Mapping the Ecological Terrain of Stroke Prehospital Delay: A Nationwide Registry Study.

BACKGROUND: Delays in hospital presentation limit access to acute stroke treatments. While prior research has focused on patient-level factors, broader ecological and social determinants have not been well studied. We aimed to create a geospatial map of prehospital delay and examine the role of community-level social vulnerability. METHODS: We studied patients with ischemic stroke who arrived by emergency medical services in 2015 to 2017 from the American Heart Association Get With The Guidelines-Stroke registry. The primary outcome was time to hospital arrival after stroke (in minutes), beginning at last known well in most cases. Using Geographic Information System mapping, we displayed the geography of delay. We then used Cox proportional hazard models to study the relationship between community-level factors and arrival time (adjusted hazard ratios [aHR] <1.0 indicate delay). The primary exposure was the social vulnerability index (SVI), a metric of social vulnerability for every ZIP Code Tabulation Area ranging from 0.0 to 1.0. RESULTS: Of 750 336 patients, 149 145 met inclusion criteria. The mean age was 73 years, and 51% were female. The median time to hospital arrival was 140 minutes (Q1: 60 minutes, Q3: 458 minutes). The geospatial map revealed that many zones of delay overlapped with socially vulnerable areas (https://harvard-cga.maps.arcgis.com/apps/webappviewer/index.html?id=08f6e885c71b457f83cefc71013bcaa7). Cox models (aHR, 95% CI) confirmed that higher SVI, including quartiles 3 (aHR, 0.96 [95% CI, 0.93-0.98]) and 4 (aHR, 0.93 [95% CI, 0.91-0.95]), was associated with delay. Patients from SVI quartile 4 neighborhoods arrived 15.6 minutes [15-16.2] slower than patients from SVI quartile 1. Specific SVI themes associated with delay were a community's socioeconomic status (aHR, 0.80 [95% CI, 0.74-0.85]) and housing type and transportation (aHR, 0.89 [95% CI, 0.84-0.94]). CONCLUSIONS: This map of acute stroke presentation times shows areas with a high incidence of delay. Increased social vulnerability characterizes these areas. Such places should be systematically targeted to improve population-level stroke presentation times.

Reappraisal of prognostic factors used in the European Pediatric Soft Tissue Sarcoma Study Group RMS 2005 study for localized rhabdomyosarcoma to optimize risk stratification and generate a prognostic nomogram.

BACKGROUND: The objective of this study was to investigate the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma (RMS) to develop a predictive model for event-free survival and provide a rationale for risk stratification in future trials. METHODS: The authors used data from patients enrolled in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 study (EpSSG RMS 2005; EudraCT number 2005-000217-35). The following baseline variables were considered for the multivariable model: age at diagnosis, sex, histology, primary tumor site, Intergroup Rhabdomyosarcoma Studies group, tumor size, nodal status, and FOXO1 fusion status. Main effects and significant second-order interactions of candidate predictors were included in a multiple Cox proportional hazards regression model. A nomogram was generated for predicting 5-year event-free survival (EFS) probabilities. RESULTS: The EFS and overall survival rates at 5 years were 70.9% (95% confidence interval, 68.6%-73.1%) and 81.0% (95% confidence interval, 78.9%-82.8%), respectively. The multivariable model retained five prognostic factors, including age at diagnosis interacting with tumor size, tumor primary site, Intergroup Rhabdomyosarcoma Studies clinical group, and FOXO1 fusion status. Based on each patient's total score in the nomogram, patients were stratified into four groups. The 5-year EFS rates were 94.1%, 78.4%, 65.2%, and 52.1% in the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively, and the corresponding 5-year overall survival rates were 97.2%, 91.5%, 74.3%, and 60.8%, respectively. CONCLUSIONS: The results presented here provide the rationale to modify the EpSSG stratification, with the most significant change represented by the replacement of histology with fusion status. This classification was adopted in the new international trial launched by the EpSSG.

Meta-research: How many diagnostic or prognostic models published in radiological journals are evaluated externally?

