Cox Proportional Hazards Model Research Articles

Cardiovascular magnetic resonance-derived left atrioventricular coupling index as a novel prognostic marker for light-chain amyloidosis

BackgroundLeft atrioventricular coupling index (LACI) is a novel biomarker, and the prognostic value of LACI to predict cardiovascular events has been validated. The present study aimed to explore the prognostic value of LACI in patients with light-chain (AL) amyloidosis. MethodsWe prospectively enrolled 179 patients with AL amyloidosis who underwent cardiovascular magnetic resonance imaging between December 2011 and January 2020. LACI was defined as the ratio between the left atrial volume and the left ventricular volume at end-diastole. The primary endpoint was all-cause mortality. Receiver operating characteristic curve was used to identify the optimal cut-off of LACI in predicting all-cause mortality. Univariable and multivariable Cox proportional hazard models were used to assess the association of LACI and primary endpoint. ResultsDuring a median follow-up of 30 months, 118 (65.9 %) patients with all-cause mortality were documented. LACI was significantly higher in patients with primary endpoint compared to those without primary endpoint (55.4 %, interquartile range: 31.6 %–71.5 % vs. 39.4 %, interquartile range: 24.1 %–54.7 %, p = 0.001). The optimal cut-off for LACI to predict mortality was 49.3 %. In multivariate Cox regression analysis, LACI≥49.3 % (HR 1.907, 95 % CI 1.273–2.857, p = 0.002) was an independent predictor of all-cause mortality. On Kaplan-Meier analysis, patients at advanced Mayo stage (IIIa and IIIb) can be further risk stratified using LACI≥49.3 % (log-rank p = 0.035, p = 0.025). ConclusionThe LACI provides powerful independent prognostic value in AL amyloidosis. The LACI has incremental prognostic value to predict all-cause mortality over the Mayo stage in patients at the advanced Mayo stage.

Eleven Years of Change: Disease Progression in Biomarker-Defined Sporadic Parkinson's Disease.

Long-term longitudinal data on outcomes in sporadic Parkinson's Disease are limited, especially from cohorts with extensive biological characterization. Recent advances in biomarkers characterization of Parkinson's Disease necessitate an updated examination of long-term progression within contemporary cohorts like the Parkinson's Progression Markers Initiative, which enrolled individuals within 2 years of clinical diagnosis of Parkinson's Disease. Our study leverages the Neuronal Synuclein Disease framework, which defines the disease based on biomarker assessed presence of neuronal alpha-synuclein and dopamine deficit, rather than based on conventional clinical diagnostic criteria. In this study we aimed to provide a comprehensive long-term description of disease progression using the integrated biological and clinical staging system framework. We analyzed data from 344 participants from the sporadic Parkinson's Disease cohort in the Parkinson's Progression Markers Initiative, who met Neuronal Synuclein Disease criteria. We assessed 11-year progression in a spectrum of clinical measures. We used Cox proportional hazards models to assess the association between baseline stage and time to key outcomes, including survival, postural instability (Hoehn & Yahr ≥ 3), loss of independence (Schwab & England < 80%), cognitive decline, and domain-based milestones such as walking and balance, motor complications, autonomic dysfunction, and activities of daily living. Additional analyses were completed to account for death and participant dropout. Biomarker analysis included dopamine transporter binding measures, as well as serum urate, neurofilament light chain and CSF amyloid-beta, phosphorylated tau and total tau. At baseline, despite the cohort consisting of individuals within 2 years of clinical diagnosis, there was clear separation of participants in Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). At 11 years, data were available for 153 participants; 35 participants had died over the follow up period. Of retained participants, 59% presented normal cognition, 24% had evidence of postural instability and mean Schwab & England score was 78.5. Serum neurofilament light chain consistently increased over time. No other biofluids had a consistent change in trajectory. Of importance, baseline Neuronal Synuclein Disease Stage predicted progression to clinically meaningful milestones. This study provides data on longitudinal, 11-year progression in Neuronal Synuclein Disease participants within 2 years of clinical diagnosis. We observed better long-term outcomes in this contemporary observational study cohort. It highlights the heterogeneity in the early Parkinson's Disease population as defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functionally based inclusion criteria in the design of new clinical trials.

Individual and joint exposures to PM2.5 constituents and mortality risk among the oldest-old in China.

