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Imbalance and dizziness are disabling symptoms for many patients with vestibular schwannomas (VS) but symptom severity typically does not correlate with the vestibulo-ocular reflex (VOR) amplitude-based metrics used to assess peripheral vestibular damage. In this study, we tested the hypothesis that imbalance and dizziness in patients with VS relate to VOR metrics that are not based on response amplitude. Twenty-four patients with unilateral, sporadic VS tumors were studied, and objective (balance) and subjective (dizziness) vestibular dysfunction was quantified. The VOR was tested using two yaw-axis motion stimuli, low-frequency en-bloc sinusoidal, and high-frequency head-on-body impulsive rotations. Imbalance correlated with VOR precision (the inverse of the trial-to-trial variability) and with low-frequency VOR dynamics (quantified with the time constant), and these two metrics were also strongly correlated. Dizziness correlated with the VOR bias caused by an imbalance in static central vestibular tone, but not with dynamic VOR metrics. VOR accuracy (mean response amplitude relative to the ideal response) was not correlated with the severity of imbalance or dizziness or with measures of VOR precision or time constant. Imbalance in patients with VS, therefore, scales with VOR precision and time constant, both of which appear to reflect the central vestibular signal-to-noise ratio, but not with VOR slow-phase accuracy, which is based on the magnitude of the central vestibular signals. Dizziness was related to the presence of a static central tone imbalance but not to any VOR metrics, suggesting that abnormal perception in VS may be affected by factors that are not captured by yaw-axis VOR measurements. NEW & NOTEWORTHY The severity of symptoms associated with unilateral vestibular schwannomas (VS) is poorly correlated with standard yaw-axis vestibulo-ocular reflex (VOR) metrics that are based on response amplitude. In this study, we show that the balance and perceptual dysfunction experienced by patients with VS scales with VOR metrics that capture information about the central signal-to-noise ratio (balance) and central static tone (dizziness), but are not correlated with the VOR gain, which reflects central signal amplitude.

Aims Lung ultrasound (LUS) relies on detecting artefacts, including A-lines and B-lines, when assessing dyspnoeic patients. A-lines are horizontal artefacts and characterize normal lung, whereas multiple vertical B-lines are associated with increased lung density. We sought to assess the prevalence of A-lines and B-lines in patients with acute heart failure (AHF) and examine their clinical correlates and their relationship with outcomes. Methods and results In a prospective cohort study of adults with AHF, eight-zone LUS and echocardiography were performed early during the hospitalization and pre-discharge at an imaging depth of 18 cm. A- and B-lines were analysed separately off-line, blinded to clinical and outcome data. Of 164 patients [median age 71 years, 61% men, mean ejection fraction (EF) 40%], the sum of A-lines at baseline ranged from 0 to 19 and B-line number from 0 to 36. One hundred and fifty-six patients (95%) had co-existing A-lines and B-lines at baseline. Lower body mass index and lower chest wall thickness were associated with a higher number of A-lines (P trend Conclusions A-lines and B-lines on LUS co-exist in the vast majority of hospitalized patients with AHF. In contrast to B-lines, A-lines were not associated with adverse outcomes.

N6-methyladenosine (m6A) has been recognized as one of the most abundant and functionally relevant modifications of RNAs and plays critical roles in biological and pathological processes. Placental trophoblast dysfunction significantly contributes to the pathogenesis of preeclampsia. The present study aimed to determine if altered m6A expression occurs in placental trophoblasts in preeclampsia. Expression of m6A methyltransferase (methyltransferase like 3 (METTL3)), m6A demethylases (fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5)), and m6A reader protein, heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC1/C2), were also examined.A total of 43 placentas (20 normal term, 5 normotensive preterm, and 18 preeclamptic) were used in the study. Expression of m6A, METTL3, FTO, ALKBH5, and hnRNPC1/C2 were examined by immunostaining in villous tissue sections and/or by Western blot of total cellular protein in trophoblasts isolated from normotensive and preeclamptic placentas. Total RNA extracted from trophoblasts was used to measure m6A RNA methylation. Effects of METTL3 on m6A RNA methylation and hnRNPC1/C2 expression were assessed by transfection of METTL3 siRNA in trophoblasts from preeclamptic placentas.Expression of m6A and m6A RNA methylation were significantly increased in trophoblasts from preeclamptic vs. normotensive placentas, p 0.05. Expression of METTL3 and hnRNPC1/C2, but not FTO and ALKBH5, was significantly upregulated in trophoblasts from preeclamptic vs. normotensive placentas, p 0.01. Transfection of METTL3 siRNA significantly reduced the level of m6A RNA methylation and hnRNPC1/C2 expression in trophoblasts from preeclamptic placentas, p 0.05.The finding of increased METTL3 expression and m6A RNA methylation associated with increased hnRNPC1/C2 expression provides a new posttranscriptional mechanism that aberrant m6A modification may contribute to trophoblast dysfunction in preeclampsia.

Background Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown. Methods In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µg/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician. Results There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µg) compared with the titration-dose group (53.6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µg and 53.6 (31.1, 89.9) µg, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) µg. Conclusions These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.

Background The relationship between blood pressure and mortality in type 2 diabetes (T2DM) is controversial, with concern for increased risk associated with excessively lowered blood pressure. Methods We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline blood pressure and all-cause mortality in 5852 patients with T2DM and a recent acute coronary syndrome (ACS) who participated in the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial. Risk of death was assessed in Cox models adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, brain natriuretic peptide (BNP), urine albumin/creatinine ratio, treatment allocation and prior coronary revascularization. Results Although overall there was no significant association between systolic blood pressure (SBP) and mortality (hazard ratio per 10 mmHg lower SBP 1.05 (95% CI 0.99–1.12) P = 0.10), lower SBP was significantly associated with higher risk of death (hazard ratio per 10 mmHg lower SBP 1.13 (95% CI 1.04–1.22) P = 0.002) in 2325 patients with additional CVD (index ACS+ at least one of the following prior to randomization: myocardial infarction other than the index ACS, stroke or heart failure). In 3527 patients with only the index ACS no significant association was observed (hazard ratio per 10 mmHg lower SBP 0.95 (0.86–1.04) P = 0.26; P for interaction 0.005). Conclusions The association between blood pressure and mortality was modified by additional CVD history in patients with type 2 diabetes and a recent coronary event. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration. Trial registration ClinicalTrials.gov number NCT01147250, first posted June 22, 2010

Intermittent inflammation of the vulval pilosebaceous units is common and usually self-limiting, but some patients experience recurrent and more troublesome symptoms. There is a scarcity of information on this problem. We describe the clinical and histological features in these patients and the response to treatment. A retrospective, observational study of 16 patients with this phenomenon of recurrent, protracted folliculocentric inflammation of the vulval pilosebaceous unit was performed. Details on the clinical features, histology and response to treatment were collected. Mean age at presentation was 32 years (range 21-45). All patients reported recurrent painful papules and pustules on the labia majora and labia minora. Nine patients reported a cyclical pattern to the development of lesions, with premenstrual exacerbation being most common. Histological examination of these lesions showed a folliculocentric microabscess formation surrounded by an acute and chronic inflammatory cell infiltrate, with a focal foreign-body granulomatous reaction. All our patients responded well to tetracycline, antiandrogenic or retinoid therapy. We propose the term 'vulval acne' for this condition and propose a stepwise approach to its management. We hope to highlight this as a common but underreported entity.

