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ImportanceAutism spectrum disorder (ASD) affects 1 in 44 children. The Autism Diagnostic Observation Schedule (ADOS) is a semi-structured observation developed for use in research but is considered a component of gold standard clinical diagnosis. The ADOS adds time and cost to diagnostic assessments.ObjectiveTo evaluate consistency between clinical diagnosis (index ASD diagnosis) and diagnosis incorporating the ADOS (reference standard ASD diagnosis) and to examine clinician and child factors that predict consistency between index diagnoses and reference standard diagnoses.Design, Setting, and ParticipantsThis prospective diagnostic study was conducted between May 2019 and February 2020. Developmental-behavioral pediatricians (DBPs) made a diagnosis based on clinical assessment (index ASD diagnosis). The ADOS was then administered, after which the DBP made a second diagnosis (reference standard ASD diagnosis). DBPs self-reported diagnostic certainty at the time of the index diagnoses and reference standard diagnoses. The study took place at 8 sites (7 US and 1 European) that provided subspecialty assessments for children with concerns for ASD. Participants included children aged 18 months to 5 years, 11 months, without a prior ASD diagnosis, consecutively referred for possible ASD. Among 648 eligible children, 23 refused, 376 enrolled, and 349 completed the study. All 40 eligible DBPs participated.ExposuresADOS administered to all child participants.Main Outcomes and MeasuresIndex diagnoses and reference standard diagnoses of ASD (yes/no).ResultsAmong the 349 children (279 [79.7%] male; mean [SD] age, 39.9 [13.4] months), index diagnoses and reference standard diagnoses were consistent for 314 (90%) (ASD = 250; not ASD = 64) and changed for 35. Clinician diagnostic certainty was the most sensitive and specific predictor of diagnostic consistency (area under curve = 0.860; P Conclusions and RelevanceIn this prospective diagnostic study, clinical diagnoses of ASD by DBPs with vs without the ADOS were consistent in 90.0% of cases. Clinician diagnostic certainty predicted consistency of index diagnoses and reference standard diagnoses. This study suggests that the ADOS is generally not required for diagnosis of ASD in young children by DBPs and that DBPs can identify children for whom the ADOS may be needed.

RATIONALE Steroid refractory graft-vs-host disease (sr-GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo-HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr-GvHD. OBJECTIVES We studied the effects of FMT on sr-GvHD in allo-HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre- and post-FMT (day -14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre- and post-FMT by 16S rRNA sequencing. RESULTS Post-FMT, we observed no intervention-associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis-each 3/11 and vomiting-1/11). Stool frequencies and volumes were significantly reduced [pre- vs post-FMT (d14): P

Background and Purpose: Rates of depression after ischemic stroke (IS) and myocardial infarction (MI) are significantly higher than in the general population and associated with morbidity and mortality. There is a lack of nationally representative data comparing depression and suicide attempt (SA) after these distinct ischemic vascular events. Methods: The 2013 Nationwide Readmissions Database contains >14 million US admissions for all payers and the uninsured. Using International Classification of Disease, 9th Revision, Clinical Modification Codes, we identified index admission with IS (n = 434,495) or MI (n = 539,550) and readmission for depression or SA. We calculated weighted frequencies of readmission. We performed adjusted Cox regression to calculate hazard ratio (HR) for readmission for depression and SA up to 1 year following IS versus MI. Analyses were stratified by discharge home versus elsewhere. Results: Weighted depression readmission rates were higher at 30, 60, and 90 days in patients with IS versus MI (0.04%, 0.09%, 0.12% vs. 0.03%, 0.05%, 0.07%, respectively). There was no significant difference in SA readmissions between groups. The adjusted HR for readmission due to depression was 1.49 for IS versus MI (95% CI 1.25–1.79, p < 0.0001). History of depression (HR 3.70 [3.07–4.46]), alcoholism (2.04 [1.34–3.09]), and smoking (1.38 [1.15–1.64]) were associated with increased risk of depression readmission. Age >70 years (0.46 [0.37–0.56]) and discharge home (0.69 [0.57–0.83]) were associated with reduced hazards of readmission due to depression. Conclusions: IS was associated with greater hazard of readmission due to depression compared to MI. Patients with a history of depression, smoking, and alcoholism were more likely to be readmitted with depression, while advanced age and discharge home were protective. It is unclear to what extent differences in type of ischemic tissue damage and disability contribute, and further investigation is warranted.

Warthin tumor is one of the most common benign salivary gland tumors. Overt lymphoma is known to occur in the lymphoid stroma of Warthin tumor. In situ follicular neoplasia is difficult to identify in routine histologic examination of lymphoid tissue and has not been reported in association with Warthin tumor. Our objective is to determine the prevalence of overt malignant lymphoma and in situ follicular neoplasia in Warthin tumor. We conducted a retrospective histological evaluation of 89 sequential Warthin tumor cases with available slides and blocks from the years 2010-2019. Of these, 84 cases were subjected to immunohistochemical testing, while 5 cases had been previously worked up for the suspicion of lymphoma. We identified two additional cases of lymphoid neoplasia associated with Warthin tumor including small lymphocytic lymphoma/chronic lymphocytic leukemia (n = 1) and in situ follicular neoplasia (n = 1) in addition to previously reported case of follicular lymphoma included in this study. The prevalence rate of first-time detected lymphoid neoplasia in Warthin tumor is 3.4%. The prevalence rate of overt lymphoma is 2.2%, while the prevalence of in situ follicular neoplasia is 1.1%. We propose histologic criteria to identify small lymphocytic lymphoma and follicular lymphoma in Warthin tumor. These include a monotonous interfollicular expansion of small lymphocytes and germinal centers composed of a monotonous population of lymphocytes without polarity or tingible body macrophages respectively. It is very important for pathologists to perform a diligent morphological examination and perform immunohistochemistry in suspected cases to identify subtle involvement of Warthin tumor by lymphoma. In patients with involvement of Warthin tumor by in situ follicular neoplasia, concurrent lymphoma in the same tissue and other sites should be considered. Patients without overt lymphoma elsewhere likely have a low risk of progression to follicular lymphoma. The low prevalence of in situ follicular neoplasia in Warthin tumor, combined with the low rate of clinical progression to lymphoma, make routine screening of Warthin tumor for in situ follicular neoplasia unnecessary.

BACKGROUND AND OBJECTIVES: Peritoneal metastases (PM) from primary colorectal cancer (pCRC) are associated with poor outcomes; however, molecular differences are not well defined. METHODS: We compared unpaired tumor profiles of patients with pCRC and PM from Caris Life Sciences. Testing included next-generation sequencing of 592 genes, microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were test-defined as pathogenic (PATH). RESULTS: Six hundred seventeen pCRC and 348 PM patients had similar gender (55% male) and age (median 59). PATHs were similar between PM and pCRC in KRAS, BRAF, SMAD2, SMAD4, and PTEN. pCRC PATHs were increased in APC (76% vs 48%, P < .01), ARID1A (29% vs 12%, P < .05), TP53 (72% vs 53%, P < .01), PIK3CA (22% vs 15%, P < .05), and FBXW7 (13% vs 7%, P < .01) compared with PM. Mucinous PM had more PATHs in GNAS (19% vs 8%, P = .032) while nonmucinous PM had more PATHs in BRAF (13% vs 8%, P = .027). Right-sided PM had decreased PATHs in APC (39% vs 68%, P < .0001), ARID1A (7% vs 38%, P < .004), and TP53 (48% vs 65%, P = .033) while there were no difference for left-sided PM. Nine percent of pCRC and 6% of PM were MSI-high (P = NS). There was no difference in TMB-high, TMB-intermediate, or TMB-low between PM and pCRC. CONCLUSIONS: PM have similar rates of KRAS mutation with increased PATHs in GNAS (mucinous) and BRAF (nonmucinous) compared to pCRC. No differences in MSI or TMB were identified between PM and pCRC tumors. These findings inform future study into the molecular profile of PM.