Cohort evidence linking long-term survival of older adults with exposure to fine particulate matter (PM2.5) constituents remains scarce in China. By constructing a dynamic cohort based on the Chinese Longitudinal Healthy Longevity Study, we aimed to assess the individual and joint associations of major PM2.5 constituents with all-cause death in Chinese oldest-old (.80 years) adults. Time-dependent Cox proportional hazards models were adopted to estimate death risks of long-term exposure to PM2.5 constituents. Among 14,884 participants, totaling 56,342 person-years of follow-up, 12,346 deaths were identified. The highest mortality risk associated with an interquartile range (IQR) increase in exposure was 1.081 (95% confidence interval [CI]: 1.055-1.108) for sulfate (IQR=4.1 μg m-3), followed by 1.078 (95% CI: 1.056-1.101) for black carbon (IQR=1.6 μg m-3), 1.056 (95% CI: 1.028-1.084) for ammonium (IQR=3.2 μg m-3), 1.050 (95% CI: 1.021-1.080) for nitrate (IQR=5.8 μg m-3), and 1.049 (95% CI: 1.024-1.074) for organic matter (IQR=10.3 μg m-3). In joint exposure, each IQRequivalent rise of all five PM2.5 constituents was associated with an 8.2% (95% CI: 4.0%-12.6%) increase in mortality risk. The weight analysis indicated the predominant role of sulfate and black carbon in driving PM2.5-related mortality. Octogenarians (aged 80-89 years) and rural dwellers were at significantly greater risk of mortality from individual and joint exposures to PM2.5 constituents. This study suggests that later-life exposure to PM2.5 constituents, particularly sulfate and black carbon, may curtail long-term survival of the oldest-old in China.

Insulin Pump Use and Diabetic Ketoacidosis Risk in Type 1 Diabetes: Secular Trends over Four Decades.

Introduction: Continuous subcutaneous insulin infusion (CSII) in type 1 diabetes has been regarded as a major diabetic ketoacidosis (DKA) risk factor. We aimed to determine secular trends in risk since CSII implementation in the 1980s. Research Design and Methods: We assessed the relationship between time-varying CSII use and DKA events from 1983 to 2017 and by each decade in the 1441 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study participants using crude and adjusted Cox proportional hazards models. Results: Time-varying CSII exposure was associated with significantly higher DKA risk in the 1980s (adjusted hazard ratio [HR] 5.81; 95% confidence interval [CI] 3.28-10.29; P < 0.001), but in the 2010s, this risk was not significantly elevated (adjusted HR 1.24; 95% CI 0.73-2.12; P = 0.43). Conclusions: DKA risk associated with CSII in type 1 diabetes has declined substantially since the 1980s such that the remaining risk in the past decade appears to be of low magnitude.

Pregnancy-related hormonal changes and thyroid growth: do they have an impact on the higher incidence of differentiated thyroid cancer in women?

To analyze whether pregnancy could play a role in the higher prevalence of differentiated thyroid carcinoma (DTC) in women. Estrogens strongly modify thyroid economy by increasing iodine clearance, thyroid hormone requirement and production. Human chorionic gonadotropin (hCG) contributes to the increased thyroid hormone synthesis. Both estrogens and hCG can interfere with the regulation of thyroid volume and with thyroid nodule development and progression. The potential effect of hCG is exclusively related to its weak agonistic activity on TSH receptor. Estrogen implication on normal and nodule-derived thyrocyte growth has been demonstrated in vitro and in animal models. Furthermore, there is solid clinical evidence showing a promoting effect of pregnancy on thyroid volume and nodule development. Two metanalysis, one including retrospective and another prospective observational studies, failed to show an association between pregnancy and DTC. A large pooled prospective analysis using multivariable-adjusted Cox proportional hazard models did not demonstrate an association between DTC and parity. Similarly, no association between PTC occurrence and parity was observed in a prospective cohort analysis by linkage to the statewide Surveillance, Epidemiology, and End Results (SEER). The presently available evidence does not support an involvement of pregnancy in DTC etiology.

Sex-differential effect of waist circumference on new-onset cerebral infarction: a nationwide cohort study.

