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Abstract Introduction Comparing sleep and rest-activity rhythms (RARs) across the spectrum of cognitive aging can reveal novel risk factors and potential mechanisms underlying dementia disorders. However, our current understanding is restricted by differences in sleep measurement, limited longitudinal data, and heterogeneous cognitive aging processes. We aimed to determine (1) which sleep/RAR features exhibit meaningful changes within three distinct cognitive pathways; and (2) which sleep/RAR features differ between cognitive aging pathways prior to and after the onset of mild cognitive impairment (MCI) and/or dementia. Methods Longitudinal self-reported sleep and actigraphy data were obtained from 1,449 participants in the Rush Memory and Aging Project (mean age= 81.2±7.1 years, 75.2% female, 5.2% Black, 94.8% White). We applied flexible cubic spline models to quantify differences in the levels and trajectories of sleep amount (self-reported duration; actigraphy rest interval length and alpha), regularity (actigraphy interdaily stability, intradaily variability, and midpoint standard deviation), and timing (self-reported midpoint; actigraphy midpoint and acrophase) within and between three cognitive aging pathways over 12 years: Normal Cognitive Aging (‘Normal’), Progression to MCI (‘Stable MCI’), and Progression to Dementia (‘Dementia’). Models were adjusted for key sociodemographic and health variables. Results Sleep amount was lowest in the Dementia pathway prior to MCI or dementia, but increased with age, most rapidly following dementia. The greatest effect was observed in self-reported duration (standardized mean change, d[95%CI]=0.912 [0.47, 1.36]. Regularity declined across all pathways, most rapidly after cognitive diagnoses, with the largest increases in intradaily variability occurring among the Stable MCI (d=0.97 [0.70, 1.23]) and Dementia paths (d=1.11 [0.84, 1.38). Shifts toward earlier sleep timing were observed in actigraphy measures across all three pathways (-0.54≤d≤-0.31). Conclusion Shorter sleep amount in cognitively healthy older adults may be a risk factor or prodromal indicator of dementia, while longer sleep amounts and decreasing regularity following dementia may reflect neurodegeneration. Advances in sleep timing may be less useful as a clinical indicator of future cognitive impairment or decline. Differences between self-reported and actigraphy-measured sleep/RAR outcomes may reflect distinct underlying mechanisms, warranting further research. Support (if any) NIH: T32HL082610, RF1AG056331, R01AG052488, R01AG071638, RF1AG070436, R01AG17917

AbstractINTRODUCTIONComparing sleep and rest–activity rhythms across different cognitive aging pathways can identify novel risk factors and potential mechanisms. However, our current understanding is restricted by differences in sleep measurement, limited longitudinal data, and heterogeneous cognitive aging processes.METHODSWe applied cubic splines to longitudinal self‐reported sleep and actigraphy data from 1449 participants in the Rush Memory and Aging Project and quantified differences in the levels and trajectories of sleep amount, regularity, and timing within and between three cognitive aging pathways: normal, stable mild cognitive impairment, dementia.RESULTSSleep amount was lowest in the dementia pathway prior to cognitive impairment but increased with age, most rapidly after dementia. Regularity declined across all pathways, most rapidly after cognitive diagnoses. Timing advanced across all pathways.DISCUSSIONShorter sleep amount in cognitively healthy older adults may be a risk factor or prodromal indicator of dementia, while longer sleep amounts and decreasing regularity may reflect neurodegeneration.Highlights We quantified longitudinal changes in sleep across three cognitive‐aging pathways. We incorporated both subjective and objective measures of sleep health. Self‐report duration increased noticeably from before to after cognitive diagnosis. Sleep irregularity increased most prominently after cognitive diagnosis. Advances in sleep timing occurred in both normal and pathological aging.

Background/Purpose APS ACTION Registry was created to study the natural course of antiphospholipid syndrome (APS) over 10 years in persistently antiphospholipid antibody (aPL) positive patients with or without systemic autoimmune rheumatic diseases (SARDs). Our primary objective was to compare the characteristics of aPL-positive patients with or without thrombocytopenia (TP) and/or autoimmune hemolytic anemia (AIHA). Methods The registry inclusion criteria are positive aPL based on the Revised Sapporo APS Classification Criteria, tested at least twice within 1 year prior to enrollment. For the primary comparison of demographic, clinical, and serologic characteristics in this retrospective study, we divided patients into two groups: TP/AIHA ever and never. Thrombocytopenia was defined as a platelet count of <100,000 x 10 9 /L tested twice at least 12 weeks apart, and AIHA was defined as anemia with hemolysis and a positive direct antiglobulin test (DAT). For the secondary analysis, we compared patients with TP versus AIHA, and the immunosuppressive use stratified by systemic lupus erythematosus (SLE) classification. Results As of April 2022, of 1,039 patients (primary aPL/APS: 618 [59%]; SLE classification: 334 [31%]) included in the registry, 228 (22%) had baseline (historical or current) TP and/or AIHA (TP only: 176 [17%]; AIHA only: 35 [3%], and both: 17 [2%]). Thrombocytopenia and/or AIHA was significantly associated with Asian race, SLE classification, cardiac valve disease, catastrophic/microvascular APS, triple aPL (lupus anticoagulant, anticardiolipin antibody, and anti-β 2 -glycoprotein-I antibody) positivity, and SLE-related serologic and inflammatory markers. When 101/618 (16%) primary aPL/APS patients and 101/334 (34%) SLE patients with TP and/or AIHA were compared, azathioprine and mycophenolate mofetil were more commonly reported in lupus patients, however corticosteroid, intravenous immunoglobulin, and rituximab use were similar between groups. Conclusion In our large multi-center international cohort of persistently aPL-positive patients, approximately one-fifth had active or historical TP and/or AIHA at registry entry; half of these patients had additional SLE. Cardiac valve disease, catastrophic/microvascular APS, and triple aPL-positivity were aPL-related clinical and laboratory manifestations associated with TP and/or AIHA, suggesting a more severe APS clinical phenotype in aPL-patients with TP and/or AIHA.

