Search

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]

Background: A retrospective analysis was conducted on necropsy records from a large rhesus monkey colony to evaluate the age-related prevalence of endometriosis.Methods: A total of 314 records collected over a 15-year period were analyzed, yielding 66 monkeys with histologically verified endometriosis and 248 control subjects.Results: The analyses demonstrated that the incidence of endometriosis increases progressively across the life span, ultimately impacting 21-45% of aged monkeys over 20 years of age.Conclusions: Because mild disease is often not diagnosed premortem, the endocrine and immune sequelae of endometriosis may be a potential confound in even nonreproductive research with aging primates. Prior research-related events influence the occurrence and severity of endometriosis in these long-lived animals, and specifically could have contributed to the high prevalence of endometriosis in this particular monkey colony. [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 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 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 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]

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]

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]

For survival analysis in comparative coronavirus disease 2019 trials, the routinely used hazard ratio may not provide a meaningful summary of the treatment effect. The mean survival time difference/ratio is an intuitive, assumption-free alternative. However, for short-term studies, landmark mortality rate differences/ratios are more clinically relevant and should be formally analyzed and reported. [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]

Background: It is unclear whether pathological staging is significant prognostically and can inform the delivery of adjuvant therapy after pancreatectomy preceded by neoadjuvant therapy. Methods: This multicentre retrospective study included patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma after neoadjuvant treatment at two Italian centres between 2013 and 2017. T and N status were assigned in accordance with the seventh and eighth editions of the AJCC staging system, as well as according to a modified system with T status definition combining extrapancreatic invasion and tumour size. Patients were then stratified by receipt of adjuvant therapy. Survival analysis and multivariable interaction analysis of adjuvant therapy with pathological parameters were performed. The results were validated in an external cohort from the USA. Results: The developmental set consisted of 389 patients, with a median survival of 34.6 months. The modified staging system displayed the best prognostic stratification and the highest discrimination (C-index 0.763; 1-, 2- and 3-year time-dependent area under the curve (AUC) 0.746, 0.722, and 0.705; Uno's AUC 0.710). Overall, 67.0 per cent of patients received adjuvant therapy. There was no survival difference by receipt of adjuvant therapy (35.0 versus 36.0 months; P = 0.772). After multivariable adjustment, interaction analysis suggested a benefit of adjuvant therapy for patients with nodal metastases or with tumours larger than 2 cm with extrapancreatic extension, regardless of nodal status. These results were confirmed in the external cohort of 216 patients. Conclusion: Modified staging with a T status definition combining extrapancreatic invasion and tumour size is associated with better prognostic segregation after postneoadjuvant pancreatectomy. This system allows identification of patients who might benefit from adjuvant therapy. [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]

Prediction models are often built and evaluated using data from a population that differs from the target population where model-derived predictions are intended to be used in. In this article, we present methods for evaluating model performance in the target population when some observations are right censored. The methods assume that outcome and covariate data are available from a source population used for model development and covariates, but no outcome data, are available from the target population. We evaluate the finite sample performance of the proposed estimators using simulations and apply the methods to transport a prediction model built using data from a lung cancer screening trial to a nationally representative population of participants eligible for lung cancer screening. [ABSTRACT FROM AUTHOR]

Leveraging large-scale electronic health record (EHR) data to estimate survival curves for clinical events can enable more powerful risk estimation and comparative effectiveness research. However, use of EHR data is hindered by a lack of direct event time observations. Occurrence times of relevant diagnostic codes or target disease mentions in clinical notes are at best a good approximation of the true disease onset time. On the other hand, extracting precise information on the exact event time requires laborious manual chart review and is sometimes altogether infeasible due to a lack of detailed documentation. Current status labels—binary indicators of phenotype status during follow-up—are significantly more efficient and feasible to compile, enabling more precise survival curve estimation given limited resources. Existing survival analysis methods using current status labels focus almost entirely on supervised estimation, and naive incorporation of unlabeled data into these methods may lead to biased estimates. In this article, we propose Semisupervised Calibration of Risk with Noisy Event Times (SCORNET), which yields a consistent and efficient survival function estimator by leveraging a small set of current status labels and a large set of informative features. In addition to providing theoretical justification of SCORNET, we demonstrate in both simulation and real-world EHR settings that SCORNET achieves efficiency akin to the parametric Weibull regression model, while also exhibiting semi-nonparametric flexibility and relatively low empirical bias in a variety of generative settings. [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]