Excessive abdominal adiposity represents a cardiovascular disease risk factor. Waist circumference (WC) reflects abdominal adiposity and is known as an easy-to-measure indicator of obesity. This study aimed to evaluate the relationship between WC level and the development of cerebral infarction in Koreans. 209,442 Koreans were included among the general population registered in the National Health Information Database. Depending on the degree of WC, the possibility of cerebral infarction was tracked for 4.37 person-years. Identification of patients with cerebral infarction was confirmed through the diagnostic code ICD I63 of inpatient or outpatient. Participants' data were analyzed by sex. The hazard ratios (HRs) and confidence interval (CI) for cerebral infarction were calculated using the Cox proportional hazards model. Between 2009 and 2013, 2,403 cases (1.15%) of cerebral infarction occurred during the follow-up period of 915,223.6 person-years. The HRs (95% CI) for incident cerebral infarction in men was adjusted for multiple covariates, and comparison of WC levels second, third, and fourth quartile with the first quartile showed 1.10 (0.94-1.28), 1.11 (0.95-1.30), and 1.24 (1.07-1.45), respectively (P for trend 0.045). This association was not significant in women (P for trend 0.619). The severity of WC levels in men is significantly associated with the risk of developing cerebral infarction in Koreans. This finding indicates that other measurements for excessive adipose visceral tissue, except abdominal circumference, need to be taken into account to identify the risk of cerebral infarction in women.

Degree of food processing and breast cancer risk: a prospective study in 9 European countries.

The online version contains supplementary material available at 10.1186/s43014-024-00264-2.

The impact of different dietary flavonoids on the risk of coronary heart disease in cancer patients and that on the prognosis of patients with cancer and coronary heart disease.

The purpose of this study is to explore the risk of coronary heart disease (CHD) in cancer patients who consume different flavonoids, and the impact of flavonoids on the prognosis of cancer patients with CHD. We extracted dietary flavonoids data on 1454 patients diagnosed with cancer from the National Health and Nutrition Examination Survey and Food and Nutrient Database for Dietary Studies. Logistic regression analysis was used to explore the relationship between the intake of flavonoids and the risk of CHD. Cox proportional hazard model was used to explore the impact of flavonoids intake on prognosis in 148 patients with cancer and CHD. Malvidin intake increased the risk of CHD by 1% [odds ratio (OR) = 1.01, 95% confidence interval (CI): 1.00-1.02, P < 0.05] in cancer patients, while epicatechin and isorhamnetin reduced the risk of CHD by 3% (OR = 0.97, 95% CI: 0.94-1.00, P < 0.05) and 15% (OR = 0.85, 95% CI: 0.72-1.00, P < 0.05), respectively. Adjusted by age, sex, and race, malvidin intake increased the risk of CHD in cancer patients by 1% (OR = 1.01, 95% CI: 1.00-1.02, P < 0.05), isorhamnetin decreased the risk by 15% (OR = 0.85, 95% CI: 0.72-1.00, P < 0.05), and epicatechin showed no effect on the risk of CHD (P > 0.05). No flavonoids had impact on the prognosis of patients with cancer and CHD (P > 0.05). For patients with cancer, consuming malvidin increases the risk of CHD, while isorhamnetin reduces the risk. Consuming flavonoids has no impact on the prognosis of patients with cancer and CHD.

Ultra-processed foods and the incidence of pre-diabetes and type 2 diabetes among Iranian adults: the Tehran lipid and glucose study

BackgroundNo study has investigated the association between ultra-processed food (UPF) and pre-diabetes development. Furthermore, prior investigations on the association between UPF and the risk of type 2 diabetes (T2D) were primarily conducted in Europe and America, and studies in other regions are lacking. We investigated the association between ultra-processed foods and the risk of pre-diabetes and T2D in a cohort of Iranians.MethodsThis prospective study, with a sample size of 1954 for pre-diabetes and 2457 for T2D, was conducted among adults’ participants (aged ≥ 18 years) from the Tehran Lipid and Glucose Study (TLGS). We defined UPF intake using NOVA calcification as a proportion of total energy, and calculated its average intake during the follow-ups. The hazard ratios (HR) and 95% confidence intervals (95% CI) for pre-diabetes/T2D across tertiles of total UPF and per 10% of its increment were examined using Cox proportional hazards models. We also investigated the possibility of non-linear association using a restricted cubic spline regression.ResultsWe identified 766 and 256 cases of pre-diabetes and T2D, respectively, during a median follow-up of 7 years for pre-diabetes and 8.6 years for T2D. In the multivariable adjusted model, a 10% increase in total UPF intake was associated with a 12% higher risk of pre-diabetes (HR = 1.12; 95% 1.02, 1.23). The incidence of pre-diabetes was also higher in those in tertile 3 than those in tertile 1 (HR = 1.28; 95% CI = 1.07, 1.52). Following additional adjustment for diet quality, the results remained unchanged. Spline regression demonstrated a J-shaped association between UPF and the risk of pre-diabetes; the risk of pre-diabetes did not increase until UPF consumption exceeded about 24% of total energy intake. Of the individual UPF, hydrogenated fat/mayonnaise/ margarine group was related to an increased risk of pre-diabetes. The total UPF and its individual items were not associated with T2D.ConclusionsThis study found a positive, non-linear relationship between total UPF and the risk of pre-diabetes in Iranian adults. Our data could not show any significant association between UPF and T2D risk.

