated with a reduction in mortality 1.62 (95% CI 1.13 to 2.33; p=0.009) times greater than the HR per SD change in LVEF. Conclusions There is strong evidence of the prognostic value of GLS, which appears to have superior prognostic value to EF for predicting major adverse cardiac events. [ABSTRACT FROM AUTHOR]

The article presents information on researches made in the diagnosis, and treatment of coronary diseases. As stated, primary percutaneous coronary intervention is the most effective treatment for myocardial infarctions that continues to evolve and make essential advances. As further stated, the researchers of cardiovascular disorders are now keen to implement the advances related to coronary diseases globally.

The article presents information on clinical management practices involved in patients suffering with atrial fibrillation in order to reduce occurrence of the cardiac arrhythmias and to decrease the cardiovascular disorder risks. Further, it discusses the strategies to prevent thromboembolism and sudden cardiac death. It also discussed the significance of the occurrence of ventricular arrhythmias in coronary artery bypass surgery.

Background Left atrial (LA) maximal volume is of prognostic value in patients after acute myocardial infarction (AMI). Recently, LA mechanical function and LA strain have been introduced as alternative methods to assess LA performance more accurately. Objective To evaluate the relation between LA volume, mechanical function and strain, and adverse events in patients after AMI. Methods Patients with AMI underwent two-dimensional echocardiography within 48 h of admission. LA volume and LA performance {mechanical function and systolic strain) were quantified. The endpointwas a composite of all-cause mortality, reinfarction and hospitalisation for heart failure. Results 320 patients (mean age 60± 12 years, 78% men) were followed up for 27± 14 months. During follow-up, 48 patients (15%) reached the composite endpoint. After adjustment for clinical and echocardiographic parameters, LA maximal volume (HR 1.05, Cl 1.00 to 1.10, p=0.04) and LA strain (HR 0.94, CI 0.89 to 0.99, p=0.02) were independently associated with adverse outcome. In addition, LA strain provided incremental value to LA maximal volume (p=0.03) for the prediction of adverse outcome. Conclusions After AMI treated with primary percutaneous coronary intervention, LA strain provides additional prognostic value beyond LA maximal volume. [ABSTRACT FROM AUTHOR]