OBJECTIVES: Prognostic and diagnostic models must work in their intended clinical setting, proven via "external evaluation", preferably by authors uninvolved with model development. By systematic review, we determined the proportion of models published in high-impact radiological journals that are evaluated subsequently. METHODS: We hand-searched three radiological journals for multivariable diagnostic/prognostic models 2013-2015 inclusive, developed using regression. We assessed completeness of data presentation to allow subsequent external evaluation. We then searched literature to August 2022 to identify external evaluations of these index models. RESULTS: We identified 98 index studies (73 prognostic; 25 diagnostic) describing 145 models. Only 15 (15%) index studies presented an evaluation (two external). No model was updated. Only 20 (20%) studies presented a model equation. Just 7 (15%) studies developing Cox models presented a risk table, and just 4 (9%) presented the baseline hazard. Two (4%) studies developing non-Cox models presented the intercept. Just 20 (20%) articles presented a Kaplan-Meier curve of the final model. The 98 index studies attracted 4224 citations (including 559 self-citations), median 28 per study. We identified just six (6%) subsequent external evaluations of an index model, five of which were external evaluations by researchers uninvolved with model development, and from a different institution. CONCLUSIONS: Very few prognostic or diagnostic models published in radiological literature are evaluated externally, suggesting wasted research effort and resources. Authors' published models should present data sufficient to allow external evaluation by others. To achieve clinical utility, researchers should concentrate on model evaluation and updating rather than continual redevelopment. CLINICAL RELEVANCE STATEMENT: The large majority of prognostic and diagnostic models published in high-impact radiological journals are never evaluated. It would be more efficient for researchers to evaluate existing models rather than practice continual redevelopment. KEY POINTS: • Systematic review of highly cited radiological literature identified few diagnostic or prognostic models that were evaluated subsequently by researchers uninvolved with the original model. • Published radiological models frequently omit important information necessary for others to perform an external evaluation: Only 20% of studies presented a model equation or nomogram. • A large proportion of research citing published models focuses on redevelopment and ignores evaluation and updating, which would be a more efficient use of research resources.

Comparison of Different Modeling Approaches for Prescription Opioid Use and Its Association With Adverse Events.

Previous research linking opioid prescribing to adverse drug events has failed to properly account for the time-varying nature of opioid exposure. This study aimed to explore how the risk of opioid-related emergency department visits, readmissions, or deaths (composite outcome) varies with opioid dose and duration, comparing different novel modeling techniques. A prospective cohort of 1,511 hospitalized patients discharged from 2 McGill-affiliated hospitals in Montreal, 2014-2016, was followed from the first postdischarge opioid dispensation until 1 year after discharge. Marginal structural Cox proportional hazards models and their flexible extensions were used to explore the association between time-varying opioid use and the composite outcome. Weighted cumulative exposure models assessed cumulative effects of past use and explored how its impact depends on the recency of exposure. The patient mean age was 69.6 (standard deviation = 14.9) years; 57.7% were male. In marginal structural model analyses, current opioid use was associated with a 71% increase in the hazard of opioid-related adverse events (adjusted hazard ratio = 1.71, 95% confidence interval: 1.21, 2.43). The weighted cumulative exposure results suggested that the risk cumulates over the previous 50 days of opioid consumption. Flexible modeling techniques helped assess how the risk of opioid-related adverse events may be associated with time-varying opioid exposures while accounting for nonlinear relationships and the recency of past use.

Exposure to Metalworking Fluids and Cancer Incidence in the United Auto Workers-General Motors Cohort.

In previous studies, investigators have reported increased risks of specific cancers associated with exposure to metalworking fluids (MWFs). In this report we broadly examine the incidence of 14 types of cancer, with a focus on digestive, respiratory, and hormonal cancers, in the United Auto Workers-General Motors (UAW-GM) cohort, a cohort of workers exposed to MWFs (1973-2015). The cohort included 39,132 workers followed for cancer incidence. Cox models yielded estimates of adjusted hazard ratios, with categorical variables for lagged cumulative exposure to 3 types of MWF (straight, soluble, and synthetic). We fitted penalized splines to examine the shape of the exposure-response relationships. There were 7,809 incident cancer cases of interest. Oil-based straight and soluble MWFs were each modestly associated with all cancers combined. Exposure-response patterns were consistent with prior reports from this cohort, and results for splined exposures generally reflected their categorically modeled counterparts. We found significantly increased incidence of stomach and kidney cancer with higher levels of straight MWF exposure and increased rectal and prostate cancer with increasing water-based synthetic MWF exposure. Only non-Hodgkin lymphoma and prostate cancer were associated with soluble MWF. All results for colon and lung cancers were null. Our results provide updated evidence for associations between MWF exposure and incidence of several types of cancer.

External Validation of a Prognostic Model for Survival of Patients With Abdominal Aortic Aneurysms Treated by Endovascular Aneurysm Repair.