Non-reassuring fetal tracing is the second leading cause of primary cesarean delivery in the United States. Prolonged fetal heart rate decelerations are non-reassuring fetal heart rate characteristics, which do not uniformly predict poor fetal outcome but can prompt obstetricians to proceed with cesarean delivery. The objective of this manuscript is to identify a strategy to reduce the primary cesarean section rate in patients with prolonged fetal heart rate decelerations in labor. This is a retrospective cohort study over a 5-year period at an academic medical center, including patients undergoing primary cesarean section following labor induction, augmentation, or spontaneous labor who were noted to have prolonged fetal heart rate deceleration(s) in the 1 h prior to the time of delivery. Two groups were compared: “crash” cesarean sections versus “emergent” cesarean sections. The primary outcome was if fetal heart tones were rechecked in the operating room prior to cesarean section incision. Secondary outcomes included maternal–fetal monitoring versus Doppler fetal heart tones in the operating room, return to baseline noted in the operating room, fetal outcomes, fetal monitoring characteristics, and anesthesia type between crash versus emergent groups. Of 1969 term singleton cesarean sections, 119 patients met our inclusion criteria (emergent group n = 80) (crash group n = 39), which accounted for 13.9% of all primary cesarean sections during the study period. The emergent group had a significantly higher rate of reassessment of fetal heart tones in the operating room n = 61 (76.2%) versus the crash group n = 15 (38.4%) (p ≤ 0.0001). There were no statistically significant differences regarding fetal outcomes between the two groups. The crash group had a higher rate of category 1 fetal heart rate tracing prior to the prolonged deceleration, a longer median prolonged deceleration, and a deeper median nadir of the prolonged deceleration; these differences were statistically significant. The prolonged-to-delivery interval was significantly shorter in the crash group (median = 15 min) than tin he emergent group (median = 33 min) (p ≤ 0.0001). The crash group also had a higher rate of general anesthesia (n = 11, 28.2%) than the emergent group (n = 6, 7.5%) (p = 0.002). The crash group was specifically investigated. Of the 15 patients with fetal heart tones rechecked in the crash group, 7 had returned to baseline in the operating room, but underwent cesarean section without fetal monitoring. Our results indicate that the practice of placing patients on fetal monitor upon arrival to the operating room prior to performing crash cesarean delivery could reduce the rate of primary cesarean deliveries performed for prolonged decelerations in labor. When fetal heart tones have returned to baseline upon arrival in the operating room, the decision to proceed with cesarean delivery can be reconsidered. However, many clinical factors must be taken into consideration, and the decision to proceed is ultimately at the discretion of the obstetrics provider.

Background: Although pleural effusions are common among patients with acute heart failure, the relevance of pleural effusion size assessed on thoracic ultrasound has not been investigated systematically. Methods: In this prospective observational study, we included patients hospitalised for acute heart failure and performed a thoracic ultrasound early after admission (thoracic ultrasound 1) and at discharge (thoracic ultrasound 2) independently of routine clinical management. A semiquantitative score was applied offline blinded to clinical findings to categorise and monitor pleural effusion size. Results: Among 188 patients (median age 72 years, 62% men, 78% white, median left ventricular ejection fraction 38%), pleural effusions on thoracic ultrasound 1 were present in 66% of patients and decreased in size during the hospitalisation in 75% based on the pleural effusion score (P Conclusion: Among patients with acute heart failure, pleural effusions are associated with other clinical, imaging and laboratory markers of congestion and improve with heart failure therapy. The prognostic relevance of persistent pleural effusions at discharge should be investigated in larger studies.

Aims Increased body mass index (BMI) is common in heart failure (HF) patients and is associated with lower levels of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). We evaluated the influence of BMI on lung ultrasonography (LUS) findings indicative of pulmonary congestion (i.e. B‐lines) in patients with chronic and acute HF (AHF). Methods and results We analysed ambulatory chronic HF (n = 118) and hospitalized AHF (n = 177) patients (mean age 70 years, 64% men, mean BMI 29 kg/m2, mean ejection fraction 42%) undergoing echocardiography and LUS in eight chest zones. B‐lines and chest wall thickness (skin to pleura) on ultrasound were quantified offline and blinded to clinical findings. NT‐proBNP was available in AHF patients (n = 167). In chronic HF, B‐line number decreased by 18% per 5 unit increase in BMI [95% confidence interval (CI) −35% to +5%, P = 0.11]. In AHF, the number of B‐lines decreased by 12% per 5 unit increase in BMI (95% CI −19% to −5%, P = 0.001), whereas NT‐proBNP concentration decreased by 28% per 5 unit increase in BMI (95% CI −40% to −16%, P 6 B‐lines were observed in half of AHF patients with severe obesity. There was an inverse relationship between B‐line number and chest wall thickness, and this association varied by chest region. Conclusions Despite an inverse relationship between B‐lines and BMI, B‐lines declined to a lesser degree than NT‐proBNP with increasing BMI. These data suggest that LUS may be useful in patients with HF despite obesity.

Background. Despite demonstrated efficacy, patient decision aids (DAs) are rarely used in clinical practice in the absence of coverage mandates. Deciding whether to pursue a left ventricular assist device (LVAD) is a major, preference-sensitive decision—ideal for exploring implementation of a DA. Methods. We conducted a type II effectiveness-implementation hybrid trial at 6 LVAD programs using a stepped-wedge cluster-randomized design. Using the RE-AIM framework, we collected both quantitative and qualitative outcomes, including a checklist collected by study staff for each enrolled patient regarding DA use and interviews with LVAD program clinicians preintervention, 6 months postintervention, and at the conclusion of the study. Results. From June 2015 to January 2017, 248 patients and their caregivers were enrolled. A total of 69 interviews were conducted with 48 clinicians at 3 time points. The DA reached 95% of eligible patients. Adoption was 100%, as all sites approached agreed to participate in the trial. Interviews revealed several themes related to the implementation of the DA: clinicians had a strong desire to ensure patients were informed and embraced the DA. Despite this, they reported communication challenges among their team that impeded implementation. Five of the 6 sites have maintained use of the DA following the trial; 1 site reported concerns about decreased procedural volume with use of the DA as a reason for discontinuation. Conclusions. In this hybrid trial, a DA for patients considering LVADs and their caregivers demonstrated high reach. Adoption and implementation were facilitated by a strong desire to ensure that patients were well informed. Future dissemination research and practice should attend to concerns about procedure volume and coverage mandates and facilitate ongoing communication at sites using the DA.

Background The influence of cutting the sub-diaphragmatic branch of the vagus nerve on heart rate variability (HRV) and inflammatory reaction to severe hemorrhagic shock has not been determined prior to this study. Methods Male Sprague–Dawley rats were divided into four groups of Sham, sub-diaphragmatic vagotomized (Vag), subacute (135 ± 2 min) hemorrhagic shock (SHS), and sub-diaphragmatic vagotomized with SHS (Vag + SHS). Hemodynamic parameters were recorded and HRV calculated during multiple phases in a conscious model of hemorrhagic shock. The expressions of TNF-α and iNOS were measured in the spleen and lung tissues at the conclusion of the protocol. Results Decreases in blood pressure during blood withdrawal were identical in the SHS and Vag + SHS groups. However, heart rate only decreased in the Nadir-1 phase of the SHS group. HRV indicated increased power in the very-low, low, and high (VLF, LF, and HF) frequency bands during the Nadir-1 phase of the SHS and Vag + SHS groups, albeit the values were higher in the SHS group. In the recovery phase, the HF bands were only lower in the SHS group. After hemorrhagic shock followed by resuscitation, the expression of TNF-α and iNOS increased in the spleen and lung of the SHS group, and the expression of these genes was significantly lower in the Vag + SHS group than in the SHS group. Conclusion Parasympathetic activity increases during the hypotensive phase of hemorrhagic shock, whereas the cardiac vagal tone decreases in the recovery phase. Sub-diapragmatic vagotomy blunts the cardiac vagal tone during hemorrhagic shock, but its effect is reversed in the recovery phase. The vagus nerve plays a role in proinflammatory responses in the lungs and spleen in subacute hemorrhagic shock followed by resuscitation.