Sinonasal adenoid cystic carcinoma: preoperative apparent diffusion coefficient histogram analysis in prediction of prognosis and Ki-67 proliferation status.

To investigate the value of preoperative apparent diffusion coefficient (ADC) histogram analysis in predicting the prognosis of patients with sinonasal adenoid cystic carcinoma (ACC) and the correlation between ADC histogram parameters and Ki-67 labeling index (LI). The study enrolled 66 patients with sinonasal ACC who were surgically resected and confirmed by histopathology. The disease-free survival (DFS) was evaluated with clinical-pathologic and radiologic characteristics using the Cox proportion hazard model. Spearman correlation analysis was used to evaluate the correlation between ADC histogram parameters and Ki-67 LI. The predictive performance of ADC histogram parameters for Ki-67 LI was assessed using the receiver operating characteristic (ROC) curve. Multivariable analysis showed Ki-67 LI (hazard ratio: 9.279; 95% confidence interval 1.099-78.338; P = 0.041) and ADCskewness (hazard ratio: 5.942; 95% confidence interval 1.832-19.268; P = 0.003) were significant independent predictors of DFS. The combination of these two variables achieved the predictive ability with a C-index of 0.717 (95% confidence interval 0.607-0.826). ADCmean and all ADC percentiles (10th, 50th, and 90th) significantly and inversely correlated with Ki-67 LI of ACC (Correlation coefficients = -0.574 to -0.591, Ps < 0.001). Among the ADC histogram parameters, the ADC50th showed superior performance for the differentiation of the high from low Ki-67 LI groups with an area under the curve (AUC) of 0.834 and an accuracy of 80.30%. ADC histogram analysis had predictive value for DFS and Ki-67 LI, which may be a valuable biomarker for prognosis and proliferation status for ACC in clinical practice.

Implementation of an AI Algorithm in Clinical Practice to Reduce Missed Incidental Pulmonary Embolisms on Chest CT and Its Impact on Short-Term Survival.

A substantial number of incidental pulmonary embolisms (iPEs) in computed tomography scans are missed by radiologists in their daily routine. This study analyzes the radiological reports of iPE cases before and after implementation of an artificial intelligence (AI) algorithm for iPE detection. Furthermore, we investigate the anatomic distribution patterns within missed iPE cases and mortality within a 90-day follow-up in patients before and after AI use. This institutional review board-approved observational single-center study included 5298 chest computed tomography scans performed for reasons other than suspected pulmonary embolism (PE). We compared 2 cohorts: cohort 1, consisting of 1964 patients whose original radiology reports were generated before the implementation of an AI algorithm, and cohort 2, consisting of 3334 patients whose scans were analyzed after the implementation of an Food and Drug Administration-approved and CE-certified AI algorithm for iPE detection (Aidoc Medical, Tel Aviv, Israel). For both cohorts, any discrepancies between the original radiology reports and the AI results were reviewed by 2 thoracic imaging subspecialized radiologists. In the original radiology report and in case of discrepancies with the AI algorithm, the expert review served as reference standard. Sensitivity, specificity, prevalence, negative predictive value (NPV), and positive predictive value (PPV) were calculated. The rates of missed iPEs in both cohorts were compared statistically using STATA (Version 17.1). Kaplan-Meier curves and Cox proportional hazards models were used for survival analysis. In cohort 1 (mean age 70.6 years, 48% female [n = 944], 52% male [n = 1020]), the prevalence of confirmed iPE was 2.2% (n = 42), and the AI detected 61 suspicious iPEs, resulting in a sensitivity of 95%, a specificity of 99%, a PPV of 69%, and an NPV of 99%. Radiologists missed 50% of iPE cases in cohort 1. In cohort 2 (mean age 69 years, 47% female [n = 1567], 53% male [n = 1767]), the prevalence of confirmed iPEs was 1.7% (56/3334), with AI detecting 59 suspicious cases (sensitivity 90%, specificity 99%, PPV 95%, NPV 99%). The rate of missed iPEs by radiologists dropped to 7.1% after AI implementation, showing a significant improvement (P < 0.001). Most overlooked iPEs (61%) were in the right lower lobe. The survival analysis showed no significantly decreased 90-day mortality rate, with a hazards ratio of 0.95 (95% confidence interval, 0.45-1.96; P = 0.88). The implementation of an AI algorithm significantly reduced the rate of missed iPEs from 50% to 7.1%, thereby enhancing diagnostic accuracy. Despite this improvement, the 90-day mortality rate remained unchanged. These findings highlight the AI tool's potential to assist radiologists in accurately identifying iPEs, although its implementation does not significantly affect short-term survival. Notably, most missed iPEs were located in the right lower lobe, suggesting that radiologists should pay particular attention to this area during evaluations.