OBJECTIVE: Current guidelines recommend diameter monitoring of small and asymptomatic abdominal aortic aneurysms (AAAs) due to the low risk of rupture. Elective AAA repair is recommended for diameters ≥ 5.5 cm in men and ≥ 5.0 cm in women. However, data supporting the efficacy of elective treatment for all patients above these thresholds are diverging. For a subgroup of patients, life expectancy might be very short, and elective AAA repair at the current threshold may not be justified. This study aimed to externally validate a predictive model for survival of patients with an asymptomatic AAA treated by endovascular aneurysm repair (EVAR). METHODS: This was a multicentre international retrospective observational cohort study. Data were collected from four European aortic centres treating patients between 2001 and 2021. The initial model included age, estimated glomerular filtration rate (eGFR), and chronic obstructive pulmonary disease (COPD) as independent predictors for survival. Model performance was measured by discrimination and calibration. RESULTS: The validation cohort included 1 500 patients with a median follow up of 65 months, during which 54.6% of the patients died. The external validation showed slightly decreased discrimination ability and signs of overfitting in model calibration. However, a high risk subgroup of patients with impaired survival rates was identified: octogenarians with eGFR < 60 OR COPD, septuagenarians with eGFR < 30, and septuagenarians with eGFR < 60 and COPD having survival rates of only 55.2% and 15.5% at five and 10 years, respectively. CONCLUSION: EVAR is a valuable treatment option for AAA, especially for patients unsuitable for open repair. Nonetheless, not all these patients will benefit from EVAR, and an individualised treatment recommendation should include considerations on life expectancy. This study provides a risk stratification to identify patients who may not benefit from EVAR using the present diameter thresholds.

Cox regression can be collapsible and Aalen regression can be non-collapsible.

It is well-known that the additive hazards model is collapsible, in the sense that when omitting one covariate from a model with two independent covariates, the marginal model is still an additive hazards model with the same regression coefficient or function for the remaining covariate. In contrast, for the proportional hazards model under the same covariate assumption, the marginal model is no longer a proportional hazards model and is not collapsible. These results, however, relate to the model specification and not to the regression parameter estimators. We point out that if covariates in risk sets at all event times are independent then both Cox and Aalen regression estimators are collapsible, in the sense that the parameter estimators in the full and marginal models are consistent for the same value. Vice-versa, if this assumption fails, then the estimates will change systematically both for Cox and Aalen regression. In particular, if the data are generated by an Aalen model with censoring independent of covariates both Cox and Aalen regression is collapsible, but if generated by a proportional hazards model neither estimators are. We will also discuss settings where survival times are generated by proportional hazards models with censoring patterns providing uncorrelated covariates and hence collapsible Cox and Aalen regression estimates. Furthermore, possible consequences for instrumental variable analyses are discussed.

Age and product dependent vaccine effectiveness against SARS-CoV-2 infection and hospitalisation among adults in Norway: a national cohort study, July-November 2021.

BACKGROUND: COVID-19 vaccines have been crucial in the pandemic response and understanding changes in vaccines effectiveness is essential to guide vaccine policies. Although the Delta variant is no longer dominant, understanding vaccine effectiveness properties will provide essential knowledge to comprehend the development of the pandemic and estimate potential changes over time. METHODS: In this population-based cohort study, we estimated the vaccine effectiveness of Comirnaty (Pfizer/BioNTech; BNT162b2), Spikevax (Moderna; mRNA-1273), Vaxzevria (AstraZeneca; ChAdOx nCoV-19; AZD1222), or a combination against SARS-CoV-2 infections, hospitalisations, intensive care admissions, and death using Cox proportional hazard models, across different vaccine product regimens and age groups, between 15 July and 31 November 2021 (Delta variant period). Vaccine status is included as a time-varying covariate and all models were adjusted for age, sex, comorbidities, county of residence, country of birth, and living conditions. Data from the entire adult Norwegian population were collated from the National Preparedness Register for COVID-19 (Beredt C19). RESULTS: The overall adjusted vaccine effectiveness against infection decreased from 81.3% (confidence interval (CI): 80.7 to 81.9) in the first 2 to 9 weeks after receiving a second dose to 8.6% (CI: 4.0 to 13.1) after more than 33 weeks, compared to 98.6% (CI: 97.5 to 99.2) and 66.6% (CI: 57.9 to 73.6) against hospitalisation respectively. After the third dose (booster), the effectiveness was 75.9% (CI: 73.4 to 78.1) against infection and 95.0% (CI: 92.6 to 96.6) against hospitalisation. Spikevax or a combination of mRNA products provided the highest protection, but the vaccine effectiveness decreased with time since vaccination for all vaccine regimens. CONCLUSIONS: Even though the vaccine effectiveness against infection waned over time, all vaccine regimens remained effective against hospitalisation after the second vaccine dose. For all vaccine regimens, a booster facilitated recovery of effectiveness. The results from this support the use of heterologous schedules, increasing flexibility in vaccination policy.