Introduction: Intracerebral hemorrhage (ICH) comprises 15–20% of all strokes with debilitating consequences. Data regarding characteristics and outcomes of primary ICH in the young are lacking, given its rarity, making comparisons between younger and older cohorts difficult to perform. Nationally representative administrative databases enable analysis of such rare events. Objective: To determine the baseline characteristics, all-cause readmission rates, and reasons for primary ICH in younger and older adults using a nationally representative database. Methods: A retrospective cohort analysis was performed using the Nationwide Readmissions Database 2013. Validated ICD-9-CM codes identified index ICH admissions, comorbidities, demographics, behavioral risk factors, procedures, and Elixhauser and Charlson Comorbidity indices. We compared “younger” (age ≤ 45 years) and “older” (age > 45) index ICH admissions by weighted 30-day all-cause readmission rates, primary diagnosis code for 30-day readmissions, most common comorbidities during the index hospitalization, and Kaplan-Meier cumulative risk of readmission up to 1 year. Results: Older admissions had higher comorbidity scores and mortality, but both groups had similar total comorbidities. Younger admissions exhibited longer length of stay with more procedures performed. Vascular anomalies (aneurysm 7.2 vs. 4.6% and arteriovenous malformation 5.9 vs. 0.8%) and behavioral risk factors (smoking 26.5 vs. 23.0%, alcohol abuse 6.7 vs. 4.6%, and substance use 13.5 vs. 2.9%) were more prevalent in younger admissions, while older patients had more cardiovascular comorbidities. All-cause 30-day readmission rates (13.1 vs. 13.0%) and 1-year cumulative risk of readmission (log-rank p value 0.7209) were similar. Readmissions in the younger cohort were primarily for neurological conditions, and those in the older cohort were for systemic conditions. Conclusions: Adults

Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants. Purpose Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans. Methods Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI). Results There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men. Conclusions In older women, increased heart rate variation is associated with hip fracture risk.

Lactose can fuel GVHD Allogeneic hematopoietic cell transplantation (allo-HCT) is used to treat certain hematopoietic malignancies, but patients have a risk of developing graft-versus-host disease (GVHD). Stein-Thoeringer et al. performed a large-scale analysis of more than 1300 patients treated with allo-HCT across four clinical centers (see the Perspective by Zitvogel and Kroemer). High levels of bacteria from the Enterococcus genus were associated with greater incidence of GVHD and mortality. Lactose appears to provide a substrate for Enterococcus growth, and patients with a lactose-malabsorption genotype had a greater abundance of Enterococcus. A lactose-free diet limited Enterococcus growth, reduced the severity of GVHD, and improved survival in gnotobiotic mouse models. Science , this issue p. 1143 ; see also p. 1077

ObjectiveFollowing widespread acceptance of endovascular therapy (ET) for large vessel occlusion stroke in 2015, we assessed nationwide utilization of revascularization for acute ischemic stroke (AIS).MethodsWe utilized the 2013–2016 Healthcare Cost and Utilization Project Nationwide Readmissions Database. We identified AIS admissions, treatment with intravenous thrombolysis (IVT), ET, and vascular risk factors using International Classification of Disease Clinical Modification codes. Main predictor of outcome was the time period of index admission (‘pre-endovascular era (pre-EA)’ January 2013–January 2015 and ‘endovascular era (EA)’ February 2015– December 2016). We calculated the proportion of AIS admissions in which, first, VT and second, ET was performed. Among patients treated with ET, we examined the association between era and discharge disposition, in-hospital mortality during index admission, and 30-day readmission.ResultsThere were 925 363 index AIS admissions before the EA and 857 347 during. A higher proportion of AIS patients received IVT (8.4% vs 7.8%) and ET (2.6% vs 1.3%) in the EA. Although length of stay (LOS) was shorter in the EA (5.70 vs 6.80 days), total charges were greater ($56 691 vs $53 878), and admissions were more often to a metropolitan hospital (65.2% vs 57.2%). Among those treated with ET, a smaller proportion received IVT (29.7% vs 44.9%), LOS was substantively shorter (9.75 vs 12.76 days), and patients had a lower odds of discharge home.ConclusionsThe utilization of ET has doubled in the EA but ET remains underutilized. ET is predominantly provided at metropolitan teaching hospitals and associated with higher charges despite shorter LOS and unchanged in-hospital mortality.

Background Chronic multisymptom illness (CMI) is more prevalent among deployed than nondeployed veterans from the first Gulf War. Objective physiologic markers of CMI are lacking. The purpose of this study is to determine whether measurable abnormalities in the autonomic nervous system or hypothalamic-pituitary adrenal axis would distinguish CMI cases (CMI+) from controls (CMI-) among deployed veterans of the 1990-1991 Gulf War. Methods This is a cross-sectional case-control cohort study that examined deployed veterans who participated in the Phase III study: National Health Survey of Gulf War Veterans and Their Families. Autonomic nervous system and hypothalamic-pituitary adrenal axis function-related measures included: 24-hour heart-rate variability, urinary catecholamines and cortisol, hypertension, insulin sensitivity, dyslipidemia, body fat, bone mineral density, and ultrasensitive C-reactive protein. Results Veterans of the first Gulf War with CMI (n = 73) and without the condition (n = 111) were studied. Sociodemographic characteristics were similar. Veterans with CMI reported poorer mental and physical functioning, greater use of prescription medications, and more nonroutine clinic visits. These veterans were also more likely to have fibromyalgia syndrome, irritable bowel syndrome, metabolic syndrome, and among males, a larger waist-to-hip ratio. Lower values for a nonlinear heart-rate-variability parameter—the short-term fractal scaling exponent (DFA1), reflecting an increased randomness of beat-to-beat changes in heart rate—were observed in veterans with CMI than those veterans without it (1.28±0.16vs 1.35±0.15; p=0.005). Hypothalamic-pituitary-adrenal axis function measures were similar between the two groups. Conclusion In this cohort of deployed veterans from the first Gulf War, we identified abnormal heart-rate variability in veterans with CMI compared to veterans without the condition, which suggests abnormal functioning of the autonomic nervous system and possible long-term cardiovascular effects.

Background Several operative interventions are performed to reduce the mortality and morbidity of Intracerebral hemorrhage (ICH) in the acute setting, including: craniotomy or craniectomy, placement of an external ventricular drain (EVD), placement of a ventriculo-peritoneal shunt (VPS) and stereotactic craniotomy. Infections are a major source of readmissions following ICH. We explored the association between operative interventions for ICH and 30-day readmissions for infection-related causes. Methods The Nationwide Readmissions Database contains >14 million discharges for all payers and uninsured in 2013. International Classification of Disease, Ninth Revision, Clinical Modification codes were used to identify index cases of ICH, intracranial procedures, and comorbidities. We summarized demographics and comorbidities during index admission, stratified by receipt of operative interventions. We calculated differences in means (using t-tests) and frequencies (using chi-square) by group (any intervention versus none). Top 5 causes of 30-day readmission and top 5 causes for infectious readmissions were identified. Cox regression analysis was performed for time to readmission for infectious causes. Results There were 27,739 index admissions with ICH, 13% had operative interventions. In the operative group, 45.5% underwent craniotomy, 65.4% had EVD placement and 7.6% had VPS placement. Acute cerebrovascular disease was the top cause of readmission followed by infection in the entire cohort and those with interventions. Among infectious causes of readmissions, septicemia was the largest in the intervention group (65%). In both adjusted and unadjusted models, there was significant association between ICH intervention and risk of readmission for infectious causes. Among those with operative interventions for ICH, risk of readmission with infection is double the risk in the non-intervention group. Cumulative risk of readmission was higher for infection following ICH, starting after approximately 50 days, in the intervention group (log-rank p-value Conclusions Infections and cerebrovascular complications contribute to most readmissions after ICH. There is a dose-response relationship between number of interventions and risk of infectious readmission, and this risk significantly increases after approximately 50-days.