The restricted mean survival time (RMST) evaluates the expectation of survival time truncated by a prespecified time point, because the mean survival time in the presence of censoring is typically not estimable. The frequentist inference procedure for RMST has been widely advocated for comparison of two survival curves, while research from the Bayesian perspective is rather limited. For the RMST of both right‐ and interval‐censored data, we propose Bayesian nonparametric estimation and inference procedures. By assigning a mixture of Dirichlet processes (MDP) prior to the distribution function, we can estimate the posterior distribution of RMST. We also explore another Bayesian nonparametric approach using the Dirichlet process mixture model and make comparisons with the frequentist nonparametric method. Simulation studies demonstrate that the Bayesian nonparametric RMST under diffuse MDP priors leads to robust estimation and under informative priors it can incorporate prior knowledge into the nonparametric estimator. Analysis of real trial examples demonstrates the flexibility and interpretability of the Bayesian nonparametric RMST for both right‐ and interval‐censored data. [ABSTRACT FROM AUTHOR]

Screening mammography aims to identify breast cancer early and secondarily measures breast density to classify women at higher or lower than average risk for future breast cancer in the general population. Despite the strong association of individual mammography features to breast cancer risk, the statistical literature on mammogram imaging data is limited. While functional principal component analysis (FPCA) has been studied in the literature for extracting image‐based features, it is conducted independently of the time‐to‐event response variable. With the consideration of building a prognostic model for precision prevention, we present a set of flexible methods, supervised FPCA (sFPCA) and functional partial least squares (FPLS), to extract image‐based features associated with the failure time while accommodating the added complication from right censoring. Throughout the article, we hope to demonstrate that one method is favored over the other under different clinical setups. The proposed methods are applied to the motivating data set from the Joanne Knight Breast Health cohort at Siteman Cancer Center. Our approaches not only obtain the best prediction performance compared to the benchmark model, but also reveal different risk patterns within the mammograms. [ABSTRACT FROM AUTHOR]

Objective: Pituitary adenomas and their consequences impact mortality and morbidity. We studied the healthcare costs, survival, and cost-effectiveness of growth hormone (GH) vs no GH replacement in patients with non-functioning pituitary adenoma (NFPA). Design and methods: A cohort study including all NFPA patients followed from 1987 or the date of diagnosis until the time of death or December 31, 2019, in the Västra Gotaland region, Sweden. Data to assess resource use, costs, survival, and cost-effectiveness were collected from patient records and regional/national healthcare registries. Results: A total of 426 patients with NFPA (274 men) with a follow-up of 13.6 ± 6.8 years (mean ± SD) were included. The total annual healthcare cost was higher in patients receiving GH (€9287) than those without GH (€6770), mainly driven by a higher pharmaceutical cost. Glucocorticoid replacement therapy (P = .02), diabetes insipidus (P = .04), body mass index (BMI) (P < .01), and hypertension (P < .01) were all individually associated with a higher total annual cost. The survival rate was higher in the GH group (HR [hazard ratio] 0.60; P = .01) and reduced in patients with glucocorticoid replacement (HR 2.02; P< .01) or diabetes insipidus (HR 1.67; P = .04). The cost per gained life-year for GH vs no GH replacement was about €37 000. Conclusions: This healthcare utilization study identified several factors driving the cost of care in NFPA patients, such as GH replacement, adrenal insufficiency, and diabetes insipidus. Life expectancy was increased in those with GH replacement and reduced in patients with B adrenal insufficiency and diabetes insipidus. [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]