Importance Multiple guideline-recommended therapies for heart failure with reduced ejection fraction (HFrEF) are available and promoted by performance measures. However, contemporary data on the use of these therapies are limited. Objective To evaluate trends in guideline-directed medical therapy, implantable cardioverter-defibrillator (ICD) use, and risk-adjusted mortality among patients with recent-onset HFrEF. Design, setting, and participants This cohort study analyzed claims and electronic health record data of patients with recent-onset HFrEF diagnosed at US Department of Veterans Affairs (VA) health care system facilities from July 1, 2013, through June 30, 2019. Veterans who had a history of heart transplant or used a ventricular assist device were among the patients who were excluded. Exposures Guideline-directed medical therapy (any β-blocker, guideline-recommended β-blocker [bisoprolol, carvedilol, or metoprolol succinate], angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonist, and hydralazine plus nitrate) and ICD. Main outcomes and measures Treatment rates for guideline-directed medical therapies and ICDs were calculated within 6 months of the index HFrEF date using medication fills, procedural codes for implantation and monitoring, and diagnosis codes. Risk-adjusted mortality was calculated after adjusting for baseline patient characteristics. For both treatment rates and risk-adjusted mortality, we evaluated the change over 3 periods (period 1: July 1, 2013, to June 30, 2015; period 2: July 1, 2015, to June 30, 2017; and period 3: July 1, 2017, to June 30, 2019) and variation across VA facilities. Results The final cohort comprised 144 074 eligible patients with incident HFrEF that was diagnosed between July 1, 2013, and June 30, 2019. The cohort had a mean (SD) age of 71.0 (11.4) years and was mostly composed of men (140 765 [97.7%]). Overall, changes in medical therapy rates were minimal over time, with the use of a guideline-recommended β-blocker increasing from 64.2% in 2013 to 72.0% in 2019. Rates for mineralocorticoid receptor antagonist therapy increased from 23.9% in 2013 to 26.9% in 2019, and rates for hydralazine plus nitrate therapy remained stable at 24.2% over the study period. Rates for angiotensin receptor-neprilysin inhibitor therapy increased since its introduction in 2015 but only to 22.6% in 2019. Among patients with an ICD indication, early use rates decreased over time. Substantial variation in medical therapy rates persisted across VA facilities. Risk-adjusted mortality decreased over the study period from 19.9% (95% CI, 19.6%-20.2%) in July 1, 2013, to June 30, 2015, to 18.4% (95% CI, 18.0%-18.7%) in July 1, 2017, to June 30, 2019 (OR, 0.96 per additional year; 95% CI, 0.96-0.97). Conclusions and relevance This study found only marginal improvement between 2013 and 2019 in the guideline-recommended therapy and mortality rates among patients with recent-onset HFrEF. New approaches to increase the uptake of evidence-based HFrEF treatment are urgently needed and could lead to larger reductions in mortality.

Background: Polypharmacy is associated with a poor prognosis in the elderly, however, information on the association of polypharmacy with cardiovascular outcomes in heart failure with preserved ejection fraction is sparse. This study sought to investigate the relationship between polypharmacy and adverse cardiovascular events in patients with heart failure with preserved ejection fraction. Methods: Baseline total number of medications was determined in 1758 patients with heart failure with preserved ejection fraction enrolled in the Americas regions of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), by 3 categories: nonpolypharmacy ( Results: The proportion of patients taking 5 or more medications was 92.5% (inclusive of polypharmacy [38.7%] and hyper-polypharmacy [53.8%]). Over a 2.9-year median follow-up, compared with patients with polypharmacy, hyper-polypharmacy was associated with an increased risk for the primary outcome, hospitalization for any reason and any serious adverse events in the univariable analysis, but not significantly associated with mortality. After multivariable adjustment for demographic and comorbidities, hyper-polypharmacy remained significantly associated with an increased risk for hospitalization for any reason (hazard ratio, 1.22 [95% CI, 1.05–1.41]; P =0.009) and any serious adverse events (hazard ratio, 1.23 [95% CI, 1.07–1.42]; P =0.005), whereas the primary outcome was no longer statistically significant. Conclusions: Hyper-polypharmacy was common and associated with an elevated risk of hospitalization for any reason and any serious adverse events in patients with heart failure with preserved ejection fraction. There were no significant associations between polypharmacy status and mortality.

Caregiver voices may provide cues to mobilize or calm infants. This study examined whether maternal prosody predicted changes in infants' biobehavioral state after the still face, a stressor in which the mother withdraws and reinstates social engagement. Ninety-four dyads participated in the study (infant age 4-8 months). Infants' heart rate and respiratory sinus arrhythmia (measuring cardiac vagal tone) were derived from an electrocardiogram (ECG). Infants' behavioral distress was measured by negative vocalizations, facial expressions, and gaze aversion. Mothers' vocalizations were measured via a composite of spectral analysis and spectro-temporal modulation using a two-dimensional fast Fourier transformation of the audio spectrogram. High values on the maternal prosody composite were associated with decreases in infants' heart rate (β = -.26, 95% CI: [-0.46, -0.05]) and behavioral distress (β = -.23, 95% CI: [-0.42, -0.03]), and increases in cardiac vagal tone in infants whose vagal tone was low during the stressor (1 SD below mean β = .39, 95% CI: [0.06, 0.73]). High infant heart rate predicted increases in the maternal prosody composite (β = .18, 95% CI: [0.03, 0.33]). These results suggest specific vocal acoustic features of speech that are relevant for regulating infants' biobehavioral state and demonstrate mother-infant bi-directional dynamics.

Diffusion tensor imaging (DTI) can be used to index white matter integrity of the corticospinal tract (CST) after stroke; however, the psychometric properties of DTI‐based measures of white matter integrity are unknown. The purpose of this study was to examine test–retest reliability as determined by intraclass correlation coefficients (ICC) and calculate minimal detectable change (MDC) of DTI‐based measures of CST integrity using three different approaches: a Cerebral Peduncle approach, a Probabilistic Tract approach, and a Tract Template approach. Eighteen participants with chronic stroke underwent DTI on the same magnetic resonance imaging scanner 4 days apart. For the Cerebral Peduncle approach, a researcher hand drew masks at the cerebral peduncle. For the Probabilistic Tract approach, tractography was seeded in motor areas of the cortex to the cerebral peduncle. For the Tract Template approach, a standard CST template was transformed into native space. For all approaches, the researcher performing analyses was blind to participant number and day of data collection. All three approaches had good to excellent test–retest reliability for fractional anisotropy (FA; ICCs >0.786). Mean diffusivity, axial diffusivity, and radial diffusivity were less reliable than FA. The ICC values were highest and MDC values were the smallest for the most automated approach (Tract Template), followed by the combined manual/automated approach (Probabilistic Tract) then the manual approach (Cerebral Peduncle). The results of this study may have implications for how DTI‐based measures of CST integrity are used to define impairment, predict outcomes, and interpret change after stroke.