Background: Infants with complex congenital heart disease (CCHD) often develop neurodevelopmental disabilities. Cognitive abilities are associated with vagally mediated autonomic function. Skin-to-skin contact (SSC) interventions enhance infant neurodevelopment and autonomic function in other high-risk populations. Aim: To examine the effects of a neonatal SSC intervention on learning and autonomic function in 3-month-old infants: infants with CCHD who received neonatal SSC ( n = 10), typically developing (TD) infants ( n = 16), and infants with CCHD without SSC ( n = 10). Methods: This secondary data analysis measured cognitive function using the mobile paradigm (MP), a classic measure of learning based on operant conditioning. Autonomic function was assessed with heart rate (HR) and HR variability (HRV). Data were analyzed with repeated-measures general linear mixed modeling with α = .10 for this exploratory study. Results: Learning rates were TD = 75%, cardiac-SSC = 70%, and cardiac-control = 40%. Learners demonstrated significant reductions in HRV during the MP; nonlearners exhibited no change. TD and cardiac-SSC groups exhibited increases in HR and reductions in HRV during the MP. No significant changes occurred in the cardiac-control group. Nonlinear HRV during the MP differed only in the TD group. Conclusions: Findings suggest improvements in cognitive and autonomic development in 3-month-old infants with CCHD who received neonatal SSC. Learning and autonomic function results in infants with CCHD who had not received SSC suggest reduced capacity to muster the physiologic resources to carry out this cognitive task. Findings provide preliminary evidence in support of implementation of SSC with infants with CCHD and support additional research.

Purpose Multiple myeloma (MM) is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated postgerminal B cells. It is a heterogeneous disease both at the genetic level and in terms of clinical outcome. Immunoglobulin M (IgM) MM is a rare subtype of myeloma. Similar to Waldenström macroglobulinemia (WM), patients with MM experience IgM monoclonal gammopathy; however, both diseases are distinct in terms of treatment and clinical behavior. Materials and Methods To shed light on the presentation of IgM MM, its prognosis, and its gene expression profiling, we identified and characterized 21 patients with IgM MM from our database. Results One of these patients presented with a rare IgM monoclonal gammopathy of undetermined significance that progressed to smoldering myeloma. The median survival of the 21 patients was 4.9 years, which was comparable to a matched group of patients with non-IgM MM with similar myeloma prognostic factors (age, gender, albumin, creatinine, anemia, lactate dehydrogenase, β2-microglobulin, cytogenetics abnormalities), but much less than the median survival reported for patients with WM (9 years). We identified a cluster of genes that differ in their expression profile between MM and WM and found that the patients with IgM MM displayed a gene expression profile most similar to patients with non-IgM MM, confirming that IgM MM is a subtype of MM that should be differentiated from WM. Conclusion Because the prognosis of IgM MM and WM differ significantly, an accurate diagnosis is essential. Our gene expression model can assist with the differential diagnosis in controversial cases.

OBJECTIVE Post-stroke depression (PSD) occurs in approximately one-third of ischemic stroke patients. However, there is conflicting evidence on sex differences in PSD. We sought to assess sex differences in risk and time course of PSD in US ischemic stroke (IS) patients. We hypothesized that women are at greater risk of PSD than men, and that a greater proportion of women experience PSD in the acute post-stroke phase. MATERIALS AND METHODS We conducted a retrospective cohort study of 100% de-identified data for US Medicare beneficiaries admitted for ischemic stroke from July 1, 2016 to December 31, 2017. We calculated Kaplan-Meier unadjusted cumulative risk of depression, stratified by sex, up to 1.5 years following index admission. We performed Cox regression to report the hazard ratio (HR) for diagnosis of depression up to 1.5 years post-stroke in females vs. males, adjusting for patient demographics, comorbidities, length of stay, and acute stroke interventions. RESULTS In elderly stroke patients, females (n=90,474) were 20% more likely to develop PSD than males (n=84,427) in adjusted models. Cumulative risk of depression was consistently elevated for females throughout 1.5 years of follow-up (0.2055 [95% CI 0.2013-0.2097] vs. 0.1690 [95% CI 0.1639-0.1741] (log-rank p

Objectives Stroke and post-stroke complications are associated with high morbidity, mortality, and cost. Our objective was to examine healthcare utilization and hospice enrollment for stroke patients at the end of life. Materials and methods The 2014 Nationwide Readmissions Database is a national database of > 14 million admissions. We used validated ICD-9 codes to identify fatal ischemic stroke, summarized demographics and hospitalization characteristics, and examined healthcare use within 30 days before fatal stroke admission. We used de-identified 2014 Medicare hospice data to identify stroke and non-stroke patients admitted to hospice. Results Among IS admissions in 2014 (n = 472,969), 22652 (4.8%) had in-hospital death. 28.2% with fatal IS had two or more hospitalizations in 2014. Among those with fatal IS admission, 13.0% were admitted with cerebrovascular disease within 30 days of fatal IS admission. Half of stroke patients discharged to hospice from the Medicare dataset were hospitalized with cerebrovascular disease within the thirty days prior to hospice enrollment. Within the study year, 6.9% of hospice enrollees had one or more emergency room visits, 31.7% had one or more inpatient encounters, and 5.2% had one or more nursing facility encounters (compared to 21.4%, 70.6%, and 27.2% respectively in the 30-day period prior to enrollment). Conclusions High rates of readmission prior to fatal stroke may indicate opportunity for improvement in acute stroke management, secondary prevention, and palliative care involvement as encouraged by AHA/ASA guidelines. For patients who are expected to survive 6 months or less, hospice may offer goal-concordant services for patients and caregivers who desire comfort-focused care.

Background While morbid obesity is associated with increased infection after total hip arthroplasty, little is known on the outcomes after 2-stage reimplantation for prosthetic joint infection (PJI) in this population. The purpose of this study is to evaluate the impact of morbid obesity (body mass index>40 kg/m2) on reinfection, postoperative complications, readmissions, and reoperations. Methods We conducted a retrospective review of 107 patients undergoing first time 2-stage reimplantation for PJI from 2013 to 2019. 18 patients (50% women) with body mass index>40 kg/m2 were identified. To minimize confounders, three propensity score matched cohorts were created, yielding 16 nonobese ( 40 kg/m2) patients. Outcomes were compared using chi-square or Fisher’s exact tests. All patients had minimum 12-month follow-up, with mean follow-up of 36.3, 30.1, and 40.0 months in the nonobese, obese, and morbidly obese cohorts, respectively. Results Compared with nonobese patients, morbidly obese patients had a higher rate of reinfection (0% vs 33%, P = .020 and higher likelihood of length of stay>4 days (19% vs 61%, P = .012). In addition, compared with nonobese and obese patients, morbidly obese patients had higher rate of return to the operating room for any reason (13% vs 19% vs 50%, respectively, P = .020). No differences between cohorts were found regarding complications, death, or revision surgery. Conclusion Morbidly obese patients have significantly increased risk of reinfection and reoperation after 2-stage reimplantation for PJI when compared with obese and nonobese patients. These data can be used to counsel morbidly obese patients contemplating total hip arthroplasty and supports the notion of deferring arthroplasty in this population pending optimization.