Outcomes of haploidentical transplants with PT-CY vs 10/10 MUD transplants with ATG in Germany

AbstractAllogeneic stem cell transplantation (allo-HSCT) is the best curative treatment modality for many malignant hematologic disorders. In the absence of a matched related donor, matched unrelated donors (MUDs) and haploidentical donors (Haplo-Tx) are the most important sources of stem cells. However, multicenter real-life data that compare 10/10 MUD transplantations with Haplo-Tx are still limited. In this registry-based retrospective study, we compared the outcomes of allo-HSCTs from 10/10 MUDs with antithymocyte globulin (ATG)–based regimens (n = 7050) vs Haplo-Tx using posttransplant cyclophosphamide (PT-CY Haplo; n = 487) in adult patients with hematologic malignancies between 2010 and 2020. Cox proportional hazard models and competing risks regression models were formed to compare the outcomes of the groups. Overall survival (OS), Disease-free survival (DFS), and graft-versus-host disease (GVHD)–free and relapse-free survival (GRFS) were superior for 10/10 MUDs (OS [hazard ratio (HR), 1.27; confidence interval (CI), 1.10-1.47; P = .001]; DFS [HR, 1.17; CI, 1.02-1.34; P = .022]; GRFS [HR, 1.34; CI, 1.19-1.50; P < .001]). The risk of acute GVHD (aGVHD) grade 2 to 4, aGVHD grade 3 to 4, and chronic GVHD (cGVHD) was higher in the PT-CY Haplo group than the 10/10 MUD group (aGVHD grade 2-4 [HR, 1.46; CI, 1.25-1.71; P < .001]; aGVHD grade 3-4 [HR, 1.74; CI, 1.37- 2.20; P < .001]; cGVHD [HR, 1.30; CI, 1.11-1.51; P = .001]). A lower incidence of relapse was observed in the PT-CY Haplo group (relapse: HR, 0.83; CI, 0.69-0.99; P = .038). Unrelated 10/10 matched transplantation with ATG treatment leads to lower GVHD rates and improved survival rates compared with PT-CY Haplo transplantation in Germany.

Insulin resistance and sarcopenia: a prognostic longitudinal link to stroke risk in middle-aged and elderly Chinese population

BackgroundStroke is the leading cause of death in middle-aged and elderly people in China. Insulin resistance (IR) and sarcopenia are both closely associated with metabolic diseases. However, the relationship between these two indicators and stroke has not been fully investigated. The aim of this study was to investigate the relationship between IR and sarcopenia and the risk of new-onset stroke.MethodsUsing longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018, Cox proportional hazards models were used to determine the association between IR surrogate indicators and sarcopenia status with stroke incidence.ResultsIn the present study, during a median 7 years of follow-up, we included 7009 middle-aged and elderly residents, of whom 515 presented with stroke incidence. After adjustment for potential confounders, both baseline IR surrogates and sarcopenia independently predicted stroke risk. In addition, co-morbidities had a higher risk of stroke than other groups. The positive association between TyG-WC and sarcopenia on stroke risk was particularly significant [HR (95% CI): 2.03 (1.52, 2.70)]. In subgroups of different ages and sexes, the combination of IR and sarcopenia is associated with the highest risk of stroke.ConclusionsWe found that IR and sarcopenia synergistically increase the incidence of stroke in older adults. This finding provides new perspectives for stroke detection and intervention and highlights the importance of early detection and management of IR and sarcopenia in older adults.

Comparison of waitlist and post-transplant outcomes in patients supported with total artificial heart versus continuous biventricular assist devices.