Vestibular migraine (VM) is the most common cause of spontaneous vertigo but remains poorly understood. We investigated the hypothesis that central vestibular pathways are sensitized in VM by measuring self-motion perceptual thresholds in patients and control subjects and by characterizing the vestibulo-ocular reflex (VOR) and vestibular and headache symptom severity. VM patients were abnormally sensitive to roll tilt, which co-modulates semicircular canal and otolith organ activity, but not to motions that activate the canals or otolith organs in isolation, implying sensitization of canal-otolith integration. When tilt thresholds were considered together with vestibular symptom severity or VOR dynamics, VM patients segregated into two clusters. Thresholds in one cluster correlated positively with symptoms and with the VOR time constant; thresholds in the second cluster were uniformly low and independent of symptoms and the time constant. The VM threshold abnormality showed a frequency-dependence that paralleled the brain stem velocity storage mechanism. These results support a pathogenic model where vestibular symptoms emanate from the vestibular nuclei, which are sensitized by migraine-related brainstem regions and simultaneously suppressed by inhibitory feedback from the cerebellar nodulus and uvula, the site of canal-otolith integration. This conceptual framework elucidates VM pathophysiology and could potentially facilitate its diagnosis and treatment.

Background Patient limitations guide selection of heart failure therapies, for which indications often specify New York Heart Association Class. Objectives To determine the extent of patient‐reported limitations during daily activities and compare to New York Heart Association class assigned by providers during the same visit, and to left ventricular ejection fraction (LVEF) group. Methods and Results While waiting for their appointment, 948 patients on return visits to an ambulatory HF clinic completed a written questionnaire assessing specific activity limitations, which were compared to physician‐assigned NYHA class during the same visit. Patient‐reported limitation to perform daily activity ranged from 25% for bathing to 61% for yardwork or housework and 71% for jogging or hurrying. Most patients who did not report limitations to perform daily life activities were correctly classified as NYHA I by the physicians (76%), but 12% of the 376 patients classified as NYHA I reported limitations to showering or bathing and 73% reported limitations while doing yardwork or house work. Limitation to walking was reported by 172 patients (50%) classified as class II. Limitations to walking one block were most common in patients with LVEF ≥40% compared to patients with LVEF

Background Our objective was to evaluate the relationship between the “Make The Call, Don't Miss a Beat” national mass media campaign and emergency medical services (EMS) use among women with possible heart attack symptoms. Methods We linked campaign TV public service advertisement data with national EMS activation data for 2010 to 2014. We identified EMS activations (i.e., responses) for possible heart attack symptoms and for unintentional injuries for both women and men. We estimated the impact of the campaign on the fraction of the 1.7 to 15.9 million activations of women with possible heart attack symptoms compared with 1.9 million female activations for unintentional injuries within each EMS agency and month using quasi-binomial logistic regression controlling for time and state. Results Of the 3,175 U S. counties, 90% were exposed to the campaign. However, less than 2% of U.S. counties reached moderate TV exposure (≥300 gross rating points) during the entire campaign period. We did not observe an increase in the fraction of female activations for possible heart attack during periods or in counties with higher campaign exposure. Conclusions This mass media campaign that relied heavily on TV public service advertisements was not associated with increased EMS use by women with possible heart attack symptoms, even among counties that were more highly exposed to the campaign advertisements.

BACKGROUND: A relatively large body of evidence indicates that coping motives for cigarette smoking are associated with a number of problematic outcomes (e.g., greater smoking frequency) among adolescents. Evidence also indicates that lower distress tolerance (or higher distress intolerance) is related to higher levels of coping motives for cigarette smoking among adults and adolescents. Therefore, it is critical to improve our understanding of factors that may increase the likelihood of smoking to cope among adolescents. In addition, evidence suggests that a number of parenting behaviors may affect adolescent smoking behavior. No work to date, however, has examined the relation between parental distress intolerance and adolescent smoking motives, or adolescent smoking behavior. OBJECTIVE/METHODS: The current study involving adolescents (n = 46) and one of their parents aimed to address this gap in the literature by examining the association between parent-reported parental distress intolerance, self-reported adolescent motives for cigarette use, and self-reported adolescent cigarette smoking levels. RESULTS: Results indicated that parental distress intolerance was related to greater adolescent coping motives for cigarette smoking, but not to other motives for adolescent cigarette use. Furthermore, results indicated that parental distress intolerance was indirectly associated with higher adolescent cigarette smoking levels through adolescent coping motives for cigarette smoking. CONCLUSIONS: Parental distress intolerance is associated with coping motives for adolescent cigarette smoking. This suggests parental emotional factors may be associated with adolescent cigarette use.

We sought to determine whether gender disparities exist in the prehospital management of chest pain (CP) or out-of-hospital cardiac arrest (OHCA) among patients who accessed the emergency medical services (EMS) system.We obtained 2010-2013 data from the National Emergency Medical Services Information System and identified all EMS activations for CP or OHCA by adults 40 years of age or older. We selected American Heart Association medications and procedures to manage cardiovascular events. We stratified women and men by age (65 years vs. ≥65 years), race (White vs. Black), clinical condition (CP vs. OHCA), same EMS agency, and calendar year. We determined the gender-specific treatment proportions for each stratum and calculated the weighted percentage difference in treatment between women and men.Approximately 2.4 million CP and 284,000 OHCA activations were analyzed. Women with CP received a lower percentage of recommended treatments than men. For every 100 EMS activations by women with CP, 2.8 fewer received aspirin (95% CI, -4.8 to -0.8). The greatest gap in CP care was that women were significantly less likely to be transported using lights and sirens than men (-4.6%; 95% CI, -8.7% to -0.5%). More than 90% of OHCA activations were resuscitated; however, women were significantly less likely to be resuscitated compared with men (-1.3%; 95% CI, -2.4% to -0.2%).Small to modest disparities between otherwise similar women and men in the EMS treatment of CP and OHCA suggest the need for further evaluation and research with detailed contextual and outcome data.