Decompressive hemicraniectomy can be life-saving for malignant middle cerebral artery acute ischemic stroke (AIS). However, utilization and outcomes for hemicraniectomy in the US are not known. We sought to analyze baseline characteristics and outcomes of patients receiving hemicraniectomy for AIS in the US.We identified adults who received hemicraniectomy for AIS, identified with validated International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9) code in the Nationwide Readmissions Database 2014. We calculated 30-day readmission rates, reasons for readmission, and procedures performed.2850 of 531,896 AIS patients (0.54%) received hemicraniectomy. Although patients receiving hemicraniectomy were more likely to be younger (57.0, 95% CI 56.0-58.0; vs 70.9, 95% CI 70.6-71.2; p 0.0001) and male (40% vs 51.2% female; p0.0001), 46.3% of patients who received hemicraniectomy were age 60 years and older. Patients 60 years or older receiving hemicraniectomy were more likely to die (29.9% vs 21.9%, p = 0.0081). Hemicraniectomy was more frequently performed at large hospitals (75.3% vs 57.7%; p 0.0001) in urban areas (99.1% vs 90.3%; p 0.0001) designated as metropolitan teaching hospitals (88.3% vs 63.4%; p 0.0001). 30-day readmissions were most commonly due to infection (31.5%), non-infectious medical complications (17.7%), and surgical complications (13.8%). These readmissions were critical.Although hemicraniectomy is used more frequently in the treatment of younger, male, ischemic stroke patients, only half of the patients receiving hemicraniectomy in 2014 were60 years old. Regardless of age, hemicraniectomy is a geographically segregated procedure, only being performed in large metropolitan teaching hospitals.

Background and Purpose: Coronavirus disease 2019 (COVID-19) has been associated with an increased incidence of thrombotic events, including stroke. However, characteristics and outcomes of COVID-19 patients with stroke are not well known. Methods: We conducted a retrospective observational study of risk factors, stroke characteristics, and short-term outcomes in a large health system in New York City. We included consecutively admitted patients with acute cerebrovascular events from March 1, 2020 through April 30, 2020. Data were stratified by COVID-19 status, and demographic variables, medical comorbidities, stroke characteristics, imaging results, and in-hospital outcomes were examined. Among COVID-19-positive patients, we also summarized laboratory test results. Results: Of 277 patients with stroke, 105 (38.0%) were COVID-19-positive. Compared with COVID-19-negative patients, COVID-19-positive patients were more likely to have a cryptogenic (51.8% versus 22.3%, P P =0.02), parietal ( P =0.002), occipital ( P =0.002), and cerebellar ( P =0.028) regions. In COVID-19-positive patients, mean coagulation markers were slightly elevated (prothrombin time 15.4±3.6 seconds, partial thromboplastin time 38.6±24.5 seconds, and international normalized ratio 1.4±1.3). Outcomes were worse among COVID-19-positive patients, including longer length of stay ( P P =0.017), and greater rate of neurological worsening during admission ( P P Conclusions: Baseline characteristics in patients with stroke were similar comparing those with and without COVID-19. However, COVID-19-positive patients were more likely to experience stroke in a lobar location, more commonly had a cryptogenic cause, and had worse outcomes.

Background and Purpose: Determine the extent of cerebrovascular expertise among the specialties of proceduralists providing endovascular thrombectomy (ET) for emergent large vessel occlusion stroke in the modern era of acute stroke among Medicare beneficiaries Methods: Retrospective cohort study using validated International Classification of Diseases, Tenth Revision , Clinical Modification codes to identify admissions with acute ischemic stroke and treatment with ET. We identified proceduralist specialty by linking the National Provider Identifier provided by Medicare to the specialty listed in the National Provider Identifier database, grouping into radiology, neurology, neurosurgery, other surgical, and internal medicine. We calculated the number of proceduralists and hospitals who performed ET, ET team specialty composition by hospital, and number of proceduralists who performed ET at multiple hospitals. Results: Forty-two percent (n=5612) of ET were performed by radiology-background proceduralists, with unclear knowledge of how many were cerebrovascular specialists. Neurosurgery- and neurology-background interventionalists performed fewer but substantial numbers of cases, accounting for 24% (n=3217) and 23% (n=3124) of total cases, respectively. ET teams included a neurology- or neurosurgery-background proceduralist at 65% (n=407) of hospitals that performed ET and included both in 26% (n=160) of teams. Conclusions: Almost two-thirds of ET teams nationwide include a neurology- or neurosurgery-background proceduralist and higher volume centers in urban areas were more likely to have neurology- or neurosurgery-background proceduralists with cerebrovascular expertise on their team. It is unclear how many radiology-background interventionalists are cerebrovascular specialists versus generalists. Significant work remains to be done to understand the impact of proceduralist specialty, training, and cerebrovascular expertise on ET outcomes.

Background and Purpose: The 2019 novel coronavirus outbreak and its associated disease (coronavirus disease 2019 [COVID-19]) have created a worldwide pandemic. Early data suggest higher rate of ischemic stroke in severe COVID-19 infection. We evaluated whether a relationship exists between emergent large vessel occlusion (ELVO) and the ongoing COVID-19 outbreak. Methods: This is a retrospective, observational case series. Data were collected from all patients who presented with ELVO to the Mount Sinai Health System Hospitals across New York City during the peak 3 weeks of hospitalization and death from COVID-19. Patients’ demographic, comorbid conditions, cardiovascular risk factors, COVID-19 disease status, and clinical presentation were extracted from the electronic medical record. Comparison was made between COVID-19 positive and negative cohorts. The incidence of ELVO stroke was compared with the pre-COVID period. Results: Forty-five consecutive ELVO patients presented during the observation period. Fifty-three percent of patients tested positive for COVID-19. Total patients’ mean (±SD) age was 66 (±17). Patients with COVID-19 were significantly younger than patients without COVID-19, 59±13 versus 74±17 (odds ratio [95% CI], 0.94 [0.81–0.98]; P =0.004). Seventy-five percent of patients with COVID-19 were male compared with 43% of patients without COVID-19 (odds ratio [95% CI], 3.99 [1.12–14.17]; P =0.032). Patients with COVID-19 were less likely to be White (8% versus 38% [odds ratio (95% CI), 0.15 (0.04–0.81); P =0.027]). In comparison to a similar time duration before the COVID-19 outbreak, a 2-fold increase in the total number of ELVO was observed (estimate: 0.78 [95% CI, 0.47–1.08], P ≤0.0001). Conclusions: More than half of the ELVO stroke patients during the peak time of the New York City’s COVID-19 outbreak were COVID-19 positive, and those patients with COVID-19 were younger, more likely to be male, and less likely to be White. Our findings also suggest an increase in the incidence of ELVO stroke during the peak of the COVID-19 outbreak.

Background and Purpose Prior studies examining sex-related risk of readmission for ischemic stroke (IS) after coronary artery bypass grafting (CABG) did not adjust for preoperative comorbidities and used small study samples that were single-center or otherwise poorly generalizable. We assessed risk of readmission for IS after CABG for females compared to males in a nationwide sample. Methods The 2013 Nationwide Readmissions Database contains data on 49% of all U.S. hospitalizations. We used population weighting to determine national estimates. Using all follow-up data up to 1 year after discharge from CABG hospitalization, we estimated Kaplan-Meier cumulative risk of IS, stratified by sex, using the log-rank test for significance. We created Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for IS readmission, with sex as the main independent variable. We ran unadjusted models and models adjusted for age, vascular risk factors, estimated severity of illness and risk of mortality, hospital characteristics, and income quartile of patient's zip code. Results An estimated 53,270 females and 147,396 males survived index CABG admission in 2013. There was a consistently elevated cumulative risk of readmission for IS after CABG for females versus males (log-rank p-value = 0.0014). In the unadjusted Cox model, the HR of IS in females vs. males was 1.35 (95% CI 1.12–1.62, p = 0.0015). The elevated risk for females remained after adjusting for severity of illness (1.30 [1.08–1.56], p = 0.0056) and risk of mortality (1.28 [1.07–1.54], p = 0.0086). This elevated risk persisted after adjusting for multiple vascular risk factors, hospital characteristics, and income quartile of patient's zip code (1.23 [1.02–1.48], p = 0.03). Conclusions We found a 23% increased risk of readmission for IS up to 1 year after CABG for females compared to males in a fully adjusted model utilizing a large, contemporary, nationwide database. Further research would clarify mechanisms of this increased risk among women.