Early prediction of decompensation (EPOD) score: Non-invasive determination of cirrhosis decompensation risk.

BACKGROUND & AIMS: Decompensation is a hallmark of disease progression in cirrhotic patients. Early detection of a phase transition from compensated cirrhosis to decompensation would enable targeted therapeutic interventions potentially extending life expectancy. This study aims to (a) identify the predictors of decompensation in a large, multicentric cohort of patients with compensated cirrhosis, (b) to build a reliable prognostic score for decompensation and (c) to evaluate the score in independent cohorts. METHODS: Decompensation was identified in electronic health records data from 6049 cirrhosis patients in the IBM Explorys database training cohort by diagnostic codes for variceal bleeding, encephalopathy, ascites, hepato-renal syndrome and/or jaundice. We identified predictors of clinical decompensation and developed a prognostic score using Cox regression analysis. The score was evaluated using the IBM Explorys database validation cohort (N = 17662), the Penn Medicine BioBank (N = 1326) and the UK Biobank (N = 317). RESULTS: The new Early Prediction of Decompensation (EPOD) score uses platelet count, albumin, and bilirubin concentration. It predicts decompensation during a 3-year follow-up in three validation cohorts with AUROCs of 0.69, 0.69 and 0.77, respectively, and outperforms the well-known MELD and Child-Pugh score in predicting decompensation. Furthermore, the EPOD score predicted the 3-year probability of decompensation. CONCLUSIONS: The EPOD score provides a prediction tool for the risk of decompensation in patients with cirrhosis that outperforms well-known cirrhosis scores. Since EPOD is based on three blood parameters, only, it provides maximal clinical feasibility at minimal costs.

Causes of death and associated factors over a decade of follow-up in a cohort of people living with HIV in rural Tanzania.

BACKGROUND: Nearly half of HIV-related deaths occur in East and Southern Africa, yet data on causes of death (COD) are scarce. We determined COD and associated factors among people living with HIV (PLHIV) in rural Tanzania. METHODS: PLHIV attending the Chronic Diseases Clinic of Ifakara, Morogoro are invited to enrol in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO). Among adults (≥ 15 years) enrolled in 2005-2018, with follow-up through April 2019, we classified COD in comprehensive classes and as HIV- or non-HIV-related. In the subset of participants enrolled in 2013-2018 (when data were more complete), we assessed cause-specific mortality using cumulative incidences, and associated factors using proportional hazards models. RESULTS: Among 9871 adults (65% female, 26% CD4 count < 100 cells/mm3), 926 (9%) died, among whom COD were available for 474 (51%), with missing COD mainly in earlier years. The most common COD were tuberculosis (N = 127, 27%), non-AIDS-related infections (N = 72, 15%), and other AIDS-related infections (N = 59, 12%). Cardiovascular and renal deaths emerged as important COD in later calendar years, with 27% of deaths in 2018 attributable to cardiovascular causes. Most deaths (51%) occurred within the first six months following enrolment. Among 3956 participants enrolled in 2013-2018 (N = 203 deaths, 200 with COD ascertained), tuberculosis persisted as the most common COD (25%), but substantial proportions of deaths from six months after enrolment onwards were attributable to renal (14%), non-AIDS-related infections (13%), other AIDS-related infections (10%) and cardiovascular (10%) causes. Factors associated with higher HIV-related mortality were sex, younger age, living in Ifakara town, HIV status disclosure, hospitalisation, not being underweight, lower CD4 count, advanced WHO stage, and gaps in care. Factors associated with higher non-HIV-related mortality included not having an HIV-positive partner, lower CD4 count, advanced WHO stage, and gaps in care. CONCLUSION: Incidence of HIV-related mortality was higher than that of non-HIV-related mortality, even in more recent years, likely due to late presentation. Tuberculosis was the leading specific COD identified, particularly soon after enrolment, while in later calendar years cardiovascular and renal causes emerged as important, emphasising the need for improved screening and management.

Bidirectional association between knee osteoarthritis and depressive symptoms: evidence from a nationwide population-based cohort.