Durable biventricular support may be necessary to bridge patients with end-stage biventricular failure to heart transplantation. This study compares waitlist and post-transplant outcomes between patients supported with continuous flow, durable biventricular assist devices (BiVAD), and total artificial heart (TAH). Using the UNOS registry, we analyzed adult (≥18 years old), first-time transplant candidates with TAH or BiVAD at the time of listing or transplantation from 10/1/2010-10/31/2020, with follow-up through 3/31/2022. Multivariable proportional subdistribution hazards models and cause-specific Cox proportional hazards models were used to compare death/deterioration or heart transplantation on the waitlist between cohorts. Kaplan-Meier and multivariable Cox proportional hazards model were used to evaluate one-year post-transplant survival and evaluate difference in outcomes based on annual transplant center volume. The waitlist cohort included a total of 228 patients (25% BiVAD). Waitlist outcomes between device types were similar. The transplanted cohort included a total of 352 patients (25% BiVAD). There was a trend towards worse one-year post-transplant survival in patients bridged with TAH versus BiVAD (log-rank p-value = 0.072) that persisted after adjusting for age, gender, policy, and removing dual-organ recipients (HR 1.94 (0.94, 3.98) p-value = 0.07). There was a difference in one-year post-transplant survival amongst TAH-bridged patients when stratified by annual transplant center volume (log-rank p-value = 0.013). One-year post-transplant survival between TAH-supported patients from high annual transplant volume centers and BiVAD-supported patients was similar (p-value = 0.815). BiVAD and TAH are reasonable support strategies with TAH implantation at high-volume transplant centers (51+ transplants/year) having similar 1-year post-transplant survival to BiVAD-supported patients.

Albuminuria-based stratification of end-stage kidney disease progression and mortality with sodium-glucose cotransporter 2 inhibitors (SGLT2i): A retrospective cohort study in type 2 diabetes and chronic kidney disease.

Clinical trials have shown the kidney-protective benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, their real-world impact, particularly across varying levels of albuminuria, remains less well understood. This study aimed to evaluate the association of SGLT2i, compared with other oral glucose-lowering drugs, with end-stage kidney disease (ESKD) progression in patients with type 2 diabetes and chronic kidney disease (CKD) stratified by urine albumin-to-creatinine ratio (UACR) levels. Using data from a national database spanning from 2016 to 2021, the study included patients with type 2 diabetes and CKD with estimated glomerular filtration rates (eGFRs) below 60 mL/min/1.73 m2 and who started on SGLT2i or other oral glucose-lowering drugs. Patients were stratified into groups by UACR ≥300 mg/g and <300 mg/g. Propensity score matching was used to minimize confounding, and progression to ESKD was evaluated using competing risks and Cox proportional-hazards models. All-cause mortality was also analyzed. Following propensity score matching, 18,514 patients in the severely increased albuminuria group (UACR ≥300 mg/g) were tracked, with 2.6% progressing to ESKD over 3 years. In contrast, only 0.3% of the 26,946 patients with UACR <300 mg/g progressed to ESKD. SGLT2i use was associated with a 30% reduction in risk of ESKD progression, compared with the use of other oral glucose-lowering drugs, in the severely increased albuminuria group (hazard ratio[HR]: 0.70, 95% confidence interval [CI]: 0.61-0.80). In the lower albuminuria group, no significant association was evident, though there was a nonsignificant trend toward protection over time. A consistent reduction in mortality risk was observed across all albuminuria levels. SGLT2i are associated with a reduction in the progression to ESKD among patients with severely increased albuminuria, with less pronounced effects observed in those with lower albuminuria levels, suggesting variability in renal outcomes based on albuminuria severity. The consistent survival benefit across all albuminuria levels supports the potential utility of SGLT2i in diabetes and CKD treatment strategies, emphasizing the need for more targeted research.

Risks of Long-Term Psychiatric Disease in Women with a History of Primary Infertility: A Historical Cohort Study.