Vitamin D deficiency is a widespread health problem globally and vitamin D deficiency/ insufficiency in pregnancy is a risk factor for preeclampsia, a hypertensive disorder in human pregnancy. Vitamin D elicits its biological effects through binding to its receptor VDR. In the present study, we determined maternal vascular expression of VDR and hnRNPC1/C2, a native repressor of VDR, in subcutaneous adipose tissue from women with normal pregnancy and preeclampsia. Maternal antenatal and postnatal vitamin D levels were measured. We found that hnRNPC1/C2 expression was markedly increased, while VDR expression was markedly reduced, in maternal vessel endothelium and smooth muscle cells from women with preeclampsia compared to that from normal pregnant controls. Reduced VDR expression was relevant to low maternal antenatal and postnatal vitamin D levels in women with preeclampsia. Using human umbilical vein endothelial cells (HUVECs) as an endothelial model, we further investigated the role of hnRNPC1/C2-mediated VDR expression in endothelial cells, and tested effect of hnRNPC1/C2 inhibition on endothelial response to bioactive vitamin D, 1,25(OH)

Background: Early heart failure (HF) recognition can reduce morbidity, yet HF is often initially diagnosed only after a patient clinically worsens. We sought to identify characteristics that predict diagnosis in the acute care setting versus the outpatient setting. Methods: We estimated the proportion of incident HF diagnosed in the acute care setting (inpatient hospital or emergency department) versus outpatient setting based on diagnostic codes from a claims database covering commercial insurance and Medicare Advantage between 2003 and 2019. After excluding new-onset HF potentially caused by a concurrent acute cause (eg, acute myocardial infarction), we identified demographic, clinical, and socioeconomic predictors of diagnosis setting. Patients were linked to their primary care clinicians to evaluate diagnosis setting variation across clinicians. Results: Of 959 438 patients with new HF, 38% were diagnosed in acute care. Of these, 46% had potential HF symptoms in the prior 6 months. Over time, the relative odds of acute care diagnosis increased by 3.2% annually after adjustment for patient characteristics (95% CI, 3.1%–3.3%). Acute care diagnosis setting was more likely for women compared with men (adjusted odds ratio, 1.11 [95% CI, 1.10–1.12]) and for Black patients compared with White patients (adjusted odds ratio, 1.18 [95% CI, 1.16–1.19]). The proportion of acute care diagnosis varied substantially (interquartile range: 24%–39%) among clinicians after adjusting for patient-level risk factors. Conclusions: A large proportion of first HF diagnoses occur in the acute care setting, particularly among women and Black patients, yet many had potential HF symptoms in the months before acute care visits. These results raise concerns that many HF diagnoses are missed in the outpatient setting. Earlier diagnosis could allow for timelier high-value interventions, addressing disparities and reducing the progression of HF.

Background Falls are the leading cause of fatal and nonfatal injuries among adults over 65 years old. The increase in fall mortality rates is likely multifactorial. With a lack of key drivers identified to explain rising rates of death from falls, accurate predictive modelling can be challenging, hindering evidence-based health resource and policy efforts. The objective of this work is to examine the predictive power of geographic utilization and longitudinal trends in mortality from unintentional falls amongst different demographic and geographic strata. Methods This is a nationwide, retrospective cohort study using the United States Centers for Disease Control (CDC) Web-based Injury Statistics Query and Reporting System (WISQARS) database. The exposure was death from an unintentional fall as determined by the CDC. Outcomes included aggregate and trend crude and age-adjusted death rates. Health care utilization, reimbursement, and cost metrics were also compared. Results Over 2001 to 2018, 465,486 total deaths due to unintentional falls were recorded with crude and age-adjusted rates of 8.42 and 7.76 per 100,000 population respectively. Comparing age-adjusted rates, males had a significantly higher age-adjusted death rate (9.89 vs. 6.17; p 2= 0.98; Female: + 0.22 rate/year, R2= 0.99). There were significant increases in death rates commensurate with increasing age, with the adults aged 85 years or older having the highest aggregate (201.1 per 100,000) and trending death rates (+ 8.75 deaths per 100,000/year, R2= 0.99). Machine learning algorithms using health care utilization data were accurate in predicting geographic age-adjusted death rates. Conclusions Machine learning models have high accuracy in predicting geographic age-adjusted mortality rates from health care utilization data. In the United States from 2001 through 2018, adults aged 85+ years carried the highest death rate from unintentional falls and this rate is forecasted to accelerate.

Aims:\ud We sought to examine sex differences in congestion in patients hospitalized for acute heart failure (AHF). Understanding congestive patterns in women and men with AHF may provide insights into sex differences in the presentation and prognosis of AHF patients.\ud \ud Methods and results:\ud In a prospective, two-site study in adults hospitalized for AHF, four-zone lung ultrasound (LUS) was performed at the time of echocardiography at baseline (LUS1) and, in a subset, pre-discharge (LUS2). B-lines on LUS and echocardiographic images were analysed offline, blinded to clinical information and outcomes. Among 349 patients with LUS1 data (median age 74, 59% male, and 87% White), women had higher left ventricular ejection fraction (mean 43% vs. 36%, P < 0.001), higher tricuspid annular plane systolic excursion (mean 17 vs. 15 mm, P = 0.021), and higher measures of filling pressures (median E/e′ 20 vs. 16, P < 0.001). B-line number on LUS1 (median 6 vs. 6, P = 0.69) and admission N-terminal pro-B-type natriuretic peptide levels (median 3932 vs. 3483 pg/mL, P = 0.77) were similar in women and men. In 121 patients with both LUS1 and LUS2 data, there was a similar and significant decrease in B-lines from baseline to discharge in both women and men. The risk of the composite 90 day outcome increased with higher B-line number on four-zone LUS2: unadjusted hazard ratio for each B-line tertile was 1.86 (95% confidence interval 1.08–3.20, P = 0.025) in women and 1.65 (95% confidence interval 1.03–2.64, P = 0.037) in men (interaction P = 0.72).\ud \ud Conclusions:\ud Among patients with AHF, echocardiographic markers differed between women and men at baseline, whereas B-line number on LUS did not. The dynamic changes in B-lines during a hospitalization for AHF were similar in women and men.

Background Joint hypermobility (JH) is associated with autonomic nervous system dysregulation and functional abdominal pain disorders (FAPDs). Understanding the neurophysiological processes linking these conditions can inform clinical interventions. Autonomic activity regulates gastrointestinal (GI) sensorimotor function and may be a key mechanism. The aims of this study were to examine the relation of JH with dynamic autonomic activity and parasympathetic regulation in adolescents with FAPDs and identify optimal JH cutoff scores that best index autonomic regulation in FAPDs. Methods A total of 92 adolescents with FAPDs and 27 healthy controls (age 8-18 years; 80% female) were prospectively enrolled. JH was assessed by Beighton scores. ECG recordings were conducted during supine, sitting, and standing posture challenges. ECG-derived variables-heart period (HP), respiratory sinus arrhythmia (RSA), and vagal efficiency (VE)-were analyzed using linear regression and mixed effects modeling. Key results Beighton scores of ≥4 optimally distinguished autonomic function. Adolescents with FAPD and JH had reduced VE compared to adolescents with FAPDs without JH (B = 18.88, SE = 6.25, p = 0.003) and healthy controls (B = 17.56, SE = 8.63, p = 0.044). These subjects also had lower and less dynamic RSA and HP values during posture shifts, with strongest differences in supine position and using the VE metric. Conclusions & inferences Suboptimal autonomic regulation indexed by reduced vagal efficiency may be a mechanism of symptoms in hypermobile FAPD patients with Beighton score ≥ 4. Autonomic disturbance may serve as potential intervention target for patients with JH and functional GI disorders.