BACKGROUND: Both knee osteoarthritis (KOA) and depressive symptoms (DS) are major public health issues affecting the quality of life. This study aimed to examine the association between KOA and DS. METHODS: Data were gathered from the China Health and Retirement Longitudinal Study in 2011-2015 which surveyed middle-aged to elderly individuals and their spouses in 28 provinces in China. An adjusted Cox proportional hazards regression model was used to estimate hazard ratios (HRs). RESULTS: The analysis for baseline KOA and the subsequent risk of DS was based on 2582 participants without baseline DS. During the follow-up, KOA patients were more likely to have DS than non-KOA participants (adjusted HR = 1.38: 95% CI = 1.23 to 1.83). The analysis for baseline DS and the subsequent risk of KOA was based on 4293 participants without baseline KOA, those with DS were more likely to develop KOA than non-DS participants (adjusted HR = 1.51: 95% CI = 1.26 to 1.81). Subgroup analysis showed sex and age had no significant moderating effect on the KOA-DS association. CONCLUSIONS: Our results provide evidence that the association between KOA and DS is bidirectional. Therefore, primary prevention and management of KOA and DS should consider this relationship.

Persistence, use of resources and costs in patients under migraine preventive treatment: the PERSEC study.

BACKGROUND: Migraine represents a serious burden for national health systems. However, preventive treatment is not optimally applied to reduce the severity and frequency of headache attacks and the related expenses. Our aim was to assess the persistence to traditional migraine prophylaxis available in Spain and its relationship with the healthcare resource use (HRU) and costs. METHODS: Retrospective observational study with retrospective cohort design of individuals with migraine treated with oral preventive medication for the first time from 01/01/2016 to 30/06/2018. One-year follow-up information was retrieved from the Big-Pac™ database. According to their one-year persistence to oral prophylaxis, two study groups were created and describe regarding HRU and healthcare direct and indirect costs using 95% confidence intervals (CI). The analysis of covariance (ANCOVA) was performed as a sensitivity analysis. Patients were considered persistent if they continued on preventive treatment until the end of the study or switched medications within 60 days or less since the last prescription. Non-persistent were those who permanently discontinued or re-initiated a treatment after 60 days. RESULTS: Seven thousand eight hundred sixty-six patients started preventive treatment (mean age (SD) 48.2 (14.8) and 80.4% women), of whom 2,545 (32.4%) were persistent for 6 months and 2,390 (30.4%) for 12 months. Most used first-line preventive treatments were antidepressants (3,642; 46.3%) followed by antiepileptics (1,738; 22.1%) and beta-blockers (1,399; 17.8%). The acute treatments prescribed concomitantly with preventives were NSAIDs (4,530; 57.6%), followed by triptans (2,217; 28.2%). First-time preventive treatment prescribers were mostly primary care physicians (6,044; 76.8%) followed by neurologists (1,221; 15.5%). Non-persistent patients required a higher number of primary care visits (mean difference (95%CI): 3.0 (2.6;3.4)) and days of sick leave (2.7 (0.8;4.5)) than the persistent ones. The mean annual expenditure was €622 (415; 829) higher in patients who not persisted on migraine prophylactic treatment. CONCLUSIONS: In this study, we observed a high discontinuation rate for migraine prophylaxis which is related to an increase in HRU and costs for non-persistent patients. These results suggest that the treatment adherence implies not only a clinical benefit but also a reduction in HRU and costs.

Carotid Stenosis and Recurrent Ischemic Stroke: A Post-Hoc Analysis of the POINT Trial.

BACKGROUND AND PURPOSE: Randomized trials demonstrated the benefit of dual antiplatelet therapy in patients with minor ischemic stroke or high-risk transient ischemic attack. We sought to determine whether the presence of carotid stenosis was associated with increased risk of ischemic stroke and whether the addition of clopidogrel to aspirin was associated with more benefit in patients with versus without carotid stenosis. METHODS: This is a post-hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) that randomized patients with minor ischemic stroke or high-risk transient ischemic attack within 12 hours from last known normal to receive either clopidogrel plus aspirin or aspirin alone. The primary predictor was the presence of ≥50% stenosis in either cervical internal carotid artery. The primary outcome was ischemic stroke. We built Cox regression models to determine the association between carotid stenosis and ischemic stroke and whether the effect of clopidogrel was modified by ≥50% carotid stenosis. RESULTS: Among 4881 patients enrolled POINT, 3941 patients met the inclusion criteria. In adjusted models, ≥50% carotid stenosis was associated with ischemic stroke risk (hazard ratio, 2.45 [95% CI, 1.68-3.57], P<0.001). The effect of clopidogrel (versus placebo) on ischemic stroke risk was not significantly different in patients with <50% carotid stenosis (adjusted hazard ratio, 0.68 [95% CI, 0.50-0.93], P=0.014) versus those with ≥50% carotid stenosis (adjusted hazard ratio, 0.88 [95% CI, 0.45-1.72], P=0.703), P value for interaction=0.573. CONCLUSIONS: The presence of carotid stenosis was associated with increased risk of ischemic stroke during follow-up. The effect of added clopidogrel was not significantly different in patients with versus without carotid stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.