Background and Purpose: In December 2019, an outbreak of severe acute respiratory syndrome coronavirus causing coronavirus disease 2019 (COVID-19) occurred in China, and evolved into a worldwide pandemic. It remains unclear whether the history of cerebrovascular disease is associated with in-hospital death in patients with COVID-19. Methods: We conducted a retrospective, multicenter cohort study at Mount Sinai Health System in New York City. Using our institutional data warehouse, we identified all adult patients who were admitted to the hospital between March 1, 2020 and May 1, 2020 and had a positive nasopharyngeal swab polymerase chain reaction test for severe acute respiratory syndrome coronavirus in the emergency department. Using our institutional electronic health record, we extracted clinical characteristics of the cohort, including age, sex, and comorbidities. Using multivariable logistic regression to control for medical comorbidities, we modeled the relationship between history of stroke and all-cause, in-hospital death. Results: We identified 3248 patients, of whom 387 (11.9%) had a history of stroke. Compared with patients without history of stroke, patients with a history of stroke were significantly older, and were significantly more likely to have a history of all medical comorbidities except for obesity, which was more prevalent in patients without a history of stroke. Compared with patients without history of stroke, patients with a history of stroke had higher in-hospital death rates during the study period (48.6% versus 31.7%, P Conclusions: We found that history of stroke was associated with in-hospital death among hospitalized patients with COVID-19. Further studies should confirm these results.

Background Infection may be an acute precipitant of cardiovascular events. However, the relationships between different types of infection and cardiovascular events are less known. Our objective was to determine if exposure to infections of different organ systems in different time periods increases risk of myocardial infarction or venous thromboembolism. Method We used case-crossover analysis with conditional logistic regression to estimate odds ratios (OR) for the association for each infection type during 3 case periods (30, 60, and 90 days prior to index event) compared with control periods (exactly 1 year before). Results This study had a total number of index admissions of 338,021 individuals, of which 82,986 were female; the mean age for individuals with myocardial infarction and venous thromboembolism was 68.48 years and 62.33 years, respectively. With every infection type, there was an increased likelihood of venous thromboembolism. The greatest association was for skin infections, with an OR of 5.39 (95% confidence interval, 4.08- 7.12) within the 7-day window. The association between myocardial infarction and skin infections was of lesser magnitude, with an OR of 2.89 (confidence interval, 1.97-4.24) in the 7-day exposure period. Conclusion We found a gradient of decreasing magnitudes of association with longer time periods, across the majority of infection types and cardiovascular events. This warrants potential interventions to prevent infection or cardiovascular disease prophylaxis in individuals with infection.

BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.)

International trials suggest benefit of revascularization surgery (RS) for moyamoya disease (MMD). However, nationally representative US data on demographics and outcomes after RS in MMD are lacking. To estimate causes and rates of readmission after RS for MMD. In the Nationwide Readmissions Database, index admissions for ECICB for MMD and readmissions for ischemic stroke (IS), subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH) were identified using validated International Classification of Diseases, Ninth Revision, Clinical Modification codes. We summarized demographics and comorbidities, and calculated 30-, 60-, and 90-day readmission rates per 100,000 index admissions. Among 201 index admissions for RS for MMD, mean age (SD) was 41.7 (12.6) years; 75% were female; 24% had diabetes; 53% had hypertension; 40% had hypercholesterolemia; 3% had ICH; 16% had IS; and 1% had SAH. RS was performed at large hospitals in 83%, urban hospitals in 85%, and teaching hospitals in 97%. 80% were discharged home. 34% had a readmission during follow-up. Leading reasons for readmission up to 90 days included MMD (62%), postoperative infection (10%), sickle cell crisis (4%), ischemic stroke (4%), epilepsy (2%), subdural hemorrhage (2%) and headache (2%). Readmission rates (per 100,000 index admissions) were 559 at 30 days, 1829 at 60 days, and 2027 at 90 days for IS. There were no readmissions for SAH or ICH. This analysis of nationally representative US data suggests that although readmission after RS for MMD is not uncommon, cerebral hemorrhagic events during the 90-day postoperative period are rare.

Specific diets to manage sugar malabsorption are reported to reduce clinical symptoms of irritable bowel syndrome (IBS). However, the effects of diets for malabsorbed sugars on gut microbiota signatures have not been studied, and associations with clinical outcomes in IBS have not been characterized. 22 IBS patients positively tested for either lactose-, fructose-, sorbitol- or combined malabsorptions were subjected to 2-weeks sugar elimination and subsequent 4-weeks re-introduction. 7 IBS patients tested negative for sugar malabsorption were used as controls. Nutrition and clinical symptoms were recorded throughout the study. Fecal samples were serially collected for 16S rRNA amplicon and shotgun-metagenome sequencing. Dietary intervention supervised by nutrition counseling reduced IBS symptoms during the elimination and tolerance phases. Varying clinical response rates were observed between subjects, and used to dichotomize our cohort into visual analogue scale (VAS) responders and non-responders. Alpha -and beta-diversity analyzes revealed only minor differences regarding 16S rRNA-based fecal microbiota compositions between responder and non-responder patients during baseline or tolerance phase. In shotgun-metagenome analyzes, however, we analyzed microbial metabolic pathways and found significant differences in pathways encoding starch degradation and complex amino acid biosynthesis at baseline between IBS controls and malabsorbers, and notably, between diet responder and non-responders. Faecalibacterium prausnitzii, Ruminococcus spp. and Bifidobacterium longum largely informed these metabolic pathways. Our study demonstrates that diet interventions for specific, malabsorbed carbohydrates reshaped the metagenomic composition of the gut microbiota, with a small community of bacterial taxa contributing to these changes rather than a single species.

Background and Purpose— Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke. Methods— The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V 1 , left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors. Results— Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V 1 (hazard ratio per 1000 μV*ms 1.04; 95% confidence interval, 1.001–1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT-proBNP, 1.09; 95% confidence interval, 1.03–1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67–2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84–1.10). Conclusions— In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease.

In all animals, oocytes are surrounded by an extracellular matrix upon fertilization. This matrix serves similar purposes in each animal. It functions to mediate sperm binding, to prevent polyspermy, to control the chemical environment of the embryo, and to provide physical protection to the embryo as it developes. The synthesis of the C. elegans matrix, or eggshell, begins when the oocyte enters the spermatheca and is fertilized by a single sperm. The process of eggshell synthesis is thought to take place during the completion of the maternal meiotic divisions such that the multi-layered eggshell is completed by anaphase II. The synthesis of the eggshell occurs in a hierarchical pattern in which the outermost layers are synthesized first in order to capture and retain the innermost layers as they form. Recent studies have revealed that the lipid-rich permeability barrier is distinct from the outer trilaminar eggshell. These new findings alter our previous understanding of the eggshell. This chapter aims to define each of the eggshell layers and the molecules that are known to play significant roles in their formation.