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO

The mechanism of increased postprandial nonesterified fatty acid (NEFA) appearance in the circulation in impaired glucose tolerance (IGT) is due to increased adipose tissue lipolysis but could also be contributed to by reduced adipose tissue (AT) dietary fatty acid (DFA) trapping and increased "spillover" into the circulation. Thirty-one subjects with IGT (14 women, 17 men) and 29 with normal glucose tolerance (NGT, 15 women, 14 men) underwent a meal test with oral and intravenous palmitate tracers and the oral [18F]-fluoro-thia-heptadecanoic acid positron emission tomography method. Postprandial palmitate appearance (Rapalmitate) was higher in IGT versus NGT (P < 0.001), driven exclusively by Rapalmitate from obesity-associated increase in intracellular lipolysis (P = 0.01), as Rapalmitate from DFA spillover was not different between the groups (P = 0.19) and visceral AT DFA trapping was even higher in IGT versus NGT (P = 0.02). Plasma glycerol appearance was lower in IGT (P = 0.01), driven down by insulin resistance and increased insulin secretion. Thus, we found higher AT DFA trapping, limiting spillover to lean organs and in part offsetting the increase in Rapalmitate from intracellular lipolysis. Whether similar findings occur in frank diabetes, a condition also characterized by insulin resistance but relative insulin deficiency, requires further investigation (Clinicaltrials.gov: NCT04088344, NCT02808182).NEW & NOTEWORTHY We found higher adipose tissue dietary fatty acid trapping, limiting spillover to lean organs, that in part offsets the increase in appearance rate of palmitate from intracellular lipolysis in prediabetes. These results point to the adaptive nature of adipose tissue trapping and dietary fatty acid spillover as a protective mechanism against excess obesity-related palmitate appearance rate from intracellular adipose tissue lipolysis.

AIMS Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial. METHODS AND RESULTS PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate

BACKGROUND Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood.OBJECTIVES The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF.METHODS In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term.RESULTS WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF.CONCLUSIONS Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF. (c) 2021 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.

Sacubitril-Valsartan in Acute Myocardial Infarction In a randomized trial, 5661 patients with acute myocardial infarction and a reduced left ventricular ejection fraction, pulmonary congestion, or both were assigned to receive either sacubitril-valsartan or ramipril. At a median of 22 months, there was no significant difference between the two groups in the incidence of death from cardiovascular causes or incident heart failure. Background In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. Methods We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. Results A total of 5661 patients underwent randomization ; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90 ; 95% confidence interval [CI], 0.78 to 1.04 ; P=0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91 ; 95% CI, 0.78 to 1.07) ; death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87 ; 95% CI, 0.71 to 1.08) ; and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88 ; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. Conclusions Sacubitril- valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis ; PARADISE-MI ClinicalTrials.gov number, NCT02924727.)

MiR-126-3p is a prototype of an endothelial miRNA and has protective effects on endothelial cells. However, little is known about the effects of miR-126-3p on placental trophoblasts. In the present study, we tested the hypothesis that aberrant miR-126-3p expression is present in preeclamptic placenta which contributes to increased inflammatory response in trophoblasts. Placentas were obtained immediately after delivery from normotensive and preeclamptic pregnancies. Villous tissue was either fixed with formalin or used for trophoblast isolation. Trophoblast miR-126-3p expression was assessed by in situ hybridization of formalin-fixed tissue sections and by RT-PCR in cultured syncytiotrophoblasts. Culture medium was collected for measurement of IL-6, TNFα, and 8-Isoprostane production by ELISA and total cellular protein was collected for evaluation of HIF1α expression by Western blot. Effects of overexpression of miR-126-3p in trophoblasts on cytokine production were tested by transfection of pre-mir-126, a precursor of miR-126, into primary isolated trophoblasts. We found that downregulation of miR-126-3p expression was associated with increased IL-6 and TNFα production in trophoblasts from preeclamptic placentas vs. normal placentas. Moreover, transient overexpression of miR-126-3p significantly reduced IL-6 and TNFα production in trophoblasts from both normal and preeclamptic placentas. We further found that increase in miR-126-3p expression not only suppressed hypoxia-induced increases in IL-6 and TNFα production, but also attenuated hypoxia-induced increases in HIF1α expression and 8-Isoprostane production in trophoblasts cultured under hypoxic condition. These results provide plausible evidence that downregulation of miR-126-3p expression reduces anti-inflammatory and anti-oxidative stress activities in placental trophoblasts in preeclampsia.

Current clinical practice guidelines for anemia management in non–dialysis-dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises 2 global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N = 1751) had hemoglobin

Gravity is a pervasive environmental stimulus, and accurate graviception is required for optimal spatial orientation and postural stability. The primary graviceptors are the vestibular organs, which include angular velocity (semicircular canals) and linear acceleration (otolith organs) sensors. Graviception is degraded in patients with vestibular damage, resulting in spatial misperception and imbalance. Since minimal therapy is available for these patients, substantial effort has focused on developing a vestibular prosthesis or vestibular implant (VI) that reproduces information normally provided by the canals (since reproducing otolith function is very challenging technically). Prior studies demonstrated that angular eye velocity responses could be driven by canal VI-mediated angular head velocity information, but it remains unknown whether a canal VI could improve spatial perception and posture since these behaviors require accurate estimates of angular head position in space relative to gravity. Here, we tested the hypothesis that a canal VI that transduces angular head velocity and provides this information to the brain via motion-modulated electrical stimulation of canal afferent nerves could improve the perception of angular head position relative to gravity in monkeys with severe vestibular damage. Using a subjective visual vertical task, we found that normal female monkeys accurately sensed the orientation of the head relative to gravity during dynamic tilts, that this ability was degraded following bilateral vestibular damage, and improved when the canal VI was used. These results demonstrate that a canal VI can improve graviception in vestibulopathic animals, suggesting that it could reduce the disabling perceptual and postural deficits experienced by patients with severe vestibular damage.SIGNIFICANCE STATEMENTPatients with vestibular damage experience impaired vision, spatial perception, and balance, symptoms that could potentially respond to a vestibular implant (VI). Anatomic features facilitate semicircular canal (angular velocity) prosthetics but inhibit approaches with the otolith (linear acceleration) organs, and canal VIs that sense angular head velocity can generate compensatory eye velocity responses in vestibulopathic subjects. Can the brain use canal VI head velocity information to improve estimates of head orientation (e.g., head position relative to gravity), which is a prerequisite for accurate spatial perception and posture? Here we show that a canal VI can improve the perception of head orientation in vestibulopathic monkeys, results that are highly significant because they suggest that VIs mimicking canal function can improve spatial orientation and balance in vestibulopathic patients.

Introduction To determine whether pretreatment vagal efficiency (VE), respiratory sinus arrhythmia, and heart period can predict pain improvement with auricular neurostimulation in pediatric functional abdominal pain disorders. Methods A total of 92 adolescents with functional abdominal pain disorders underwent a 4-week randomized, double-blinded, sham-controlled auricular neurostimulation trial. Electrocardiogram-derived variables at baseline were used to predict pain using mixed effects modeling. Results A 3-way interaction (95% confidence intervals: 0.004-0.494) showed that the treatment group subjects with low baseline VE had lower pain scores at week 3. There was no substantial change in the placebo or high VE treatment group subjects. This effect was supported by a significant correlation between baseline VE and degree of pain reduction only in the treatment group. Discussion Impaired cardiac vagal regulation measured by VE predicts pain improvement with auricular neurostimulation.

The measurement of respiratory sinus arrythmia (RSA) in infants, children and adults is critical to the study of physiological regulation, and more recently, interpersonal physiological covariation, but it has been impeded by methods that limit its resolution to 30 s or longer. Recent analytical developments have suggested methods for studying dynamic RSA in adults, and we have extended this work to the study of infants and mothers. In the current paper, we describe a new analytical strategy for estimating RSA time series for infants and adults. Our new method provides a means for studying physiological synchrony in infant-mother dyads that offers some important advantages relative to existing methods that use inter-beat-intervals (e.g. Feldman, Magori-Cohen, Galili, Singer, & Louzoun, 2011). In the middle sections of this paper, we offer a brief tutorial on calculating RSA continuously with a sliding window and review the empirical evidence for determining the optimal window size. In order to confirm the reliability of our results, we briefly discuss testing synchrony by randomly shuffling the dyads to control for spurious correlations, and also by using a bootstrapping technique for calculating confidence intervals in the cross-correlation function. One important implication that emerges from applying this method is that it is possible to measure both positive and negative physiological synchrony and that these categorical measures are differentially predictive of future outcomes.