Association between Birth Region and Time to Tuberculosis Diagnosis among Non-US-Born Persons in the United States.

Approximately 90% of tuberculosis (TB) cases among non-US-born persons in the United States are attributable to progression of latent TB infection to TB disease. Using survival analysis, we investigated whether birthplace is associated with time to disease progression among non-US-born persons in whom TB disease developed. We derived a Cox regression model comparing differences in time to TB diagnosis after US entry among 19 birth regions, adjusting for sex, birth year, and age at entry. After adjusting for age at entry and birth year, the median time to TB diagnosis was lowest among persons from Middle Africa, 128 months (95% CI 116-146 months) for male persons and 121 months (95% CI 108-136 months) for female persons. We found time to TB diagnosis among non-US-born persons varied by birth region, which represents a prognostic indicator for progression of latent TB infection to TB disease.

Mortality Rate in a Cohort of People Living With HIV in Rural Tanzania After Accounting for Unseen Deaths Among Those Lost to Follow-up.

Mortality assessment in cohorts with high numbers of persons lost to follow-up (LTFU) is challenging in settings with limited civil registration systems. We aimed to assess mortality in a clinical cohort (the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO)) of human immunodeficiency virus (HIV)-infected persons in rural Tanzania, accounting for unseen deaths among participants LTFU. We included adults enrolled in 2005-2015 and traced a nonrandom sample of those LTFU. We estimated mortality using Kaplan-Meier methods 1) with routinely captured data (method A), 2) crudely incorporating tracing data (method B), 3) weighting using tracing data to crudely correct for unobserved deaths among participants LTFU (method C), and 4) weighting using tracing data accounting for participant characteristics (method D). We investigated associated factors using proportional hazards models. Among 7,460 adults, 646 (9%) died, 883 (12%) transferred to other clinics, and 2,911 (39%) were LTFU. Of 2,010 (69%) traced participants, 325 (16%) were found: 131 (40%) had died and 130 (40%) had transferred. Five-year mortality estimates derived using the 4 methods were 13.1% (A), 16.2% (B), 36.8% (C), and 35.1% (D), respectively. Higher mortality was associated with male sex, referral as a hospital inpatient, living close to the index clinic, lower body mass index, more advanced World Health Organization HIV clinical stage, lower CD4 cell count, and less time since initiation of antiretroviral therapy. Adjusting for unseen deaths among participants LTFU approximately doubled the 5-year mortality estimates. Our approach is applicable to other cohort studies adopting targeted tracing.

The Southern European Atlantic Diet and all-cause mortality in older adults.

BACKGROUND: The Southern European Atlantic Diet (SEAD) is the traditional diet of Northern Portugal and North-Western Spain. Higher adherence to the SEAD has been associated with lower levels of some cardiovascular risk factors and reduced risk for myocardial infarction, but whether this translates into lower all-cause mortality is uncertain. We hence examined the association between adherence to the SEAD and all-cause mortality in older adults. METHODS: Data were taken from the Seniors-ENRICA-1 cohort, which included 3165 individuals representative of the non-institutionalized population aged ≥ 60 years in Spain. Food consumption was assessed with a validated diet history, and adherence to the SEAD was measured with an index comprising 9 food components: fresh fish, cod, red meat and pork products, dairy products, legumes and vegetables, vegetable soup, potatoes, whole-grain bread, and wine. Vital status was ascertained with the National Death Index of Spain. Statistical analyses were performed with Cox regression models and adjusted for the main confounders. RESULTS: During a median follow-up of 10.9 years, 646 deaths occurred. Higher adherence to the SEAD was associated with lower all-cause mortality (fully adjusted hazard ratio [95% confidence interval] per 1-SD increment in the SEAD score 0.86 [0.79, 0.94]; p-trend < 0.001). Most food components of the SEAD showed some tendency to lower all-cause mortality, especially moderate wine consumption (hazard ratio [95% confidence interval] 0.71 [0.59, 0.86]). The results were robust in several sensitivity analyses. The protective association between SEAD and all-cause death was of similar magnitude to that found for the Mediterranean Diet Adherence Screener (hazard ratio [95% confidence interval] per 1-SD increment 0.89 [0.80, 0.98]) and the Alternate Healthy Eating Index (0.83 [0.76, 0.92]). CONCLUSIONS: Adherence to the SEAD is associated with a lower risk of all-cause death among older adults in Spain.