Background Heart rate variability ( HRV ) characterizes cardiac autonomic functioning. The association of HRV with stroke is uncertain. We examined whether 24‐hour HRV added predictive value to the Cardiovascular Health Study clinical stroke risk score ( CHS ‐ SCORE ), previously developed at the baseline examination. Methods and Results N=884 stroke‐free CHS participants (age 75.3±4.6), with 24‐hour Holters adequate for HRV analysis at the 1994–1995 examination, had 68 strokes over ≤8 year follow‐up (median 7.3 [interquartile range 7.1–7.6] years). The value of adding HRV to the CHS ‐ SCORE was assessed with stepwise Cox regression analysis. The CHS ‐ SCORE predicted incident stroke ( HR =1.06 per unit increment, P =0.005). Two HRV parameters, decreased coefficient of variance of NN intervals ( CV %, P =0.031) and decreased power law slope ( SLOPE , P =0.033) also entered the model, but these did not significantly improve the c‐statistic ( P =0.47). In a secondary analysis, dichotomization of CV % ( LOWCV % ≤12.8%) was found to maximally stratify higher‐risk participants after adjustment for CHS ‐ SCORE . Similarly, dichotomizing SLOPE ( LOWSLOPE HRV categories were combined (eg, HIGHCV % with HIGHSLOPE ), the c‐statistic for the model with the CHS ‐ SCORE and combined HRV categories was 0.68, significantly higher than 0.61 for the CHS ‐ SCORE alone ( P =0.02). Conclusions In this sample of older adults, 2 HRV parameters, CV % and power law slope, emerged as significantly associated with incident stroke when added to a validated clinical risk score. After each parameter was dichotomized based on its optimal cut point in this sample, their composite significantly improved prediction of incident stroke during ≤8‐year follow‐up. These findings will require validation in separate, larger cohorts.

Background and Purpose- The relationships between different infection types and stroke subtype are not well-characterized. We examined exposure to infections in different organ systems in different time periods before the acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Methods- We used the New York State Inpatient Databases and Emergency Department Databases (2006-2013). Validated International Classification of Diseases, Ninth Edition definitions identified index hospitalizations for acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, and emergency department visits and hospitalizations for infection (skin, urinary tract infection, septicemia, abdominal, and respiratory). We used case cross-over analysis with conditional logistic regression to estimate odds ratios (OR) for the association between each infection type during case periods compared with control periods 1 year before. Results- Every infection type was associated with an increased likelihood of acute ischemic stroke. The greatest association was for urinary tract infection, with OR of 5.32 (95% CI, 3.69-7.68) within the 7-day window. The magnitude of association between urinary tract infection and intracerebral hemorrhage was of lesser magnitude, with OR of 1.80 (1.04-3.11) in the 14-day exposure period and OR of 1.54 (1.23-1.94) in the 120-day exposure period. Only respiratory infection was associated with subarachnoid hemorrhage, with OR of 3.67 (1.49-9.04) in the 14-day window and 1.95 (1.44-2.64) in the 120-day window. Conclusions- All infection types were associated with subsequent acute ischemic stroke, with the greatest association for urinary tract infection.

Background and Purpose- Multiple randomized clinical trials have demonstrated the superiority of endovascular therapy (ET) for large vessel occlusion acute ischemic stroke (AIS). Few centers can provide ET, and significant debate exists about the most efficient and effective ways to provide ET. We sought to assess real-world utilization of ET, the extent to which patients are transferred from one hospital to another for therapy and the implications of transfer status on outcomes. Methods- We used the 2015 to 2016 Healthcare Cost and Utilization Project Nationwide Readmissions Database, which contains nationwide data on nearly half of US admissions. We identified index AIS admissions, vascular risk factors, and treatment with intravenous thrombolysis and ET using International Classification of Disease, Ninth Revision, and International Classification of Disease, Tenth Revision Clinical Modification codes. Main predictors of outcome were treatment with ET and whether there was an interhospital transfer during the index AIS hospitalization. Among patients with AIS readmitted within 30 days, we examined 3 main outcomes: total charges, length of stay, and in-hospital mortality. Results- A total of 23 121 AIS admissions were treated with ET and 874 229 without. Over 5% of patients who received ET were transferred during the index admission compared with2% of those not treated with ET. Length of stay and total charges were significantly higher in patients transferred (12.3 versus 9.6 days and $233 626 versus $182 881, respectively). More patients treated with ET who were not transferred to the index hospital were discharged home (25.3% versus 44.4%), and ≈25% of patients transferred for ET died during the hospitalization compared with 15.5% not transferred. Conclusions- The minority of all patients with AIS receive ET. The majority of patients who receive ET present directly to the center that performs the procedure, and those transferred for ET have higher length of stay, cost, and mortality that those not transferred.

AIMS: Premature atrial contractions (PACs) are known to trigger and predict atrial fibrillation (AF). We sought to identify the determinants of PACs and the degree to which PACs mediate the effects of established risk factors for AF. METHODS AND RESULTS: Predictors of baseline PAC frequency were examined using a Holter Study among 1392 participants in the Cardiovascular Health Study, a community-based cohort of individuals aged ≥65 years. Participants were then followed for their first diagnosis of AF. Independent predictors of PACs were identified, and the extent to which PACs might mediate the relationship between those predictors and AF was determined. The median hourly frequency of PACs was 2.7 (interquartile range 0.8–12.1). After multivariable adjustment, increasing age, increasing height, decreasing body mass index, and a history of myocardial infarction were each associated with more PACs. Regarding modifiable predictors, participants using beta-blockers had 21% less [95% confidence interval (95% CI) 9–30%, P = 0.001] and those performing at least moderate intensity exercise vs. lower intensity exercisers had 10% less (95% CI 1–18%, P = 0.03) PACs. Higher PAC frequency explained 34% (95% CI 22–57%, P

PurposeCardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson's disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation.MethodsShort-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls.ResultsBeat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls.ConclusionsIncreased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD.

Hyperhaploid clones (24-34 chromosomes) were identified in 33 patients with multiple myeloma (MM), identifying a novel numerical cytogenetic subgroup. Strikingly, all hyperhaploid karyotypes were found to harbor monosomy 17p, the single most important risk stratification lesion in MM. A catastrophic loss of nearly a haploid set of chromosomes results in disomies of chromosomes 3, 5, 7, 9, 11, 15, 18, 19, and 21, the same basic set of odd-numbered chromosomes found in trisomy in hyperdiploid myeloma. All other autosomes are found in monosomy, resulting in additional clinically relevant monosomies of 1p, 6q, 13q, and 16q. Hypotriploid subclones (58-68 chromosomes) were also identified in 11 of the 33 patients and represent a duplication of the hyperhaploid clone. Analysis of clones utilizing interphase fluorescence in-situ hybridization (iFISH), metaphase FISH, and spectral karyotyping identified either monosomy 17 or del17p in all patients. Amplification of 1q21 was identified in eight patients, demonstrating an additional high-risk marker. Importantly, our findings indicate that current iFISH strategies may be uninformative or ambiguous in the detection of these clones, suggesting this patient subgroup maybe under-reported. Overall survival for patients with hyperhaploid clones was poor, with a five-year survival rate of 23.1%. These findings identify a distinct numerical subgroup with cytogenetically defined high-risk disease.

Atrial fibrillation (AF) is likely secondary to multiple different pathophysiological mechanisms that are increasingly but incompletely understood. Motivated by the hypothesis that 3 previously described electrocardiographic predictors of AF identify distinct AF mechanisms, we sought to determine if these electrocardiographic findings independently predict incident disease. Among Cardiovascular Health Study participants without prevalent AF, we determined whether left anterior fascicular block (LAFB), a prolonged QTC, and atrial premature complexes (APCs) each predicted AF after adjusting for each other. We then calculated the attributable risk in the exposed for each electrocardiographic marker. LAFB and QTC intervals were assessed on baseline 12-lead electrocardiogram (n= 4,696). APC count was determined using 24-hour Holter recordings obtained in a random subsample (n= 1,234). After adjusting for potential confounders and each electrocardiographic marker, LAFB (hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.1 to 3.9, p= 0.023), a prolonged QTC (HR 2.5, 95% CI 1.4 to 4.3, p= 0.002), and every doubling of APC count (HR 1.2, 95% CI 1.1 to 1.3, p

Background Previous studies suggest that patients with coronary heart disease (CHD) who do not respond to treatment for depression are at higher risk of mortality than are treatment responders. The purpose of this study was to determine whether elevated nighttime heart rate (HR) and low heart rate variability (HRV), both of which have been associated with depression and with cardiac events in patients with CHD, predict poor response to depression treatment in patients with CHD. Methods Patients with stable CHD and a current major depressive episode completed 24 h ambulatory ECG monitoring and were then treated for up to 16 weeks with cognitive behavior therapy (CBT), either alone or in combination with an antidepressant. Pre-treatment HR and HRV were calculated for 124 patients who had continuous ECG from early evening to mid-morning. Results Following treatment, 64 of the 124 patients (52%) met study criteria for remission (Hamilton Rating Scale for Depression score≤7). Prior to treatment, non-remitters had higher nighttime HR (p=0.03) and lower nighttime HRV (p=0.01) than did the remitters, even after adjusting for potential confounds. Limitations Polysomnography would have provided information about objective sleep characteristics and sleep disorders. More CBT sessions and higher doses of antidepressants may have resulted in more participants in remission. Conclusions High nighttime HR and low nighttime HRV predict a poor response to treatment of major depression in patients with stable CHD. These findings may help explain why patients with CHD who do not respond to treatment are at higher risk for mortality.