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function. Due to marked regional differences in characteristics and outcomes of the TOPCAT patients, with much lower events in patients enrolled in Russia/Georgia, we restricted our analyses on findings from patients enrolled from the Americas. Compared to patients without DM, patients with ITDM had approximately 2-fold increased risk for the primary end point, heart failure hospitalization, and myocardial infarction (hazard ratios: 1.80, 1.97, and 2.27, respectively) and approximately 50% increases in all-cause and CV mortality. The risks for these outcomes were also increased in patients with ITDM in comparison to patients with NITDM as well (hazard ratios: 1.63, 1.65, and 2.73, respectively, and approximately 40% increases in all-cause and CV mortality). Patients with NITDM had similar risks for the primary end point and all secondary end points as patients without DM. In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients.

Adverse intrauterine environment has been considered a predisposing factor for fetal programming in preeclampsia. Using human umbilical vein endothelial cells (HUVECs), we specifically explored if aberrant histone methylation occurs in fetal endothelial cells in preeclampsia. Strikingly, we found that increased di-, and tri-methylation of histone H3 lysine 9 (H3K9me2 and H3K9me3) expression were associated with upregulation of methyltransferase G9a and downregulation of endothelial nitric oxide synthase and CuZn-SOD expression in preeclamptic HUVECs. We further demonstrated that hypoxia-induced hypermethylation of H3K9 and reduced CuZn-SOD expression mimicked what were seen in preeclamptic HUVECs and inhibition of G9a could attenuate these hypoxia-induced adverse events. Our study was the first to identify hypermethylation status in fetal endothelial cells in preeclampsia, which provides plausible evidence that increased oxidative stress in the intrauterine environment is likely a mechanism to induce aberrant histone modification in fetal endothelial cells which may have a significant impact on fetal programming in preeclampsia.

The aim of this study was to assess the efficacy of a postoperative steroid regimen in maintaining vulvovaginal architecture and vaginal patency following surgical adhesiolysis in severe erosive lichen planus (ELP) and genital graft versus host disease (GVHD). Sixteen women applied potent topical steroids to the vulva and vagina from 48 hours after surgery. Sexual and urinary function and vulvovaginal anatomy were assessed at 6 weeks, 6, 12 and 24 months. All of the patients had failed sexual function due to vaginal stenosis. Eleven patients were unable to have cervical smears and three had associated haematocolpos. Vaginal adhesiolysis achieving complete patency occurred in all patients with stenosis. Fifteen (93.7%) patients were compliant with the regimen. After two years, 12 (75%) patients had maintained complete vaginal patency. Four patients (25%) developed vaginal restenosis. This study demonstrates that the potent topical steroids used post-operatively are very effective in maintaining vaginal patency and function. Impact statement What is already known on this subject? Potent topical steroids are the first line treatment for ELP and GVHD and have been reported to be helpful after surgery to release adhesions. What do the results of this study add? Topical steroids used immediately after surgical adhesiolysis in patients with vulvo-vaginal lichen planus and graft-versus-host disease improves the outcomes and maintains function, which can give a prolonged benefit. What are the implications of these findings for clinical practice and/or further research? The use of potent topical steroids should be considered as routine practice after surgery in erosive inflammatory disease to control inflammation and improve the long term outcomes for these patients.

Objectives This study sought to determine whether the likelihood of receiving primary intensive care unit (ICU) care by a cardiologist versus a noncardiologist was greater for Caucasians than for African Americans admitted to an ICU for heart failure (HF). The authors further evaluated whether primary ICU care by a cardiologist is associated with higher in-hospital survival, irrespective of race. Background Increasing data demonstrate an association between better HF outcomes and care by a cardiologist. It is unclear if previously noted racial differences in cardiology care persist in an ICU setting. Methods Using the Premier database, adult patients admitted to an ICU with a primary discharge diagnosis of HF from 2010 to 2014 were included. Hierarchical logistic regression models were used to determine the association between race and primary ICU care by a cardiologist, adjusting for patient and hospital variables. Cox regression with inverse probability weighting was used to assess the association between cardiology care and in-hospital mortality. Results Among 104,835 patients (80.3% Caucasians, 19.7% African Americans), Caucasians had higher odds of care by a cardiologist than African Americans (adjusted odds ratio: 1.42; 95% confidence interval: 1.34 to 1.51). Compared with a noncardiologist, primary ICU care by a cardiologist was associated with higher in-hospital survival (adjusted hazard ratio: 1.20, 95% confidence interval: 1.11 to 1.28). The higher likelihood of survival did not differ by patient race (interaction p = 0.32). Conclusions Among patients admitted to an ICU for HF, African Americans were less likely than Caucasians to receive primary care by a cardiologist. Primary care by a cardiologist was associated with higher survival for both Caucasians and African Americans.

In patients with heart failure and preserved ejection fraction (HF-PEF) randomized in the Americas as part of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, treatment with spironolactone enhanced the risk of hyperkalemia but reduced the risk of hypokalemia. We examined the clinical correlates and prognostic implications of incident hypo- and hyperkalemia during study follow-up.We defined the region-specific incidence of hypokalemia (potassium [KIn the Americas, assignment to spironolactone increased risk for hyperkalemia (hazard ratio 3.21, 95% confidence interval 2.46-4.20, P .001) and reduced risk of hypokalemia (hazard ratio 0.43, 95% confidence interval 0.34-0.55, P .001). Assignment to spironolactone, lower estimated glomerular filtration rate, higher baseline KBoth hyperkalemia and hypokalemia are associated with heightened risk for mortality in HF-PEF. Use of spironolactone in this population requires careful laboratory surveillance of K

Although pulmonary congestion can be quantified in heart failure (HF) by means of lung ultrasonography (LUS), little is known about LUS findings (B-lines) in different HF phenotypes. This prospective cohort study investigated the prevalence and clinical and echocardiographic correlates of B-lines in ambulatory HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared with hypertensive patients. We related LUS findings to 12-month HF hospitalizations and all-cause mortality.We used LUS to examine hypertensive (n = 111), HFpEF (n = 46), and HFrEF (n = 73) patients (median age 66 y, 56% male, 79% white, and median EF 55%) undergoing clinically indicated outpatient echocardiography. B-line number was quantified offline, across 8 chest zones, blinded to clinical and echocardiographic characteristics. The proportion of patients with ≥3 B-lines was lower in hypertensive patients (13.5%) compared with both HFrEF (45.2%, P .001) and HFpEF (34.8%; P = .05). HF patients with ≥3 B-lines had a higher risk of the composite outcome (age- and sex-adjusted hazard ratio 2.62, 95% confidence interval 1.15-5.96; P = .022).When performed at the time of outpatient echocardiography, LUS findings of pulmonary congestion differ between patients with known HF and those with hypertension, and may be associated with adverse outcomes.