Abstract Aims Functional tricuspid regurgitation (FTR) associated with degenerative mitral regurgitation (DMR) accentuates the severity of heart failure and is a marker of poor prognosis. Little is known about FTR associated with asymptomatic DMR. Methods and results The study included 1249 asymptomatic patients with moderate or severe DMR from the Mitral Regurgitation International Database-Quantitative (MIDA-Q) registry (mean age 64 ± 15 years, 25% female). Despite the asymptomatic status, absent/trivial FTR was noted in only 42%, mild in 34.5%, moderate in 11%, and severe FTR in 12.5%. Patients with higher FTR grades were older and more often female and had higher EuroScore II, larger left atrial volumes, and more atrial fibrillation (all P &lt; 0.05). Patients with moderate or severe FTR had comparable 5-year survival (64 ± 4% and 65 ± 4%) and lower than patients with no/trivial FTR(96 ± 1%, P &lt; 0.001). After adjustment for key prognostic factors, including age, left ventricular dilatation and dysfunction, DMR severity, left atrial dilatation, and pulmonary hypertension, ≥moderate FTR remained a strong predictor of mortality (HR = 2.08 [1.17–3.72], P = 0.013). Sensitivity analysis showed stable impact of ≥moderate FTR among patients with/without pulmonary hypertension, in women and men and for any other subset. For patients who underwent mitral valve surgery, post-operative survival rates were similar between those with no/trivial FTR and those with ≥moderate or severe FTR (P = 0.76), suggesting that surgery could reduce the excess mortality related to preoperative FTR. Conclusions Among asymptomatic patients with significant DMR, ≥moderate FTR is frequent and independently associated with higher mortality, independently of traditional guideline-based risk factors. These findings suggest that ≥moderate FTR should lead to consideration of early mitral surgery to improve outcomes.

ImportanceCutaneous squamous cell carcinoma (CSCC) risk stratification is central to management, and physicians rely on tumor staging systems to estimate risk. The Brigham and Women’s Hospital (BWH) T staging system predicts risk based on 4 tumor risk factors (RFs). However, stage is not precisely associated with the number of RFs, as BWH stage T2b includes CSCCs with 2 and 3 RFs.ObjectiveTo determine how RF number is associated with the risk of recurrence, metastasis, and disease-related death.Design, Setting, and ParticipantsThis retrospective multination cohort study of CSCCs diagnosed between October 1, 1991, and July 19, 2023, was conducted at 12 centers in the US (10), Spain (1), and Brazil (1). Invasive CSCCs with confirmed negative margins longer than 14 days were included. Tumors were excluded if they were metastatic at presentation or received adjuvant therapy. Data were analyzed from October 2023 to August 2024.Interventions or ExposuresCSCCs were stratified by the number of the following RFs (0, 1, 2, 3, or 4): a diameter of 2 cm or larger, poorly differentiated histology, tumor extension beyond subcutaneous fat, and large caliber nerve invasion.Main Outcomes and MeasuresFive-year cumulative incidences of local recurrence, nodal metastasis, distant metastasis, and disease-specific death.ResultsA total of 16 844 CSCCs were included (5978 female individuals [35.5%]; median [IQR] age, 73.9 [65.7-81.8] years), with 0 (12 657 [75.1%]), 1 (2892 [17.2%]), 2 (1015 [6.0%]), 3 ( 225 [1.3%]) or 4 (55 [0.3%]) RFs. Median (IQ) follow up time was 33.6 (14.5-60.3) months. For local recurrence, the risk increased as the number of RF increased from 0 (1.7%; 95% CI, 1.5%-2.0%) to 1 (5.0%; 95% CI, 4.1%-5.9%) to 2 (8.8%; 95% CI, 7.0%-11.0%) to 3 (16.0%; 95% CI, 11.0%-22.0%) to 4 (33.0%; 95% CI, 19.0%-47.0%; P &amp;lt; .001 for between-group differences). This increase was also observed for nodal metastasis (0.6% [95% CI, 0.4%-0.7%] vs 3.6% [95% CI, 2.9%-4.4%] vs 11.0% [95% CI, 9.2%-13.0%] vs 20.0% [95% CI, 15.0%-26.0%] vs 28.0% [95% CI, 15.0%-42.0%], respectively; P &amp;lt; .001), distant metastasis (0.2% [95% CI, 0.1%-0.3%] vs 1.1% [95% CI, 0.7%-1.6%] vs 2.3% [95% CI, 1.4%-3.4%] vs 7.9% [95% CI, 4.6%-12.0%] vs 8.4% [95% CI, 2.6%-19.0%], respectively; P &amp;lt; .001), and disease-specific death (0.3% [95% CI, 0.2%-0.4%] vs 1.9% [95% CI, 1.4%-2.7%] vs 5.4% [95% CI, 4.0%-7.0%] vs 11.0% [95% CI, 6.7%-16.0%] vs 25% [95% CI, 12%-39%], respectively; P &amp;lt; .001). CSCCs with 3 RFs had higher cumulative incidences of local recurrence (1.6-fold), nodal metastasis (1.9-fold), distant metastasis (4.3-fold), and disease-specific death (1.9-fold) compared with those with 2 RFs.Conclusions and RelevanceThe results of this cohort study suggest that the number of RFs is an indicator of risk, and among BWH T2b tumors, those with 3 RFs represent a higher risk subset.