Background Premature ventricular contractions (PVCs) predict heart failure and death. Data regarding modifiable risk factors for PVCs are scarce. Methods and Results We studied 1424 Cardiovascular Health Study participants randomly assigned to 24‐hour Holter monitoring. Demographics, comorbidities, habits, and echocardiographic measurements were examined as predictors of PVC frequency and, among 845 participants, change in PVC frequency 5 years later. Participants exhibited a median of 0.6 (interquartile range, 0.1–7.1) PVCs per hour. Of the more directly modifiable characteristics and after multivariable adjustment, every SD increase in systolic blood pressure was associated with 9% more PVCs (95% confidence interval [CI], 2%–17%; P =0.01), regularly performing no or low‐intensity exercise compared with more physical activity was associated with ≈15% more PVCs (95% CI, 3–25%; P =0.02), and those with a history of smoking exhibited an average of 18% more PVCs (95% CI, 3–36%; P =0.02) than did never smokers. After 5 years, PVC frequency increased from a median of 0.5 (IQR, 0.1–4.7) to 1.2 (IQR, 0.1–13.8) per hour ( P P =0.02) and a history of smoking (OR, 1.31; 95% CI, 1.02–1.68; P =0.04). Conclusions Enhancing physical activity, smoking cessation, and aggressive control of blood pressure may represent fruitful strategies to mitigate PVC frequency and PVC‐associated adverse outcomes.

The gut microbiota is altered in irritable bowel syndrome (IBS), and microbiota manipulations by diet or antibiotics can reduce its symptoms. As fecal microbiota transfer (FMT) in IBS is still controversial, we investigated the clinical and side effects of FMT in a cohort of IBS patients with recurrent, treatment refractory symptoms, and studied gut microbiota signatures.Using an observational, prospective study design, we applied FMTs from one unrelated, healthy donor to 13 IBS patients. Fecal samples of patients and the donor were analyzed by 16S ribosomal RNA amplicon sequencing.On a symptom level, primarily abdominal pain symptoms were reduced after FMT, and no adverse effects were observed. Studying the microbiome, we found an increase in alpha diversity and changes in the composition of the gut microbiota after FMT. Beta diversity changes after FMT were prominent in a subset of 7 patients with microbiota profiles coming very close to the donor. These patients also showed most pronounced visceral pain reduction. The relative abundance of Akkermansia muciniphila was inversely correlated with pain reduction in our cohort.Although exploratory in nature and with a pilot character, this study highlights the potential role of microbiota manipulations in IBS and describes a novel association of intestinal Akkermansia and pain modulation.

Neoplastic cellularity contributes to the analytic sensitivity of most present technologies for mutation detection, such that they underperform when stroma and inflammatory cells dilute a cancer specimen's variant fraction. Thus, tumor purity assessment by light microscopy is used to determine sample adequacy before sequencing and to interpret the significance of negative results and mutant allele fraction afterwards. However, pathologist estimates of tumor purity are imprecise and have limited reproducibility. With the advent of massively parallel sequencing, large amounts of molecular data can be analyzed by computational purity algorithms. We retrospectively compared tumor purity of 3 computational algorithms with neoplastic cellularity using hematoxylin and eosin light microscopy to determine which was best for clinical evaluation of molecular profiling. Data were analyzed from 881 cancer patients from a clinical trial cohort, LCCC1108 (UNCseq), whose tumors had targeted massively parallel sequencing. Concordance among algorithms was poor, and the specimens analyzed had high rates of algorithm failure partially due to variable tumor purity. Computational tumor purity estimates did not add value beyond the pathologist's estimate of neoplastic cellularity microscopy. To improve present methods, we propose a semiquantitative, clinically applicable strategy based on mutant allele fraction and copy number changes present within a given specimen, which when combined with the morphologic tumor purity estimate, guide the interpretation of next-generation sequencing results in cancer patients.

BackgroundBlacks have a lower risk of atrial fibrillation (AF) despite having more AF risk factors, but the mechanism remains unknown. Premature atrial contraction (PAC) burden is a recently identified risk factor for AF.ObjectiveThe purpose of this study was to determine whether the burden of PACs explains racial differences in AF risk.MethodsPAC burden (number per hour) was assessed by 24-hour ambulatory electrocardiographic (ECG) monitoring in a randomly selected subset of patients in the Cardiovascular Health Study. Participants were followed prospectively for the development of AF, diagnosed by study ECG and hospital admission records.ResultsAmong 938 participants (median age 73 years; 34% black; 58% female), 206 (22%) developed AF over a median follow-up of 11.0 years (interquartile range 6.1-13.4). After adjusting for age, sex, body mass index, coronary disease, congestive heart failure, diabetes, hypertension, alcohol consumption, smoking status, and study site, black race was associated with a 42% lower risk of AF (hazard ratio 0.58, 95% confidence interval [CI] 0.40-0.85; P = .005). The baseline PAC burden was 2.10 times (95% CI 1.57-2.83; P

Autonomic dysfunction represents a loss of normal autonomic control of the cardiovascular system associated with both sympathetic nervous system overdrive and reduced efficacy of the parasympathetic nervous system. Autonomic dysfunction is a strong predictor of future coronary heart disease, vascular disease, and sudden cardiac death. In the current review, we will discuss the clinical importance of autonomic dysfunction as a cardiovascular risk marker among breast cancer patients. We will review the effects of antineoplastic therapy on autonomic function, as well as discuss secondary exposures, such as psychological stress, sleep disturbances, weight gain/metabolic derangements, and loss of cardiorespiratory fitness, which may negatively impact autonomic function in breast cancer patients. Lastly, we review potential strategies to improve autonomic function in this population. The perspective can help guide new therapeutic interventions to promote longevity and cardiovascular health among breast cancer survivors.

Background In older adults with stroke, there is an increased risk of cardiovascular events in the intermediate period, up to one year after stroke. The risk of cardiovascular events in this period in young adults after stroke has not been studied. We hypothesized that in the intermediate risk period, young adults with ischemic stroke have an increased risk of recurrent stroke and a smaller increase of cardiac events. Methods Using the National Readmissions Database during the year 2013, we identified ischemic stroke admissions among those aged 18–45 years using International Classification of Disease, Ninth Revision, Clinical Modification codes to identify index vascular events and risk factors. Primary outcomes were readmission for cardiac events and stroke. Multivariable Cox proportional hazard models and Kaplan–Meier analysis were used to estimate risk of primary outcomes. Results We identified 12,392 young adults with index stroke. The readmission rate due to recurrent stroke was higher than for cardiac events (2913.3.1 vs. 1132.4 per 100,000 index hospitalizations at 90 days). There was a higher cumulative risk of both cardiac events and recurrent stroke in the presence of baseline diabetes and hypercholesterolemia. Conclusion In a large, nationally representative database, the intermediate risk of recurrent stroke after index stroke in young adults was higher than the risk of cardiac events. The presence of vascular risk factors augmented this risk but did not entirely account for it. The aggressive control of hypercholesterolemia and diabetes may play an important role in secondary prevention in young adults with stroke.