Objective The purpose of this systematic review was to identify and appraise externally validated prognostic models to predict a patient's health outcomes relevant to physical rehabilitation of musculoskeletal (MSK) conditions. Methods We systematically reviewed 8 databases and reported our findings according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020. An information specialist designed a search strategy to identify externally validated prognostic models for MSK conditions. Paired reviewers independently screened the title, abstract, and full text and conducted data extraction. We extracted characteristics of included studies (eg, country and study design), prognostic models (eg, performance measures and type of model) and predicted clinical outcomes (eg, pain and disability). We assessed the risk of bias and concerns of applicability using the prediction model risk of bias assessment tool. We proposed and used a 5-step method to determine which prognostic models were clinically valuable. Results We found 4896 citations, read 300 full-text articles, and included 46 papers (37 distinct models). Prognostic models were externally validated for the spine, upper limb, lower limb conditions, and MSK trauma, injuries, and pain. All studies presented a high risk of bias. Half of the models showed low concerns for applicability. Reporting of calibration and discrimination performance measures was often lacking. We found 6 externally validated models with adequate measures, which could be deemed clinically valuable [ie, (1) STart Back Screening Tool, (2) Wallis Occupational Rehabilitation RisK model, (3) Da Silva model, (4) PICKUP model, (5) Schellingerhout rule, and (6) Keene model]. Despite having a high risk of bias, which is mostly explained by the very conservative properties of the PROBAST tool, the 6 models remain clinically relevant. Conclusion We found 6 externally validated prognostic models developed to predict patients' health outcomes that were clinically relevant to the physical rehabilitation of MSK conditions. Impact Our results provide clinicians with externally validated prognostic models to help them better predict patients' clinical outcomes and facilitate personalized treatment plans. Incorporating clinically valuable prognostic models could inherently improve the value of care provided by physical therapists. [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]

In the last decade, studies in persons with HIV (PWH) on antiretroviral therapy (ART) have shed light on the significance of persistently high CD8 counts and low CD4/CD8 ratios. A low CD4/CD8 ratio reflects increased immune activation and is associated with an increased risk of severe non-AIDS events. As a result, many clinicians now believe that the CD4/CD8 ratio can help in HIV monitoring, and many researchers now report it as an efficacy marker in interventional studies. However, the topic is more complex. Recent studies have not yielded unanimous conclusions on the ability of the CD4/CD8 ratio to predict adverse outcomes, and only some clinical guidelines recommend monitoring it. Knowledge gaps remain on the best cutoff points, associated clinical events, effects of treatments, and how the CD4/CD8 ratio could improve decision making in the clinic. Here, we critically review the literature, identify knowledge gaps, and discuss the role of the CD4/CD8 ratio as a marker for HIV monitoring. [ABSTRACT FROM AUTHOR]

Deer have been a major resource for human populations for thousands of years. Anthropogenic activities, such as hunting, have influenced the genetic structure and distribution of deer populations. In Japan, wild Japanese sika deer (Cervus nippon) have been hunted since ancient times but have also been historically protected as sacred animals in several sanctuaries. Sika deer have been protected for over a thousand years in the religious sanctuary around the Kasuga Taisha Shrine on the Kii Peninsula, located in the center of Japan. Here, we used short sequence repeats (SSR) and mitochondrial DNA (mtDNA) to investigate the genetic diversity, population structure, and demography of Japanese sika deer inhabiting the Kii Peninsula, Japan, and discuss possible anthropogenic influences. Using SSR, three distinct genetic groups were distinguished on the Kii Peninsula: an Eastern genetic group, a Western genetic group, and an isolated genetic group with individuals in the religious sanctuary of Kasuga Taisha Shrine in Nara city. The isolated genetic sanctuary group had only the mtDNA haplotype S4. The SSR genotype data suggested a newer divergence time of the genetic groups of the religious sanctuary than would have occurred as a result of Late Quaternary climate change. This time scale coincided with the establishment of the sanctuary with Kasuga Taisha Shrine. Thus, the religious protection conserved genetic variation over a thousand years. [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]