Abstract Objectives Studies on the impact of hormone replacement therapy (HRT) on hepatocellular carcinoma (HCC) have been investigated in the past. This study aims to further address this topic using a large population dataset of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (NIH, USA). Methods Multivariable logistic regression was used for the analysis of women in the entire PLCO cohort. Results A non-significant reduction in the risk of developing HCC was observed in women using HRT compared to never users (OR=0.61, 95 % CI: 0.21–1.79, p=0.367). Oral contraceptive use was significantly associated with reduced risk of HCC in the HRT group, (OR=0.17, 95 % CI: 0.00–0.82, p=0.028), and there was a nearly-significant interaction between HRT use and oral contraceptive use (p=0.054). Regardless of HRT use, those with pre-existing liver comorbidities of hepatitis or cirrhosis were at the highest risk of developing HCC (OR=5.09, 95 % CI: 1.13–22.81, p=0.034). However, liver comorbidities of hepatitis or cirrhosis and exposure to HRT showed a significant interaction (p=0.0001). Conclusions In those taking HRT, oral contraceptive use was significantly protective against HCC, suggesting that a longer period of hormone use (oral contraceptive plus HRT) provides additional protection against HCC than HRT alone. Overall, the low numbers of HCC diagnoses, which reflect the wider healthy female population, limited our ability to establish statistical significance regarding the impact of HRT on HCC incidence, which requires further prospective studies of larger populations.

Background: The purpose of this meta-analysis was to examine the prevalence of hypertensive disorders of pregnancy (HDPs), particularly preeclampsia (PE), in peripartum cardiomyopathy (PPCM)-affected pregnancies, and to evaluate whether a HDP significantly alters the prognosis of PPCM, with specific reference to the recovery of left ventricular function (LVEF) and mortality. Methods: A total of 5468 potentially eligible studies were identified, and 104 were included in the meta-analysis. For pooling proportions, the inverse variance methods with logit transformation were used. Complete recovery of LVEF (>50%) and mortality were expressed by odds ratios (ORs), with 95% confidence intervals (CIs). The Peto OR (POR) was used in cases of rare events. Baseline LV function and baseline LV end-diastolic diameter (LVEDD) were summarized by the mean difference (MD) and 95% confidence interval (CI). Results: The summary estimate of the prevalence of HDPs and PE in women with PPCM was 36% and 25%, respectively. Patients with HDPs and, more specifically, PE with PPCM had a higher chance of complete recovery (OR = 1.87; 95%CI = 1.64 to 2.13; p < 0.001 and OR = 1.98; 95%CI 1.69 to 2.32; p < 0.001, respectively), a higher baseline LVEF (MD, 1.42; 95% CI 0.16 to 2.67; p = 0.03 and MD, 1.69; 95% CI 0.21 to 3.18; p = 0.03, respectively), and a smaller baseline LVEDD (MD, −1.31; 95% CI −2.50 to −0.13; p = 0.03 and MD, −2.63; 95% CI −3.75 to −1.51; p < 0.001, respectively). These results, however, did not translate into a significant difference in 12-month mortality (POR = 0.80; 95% CI = 0.57 to 1.13; p = 0.21 and POR = 1.56; 95% CI 0.90 to 2.73; p = 0.12, respectively). Conclusions: The findings of this study may contribute to evidence that can be utilized to aid in the risk stratification of patients with PPCM regarding their long-term prognoses.