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Background Reduced kidney function is a risk factor of cardiovascular and all-cause mortality. This association was demonstrated for several kidney function markers, but it is unclear whether integrating multiple measured markers may improve mortality risk prediction. Methods We conducted an exploratory factor analysis (EFA) of serum creatinine– and cystatin C–based estimated glomerular filtration rate [eGFRcre and eGFRcys; derived by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) equations], blood urea nitrogen (BUN), uric acid and serum albumin among 366 758 participants in the UK Biobank without a history of kidney failure. Fitting Cox proportional hazards models, we compared the ability of the identified latent factors to predict overall mortality and mortality by cardiovascular disease (CVD), also considering CVD-specific causes like coronary heart disease (CHD) and cerebrovascular disease. Results During 12.5 years of follow-up, 26 327 participants died from any cause, 5376 died from CVD, 2908 died from CHD and 1116 died from cerebrovascular disease. We identified two latent factors, EFA1 and EFA2, both representing kidney function variations. When using the CKD-EPI equation, EFA1 performed like eGFRcys, with EFA1 showing slightly larger hazard ratios for overall and CVD-related mortality. At 10 years of follow-up, EFA1 and eGFRcys showed moderate discrimination performance for CVD-related mortality, outperforming all other kidney indices. eGFRcre was the least predictive marker across all outcomes. When using the EKFC equation, eGFRcys performed better than EFA1 while all other results remaining similar. Conclusions While EFA is an attractive approach to capture the complex effects of kidney function, eGFRcys remains the most practical and effective measurement for all-cause and CVD mortality risk prediction. [ABSTRACT FROM AUTHOR]

HLA antigens of patients with adult T cell leukaemia (ATL), T cell malignant lymphoma (T-ML), and healthy carriers of human T cell leukaemia virus type I (HTLV-I) were investigated in an endemic area of ATL in Japan. Sixty-two patients with ATL were subdivided into three groups based on their clinical features, including two unclassified patients; 36 acute type. 10 chronic type, and 14 smouldering type. The frequency of HLA-Bw62 was significantly increased in acute ATL, compared with control (Pc <0.0002). Increased frequency of HLA-DQw3 was observed in patients with ATL. T-ML positive for the antibody to HTLV-I (Ab-positive), and Ab-positive healthy carriers, compared with control (Pc < 0.001, Pc< 0.01 and Pc < 0.0001, respectively). In addition, class I HLA antigens of peripheral lymphocytes of patients with ATL, especially acute ATL, showed altered expression, either extra antigens or decreased antigens. Analysis of 21 families, where more than two members were Ab-positive, showed that there was no linkage between the HLA complex and susceptibility to the virus infection. In 44 couples, in which either or both spouses were Ab-positive, no association with class ! HLA antigens was found in either Ab-positive spouses or Ab-negative sprouses. These findings might indicate that one class II HLA-linked gene controlled susceptibility to HTLV-I infection, and another class I HLA-linked gene exerted an influence on the clinical course of ATL. [ABSTRACT FROM AUTHOR]

The autopsy records between 1980 and 1995 of 399 female rhesus monkeys (Macaca mulatta) at the Wisconsin Regional Primate Research Center were examined. Spontaneous endometriosis was found in 81 (20%) of the animals. The mean (+/- SD) ages at death for animals with and without endometriosis were 20.7 +/- 5.5 (range 10-35) and 13.4 +/- 7.7 (range 4-37) years respectively. Many of the animals had been exposed to experimental procedures, including laparoscopies, hysterotomies and oestradiol implants, and these were examined as possible risk factors for endometriosis. Of the 81 affected animals, 62 were matched to unaffected controls for age at death (to within 1 year) and year of death (to within 2 years) and the effect of various factors on the development of endometriosis was determined using conditional logistic regression. Exposure to three or more oestradiol implants or one or more hysterotomies were both significant risk factors, with estimated relative risks of 9.7 (95% confidence interval 2.5-37.2) and 5.8 (95% confidence interval 1.6-20.2) respectively. Animals that had been exposed to one or more laparoscopies showed no increased risk for developing endometriosis. These findings provide insight into the aetiology of the disease in women. ?2P51 4RR00167 [ABSTRACT FROM AUTHOR]

Introduction Studies suggest that many emergency department (ED) visits and hospitalizations for patients with cancer may be preventable. The Centers for Medicare & Medicaid Services has implemented changes to the hospital outpatient reporting program that targets acute care in-treatment patients for preventable conditions. Oncology urgent care centers aim to streamline patient care. Our cancer center developed an urgent care center called the direct referral unit in 2011. Methods We abstracted visits to our adjacent hospital ED and direct referral unit from January 2014 to June 2018. Patient demographics, cancer and visit diagnoses, visit charges, and 30-day therapy utilization were assessed. Results An analysis of 13 114 visits demonstrated that increased direct referral unit utilization was associated with decreased monthly ED visits (P  < .001). Common direct referral unit visit diagnoses were dehydration, nausea and vomiting, abdominal pain, and fever. Patients receiving active cancer treatment more frequently presented to the direct referral unit (P  < .001). The average charges were $2221 for the direct referral unit and $10 261 for the ED. Conclusion The association of decreased ED visits with increased direct referral unit utilization demonstrates the potential for urgent care centers to reduce acute care visits. Many patients presented to our direct referral unit with preventable conditions, and these visits were associated with considerable cost savings, supporting its use as a cost-effective method to reduce acute care costs. [ABSTRACT FROM AUTHOR]

Background Diabetes mellitus (DM) is associated with a greater risk of mortality in kidney transplant patients, primarily driven by a greater risk of cardiovascular disease (CVD)-related mortality. However, the associations between diabetes status at time of first allograft loss and mortality on dialysis remain unknown. Methods All patients with failed first kidney allografts transplanted in Australia and New Zealand between 2000 and 2020 were included. The associations between diabetes status at first allograft loss, all-cause and cause-specific mortality were examined using competing risk analyses, separating patients with diabetes into those with pre-transplant DM or post-transplant diabetes mellitus (PTDM). Results Of 3782 patients with a median (IQR) follow-up duration of 2.7 (1.1–5.4) years, 539 (14%) and 390 (10%) patients had pre-transplant DM or developed PTDM, respectively. In the follow-up period, 1336 (35%) patients died, with 424 (32%), 264 (20%) and 199 (15%) deaths attributed to CVD, dialysis withdrawal and infection, respectively. Compared to patients without DM, the adjusted subdistribution HRs (95% CI) for pre-transplant DM and PTDM for all-cause mortality on dialysis were 1.47 (1.17–1.84) and 1.47 (1.23–1.76), respectively; for CVD-related mortality were 0.81 (0.51–1.29) and 1.02 (0.70–1.47), respectively; for infection-related mortality were 1.84 (1.02–3.35) and 2.70 (1.73–4.20), respectively; and for dialysis withdrawal-related mortality were 1.71 (1.05–2.77) and 1.51 (1.02–2.22), respectively. Conclusions Patients with diabetes at the time of kidney allograft loss have a significant survival disadvantage, with the excess mortality risk attributed to infection and dialysis withdrawal. [ABSTRACT FROM AUTHOR]