To obtain and review workforce data, given the critical demand for developmental pediatricians (DPs).Survey of demographics and professional activities of DP physician faculty at Developmental-Behavioral Pediatric (DBP) Research Network fellowship training sites.Of the eligible providers at 12 centers, 76% (n = 50) completed surveys. They were on average 50 years old and mostly female (86%), white (82%), and working full time (74%). Full timers reported a mean 50.2-hour week made up of clinical work (23.2 hours), supervision (5.9 hours), research (8.8 hours), administration (5.2 hours), teaching (1.5 hours), advocacy (1.1 hours), and other (4.3 hours). Compared with those10 years out of training, the 20 physicians (40%) ≤10 years out of fellowship were more likely to be nonwhite (p = .003). Overall faculty interest/expertise (I/E) was highest in autism (90%) and attention deficit hyperactivity disorder (ADHD; 86%). Those ≤10 years out of fellowship had more I/E in autism (p = .05) and less in chronic illness (p = .06) and parenting (p = .06). DPs practiced most frequently in a General DBP Clinic (74%), followed by clinics specific for: Autism (36%), Toddlers (22%), ADHD (20%), Infants (18%) and Preschoolers (16%). Common clinics were Autism (9), syndrome specific (9), ADHD (6), and School-Aged (5).Developmental pediatrician faculty in DBP training sites feed the pipeline of much needed DP physicians. This survey provides baseline information on the professional activities of DP faculty and found changing demographics and I/E as well as a wide variety of clinic types.

In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of “fitter” clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma., In multiple myeloma, malignant cells expand within bone marrow. Here, the authors use multi-region sequencing in patient samples to analyse spatial clonal architecture and heterogeneity, providing novel insight into multiple myeloma progression and evolution.

Background Atrial fibrillation and heart failure are 2 of the most common diseases, yet ready means to identify individuals at risk are lacking. The 12‐lead ECG is one of the most accessible tests in medicine. Our objective was to determine whether a premature atrial contraction observed on a standard 12‐lead ECG would predict atrial fibrillation and mortality and whether a premature ventricular contraction would predict heart failure and mortality. Methods and Results We utilized the CHS (Cardiovascular Health) Study, which followed 5577 participants for a median of 12 years, as the primary cohort. The ARIC (Atherosclerosis Risk in Communities Study), the replication cohort, captured data from 15 792 participants over a median of 22 years. In the CHS , multivariable analyses revealed that a baseline 12‐lead ECG premature atrial contraction predicted a 60% increased risk of atrial fibrillation (hazard ratio, 1.6; 95% CI, 1.3–2.0; P CI , 1.0–1.6; P =0.021). In the negative control analyses, neither predicted incident myocardial infarction. A premature atrial contraction was associated with a 30% increased risk of death (hazard ratio, 1.3; 95% CI, 1.1–1.5; P =0.008) and a premature ventricular contraction was associated with a 20% increased risk of death (hazard ratio, 1.2; 95% CI, 1.0–1.3; P =0.044). Similarly statistically significant results for each analysis were also observed in ARIC . Conclusions Based on a single standard ECG , a premature atrial contraction predicted incident atrial fibrillation and death and a premature ventricular contraction predicted incident heart failure and death, suggesting that this commonly used test may predict future disease.

While conventional organization of EGFR mutations in non-small cell lung cancer (NSCLC) includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to the tyrosine kinase domain (TKD) in exons 18–21, next-generation sequencing (NGS) raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. NSCLC patients at our institution who received tumor profiling with NGS from 2013 to 2015 were identified. EGFR mutations were arranged based upon their distribution relative to the TKD. In silico analysis was performed to predict non-synonymous single nucleotide polymorphism (nsSNP) pathogenicity. Of 247 patients, 43 EGFR variants were seen in 39 patients (16%). While 32 had TKD lesions demonstrable through standard testing, 7 had extra-TKD nsSNPs (7/43), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 1 carboxy-terminal (CT). Aside from known pathogenic ECD mutation G598V, 5/6 extra-TKD nsSNPs were predicted damaging with in silico analysis. Seven of 7 extra-TKD nsSNP+ patients smoked and were stage IV; 5/7 were adenocarcinoma. An adenocarcinoma patient with JM R675Q had erlotinib, 150 mg daily, added following progression of disease on carboplatin and paclitaxel and had a partial response for 4 months. No other extra-TKD nsSNP+ patient received EGFR-directed therapy. >2% NSCLC cases in our cohort had EGFR nsSNPs located outside of the TKD, representing >16% of all EGFR mutations. Extra-TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets.

Background and Purpose— Endovascular recanalization treatment for acute ischemic stroke is a complex, time-sensitive intervention. Trip-and-treat is an interhospital service delivery model that has not previously been evaluated in the literature and consists of a shared mobile interventional stroke team that travels to primary stroke centers to provide on-site interventional capability. We compared treatment times between the trip-and-treat model and the traditional drip-and-ship model. Methods— We performed a retrospective analysis on 86 consecutive eligible patients with acute ischemic stroke secondary to large vessel occlusion who received endovascular treatment at 4 hospitals in Manhattan. Patients were divided into 2 cohorts: trip-and-treat (n=39) and drip-and-ship (n=47). The primary outcome was initial door-to-puncture time, defined as the time between arrival at any hospital and arterial puncture. We also recorded and analyzed the times of last known well, IV-tPA (intravenous tissue-type plasminogen activator) administration, transfer, and reperfusion. Results— Mean initial door-to-puncture time was 143 minutes for trip-and-treat and 222 minutes for drip-and-ship ( P P =0.0887), initial door-to-recanalization was nonetheless 79 minutes faster for trip-and-treat ( P P =0.0704). Conclusions— Compared with drip-and-ship, the trip-and-treat model demonstrated shorter treatment times for endovascular therapy in our series. The trip-and-treat model offers a valid alternative to current interhospital stroke transfers in urban environments.

18F-Fluorodeoxyglucose (FDG)–positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging with background signal suppression (DWIBS) are 2 powerful functional imaging modalities in the evaluation of malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET (“PET false-negative”). The aim of this study was to describe the proportion of PET false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET false-negativity to be 11%. Neither tumor load–associated parameters, such as degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P < .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers.

Background Despite increasing evidence of a common link between bone and heart health, the relationship between bone mineral density ( BMD ) and heart failure ( HF ) risk remains insufficiently studied. Methods and Results We investigated whether BMD measured by dual‐energy x‐ray absorptiometry was associated with incident HF in an older cohort. Cox models were stratified by sex and interactions of BMD with race assessed. BMD was examined at the total hip and femoral neck separately, both continuously and by World Health Organization categories. Of 1250 participants, 442 (55% women) developed HF during the median follow‐up of 10.5 years. In both black and nonblack women, neither total hip nor femoral neck BMD was significantly associated with HF ; there was no significant interaction by race. In black and nonblack men, total hip, but not femoral neck, BMD was significantly associated with HF , with evidence of an interaction by race. In nonblack men, lower total hip BMD was associated with higher HF risk (hazard ratio, 1.13 [95% CI, 1.01–1.26] per 0.1 g/cm 2 decrement), whereas in black men, lower total hip BMD was associated with lower HF risk (hazard ratio, 0.74 [95% CI, 0.59–0.94]). There were no black men with total hip osteoporosis. Among nonblack men, total hip osteoporosis was associated with higher HF risk (hazard ratio, 2.83 [95% CI, 1.39–5.74]) compared with normal BMD . Conclusions Among older adults, lower total hip BMD was associated with higher HF risk in nonblack men but lower risk in black men, with no evidence of an association in women. Further research is needed to replicate these findings and to study potential underlying pathways.