Serial changes of CT findings in patients with chronic hypersensitivity pneumonitis: imaging trajectories and predictors of fibrotic progression and acute exacerbation.

OBJECTIVES: To evaluate the longitudinal changes of chest CT findings in patients with chronic hypersensitivity pneumonitis (HP) and identify risk factors for fibrotic progression and acute exacerbation (AE). METHODS: This retrospective study included patients with chronic HP with follow-up CT. Baseline and serial follow-up CT were evaluated semi-quantitatively. Fibrosis score was defined as the sum of the area with reticulation and honeycombing. The modified CT pattern of Fleischner Society idiopathic pulmonary fibrosis diagnostic guidelines was evaluated. Cox proportional hazards regression was performed to determine significant variables associated with fibrotic progression and AEs. RESULTS: Of 91 patients, mean age was 59.1 years and 61.5% were women. The median follow-up period was 4.9 years. Seventy-nine patients (86.8%) showed fibrotic progression with persistent areas of mosaic attenuation, finally replaced by fibrosis, and 20 (22.0%) developed AE. Baseline fibrosis score and CT pattern of usual interstitial pneumonia (UIP)/probable UIP were independent risk factors for predicting fibrotic progression (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.02-1.09, p < 0.001, for fibrosis score; HR = 2.50, CI = 1.50-4.16, p < 0.001, for CT pattern) and AEs (HR = 1.07, CI = 1.01-1.13, p = 0.019, for fibrosis score; HR = 5.47, CI = 1.23-24.45, p = 0.026, for CT pattern) after adjusting clinical covariables. CONCLUSION: Fibrotic progression and AE were identified in 86.8% and 22.0% of patients with chronic HP. Fibrosis score and CT pattern of UIP/probable UIP on baseline chest CT may predict fibrotic progression and AE. KEY POINTS: • Most patients (87%) showed fibrotic progression on long-term follow-up with persistent areas of mosaic attenuation that were finally replaced by fibrosis at a later stage. • One-fifth of patients (22%) experienced acute exacerbation associated with worse prognosis. • Fibrosis score (sum of reticulation and honeycombing) and CT pattern of UIP/probable UIP on baseline CT were independent predictors for predicting fibrotic progression and acute exacerbation.

High-Sensitivity Cardiac Troponin T for Risk Stratification in Patients With Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Optimal secondary prevention for patients with embolic stroke of undetermined source (ESUS) remains unknown. We aimed to assess whether high-sensitivity cardiac troponin T (hs-cTnT) levels are associated with major vascular events and whether hs-cTnT may identify patients who benefit from anticoagulation following ESUS. METHODS: Data were obtained from the biomarker substudy of the NAVIGATE ESUS trial, a randomized controlled trial testing the efficacy of rivaroxaban versus aspirin for secondary stroke prevention in ESUS. Patients were dichotomized at the hs-cTnT upper reference limit (14 ng/L, Gen V, Roche Diagnostics). Cox proportional hazard models were computed to explore the association between hs-cTnT, the combined cardiovascular end point (recurrent stroke, myocardial infarction, systemic embolism, cardiovascular death), and recurrent ischemic stroke. RESULTS: Among 1337 patients enrolled at 111 participating centers in 18 countries (mean age 67±9 years, 61% male), hs-cTnT was detectable in 95% and at/above the upper reference limit in 21%. During a median follow-up of 11 months, the combined cardiovascular end point occurred in 68 patients (5.0%/y, rivaroxaban 28 events, aspirin 40 events; hazard ratio, 0.67 [95% CI, 0.41-1.1]), and recurrent ischemic stroke occurred in 50 patients (4.0%/y, rivaroxaban 16 events, aspirin 34 events, hazard ratio 0.45 [95% CI, 0.25-0.81]). Annualized combined cardiovascular end point rates were 8.2% (9.5% rivaroxaban, 7.0% aspirin) for those above hs-cTnT upper reference limit and 4.8% (3.1% rivaroxaban, 6.6% aspirin) below with a significant treatment modification (P=0.04). Annualized ischemic stroke rates were 4.7% above hs-cTnT upper reference limit and 3.9% below, with no suggestion of an interaction between hs-cTnT and treatment (P=0.3). CONCLUSIONS: In patients with ESUS, hs-cTnT was associated with increased cardiovascular event rates. While fewer recurrent strokes occurred in patients receiving rivaroxaban, outcomes were not stratified by hs-cTn results. Our findings support using hs-cTnT for cardiovascular risk stratification but not for decision-making regarding anticoagulation therapy in patients with ESUS. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Validation of a subclassification for high-risk prostate cancer in a prospective cohort.