Background Anisakis infects humans by consuming contaminated undercooked or raw fish, leading to gastric anisakiasis, gastro-allergic anisakiasis, or asymptomatic contamination. Although larvae usually die when penetrating the gastric tissue, cases of intra- and extra-abdominal spread were described. We report the first probable case of pericardial anisakiasis. Case summary A 26-year-old man presented to the emergency department because of progressive lower limb oedema and exertional dyspnoea. Two months prior, he had consumed raw fish without any gastrointestinal symptoms. The echocardiogram reported a circumferential pericardial effusion ('swinging heart') and mildly reduced left ventricular ejection fraction (LVEF). He was diagnosed with myopericarditis after a cardiac magnetic resonance. A fluorodeoxyglucose positron emission tomography scan revealed an intense pericardial metabolism. Blood tests exhibited persistent eosinophilia and mild elevation of Anisakis simplex IgE—as for past infestation. A pericardial drainage was performed, subsequently, serial echocardiograms revealed a spontaneous recovery of his LVEF. No autoimmune, allergic, or onco-haematologic diseases were identified. Based on a history of feeding with potentially contaminated raw fish and on long-lasting eosinophilia, we suspected a pericardial anisakiasis, despite a low but persistent titre of specific IgE. Albendazole was administered for 21 days, along with colchicine and ibuprofen for 2 months; pericardial effusion resolution and eosinophil normalization occurred two weeks after. Discussion We hypothesized that Anisakis larvae may have migrated outside the gastrointestinal tract, penetrating the diaphragm and settling in the pericardium, causing pericarditis and pericardial effusion. Clinicians should know that the pericardium may be another extra-abdominal localization of anisakiasis, beyond pleuro-pulmonary involvement. [ABSTRACT FROM AUTHOR]

Motivation Identification of genomic, molecular and clinical markers prognostic of patient survival is important for developing personalized disease prevention, diagnostic and treatment approaches. Modern omics technologies have made it possible to investigate the prognostic impact of markers at multiple molecular levels, including genomics, epigenomics, transcriptomics, proteomics and metabolomics, and how these potential risk factors complement clinical characterization of patient outcomes for survival prognosis. However, the massive sizes of the omics datasets, along with their correlation structures, pose challenges for studying relationships between the molecular information and patients' survival outcomes. Results We present a general workflow for survival analysis that is applicable to high-dimensional omics data as inputs when identifying survival-associated features and validating survival models. In particular, we focus on the commonly used Cox-type penalized regressions and hierarchical Bayesian models for feature selection in survival analysis, which are especially useful for high-dimensional data, but the framework is applicable more generally. Availability and implementation A step-by-step R tutorial using The Cancer Genome Atlas survival and omics data for the execution and evaluation of survival models has been made available at https://ocbe-uio.github.io/survomics. [ABSTRACT FROM AUTHOR]

Background We require a clinicopathological risk stratification method for immunoglobulin A nephropathy (IgAN) to predict kidney outcomes. We examined a renal failure risk group (RF-RG) classification system created following a prior multicentre, retrospective study to determine if RF-RG could predict kidney outcomes. Methods We collected data from Japanese patients with IgAN registered between 1 April 2005 and 31 August 2015. The primary outcome was a composite 50% increase in serum creatinine from baseline or dialysis induction. The secondary outcomes were times to proteinuria remission (ProR) and haematuria remission (HemR). Results The enrolled 991 patients from 44 facilities were followed for a median of 5.5 years (interquartile range 2.5–7.5), during which 87 composite events (8.8%) occurred. RF-RG was significantly associated with the primary outcome {hazard ratio [HR] II 2.78 [95% confidence interval (CI) 1.12–6.93], III 7.15 (2.90–17.6), IV 33.4 (14.1–79.0), I as a reference, P  < .001}. The discrimination performance was good [C-statistic 0.81 (95% CI 0.76–0.86)] and the time-dependent C-statistics exceeded 0.8 over 10 years. Among the 764 patients with proteinuria and 879 patients with haematuria at baseline, 515 and 645 patients showed ProR and HemR, respectively. ProR was significantly less frequent in patients with advanced disease [subdistribution HR: II 0.79 (95% CI 0.67–0.94), III 0.53 (0.41–0.66), IV 0.15 (0.09–0.23), I as a reference, P  < .001]. We also observed an association between HemR and RF-RG. Conclusions RF-RG demonstrated good predictive ability for kidney outcomes. [ABSTRACT FROM AUTHOR]

Background Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia. Methods We selected phase 3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients. Efficacy outcomes were the changes from baseline of haemoglobin, iron parameters (hepcidin, serum iron, TIBC, TSAT, ferritin) and intravenous iron dose; as safety outcomes we considered cancer, adjudicated major adverse cardiovascular events (MACE), MACE+ (MACE plus hospitalization for hearth failure or unstable angina or thromboembolic event), thrombotic events (deep vein thrombosis, pulmonary embolism), arterovenous fistula (AVF) thrombosis and death. Results We included 26 RCTs with 24   387 patients. Random effect meta-analysis of the unstandardized mean difference between HIF-PHIs and ESAs showed a significant change in haemoglobin levels from baseline of 0.10 g/dL (95% CI 0.02 to 0.17). Meta-regression analysis showed a significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21 g/dL, 95% CI 0.12 to 0.29 versus –0.01, 95% CI –0.09 to 0.07 in studies using long-acting ESA, P  < .001). No significant effect on heterogeneity was found for type of HIF-PHIs. In comparison with ESAs, HIF-PHIs induced a significant decline in hepcidin and ferritin and a significant increase in serum iron and TIBC, while TSAT did not change; intravenous iron dose was lower with HIF-PHI (–3.1 mg/week, 95% CI –5.6 to –0.6, P  = .020). Rate ratio of cancer (0.93, 95% CI 0.76 to 1.13), MACE (1.00, 95% CI 0.94 to 1.07), MACE+ (1.01, 95% CI 0.95 to 1.06), thrombotic events (1.08, 95% CI 0.84 to 1.38), AVF thrombosis (1.02, 95% CI 0.93 to 1.13) and death (1.02, 95% CI 0.95 to 1.13) did not differ between HIF-PHIs and ESAs. Conclusions HIF-PHIs at the doses selected for the comparisons are effective in correcting anaemia in comparison with ESA therapy with a significant impact on iron metabolism without notable difference among various agents. No safety signals emerge with use of HIF-PHIs. [ABSTRACT FROM AUTHOR]

Background Current guidelines establish the same hemoglobin (Hb) and iron biomarkers targets for hemodialysis (HD) and peritoneal dialysis (PD) in patients receiving erythropoiesis-stimulating agents (ESAs) even though patients having PD are usually younger, more active and less comorbid. Unfortunately, specific renal anemia [anemia in chronic kidney disease (aCKD)] trials or observational studies on PD are scanty. The aims of this study were to describe current aCKD management, goals and adherence to clinical guidelines, identifying opportunities for healthcare improvement in PD patients. Methods This was a retrospective, nationwide, multicentre study including patients from 19 PD units. The nephrologists collected baseline data, demographics, comorbidities and data related to anemia management (laboratory values, previously prescribed treatments and subsequent adjustments) from electronic medical records. The European adaptation of KDIGO guidelines was the reference for definitions, drug prescriptions and targets. Results A total of 343 patients (mean age 62.9 years, 61.2% male) were included; 72.9% were receiving ESAs and 33.2% iron therapy [20.7% intravenously (IV)]. Eighty-two patients were receiving ESA without iron therapy, despite 53 of them having an indication according to the European Renal Best Practice guidelines. After laboratory results, iron therapy was only started in 15% of patients. Among ESA-treated patients, 51.9% had an optimal control [hemoglobin (Hb) 10–12 g/dL] and 28.3% between 12–12.9 g/dL. Seventeen patients achieved Hb >13 g/dL, and 12 of them remained on ESA after overshooting. Only three patients had Hb <10 g/dL without ESAs. Seven patients (2%) met criteria for ESA resistance (epoetin dose >300 IU/kg/week). The highest tertile of erythropoietin resistance index (>6.3 UI/kg/week/g/dL) was associated with iron deficiency and low albumin corrected by renal replacement therapy vintage and hospital admissions in the previous 3 months. Conclusion Iron therapy continues to be underused (especially IV). Low albumin, iron deficiency and prior events explain most of the ESA hyporesponsiveness. Hb targets are titrated to/above the upper limits. Thus, several missed opportunities for adequate prescriptions and adherence to guidelines were identified. [ABSTRACT FROM AUTHOR]