To examine the risks of long-term de novo psychiatric disease in women with primary infertiltiy compared to age-matched referrent women. Retrospective, population-based cohort of 1,001 women with primary infertility and 1,001 age-matched (± 1year) referent women aged 18-50. The "index date" was date of first clinical note for infertility and included visits fromJanuary 1, 1980 to December 31, 1999. Baseline characteristics were collected by chart review. Outcome data was evaluated through December 31, 2020. Primary outcomes were baseline prevalence and de novo rates of subsequent psychiatric disorders including depression, anxiety, bipolar disorder, substance abuse, suicidality, and somatization evaluated by Coxproportional hazards modeling. Among women with primary infertility and referent women, the median duration of follow-up was 23.7years. The risk of de novo psychiatric disorders was not significantly different between groups. Additionally, the risk of de novo psychiatric disorders did not significantly differ between those with isolated male factor versus isolated female factor infertility. Among women with primary infertility, the cumulative incidence of de novo depression and anxietywas significantly higher among women diagnosed with primary infertility in the 1990s compared to the 1980s. Women with primary infertility, in a historical population-based cohort, do not have a significantly different long-term risk of de novo psychiatric diagnoses compared to age-matched referent women. Our findings support the notion that infertility diagnosis and treatment present an acute period of stress and for some psychologic distress, neither of which persist or increase the risk for development of future psychiatric disease.

Risk of death in England following a positive SARS-CoV-2 test: A retrospective national cohort study (March 2020 to September 2022).

We aimed to estimate the relative risk of mortality following a first positive SARS-CoV-2 test during the first, second, and third waves of the COVID-19pandemic in England by age, sex, and vaccination status, taking into account pre-existing health conditions and lifestyle factors. We conducted a retrospective cohort study of all individuals registered with the National Health Service (NHS) in England from 1 March 2020 to September 2022. Data for all individuals were obtained and linked including primary care records, hospital admission episodes, SARS-CoV-2 test results, vaccinations, and death registrations. We fitted Cox Proportional Hazards models with time dependent covariates for confirmed SARS-CoV-2 infection to model the risk of subsequent mortality. The hazard ratio for death after testing positive for subsequent, compared with those not testing positive, amongst unvaccinated individuals, ranged from 11 to 89 by age and sex, in the first four weeks following a positive test in wave one and reduced to 14 to 50 in wave three. This hazard was further reduced amongst those who had three vaccines to between 1.4 and 7 in wave three. This study provides robust estimates of increased mortality risk among those who tested positive over the first three waves of the COVID-19 pandemic in England. The estimates show the impact of various factors affecting the risk of mortality from COVID-19. The results provide the first step towards estimating the magnitude and pattern of mortality displacement due to COVID-19, which is essential to understanding subsequent mortality rates in England.

Metformin continuation post-metabolic bariatric surgery and relapse of diabetes.

To evaluate the association of metformin continuation with relapse of diabetes after metabolic bariatric surgery (MBS) in patients with type 2 diabetes and obesity who achieved an HbA1c level of less than 6.5%. This observational, retrospective cohort study included Clalit Health Service members aged 24 years or older with obesity and diabetes, who were treated with metformin, underwent MBS during 2005-2020 and achieved an HbA1c level of less than 6.5% up to 6 months after surgery (index date). Patients who continued metformin treatment (> 2 prescriptions filled, n = 122) after the index date were matched (1:2) on age, sex and HbA1c level at index date and compared with those who stopped treatment (no filled prescriptions, n = 244). The outcome was relapse of diabetes as measured by an HbA1c level of 6.5% or higher (yes/no). The two matched groups maintained a mean HbA1c level of less than 6.5% during the follow-up (mean ~ 5 years). An adjusted Cox proportional hazards model revealed no significant association of metformin continuation after MBS with relapse of diabetes (adjusted hazard ratio = 1.70, 95% confidence interval: 0.98-2.94). No significant differences were observed between the two groups in weight loss and filled prescriptions for other diabetes medications during the follow-up period. Among individuals living with obesity and diabetes who achieved diabetes remission post-MBS, metformin continuation was not associated with relapse of diabetes. This lack of an association indicates that metformin did not provide an additional benefit for maintaining glycaemic control or weight reduction during an average of 5 years postsurgery.

Novel plasma protein biomarkers: A time-dependent predictive model for Alzheimer's disease