With mammography being the primary breast cancer screening strategy, it is essential to make full use of the mammogram imaging data to better identify women who are at higher and lower than average risk. Our primary goal in this study is to extract mammogram-based features that augment the well-established breast cancer risk factors to improve prediction accuracy. In this article, we propose a supervised functional principal component analysis (sFPCA) over triangulations method for extracting features that are ordered by the magnitude of association with the failure time outcome. The proposed method accommodates the irregular boundary issue posed by the breast area within the mammogram imaging data with flexible bivariate splines over triangulations. We also provide an eigenvalue decomposition algorithm that is computationally efficient. Compared to the conventional unsupervised FPCA method, the proposed method results in a lower Brier Score and higher area under the ROC curve (AUC) in simulation studies. We apply our method to data from the Joanne Knight Breast Health Cohort at Siteman Cancer Center. Our approach not only obtains the best prediction performance comparing to unsupervised FPCA and benchmark models but also reveals important risk patterns within the mammogram images. This demonstrates the importance of utilizing additional supervised image-based features to clarify breast cancer risk. [ABSTRACT FROM AUTHOR]

Readily available proxies for the time of disease onset such as the time of the first diagnostic code can lead to substantial risk prediction error if performing analyses based on poor proxies. Due to the lack of detailed documentation and labor intensiveness of manual annotation, it is often only feasible to ascertain for a small subset the current status of the disease by a follow‐up time rather than the exact time. In this paper, we aim to develop risk prediction models for the onset time efficiently leveraging both a small number of labels on the current status and a large number of unlabeled observations on imperfect proxies. Under a semiparametric transformation model for onset and a highly flexible measurement error model for proxy onset time, we propose the semisupervised risk prediction method by combining information from proxies and limited labels efficiently. From an initially estimator solely based on the labeled subset, we perform a one‐step correction with the full data augmenting against a mean zero rank correlation score derived from the proxies. We establish the consistency and asymptotic normality of the proposed semisupervised estimator and provide a resampling procedure for interval estimation. Simulation studies demonstrate that the proposed estimator performs well in a finite sample. We illustrate the proposed estimator by developing a genetic risk prediction model for obesity using data from Mass General Brigham Healthcare Biobank. [ABSTRACT FROM AUTHOR]

The restricted mean time in favor (RMT‐IF) of treatment is a nonparametric effect size for complex life history data. It is defined as the net average time the treated spend in a more favorable state than the untreated over a prespecified time window. It generalizes the familiar restricted mean survival time (RMST) from the two‐state life–death model to account for intermediate stages in disease progression. The overall estimand can be additively decomposed into stage‐wise effects, with the standard RMST as a component. Alternate expressions of the overall and stage‐wise estimands as integrals of the marginal survival functions for a sequence of landmark transitioning events allow them to be easily estimated by plug‐in Kaplan–Meier estimators. The dynamic profile of the estimated treatment effects as a function of follow‐up time can be visualized using a multilayer, cone‐shaped "bouquet plot." Simulation studies under realistic settings show that the RMT‐IF meaningfully and accurately quantifies the treatment effect and outperforms traditional tests on time to the first event in statistical efficiency thanks to its fuller utilization of patient data. The new methods are illustrated on a colon cancer trial with relapse and death as outcomes and a cardiovascular trial with recurrent hospitalizations and death as outcomes. The R‐package rmt implements the proposed methodology and is publicly available from the Comprehensive R Archive Network (CRAN). [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]