Aims The validated HCM Risk-Kids model provides accurate individualized estimates of sudden cardiac death risk in children with hypertrophic cardiomyopathy (HCM). A second validated model, PRIMaCY, also provides individualized estimates of risk, but its performance and clinical impact has not been independently investigated. The aim of this study was to investigate the clinical impact of using the PRIMaCY sudden cardiac death (SCD) risk model in childhood HCM. Methods and results The estimated 5-year SCD risk was calculated for children meeting diagnostic criteria for HCM in a large single-centre cohort using PRIMaCY (clinical and genetic) and HCM Risk-Kids model, and model performance was assessed. Three hundred one patients [median age 10 (interquartile range 4–14)] were followed up for an average of 4.9 (±3.8) years, during which 30 (10.0%) reached the SCD or equivalent event endpoint. Harrell's C -statistic for the clinical and genetic models was 0.66 [95% confidence interval (CI) 0.52–0.8] and 0.66 (95% CI 0.54–0.80) with a calibration slope of 0.19 (95% CI 0.04–0.54) and 0.26 (95% CI −0.03–0.62), respectively. The number needed to treat to potentially treat one life-threatening arrhythmia for the PRIMaCY clinical, PRIMaCY genetic, and HCM Risk-Kids models was 13.7, 14.5, and 9.4, respectively. Conclusion Although PRIMaCY has a similar discriminatory ability to that reported for HCM Risk-Kids, estimated risk estimates did not correlate well with observed risk. A higher proportion of patients met implantable cardioverter-defibrillator thresholds using PRIMaCY model compared with HCM Risk-Kids. This has important clinical implications as these patients will be exposed to a lifetime risk of complications and inappropriate therapies. [ABSTRACT FROM AUTHOR]

The discovery and development of erythropoiesis-stimulating agents was a journey lasting more than a century, leading to the cloning and approval of recombinant human erythropoietin (rHuEpo). This was an impressive clinical advance, providing the possibility of correcting the symptoms associated with anaemia in chronic kidney disease. Associated iron use was needed to produce new haemoglobin-containing blood red cells. Partial anaemia correction became the standard of care since trials aiming for near-normal haemoglobin levels showed a higher risk of adverse cardiovascular events. Hoping to reduce the cardiovascular risks, a new category of drugs was developed and tested. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are small molecules than can be formulated into orally active pills. They simulate reduced tissue oxygen pressure, thus stimulating the production of endogenous erythropoietin (Epo) by the kidneys and liver. Clinical trials with these compounds demonstrated that HIF-PHIs are at least as effective as rHuEpo in treating or correcting anaemia in non-dialysis and dialysis patients. Trials with HIF-PHIs did not demonstrate superiority in safety outcomes and in some trials, outcomes were worse. There was also a focus on oral delivery, a possible beneficial iron-sparing effect and the ability to overcome Epo resistance in inflamed patients. A negative effect is possible iron depletion, which may explain adverse outcomes. [ABSTRACT FROM AUTHOR]

Background Cancer-related financial hardship is a side effect of cancer diagnosis and treatment, and affects both patients and caregivers. Although many oncology clinics have increased financial navigation services, few have resources to proactively provide financial counseling and assistance to families affected by cancer before financial hardship occurs. As part of an ongoing randomized study testing a proactive financial navigation intervention, S1912CD, among sites of the National Cancer Institute Community Oncology Research Program (NCORP), we conducted a baseline survey to learn more about existing financial resources available to patients and caregivers. Methods The NCORP sites participating in the S1912CD study completed a required 10-question survey about their available financial resources and an optional 5-question survey that focused on financial screening and navigation workflow and challenges prior to starting recruitment. The proportion of NCORP sites offering financial navigation services was calculated and responses to the optional survey were reviewed to determine current screening and navigation practices and identify any challenges. Results Most sites (96%) reported offering financial navigation for cancer patients. Sites primarily identified patients needing financial assistance through social work evaluations (78%) or distress screening tools (76%). Sites revealed challenges in addressing financial needs at the outset and through diagnosis, including lack of proactive screening and referral to financial navigation services as well as staffing challenges. Conclusions Although most participating NCORP sites offer some form of financial assistance, the survey data enabled identification of gaps and challenges in providing services. Utilizing community partners to deliver comprehensive financial navigation guidance to cancer patients and caregivers may help meet needs while reducing site burden. [ABSTRACT FROM AUTHOR]

Aims To determine whether fully automated artificial intelligence-based global circumferential strain (GCS) assessed during vasodilator stress cardiovascular (CV) magnetic resonance (CMR) can provide incremental prognostic value. Methods and results Between 2016 and 2018, a longitudinal study included all consecutive patients with abnormal stress CMR defined by the presence of inducible ischaemia and/or late gadolinium enhancement. Control subjects with normal stress CMR were selected using a propensity score-matching. Stress-GCS was assessed using a fully automatic machine-learning algorithm based on featured-tracking imaging from short-axis cine images. The primary outcome was the occurrence of major adverse clinical events (MACE) defined as CV mortality or nonfatal myocardial infarction. Cox regressions evaluated the association between stress-GCS and the primary outcome after adjustment for traditional prognosticators. In 2152 patients [66 ± 12 years, 77% men, 1:1 matched patients (1076 with normal and 1076 with abnormal CMR)], stress-GCS was associated with MACE [median follow-up 5.2 (4.8–5.5) years] after adjustment for risk factors in the propensity-matched population [adjusted hazard ratio (HR), 1.12 (95% CI, 1.06–1.18)], and patients with normal CMR [adjusted HR, 1.35 (95% CI, 1.19–1.53), both P < 0.001], but not in patients with abnormal CMR (P = 0.058). In patients with normal CMR, an increased stress-GCS showed the best improvement in model discrimination and reclassification above traditional and stress CMR findings (C-statistic improvement: 0.14; NRI = 0.430; IDI = 0.089, all P < 0.001; LR-test P < 0.001). Conclusion Stress-GCS is not a predictor of MACE in patients with ischaemia, but has an incremental prognostic value in those with a normal CMR although the absolute event rate remains low. [ABSTRACT FROM AUTHOR]