BackgroundThe accurate prediction of Alzheimer's disease (AD) is crucial for the efficient management of its progression. The objective of this research was to construct a new risk predictive model utilizing novel plasma protein biomarkers for predicting AD incidence in the future and analyze their potential biological correlation with AD incidence. MethodsA cohort of 440 participants aged 60 years and older from the Alzheimer's Disease Neuroimaging Initiative (ADNI) longitudinal cohort was utilized. The baseline plasma proteomics data was employed to conduct Cox regression, LASSO regression, and cross-validation to identify plasma protein signatures predictive of AD risk. Subsequently, a multivariable Cox proportional hazards model based on these signatures was constructed. The performance of the risk prediction model was evaluated using time-dependent receiver operating characteristic (t-ROC) curves and Kaplan-Meier curves. Additionally, we analyzed the correlations between protein signature expression in plasma and predicted AD risk, the time of AD onset, the expression of protein signatures in cerebrospinal fluid (CSF), the expression of CSF and plasma biomarkers, and APOE ε4 genotypes. Colocalization and Mendelian randomization analyses was conducted to investigate the association between protein features and AD risk. GEO database was utilized to analyze the differential expression of protein features in the blood and brain of AD patients. ResultsWe identified seven protein signatures (APOE, CGA, CRP, CCL26, CCL20, NRCAM, and PYY) that independently predicted AD incidence in the future. The risk prediction model demonstrated area under the ROC curve (AUC) values of 0.77, 0.76, and 0.77 for predicting AD incidence at 4, 6, and 8 years, respectively. Furthermore, the model remained stable in the range of the 3rd to the 12th year (ROC ≥ 0.74). The low-risk group, as defined by the model, exhibited a significantly later AD onset compared to the high-risk group (P < 0.0001). Moreover, all protein signatures exhibited significant correlations with AD risk (P < 0.001) and the time of AD onset (P < 0.01). There was no strong correlation between the protein expression levels in plasma and CSF, as well as AD CSF biomarkers. APOE, CGA, and CRP exhibited significantly lower expression levels in APOE ε4 positive individuals (P < 0.05). Additionally, colocalization analysis reveals a significant association between AD and SNP loci in APOE. Mendelian randomization analysis shows a negative correlation between NRCAM and AD risk. Transcriptomic analysis indicates a significant downregulation of NRCAM and PYY in the peripheral blood of AD patients (P < 0.01), while APOE, CGA, and NRCAM are significantly downregulated in the brains of AD patients (P < 0.0001). ConclusionOur research has successfully identified protein signatures in plasma as potential risk biomarkers that can independently predict AD onset in the future. Notably, this risk prediction model has demonstrated commendable predictive performance and stability over time. These findings underscore the promising utility of plasma protein signatures in dynamically predicting the risk of AD, thereby facilitating early screening and intervention strategies.

Association between dynapenic obesity and risk of cardiovascular disease: The Hisayama study.

Dynapenic obesity is a condition characterized by high adiposity levels combined with muscle dysfunction. Although high adiposity and muscle loss/dysfunction are thought to synergistically increase the risk of cardiovascular disease (CVD), few studies have addressed the association between dynapenic and sarcopenic obesity and CVD. We aimed to investigate the association of dynapenic obesity with incident CVD events using the data from a population-based prospective longitudinal study in Japan. A total of 2490 community-dwelling Japanese aged 40-79years (42.5% males, mean age 57.7±10.6years) without a history of CVD were followed up for a median of 24years. Handgrip strength was classified as low, medium, or high by age- and sex-specific tertiles. Body mass index (BMI) levels were categorized as lean (<18.5kg/m2), normal (18.5-24.9kg/m2), or obese (≥25.0kg/m2). Dynapenic obesity was defined as having both low handgrip strength and obesity. The outcomes were defined as the first-ever development of CVD (defined as stroke or coronary heart disease). The hazard ratios (HRs) and their 95% confidence intervals (CIs) for the development of CVD were estimated using a Cox proportional hazards model, in which participants with high handgrip strength and normal BMI were used as a reference group. Mediation analyses used serum high-sensitivity C-reactive protein (hs-CRP) and homeostatic model assessment for insulin resistance (HOMA-IR) as mediators. During the follow-up period, 482 participants developed CVD events (324 cases of stroke and 209 of coronary heart disease). The multivariable-adjusted risk of CVD increased significantly among participants with dynapenic obesity compared with the reference group (HR 1.49, 95% CI 1.03-2.17). An analysis by age groups showed a further increase in the risk of CVD among participants with dynapenic obesity aged less than 65years (HR 1.66, 95% CI 1.04-2.65). In mediation analyses for participants aged less than 65years, serum hs-CRP was shown to be a significant mediator explaining 13.8% of the association between dynapenic obesity and the development of CVD, while HOMA-IR explained 12.2% of this relationship. Dynapenic obesity was a significant risk factor for the development of CVD in a general Japanese population. This association was more pronounced among those aged <65years. Inflammation, and possibly glucose metabolism, might partly mediate this association. Our findings suggest that preventing muscle dysfunction as well as appropriate weight control, especially in middle-age, are important for preventing the development of CVD.