BACKGROUND: A subgroup of men with favorable high-risk prostate cancer (T1c with either a Gleason score of 4 + 4 = 8 and a prostate-specific antigen [PSA] level <10 ng/mL or a Gleason score of 6 and a PSA level >20 ng/mL) has been associated with improved outcomes in comparison with other standard high-risk patients. This study was designed to validate the prognostic utility of a subclassification for high-risk disease with a prospectively collected data set. METHODS: This study identified 3033 men from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had been diagnosed from 1993 to 2001 with clinically localized prostate cancer-either intermediate-risk disease (clinical stage T2b-c, a Gleason score of 7, or a PSA level of 10 to 20 ng/mL) or high-risk disease (clinical stage T3-T4, a Gleason score of 8-10, or a PSA level >20 ng/mL)-that was managed with radical prostatectomy or radiation therapy. Multivariable logistic regression was used to calculate adjusted odds ratios (aORs) for pathological T3 to T4 or N1 (pT3-T4/pN1) disease. Fine and Gray competing risks regression was used to determine adjusted hazard ratios (aHRs) of prostate cancer-specific mortality (PCSM). RESULTS: The median follow-up was 5.7 years. Patients with favorable high-risk disease had lower 8-year PCSM in comparison with patients with standard high-risk disease (2.2% vs 10.8%; aHR, 0.26; 95% confidence interval [CI], 0.09-0.73; P = .01) but similar PCSM in comparison with patients with intermediate-risk disease (2.2% vs 2.2%; aHR, 0.90; 95% CI, 0.32-2.54; P = .84). Among those who underwent surgery, those with favorable high-risk disease had lower odds of pT3-T4/pN1 disease than those with standard high-risk disease (46.2% vs 63.3%; aOR, 0.50; 95% CI, 0.27-0.94; P = .03). CONCLUSIONS: This study validates the prognostic utility of a subclassification for high-risk disease in a prospectively collected patient cohort. Patients with favorable high-risk disease have PCSM similar to that of patients with intermediate-risk disease and significantly better than that of patients with standard high-risk disease. Future trials are needed to assess possible de-intensification of therapy for favorable high-risk disease.

Intratumor heterogeneity could inform the use and type of postoperative adjuvant therapy in patients with head and neck squamous cell carcinoma.

BACKGROUND: After surgery for head and neck squamous cell carcinoma (HNSCC), decisions regarding adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) are based on staging and the presence of high-risk pathology. Because higher mutant allele tumor heterogeneity (MATH; a measure of intratumor genetic heterogeneity) is associated with shorter overall survival (OS) in patients with HNSCC, the authors sought to determine whether MATH analysis might further inform these decisions. METHODS: Adjuvant therapy-associated relationships between MATH and OS were analyzed for 389 patients with HNSCC who were treated surgically. Data were obtained from The Cancer Genome Atlas and analyzed with Cox proportional hazards multiple regression accounting for 7 other patient characteristics. RESULTS: The relationship between MATH and OS differed with adjuvant therapy in a way that could inform therapy decisions. Adjuvant RT alone was found to provide substantial benefit for patients having high-MATH tumors (RT vs no adjuvant therapy: hazard ratio, 0.29 [95% CI, 0.17-0.51]) but no benefit for those having low-MATH tumors. In contrast, adjuvant CRT provided no benefit beyond that of adjuvant RT for patients with high-MATH tumors but substantially improved OS among patients with low-MATH tumors (CRT vs no adjuvant therapy: hazard ratio, 0.34 [95% CI, 0.15-0.78]). CONCLUSIONS: The results of the current analysis suggested that patients with HNSCC with high-MATH tumors who underwent surgical treatment could benefit from adjuvant RT, even when current clinical guidelines indicate otherwise. The addition of adjuvant chemotherapy for patients with high-MATH tumors would not be indicated. Adding chemotherapy might be necessary to radiosensitize low-MATH tumors to adjuvant RT. This potential predictive role of tumor MATH analysis should be evaluated in prospective clinical trials.