Background Declines in the prevalence of cigarette smoking, advances in targeted therapies, and implementation of lung cancer screening have changed the clinical landscape for lung cancer. The proportion of lung cancer deaths is increasing in those who have never smoked cigarettes. To better understand contemporary patterns in survival among patients with lung cancer, a comprehensive evaluation of factors associated with survival, including differential associations by smoking status, is needed. Methods Patients diagnosed with lung cancer between January 1, 2010, and September 30, 2019, were identified. We estimated all-cause and lung cancer-specific median, 5-year, and multivariable restricted mean survival time (RMST) to identify demographic, socioeconomic, and clinical factors associated with survival, overall and stratified by smoking status (never, former, and current). Results Analyses included 6813 patients with lung cancer: 13.9% never smoked, 54.2% formerly smoked, and 31.9% currently smoked. All-cause RMST through 5 years for those who never, formerly, and currently smoked was 32.1, 25.9, and 23.3 months, respectively. Lung cancer–specific RMST was 36.3 months, 30.3 months, and 26.0 months, respectively. Across most models, female sex, younger age, higher socioeconomic measures, first-course surgery, histology, and body mass index were positively associated, and higher stage was inversely associated with survival. Relative to White patients, Black patients had increased survival among those who formerly smoked. Conclusions We identify actionable factors associated with survival between those who never, formerly, and currently smoked cigarettes. These findings illuminate opportunities to address underlying mechanisms driving lung cancer progression, including use of first-course treatment, and enhanced implementation of tailored smoking cessation interventions for individuals diagnosed with cancer. [ABSTRACT FROM AUTHOR]

Aims We investigated the prevalence and clinical value of assessing multi-organ congestion by ultrasound in heart failure (HF) outpatients. Methods and results Ultrasound congestion was defined as inferior vena cava of ≥21 mm, highest tertile of lung B-lines, or discontinuous renal venous flow. Associations with clinical characteristics and prognosis were explored. We enrolled 310 HF patients [median age: 77 years, median NT-proBNP: 1037 ng/L, 51% with a left ventricular ejection fraction (LVEF) <50%], and 101 patients without HF. There were no clinical signs of congestion in 224 (72%) patients with HF, of whom 95 (42%) had at least one sign of congestion by ultrasound (P < 0.0001). HF patients with ≥2 ultrasound signs were older, and had greater neurohormonal activation, lower urinary sodium concentration, and larger left atria despite similar LVEF. During a median follow-up of 13 (interquartile range: 6–15) months, 77 patients (19%) died or were hospitalized for HF. HF patients without ultrasound evidence of congestion had a similar outcome to patients without HF [reference; hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.86–1.35], while those with ≥2 ultrasound signs had the worst outcome (HR 26.7, 95% CI 12.4–63.6), even after adjusting for multiple clinical variables and NT-proBNP. Adding multi-organ assessment of congestion by ultrasound to a clinical model, including NT-proBNP, provided a net reclassification improvement of 28% (P = 0.03). Conclusion Simultaneous assessment of pulmonary, venous, and kidney congestion by ultrasound is feasible, fast, and identifies a high prevalence of sub-clinical congestion associated with poor outcomes. [ABSTRACT FROM AUTHOR]

Although vocal signals, including languages and songbird syllables, are composed of a finite number of acoustic elements, diverse vocal sequences are composed of a combination of these elements, which are linked together by syntactic rules. However, the neural basis of syntactic vocalization generation remains poorly understood. Here, we report that inhibition using tetrodotoxin (TTX) and manipulations of gamma-aminobutyric acid (GABA) receptors within the basal ganglia Area X or lateral magnocellular nucleus of the anterior neostriatum (LMAN) alter and prolong repetitive vocalization in Bengalese finches (Lonchura striata var. domestica). These results suggest that repetitive vocalizations are modulated by the basal ganglia and not solely by higher motor cortical neurons. These data highlight the importance of neural circuits, including the basal ganglia, in the production of stereotyped repetitive vocalizations and demonstrate that dynamic disturbances within the basal ganglia circuitry can differentially affect the repetitive temporal features of songs. [ABSTRACT FROM AUTHOR]

Background In the I CARE study, colon cancer patients were randomly assigned to receive follow-up care from either a general practitioner (GP) or a surgeon. Here, we address a secondary outcome, namely, detection of recurrences and effect on time to detection of transferring care from surgeon to GP. Methods Pattern, stage, and treatment of recurrences were described after 3 years. Time to event was defined as date of surgery, until date of recurrence or last follow-up, with death as competing event. Effects on time to recurrence and death were estimated as hazard ratios (HRs) using Cox regression. Restricted mean survival times were estimated. Results Of 303 patients, 141 were randomly assigned to the GP and 162 to the surgeon. Patients were male (67%) with a mean age of 68.0 (8.4) years. During follow-up, 46 recurrences were detected; 18 (13%) in the GP vs 28 (17%) in the surgeon group. Most recurrences were detected via abnormal follow-up tests (74%) and treated with curative intent (59%). Hazard ratio for recurrence was 0.75 (95% confidence interval [CI] = 0.41 to 1.36) in GP vs surgeon group. Patients in the GP group remained in the disease-free state slightly longer (2.76 vs 2.71 years). Of the patients, 38 died during follow-up; 15 (11%) in the GP vs 23 (14%) in the surgeon group. Of these, 21 (55%) deaths were related to colon cancer. There were no differences in overall deaths between the groups (HR = 0.76, 95% CI = 0.39 to 1.46). Conclusion Follow-up provided by GPs vs surgeons leads to similar detection of recurrences. Also, no differences in mortality were found. [ABSTRACT FROM AUTHOR]

With the emergence of hypoxia inducible factor–prolyl hydroxylase inhibitors (HIF-PHIs) came the hope that using these oral drugs could improve the treatment of the anemia of kidney disease. In this editorial we discuss the accumulated knowledge on these agents and the clinical context for use. [ABSTRACT FROM AUTHOR]

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome due to overproduction of fibroblast growth factor 23 (FGF23), with profound effects on patient morbidity. TIO is an underdiagnosed disease, whose awareness should be increased among physicians for timely and proper management of patients. Symptoms reported by patients with TIO are usually nonspecific, thus rendering the diagnosis elusive, with an initial misdiagnosis rate of more than 95%. Biochemical features of TIO are represented by hypophosphatemia, increased or inappropriately normal levels of FGF23, and low to low normal circulating 1,25-dihydroxyvitamin D (1,25(OH)2D). Phosphaturic mesenchymal tumors are the pathological entities underlying TIO in most affected patients. There is now evidence that FN1-FGFR1 and FN1-FGF1 fusion genes are present in about half of tumors causing this paraneoplastic syndrome. Tumors causing TIO are small and grow slowly. They can occur in all parts of the body from head to toe with similar prevalence in soft tissue and bone. There are a number of functional and anatomical imaging techniques used for tumor localization; 68Ga DOTA-based technologies have better sensitivity. Surgery is the treatment of choice; several medical treatments are now available in case of inability to locate the tumor or in case of incomplete excision. [ABSTRACT FROM AUTHOR]

To grade the long-term benefit of anticancer agents, the American Society of Clinical Oncology Value Framework (ASCO-VF) awards tail-of-the-curve bonus points by using milestone survival at twice the median control survival. Here, we propose an alternative, late-life expectancy that we defined as the area under the Kaplan-Meier curve from median control survival to the end of follow-up. We analyzed all indications of immune checkpoint inhibitors with survival data and found that 9 indications out of 13 (69.2%) qualified for ASCO-VF tail-of-the-curve bonus points either in progression-free or overall survival. Our proposed score recognized a long-term benefit not captured by the ASCO-VF, for example, for CHECKMATE-66 where twice the median overall survival was not reached. We found that nivolumab was associated with an increase of 65.3% (95% CI = 38.9 to 89.5) in overall survival late-life expectancy, which highlights its important long-term benefit. In conclusion, the ASCO-VF could be improved with the use of late-life expectancy. [ABSTRACT FROM AUTHOR]