BACKGROUND: Prior studies have shown that both heart failure (HF) and atrial fibrillation (AF) are factors that impact left atrial function and structure. However, right atrial (RA) function measured as RA emptying fraction (RAEF) on echocardiography has not been analyzed systematically in a chronic HF population. The aim of this study was to assess RA volume index (RAVI) and RAEF in patients with chronic HF and patients with hypertension (HTN) and to relate these findings to other cardiopulmonary ultrasound parameters and 12-month outcomes. METHODS AND RESULTS: In this prospective observational study, we identified 119 patients with chronic HF (64 patients without a history of AF [HF without AF], 55 with AF [HF with AF]), and 127 patients with HTN but without important cardiac disease who underwent routine outpatient transthoracic echocardiography. We found that RAEF was impaired in patients with HF without AF compared to patients with HTN (35% ±2 vs 50% ±1, P < .001), whereas RAVI did not differ between these two groups. Lower RAEF was associated with larger RAVI and higher estimated RA pressures but not with a higher degree of pulmonary congestion by lung ultrasound. Both lower RAEF and higher RAVI were associated with an increased risk of 12-month HF hospitalizations or all-cause death (age, sex, and AF adjusted HR: 4.07, 95% CI: 1.69–9.79; P = .002, vs 2.74, 95% CI: 1.15–6.54, P = .023). CONCLUSIONS: In an outpatient HF cohort, both lower RAEF and increased RAVI were associated with other markers of impaired cardiac function and 12-month adverse events.

Importance Impaired myocardial flow reserve (MFR) and stress myocardial blood flow (MBF) on positron emission tomography (PET) myocardial perfusion imaging may identify adverse myocardial characteristics, including myocardial stress and injury in aortic stenosis (AS). Objective To investigate whether MFR and stress MBF are associated with LV structure and function derangements, and whether these parameters improve after aortic valve replacement (AVR). Design, setting, and participants In this single-center prospective observational study in Boston, Massachusetts, from 2018 to 2020, patients with predominantly moderate to severe AS underwent ammonia N13 PET myocardial perfusion imaging for myocardial blood flow (MBF) quantification, resting transthoracic echocardiography (TTE) for assessment of myocardial structure and function, and measurement of circulating biomarkers for myocardial injury and wall stress. Evaluation of health status and functional capacity was also performed. A subset of patients underwent repeated assessment 6 months after AVR. A control group included patients without AS matched for age, sex, and summed stress score who underwent symptom-prompted ammonia N13 PET and TTE within 90 days. Exposures MBF and MFR quantified on ammonia N13 PET myocardial perfusion imaging. Main outcomes and measures LV structure and function parameters, including echocardiographic global longitudinal strain (GLS), circulating high-sensitivity troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), health status, and functional capacity. Results There were 34 patients with AS (1 mild, 9 moderate, and 24 severe) and 34 matched control individuals. MFR was independently associated with GLS and LV ejection fraction, (β,-0.31; P = .03; β, 0.41; P = .002, respectively). Stress MBF was associated with hs-cTnT (unadjusted β, -0.48; P = .005) and log NT-pro BNP (unadjusted β, -0.37; P = .045). The combination of low stress MBF and high hs-cTnT was associated with higher interventricular septal thickness in diastole, relative wall thickness, and worse GLS compared with high stress MBF and low hs-cTnT (12.4 mm vs 10.0 mm; P = .008; 0.62 vs 0.46; P = .02; and -13.47 vs -17.11; P = .006, respectively). In 9 patients studied 6 months after AVR, mean (SD) MFR improved from 1.73 (0.57) to 2.11 (0.50) (P = .008). Conclusions and relevance In this study, in AS, MFR and stress MBF were associated with adverse myocardial characteristics, including markers of myocardial injury and wall stress, suggesting that MFR may be an early sensitive marker for myocardial decompensation.

Respiratory sinus arrhythmia (RSA) is a quantitative metric that reflects autonomic nervous system regulation and provides a physiological marker of attentional engagement that supports cognitive and affective regulatory processes. RSA can be added to executive function (EF) assessments with minimal participant burden because of the commercial availability of lightweight, wearable electrocardiogram (ECG) sensors. However, the inclusion of RSA data in large data collection efforts has been hindered by the time-intensive processing of RSA. In this study we evaluated the performance of an automated RSA-scoring method in the context of an EF study in preschool-aged children. The absolute differences in RSA across both scoring methods were small (mean RSA differences = -0.02-0.10), with little to no evidence of bias for the automated relative to the hand-scoring approach. Moreover, the relative rank-ordering of RSA across both scoring methods was strong (rs = .96-.99). Reliable changes in RSA from baseline to the EF task were highly similar across both scoring methods (96%-100% absolute agreement; Kappa = .83-1.0). On the basis of these findings, the automated RSA algorithm appears to be a suitable substitute for hand-scoring in the context of EF assessment.

Background Cognitive dysfunction in major depressive disorder (MDD) is identified as a primary therapeutic target; no current treatment is approved for the treatment of cognitive dysfunction in MDD. We examined whether intranasal insulin offered a beneficial effect across measures of cognitive function in adults with MDD. Methods Thirty-five adults (18–65 years of age: 47.09±9.89) meeting criteria for a major depressive episode as per the Diagnostic and Statistical Manual (DSM)-IV-Treatment Revised were included in this randomized, double blind, placebo-controlled, crossover design study. Subjects were not stratified based on baseline cognitive deficit. Subjects were randomized to 4 weeks of either intranasal insulin 40 International Units (IU) taken four times a day (i.e., morning, afternoon, evening, and before bed) (QID) (n=19) or placebo (n=16). Results No between group differences were observed in change from baseline on total Montgomery Asberg Depression Rating Scale (MADRS) score (25.98±2.81), in either of the Positive or Negative subscales of the Positive and Negative Affect Schedule (PANAS), or on a global index of neurocognition. The possibility of practice and/or carry over effect could not be excluded. Methodological refinement (e.g., stratification of subjects based on baseline cognitive deficit) may have augmented assay sensitivity. Conclusion Intranasal insulin did not demonstrate statistically significant improvements on overall mood, aspects of emotional processing, neurocognitive function, or self-reported quality of life patient reported outcomes.

Background: The contemporary prognostic value of the physical examination— beyond traditional risk factors including natriuretic peptides, risk scores, and symptoms—in heart failure (HF) with reduced ejection fraction is unknown. We aimed to determine the association between physical signs of congestion at baseline and during study follow-up with quality of life and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion. Methods: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and third heart sound) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up and whether improvement in congestion is related to changes in clinical outcomes and quality of life, assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores. Results: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2% of patients, respectively. Patients with baseline congestion were older, more often female, had higher MAGGIC risk scores (Meta-Analysis Global Group in Chronic Heart Failure) and lower Kansas City Cardiomyopathy Questionnaire overall summary scores ( P P P =0.16 for interaction), and treatment with the drug improved congestion to a greater extent than did enalapril ( P =0.011). Each 1-sign reduction was independently associated with a 5.1 (95% CI, 4.7–5.5) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary scores. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion ( P Conclusions: In HF with reduced ejection fraction, the physical exam continues to provide significant independent prognostic value even beyond symptoms, natriuretic peptides, and Meta-Analysis Global Group in Chronic Heart Failure risk score. Sacubitril/valsartan improved congestion to a greater extent than did enalapril. Reducing congestion in the outpatient setting is independently associated with improved quality of life and reduced cardiovascular events, including mortality. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01035255.