Aims Psoriasis has been associated with increased cardiovascular (CV) risk. We investigated whether markers of CV function and their change after treatment have a prognostic value for adverse outcomes. Methods and results In a prospective study, at baseline and after 6 months of treatment with biological agents, we assessed in 298 psoriasis patients (i) left ventricular global longitudinal strain (GLS) and (ii) carotid-femoral pulse wave velocity (PWV), to evaluate their prognostic value for major adverse cardiovascular events (MACEs), including coronary artery disease, stroke, hospitalization for heart failure, and all-cause death over a 4-year follow-up period. During follow-up, 26 (8.7%) MACEs were recorded. By univariate analysis, decreasing absolute GLS values [hazard ratio (HR): 0.73, P < 0.001], decreasing GLS change after treatment (HR: 0.53, P = 0.008), and increasing PWV values (HR: 1.16, P = 0.049) were associated with adverse outcomes. Baseline GLS and its change post-treatment remained independent predictors of adverse events after adjusting for several confounders (P < 0.05). The addition of baseline GLS and its absolute change post-treatment to SCORE2 increased Harrell's C from 0.882 to 0.941. By multivariable analysis, for each 1% increase in absolute baseline GLS values, the risk of MACE decreased by 33% and for each 1% absolute increase of GLS post-treatment compared with the baseline value, the risk of MACE decreased by 58%. Conclusion Global longitudinal strain has an independent and additive prognostic value to SCORE2 for adverse CV events in psoriasis, providing timely decision-making for intensive anti-inflammatory treatment and aggressive modification of risk factors to reduce CV risk. [ABSTRACT FROM AUTHOR]

Aims Estimation of prognosis in pulmonary arterial hypertension (PAH) has been influenced by that various risk stratification models use different numbers of prognostic parameters, as well as the lack of a comprehensive and time-saving risk assessment calculator. We therefore evaluated the various European Society of Cardiology (ESC)-/European Respiratory Society (ERS)-based three- and four-strata risk stratification models and established a comprehensive internet-based calculator to facilitate risk assessment. Methods and results Between 1 January 2000 and 26 July 2021, 773 clinical assessments on 169 incident PAH patients were evaluated at diagnosis and follow-ups. Risk scores were calculated using the original Swedish Pulmonary Arterial Hypertension Registry (SPAHR)/Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) three-strata model, the updated SPAHR three-strata model with divided intermediate risk, and the simplified three-parameter COMPERA 2.0 four-strata model. The original SPAHR/COMPERA and the updated SPAHR models were tested for both 3–6 and 7–11 available parameters, respectively. Prognostic accuracy [area under the receiver operating characteristic (ROC) curve (AUC)] and Uno's cumulative/time-dependent C-statistics (uAUC) were calculated for 1-, 3-, and 5-year mortality. At baseline, both the original SPAHR/COMPERA and the updated SPAHR models, using up to six parameters, provided the highest accuracy (uAUC = 0.73 for both models) in predicting 1-, 3-, and 5-year mortality. At follow-ups, the updated SPAHR model with divided intermediate risk (7–11 parameters) provided the highest accuracy for 1-, 3-, and 5-year mortality (uAUC = 0.90), followed by the original SPAHR/COMPERA model (7–11 parameters) (uAUC = 0.88) and the COMPERA 2.0 model (uAUC = 0.85). Conclusions The present study facilitates risk assessment in PAH by introducing a comprehensive internet-based risk score calculator (https://www.svefph.se/risk-stratification). At baseline, utilizing the original or the updated SPAHR models using up to six parameters was favourable, the latter model additionally offering sub-characterization of the intermediate risk group. Our findings support the 2022 ESC/ERS pulmonary hypertension guidelines' strategy for risk stratification suggesting the utilization of a three-strata model at baseline and a simplified four-strata model at follow-ups. Our findings furthermore support the utility of the updated SPAHR model with divided intermediate risk, when a more comprehensive assessment is needed at follow-ups, complementing the three-parameter COMPERA 2.0 model. Larger multi-centre studies are encouraged to validate the utility of the updated SPAHR model. Take home message By introducing an internet-based risk score calculator (https://www.svefph.se/risk-stratification), risk assessment is facilitated. Our results support the 2022 ESC/ERS pulmonary hypertension guidelines' risk stratification strategy, additionally suggesting the updated SPAHR three-strata model with divided intermediate risk, as a promising complement to the new simplified three-parameter COMPERA 2.0 four-strata strategy, when a more comprehensive overview is needed. [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]

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 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]

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]