Interactions between Tumor microenvironment (TME) cells shape the unique growth environment, sustaining tumor growth and causing the immune escape of tumor cells. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the identification of cancer-related TME cells. Here, we proposed a novel network-based computational method, named as iATMEcell, to identify the abnormal TME cells associated with the biological outcome of interest based on a cell–cell crosstalk network. In the method, iATMEcell first manually collected TME cell types from multiple published studies and obtained their corresponding gene signatures. Then, a weighted cell–cell crosstalk network was constructed in the context of a specific cancer bulk tissue transcriptome data, where the weight between cells reflects both their biological function similarity and the transcriptional dysregulated activities of gene signatures shared by them. Finally, it used a network propagation algorithm to identify significantly dysregulated TME cells. Using the cancer genome atlas (TCGA) Bladder Urothelial Carcinoma training set and two independent validation sets, we illustrated that iATMEcell could identify significant abnormal cells associated with patient survival and immunotherapy response. iATMEcell was further applied to a pan-cancer analysis, which revealed that four common abnormal immune cells play important roles in the patient prognosis across multiple cancer types. Collectively, we demonstrated that iATMEcell could identify potentially abnormal TME cells based on a cell–cell crosstalk network, which provided a new insight into understanding the effect of TME cells in cancer. iATMEcell is developed as an R package, which is freely available on GitHub (https://github.com/hanjunwei-lab/iATMEcell). [ABSTRACT FROM AUTHOR]

Background In kidney transplant recipients (KTR), the end-stage kidney disease (ESKD) risk dependent on the risk factors acting in native chronic kidney disease (CKD) remains undefined. Methods We compared risk and determinants of ESKD between 757 adult KTR and 1940 patients with native CKD before and after propensity-score (PS) analysis matched for unmodifiable risk factors [(age, sex, diabetes, cardiovascular disease and estimated glomerular filtration rate (eGFR)]. Results In unmatched cohorts, eGFR was lower in CKD versus KTR (45.9 ± 11.3 versus 59.2 ± 13.4 mL/min/1.73 m2, P < 0.001). During a median follow-up of 5.4 years, the unadjusted cumulative incidence of ESKD was consistently lower in unmatched KTR versus CKD. Conversely, in PS-matched analysis, the risk of ESKD in KTR was 78% lower versus CKD at 1 year of follow-up while progressively increased over time resulting similar to that of native CKD patients after 5 years and 2.3-fold higher than that observed in CKD at 10 years. R2 analysis in unmatched patients showed that the proportion of the outcome variance explained by traditional ESKD determinants was smaller in KTR versus native CKD (31% versus 70%). After PS matching, the risk of ESKD [hazard ratio (HR), 95% confidence interval (95% CI)] was significantly associated with systolic blood pressure (1.02, 1.01–1.02), phosphorus (1.31, 1.05–1.64), 24-h proteinuria (1.11, 1.05–1.17) and haemoglobin (0.85, 0.78–0.93) irrespective of KTR status. Similar data were obtained after matching also for modifiable risk factors. Conclusions In KTR, when compared with matched native CKD patients, the risk of ESKD is lower in the first 5 years and higher later on. Traditional determinants of ESKD account for one-third of the variability of time-to-graft failure. [ABSTRACT FROM AUTHOR]

Objective: Accurate and rapid phenotyping is a prerequisite to leveraging electronic health records for biomedical research. While early phenotyping relied on rule-based algorithms curated by experts, machine learning (ML) approaches have emerged as an alternative to improve scalability across phenotypes and healthcare settings. This study evaluates ML-based phenotyping with respect to (1) the data sources used, (2) the phenotypes considered, (3) the methods applied, and (4) the reporting and evaluation methods used.Materials and Methods: We searched PubMed and Web of Science for articles published between 2018 and 2022. After screening 850 articles, we recorded 37 variables on 100 studies.Results: Most studies utilized data from a single institution and included information in clinical notes. Although chronic conditions were most commonly considered, ML also enabled the characterization of nuanced phenotypes such as social determinants of health. Supervised deep learning was the most popular ML paradigm, while semi-supervised and weakly supervised learning were applied to expedite algorithm development and unsupervised learning to facilitate phenotype discovery. ML approaches did not uniformly outperform rule-based algorithms, but deep learning offered a marginal improvement over traditional ML for many conditions.Discussion: Despite the progress in ML-based phenotyping, most articles focused on binary phenotypes and few articles evaluated external validity or used multi-institution data. Study settings were infrequently reported and analytic code was rarely released.Conclusion: Continued research in ML-based phenotyping is warranted, with emphasis on characterizing nuanced phenotypes, establishing reporting and evaluation standards, and developing methods to accommodate misclassified phenotypes due to algorithm errors in downstream applications. [ABSTRACT FROM AUTHOR]

Background Timely diagnosis of heart failure (HF) is essential to optimize treatment opportunities that improve symptoms, quality of life, and survival. While most patients consult their general practitioner (GP) prior to HF, the early stages of HF may be difficult to identify. An integrated clinical support tool may aid in identifying patients at high risk of HF. We therefore constructed a prediction model using routine health care data. Methods Our study involved a dynamic cohort of patients (≥35 years) who consulted their GP with either dyspnoea and/or peripheral oedema within the Amsterdam metropolitan area from 2011 to 2020. The outcome of interest was incident HF, verified by an expert panel. We developed a regularized, cause-specific multivariable proportional hazards model (TARGET-HF). The model was evaluated with bootstrapping on an isolated validation set and compared to an existing model developed with hospital insurance data as well as patient age as a sole predictor. Results Data from 31,905 patients were included (40% male, median age 60 years) of whom 1,301 (4.1%) were diagnosed with HF over 124,676 person-years of follow-up. Data were allocated to a development (n  = 25,524) and validation (n  = 6,381) set. TARGET-HF attained a C-statistic of 0.853 (95% CI, 0.834 to 0.872) on the validation set, which proved to provide a better discrimination than C = 0.822 for age alone (95% CI, 0.801 to 0.842, P  < 0.001) and C = 0.824 for the hospital-based model (95% CI, 0.802 to 0.843, P  < 0.001). Conclusion The TARGET-HF model illustrates that routine consultation codes can be used to build a performant model to identify patients at risk for HF at the time of GP consultation. [ABSTRACT FROM AUTHOR]

Cardiometabolic diseases contribute more to global morbidity and mortality than any other group of disorders. Polygenic risk scores (PRSs), the weighted summation of individually small-effect genetic variants, represent an advance in our ability to predict the development and complications of cardiometabolic diseases. This article reviews the evidence supporting the use of PRS in seven common cardiometabolic diseases: coronary artery disease (CAD), stroke, hypertension, heart failure and cardiomyopathies, obesity, atrial fibrillation (AF), and type 2 diabetes mellitus (T2DM). Data suggest that PRS for CAD, AF, and T2DM consistently improves prediction when incorporated into existing clinical risk tools. In other areas such as ischaemic stroke and hypertension, clinical application appears premature but emerging evidence suggests that the study of larger and more diverse populations coupled with more granular phenotyping will propel the translation of PRS into practical clinical prediction tools. [ABSTRACT FROM AUTHOR]

Slowly reproducing and long-lived terrestrial mammals are often more at risk from challenges that influence fitness and survival. It is, therefore, important to understand how animals cope with such challenges and how coping mechanisms translate over generations and affect phenotypic plasticity. Rapidly escalating anthropogenic challenges may further diminish an animal's ability to reinstate homeostasis. Research to advance insights on elephant stress physiology has predominantly focused on relative or comparative analyses of a major stress response marker, glucocorticoids (GCs), across different ecological, anthropogenic, and reproductive contexts. This paper presents an extensive review of published findings on Asian and African elephants from 1980 to 2023 (May) and reveals that stress responses, as measured by alterations in GCs in different sample matrices, often are highly dynamic and vary within and across individuals exposed to similar stimuli, and not always in a predictable fashion. Such dynamicity in physiological reactivity may be mediated by individual differences in personality traits or coping styles, ecological conditions, and technical factors that often are not considered in study designs. We describe probable causations under the 'Physiological Dynamicity Model', which considers context–experience–individuality effects. Highly variable adrenal responses may affect physiological plasticity with potential fitness and survival consequences. This review also addresses the significance of cautious interpretations of GCs data in the context of normal adaptive stress versus distress. We emphasize the need for long-term assessments of GCs that incorporate multiple markers of 'stress' and 'well-being' to decipher the probable fitness consequences of highly dynamic physiological adrenal responses in elephants. Ultimately, we propose that assessing GC responses to current and future challenges is one of the most valuable and informative conservation tools we have for guiding conservation strategies. [ABSTRACT FROM AUTHOR]

One of the first studies to investigate this important question prospectively followed LS carriers getting colonoscopies every 3 years compared with those getting no screening and found that the 3-year screening interval decreased CRC risk and improved overall survival, establishing routine colonoscopy screening as the standard of care ([6]). At present, however, colonoscopy screening remains critical to LS surveillance, CRC risk reduction, and improved outcomes for all LS carriers. Lynch syndrome (LS) is one of the most common hereditary colorectal cancer (CRC) predisposition syndromes and is present in 1 out of 279 individuals in the general population ([1]) and in approximately 3% of unselected cases of CRC ([2]). [Extracted from the article]

Background The comparative effectiveness of trimodality therapy vs definitive chemoradiation for treating locally advanced esophageal cancer in older adults is uncertain. Existing trials lack generalizability to older adults, a population with heightened frailty. We sought to emulate a hypothetical trial comparing these treatments using real-world data. Methods A cohort of adults aged 66-79 years diagnosed with locally advanced esophageal cancer between 2004 and 2017 was identified in the Surveillance Epidemiology and End Results–Medicare database. The clone-censor-weight method was leveraged to eliminate time-related biases when comparing outcomes between treatments. Outcomes included overall mortality, esophageal cancer–specific mortality, functional adverse events, and healthy days at home. Results A total of 1240 individuals with adenocarcinomas and 661 with squamous cell carcinomas were identified. For adenocarcinomas, the standardized 5-year risk of mortality was 73.4% for trimodality therapy and 83.8% for definitive chemoradiation (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.82 to 0.95). Trimodality therapy was associated with mortality risk reduction for squamous cell carcinomas (RR = 0.87, 95% CI = 0.70 to 1.01). The 1-year incidence of functional adverse events was higher in the trimodality group (adenocarcinomas RR = 1.40, 95% CI = 1.22 to 1.65; squamous cell carcinomas RR = 1.21, 95% CI = 1.00 to 1.49). Over 5 years, trimodality therapy was associated with 160 (95% CI = 67 to 229) and 177 (95% CI = 51 to 313) additional home days in individuals with adenocarcinomas and squamous cell carcinomas, respectively. Conclusions Compared with definitive chemoradiation, trimodality therapy was associated with reduced mortality but increased risk of function-related adverse events. Discussing these tradeoffs may help optimize care plans. [ABSTRACT FROM AUTHOR]

Aims Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. Methods and results In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N -terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60–3.45]; fifth quintile HR 3.73 (95% CI 2.58–5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75–0.91). Conclusion It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively. [ABSTRACT FROM AUTHOR]

Background Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important. Methods The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3–5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8–10 g/dL or receiving ESAs with screening Hb of 8–12 g/dL. Participants were randomized to daprodustat or darbepoetin alfa (1:1) in an open-label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28–52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials. Results Overall, 3872 patients were randomized from 39 countries (median age 67 years, 56% female, 56% White, 27% Asian and 10% Black). The median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and estimated glomerular filtration rate was 18 mL/min/1.73 m2. Among randomized patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin–angiotensin system blockers, 55% were taking statins and 49% were taking oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials. Conclusion ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis. [ABSTRACT FROM AUTHOR]

Aims Positron emission tomography (PET) myocardial perfusion imaging (MPI) is often combined with coronary artery calcium (CAC) scanning, allowing for a combined anatomic and functional assessment. We evaluated the independent prognostic value of quantitative assessment of myocardial perfusion and CAC scores in patients undergoing PET. Methods and results Consecutive patients who underwent Rb-82 PET with CAC scoring between 2010 and 2018, with follow-up for major adverse cardiovascular events (MACE), were identified. Perfusion was quantified automatically with total perfusion deficit (TPD). Our primary outcome was MACE including all-cause mortality, myocardial infarction (MI), admission for unstable angina, and late revascularization. Associations with MACE were assessed using multivariable Cox models adjusted for age, sex, medical history, and MPI findings including myocardial flow reserve. In total, 2507 patients were included with median age 70. During median follow-up of 3.9 years (interquartile range 2.1–6.1), 594 patients experienced at least one MACE. Increasing CAC and ischaemic TPD were associated with increased MACE, with the highest risk associated with CAC > 1000 [adjusted hazard ratio (HR) 1.67, 95% CI 1.24–2.26] and ischaemic TPD > 10% (adjusted HR 1.80, 95% CI 1.40–2.32). Ischaemic TPD and CAC improved overall patient classification, but ischaemic TPD improved classification of patients who experienced MACE while CAC mostly improved classification of low-risk patients. Conclusions Ischaemic TPD and CAC were independently associated with MACE. Combining extent of atherosclerosis and functional measures improves the prediction of MACE risk, with CAC 0 identifying low-risk patients and regional ischaemia identifying high-risk patients in those with CAC > 0. [ABSTRACT FROM AUTHOR]

Formation and elimination of synapses reflect structural plasticity of neuronal connectivity. Here we performed high-resolution two-photon imaging of dendritic spines in the prefrontal cortex of four macaque monkeys and found that spines were in general highly stable, with low percentages undergoing synaptic turnover. By observing the same spines at weekly intervals, we found that newly formed spines were more susceptible to elimination, with only 40% persisting over a period of months. Analyses of spatial distribution of large numbers of spines revealed that spine distribution was neither uniform nor random, favoring inter-spine distances of 2–4 μm. Furthermore, spine formation and elimination occurred more often in low- and high-density dendritic segments, respectively, and preferentially within a hot zone of ∼4 μm from existing spines. Our results demonstrate long-term stability and spatially regulated spine dynamics in the macaque cortex and provide a structural basis for understanding neural circuit plasticity in the primate brain. [ABSTRACT FROM AUTHOR]

Motivation In this article, we consider how to evaluate survival distribution predictions with measures of discrimination. This is non-trivial as discrimination measures are the most commonly used in survival analysis and yet there is no clear method to derive a risk prediction from a distribution prediction. We survey methods proposed in literature and software and consider their respective advantages and disadvantages. Results Whilst distributions are frequently evaluated by discrimination measures, we find that the method for doing so is rarely described in the literature and often leads to unfair comparisons or 'C-hacking'. We demonstrate by example how simple it can be to manipulate results and use this to argue for better reporting guidelines and transparency in the literature. We recommend that machine learning survival analysis software implements clear transformations between distribution and risk predictions in order to allow more transparent and accessible model evaluation. Availability and implementation The code used in the final experiment is available at https://github.com/RaphaelS1/distribution_discrimination. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare the outcomes of nonfatal road traffic accidents by the victims' age group and sex. We used the Portuguese medico-legal rules for personal injury assessment, in the scope of the Civil Law in that country, which includes a three-dimensional methodology. This was a retrospective study including 667 victims of road traffic accidents aged 3–94 years old. Their final medico-legal reports all used the Portuguese methodology for personal injury assessment. Outcomes were analysed by the victims' age group (children, working-age adults, and older people) and sex. Road traffic accidents were generally serious (ISS mean 9.5), with higher severity in children and older people. The most frequent body sequelae were musculoskeletal (64.8%), which were associated with functional and situational outcomes. Temporary damage resulted in an average length of impairment of daily life of 199.6 days, 171.7 days to return to work, and an average degree of quantum doloris (noneconomic damage related to physical and psychological harm) of 3.7/7. The average permanent damage was 7.3/100 points for Permanent Functional Deficit, 0.43/3 for Permanent Professional Repercussion, 2/7 for Permanent Aesthetic Damage, 3.9/7 for Permanent Repercussion on Sexual Activity and 3.2/7 for Permanent Repercussion on Sport and Leisure Activities. Overall, 19% of people became permanently dependent (10.6% needed third-party assistance). The medico-legal methodology used, considering victims' real-life situation, allows a comprehensive assessment. There were several significant differences among the three age groups but none between sexes. These differences and the impact of the more severe cases justify further detailed medico-legal studies in these specific situations on children, older people, and severely injured victims. This was a retrospective study of accident mechanisms and injury outcomes in Portugal, and considered the outcomes in the victims' real-life situation. Lesions from road traffic accidents were generally serious, with higher severity among children and older people. The most frequent sequels were musculoskeletal, and associated with functional and situational outcomes. Both temporary and permanent outcomes had repercussions for the victims. There were significant differences between children, working-age adults and older people, but none between sexes. [ABSTRACT FROM AUTHOR]

Aims To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods and results The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9–3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n  = 118, 21%); desmoplakin (DSP) (n  = 79, 14%); other desmosomal (n  = 59, 11%); and gene elusive (n  = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. Conclusion The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to evaluate whether the MADIT-ICD benefit score can predict who benefits most from the addition of implantable cardioverter-defibrillator (ICD) to cardiac resynchronization therapy (CRT) in real-world patients with heart failure with reduced ejection fraction (HFrEF) and to compare this with selection according to a multidisciplinary expert centre approach.Methods and Results: Consecutive HFrEF patients who received a CRT for a guideline indication at a tertiary care hospital (Ziekenhuis Oost-Limburg, Genk, Belgium) between October 2008 and September 2016, were retrospectively evaluated. The MADIT-ICD benefit groups (low, intermediate, and high) were compared with the current multidisciplinary expert centre approach. Endpoints were (i) sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and (ii) non-arrhythmic mortality. Of the 475 included patients, 165 (34.7%) were in the lowest, 220 (46.3%) in the intermediate, and 90 (19.0%) in the highest benefit group. After a median follow-up of 34 months, VT/VF occurred in 3 (1.8%) patients in the lowest, 9 (4.1%) in the intermediate, and 13 (14.4%) in the highest benefit group (P < 0.001). Vice versa, non-arrhythmic death occurred in 32 (19.4%) in the lowest, 32 (14.6%) in the intermediate, and 3 (3.3%) in the highest benefit group (P = 0.002). The predictive power for ICD benefit was comparable between expert multidisciplinary judgement and the MADIT-ICD benefit score: Uno's C-statistic 0.69 vs. 0.69 (P = 0.936) for VT/VF and 0.62 vs. 0.60 (P = 0.790) for non-arrhythmic mortality.Conclusion: The MADIT-ICD benefit score can identify who benefits most from CRT-D and is comparable with multidisciplinary judgement in a CRT expert centre. [ABSTRACT FROM AUTHOR]

Aims Previously, guidelines recommended initiating therapy in patients with heart failure and reduced ejection fraction (HFrEF) in a sequence that follows the chronological order in which trials were conducted, with cautious up-titration of each treatment. It remains unclear whether this historical approach is optimal and alternative approaches may improve patient outcomes. Methods and results The potential reductions in events that might result from (i) more rapid up-titration of therapies used in the conventional order (based on the chronology of the trials), and (ii) accelerated up-titration and using treatments in different orders than is conventional were modelled using data from six pivotal trials in HFrEF. Over the first 12 months from starting therapy, using a rapid up-titration schedule led to 23 fewer patients per 1000 patients experiencing the composite of heart failure hospitalization or cardiovascular death and seven fewer deaths from any cause. In addition to accelerating up-titration of treatments, optimized alternative ordering of the drugs used resulted in a further reduction of 24 patients experiencing the composite outcome and six fewer deaths at 12 months. The optimal alternative sequences included sodium–glucose cotransporter 2 inhibition and a mineralocorticoid receptor antagonist as the first two therapies. Conclusion Modelling of accelerated up-titration schedule and optimized ordering of treatment suggested that at least 14 deaths and 47 patients experiencing the composite outcome per 1000 treated might be prevented over the first 12 months after starting therapy. Standard treatment guidance may not lead to the best patient outcomes in HFrEF, though these findings should be tested in clinical trials. [ABSTRACT FROM AUTHOR]

Background to assess the efficacy of comprehensive geriatric assessment (CGA) for preventing treatment-related toxicity in older people undergoing non-surgical cancer therapies. Methods MEDLINE, EMBASE and Cochrane library databases were searched from inception till January 2022 to identify randomised controlled trials (RCTs) on the incidence of toxicity measured by the Common Terminology Criteria for Adverse Events (primary outcome) and that of therapeutic modifications, early treatment discontinuation, progression-free survival, overall survival and hospitalisation (secondary outcomes). Results analysis of six RCTs published from 2016 to 2021 recruiting 2,126 participants (median age: 71–77) who received chemotherapy as the major therapeutic approach revealed 51.7% and 64.7% of Grade 3+ toxicity in the CGA and control (i.e. standard care) groups, respectively (RR = 0.81, 95% CI: 0.7–0.94, P  = 0.005, I 2 = 65%, certainty of evidence [COE]: moderate). There were no significant differences in the incidence of early treatment discontinuation (RR = 0.88, P  = 0.47; I 2 = 63%,1,408 participants, COE: low), initial reduction in treatment intensity (RR = 0.99, P  = 0.94; I 2 = 83%, 2055 participants, COE: low), treatment delay (RR = 1.06, P  = 0.77, I 2 = 0%, 309 participants, COE: moderate), hospitalisation (RR = 0.86, P  = 0.39, I 2 = 41%, 914 participants, COE: moderate), progression-free and overall survival with or without CGA. However, there was an association between CGA and a lower incidence of dose reduction during treatment (RR = 0.73, P  < 0.00001, 956 participants, COE: moderate). Conclusions our results demonstrated that comprehensive geriatric assessment may be associated with a lower incidence of treatment-related toxicity and dose reduction compared to standard care in older people receiving non-surgical cancer treatments. Further large-scale studies are warranted to support our findings. [ABSTRACT FROM AUTHOR]

Background: Negotiating goals of care (GoC) with patients is an essential skill for all health-care professionals (HCPs) in hospitals. End-of-Life Essentials (EOLE) is a Commonwealth-funded project that delivers free, peer-reviewed, evidence-based, online education and practice change resources. To date, around 26 000 doctors, nurses and allied health professionals have registered to access the education. 'Planning End-of-Life Care-Goals of Care' features in the suite of EOLE modules and includes education around negotiating GoC with patients and families.Objective: The aim of the study was to explore the views of module learners (HCPs) on challenges they have faced when negotiating GoC at the EOL with patients and families.Methods: Participants were learners (HCPs) who registered to the EOLE website and engaged with the GoC module. Learners' responses to the question posed at the end of the module 'What are the hardest or most challenging things about negotiating GoC with patients and families?' were extracted for a 12-month period. Qualitative data were analysed thematically in NVivo V.12, guided by the theoretical framework of pragmatism. An open, inductive approach was used to code the data, with axial coding used to refine and organize themes and subthemes.Results: A total of 451 learner statements were analysed. Five themes emerged from the data: (i) differing views and opinions; (ii) challenges to understanding; (iii) managing emotions; (iv) initiating the EOL conversation and (v) lack of professional knowledge or capacity. Five subthemes were also organized under the theme 'differing views and opinions'.Conclusion: Planning EOL care demands high-level, compassionately skilful and sensitive care and services, which are in line with the patient's and family's wishes. In practice, however, there are many challenges to this, such as ensuring that patients, families, and HCPs are aware of different expectations regarding future health-care possibilities, and that HCPs are prepared for negotiating GoC to achieve quality and safe EOL care in hospitals. [ABSTRACT FROM AUTHOR]

Motivation Multiomics cancer profiles provide essential signals for predicting cancer survival. It is challenging to reveal the complex patterns from multiple types of data and link them to survival outcomes. We aim to develop a new deep learning-based algorithm to integrate three types of high-dimensional omics data measured on the same individuals to improve cancer survival outcome prediction. Results We built a three-dimension tensor to integrate multi-omics cancer data and factorized it into two-dimension matrices of latent factors, which were fed into neural networks-based survival networks. The new algorithm and other multi-omics-based algorithms, as well as individual genomic-based survival analysis algorithms, were applied to the breast cancer data colon and rectal cancer data from The Cancer Genome Atlas (TCGA) program. We evaluated the goodness-of-fit using the concordance index (C-index) and Integrated Brier Score (IBS). We demonstrated that the proposed tight integration framework has better survival prediction performance than the models using individual genomic data and other conventional data integration methods. Availability and implementation https://github.com/jasperzyzhang/DeepTensorSurvival Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background Anemia is a common complication of chronic kidney disease (CKD), but its incidence in nephrology settings is poorly investigated. Similarly, the risks of adverse outcomes associated with new-onset anemia are not known. Methods We performed a pooled analysis of three observational cohort studies including 1031 non-anemic CKD patients with eGFR <60 mL/min/1.73 m2 regularly followed in renal clinics. We estimated the incidence of mild anemia (hemoglobin 11–12 g/dL in women and 11–13 g/dL in men) and severe anemia (hemoglobin <11 g/dL or use of erythropoiesis-stimulating agents) during a 3-year follow-up period. Thereafter we estimated the risk of end-stage kidney disease (ESKD) and all-cause death associated with new-onset mild and severe anemia. Results The mean age was 63 ± 14 years, 60% were men and 20% had diabetes. The mean estimated glomerular filtration rate (eGFR) was 37 ± 13 mL/min/1.73 m2 and the median proteinuria was 0.4 g/day [interquartile range (IQR) 0.1–1.1]. The incidence of mild and severe anemia was 13.7/100 patients-year and 6.2/100 patients-year, respectively. Basal predictors of either mild or severe anemia were diabetes, lower hemoglobin, higher serum phosphate, eGFR <30 mL/min/1.73 m2 and proteinuria >0.50 g/day. Male sex, moderate CKD (eGFR 30–44 mL/min/1.73 m2) and moderate proteinuria (0.15–0.50 g/day) predicted only mild anemia. The incidence of anemia increased progressively with CKD stages (from 8.77 to 76.59/100 patients-year) and the proteinuria category (from 13.99 to 25.02/100 patients-year). During a median follow-up of 3.1 years, 232 patients reached ESKD and 135 died. Compared with non-anemic patients, mild anemia was associated with a higher adjusted risk of ESKD {hazard ratio [HR] 1.42 [95% confidence interval (CI) 1.02–1.98]} and all-cause death [HR 1.55 (95% CI 1.04–2.32)]. Severe anemia was associated with an even higher risk of ESKD [HR 1.73 (95% CI 1.20–2.51)] and death [HR 1.83 (95% CI 1.05–3.19)]. Conclusions New-onset anemia is frequent, particularly in patients with more severe renal damage and in those with diabetes mellitus. The occurrence of anemia, even of a mild degree, is associated with mortality risk and faster progression towards ESKD. [ABSTRACT FROM AUTHOR]

Aims Left atrial (LA) function is a marker of prognosis in patients with heart failure. The prognostic implications of an improvement in LA function in addition to an improvement in left ventricular (LV) function after cardiac resynchronization therapy (CRT) implantation are unknown. This study aimed to evaluate the prognostic value of a significant change in LA reservoir strain (RS) and/or LV global longitudinal strain (GLS) after initiation of CRT. Methods and results LARS and LVGLS were measured with speckle-tracking echocardiography. Significant improvement in LARS and LVGLS was defined as a percentage change of +5% and +20% at 6 months after CRT implantation, respectively. Patients were divided into three groups: no significant reverse remodelling (no improvement in LARS and LVGLS), incomplete reverse remodelling (improvement in LARS or LVGLS), and complete reverse remodelling (improvement in LARS and LVGLS). The primary endpoint was all-cause mortality. A total of 923 patients (mean age 65 ± 10 years, 77% male) were included, of which 221 (24%) had complete reverse remodelling, 414 (45%) incomplete reverse remodelling, and 288 (31%) no significant reverse remodelling. Five-years' mortality was 24%, 29%, and 36% for patients with complete, incomplete, and no significant reverse remodelling, respectively (P < 0.001). On multivariable analysis, complete reverse remodelling (hazard ratio 0.477; 95% confidence interval: 0.362–0.628; P < 0.001) was associated with the lowest risk of mortality. Conclusions Patients with complete reverse remodelling have a lower mortality risk than those showing incomplete or no significant reverse remodelling. The use of integrated LA and LV deformation imaging may improve risk-stratification of CRT recipients. [ABSTRACT FROM AUTHOR]

Background The A nemia S tudies in chronic kidney disease (C KD): E rythropoiesis via a N ovel prolyl hydroxylase inhibitor D aprodustat- D ialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety. Methods We report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries. Results The median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries. Conclusions ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D. This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807. [ABSTRACT FROM AUTHOR]

Cellular senescence (CS), a state of permanent growth arrest, is intertwined with tumorigenesis. Due to the absence of specific markers, characterizing senescence levels and senescence-related phenotypes across cancer types remain unexplored. Here, we defined computational metrics of senescence levels as CS scores to delineate CS landscape across 33 cancer types and 29 normal tissues and explored CS-associated phenotypes by integrating multiplatform data from ~20 000 patients and ~212 000 single-cell profiles. CS scores showed cancer type-specific associations with genomic and immune characteristics and significantly predicted immunotherapy responses and patient prognosis in multiple cancers. Single-cell CS quantification revealed intra-tumor heterogeneity and activated immune microenvironment in senescent prostate cancer. Using machine learning algorithms, we identified three CS genes as potential prognostic predictors in prostate cancer and verified them by immunohistochemical assays in 72 patients. Our study provides a comprehensive framework for evaluating senescence levels and clinical relevance, gaining insights into CS roles in cancer- and senescence-related biomarker discovery. [ABSTRACT FROM AUTHOR]