Blacks have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) ...supplementation on blood pressure in blacks. During 2 winters from 2008 to 2010, 283 blacks (median age, 51 years) were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 international units of cholecalciferol per day. At baseline, 3 months, and 6 months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, -0.66 mm Hg for 1000 U/d, -3.4 mm Hg for 2000 U/d, and -4.0 mm Hg for 4000 U/d of cholecalciferol (-1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Within an unselected population of blacks, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among blacks, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension.
It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms ...suggestive of acute coronary syndromes.
In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes.
The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65).
In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.).
Objectives
Cerebrotendinous xanthomatosis (CTX) is a rare inherited neurodegenerative disorder in bile acid synthesis. The natural history of neurological abnormalities in CTX is not well understood. ...The object of this study was to determine neurological progression in CTX.
Methods
A literature search on PubMed for “cerebrotendinous xanthomatosis” yielded 91 publications that reported cases of CTX patients. Two independent reviewers abstracted information about the presence and age of onset of neurological abnormalities in published CTX cases. For each neurological abnormality, we estimated the probability of its onset at any given age using cumulative incidence function analysis. We also present our own case series, in which five CTX patients were evaluated.
Results
The literature search yielded 194 CTX cases (ages ranging from newborn to 67 years old). The most common neurological abnormalities were corticospinal tract abnormalities including weakness, hyperreflexia, spasticity, Babinski sign (59.8%), ataxia (58.8%), cognitive decline (46.4%), and gait difficulty (38.1%); 68 (35.0%) had baseline cognitive problems. Cumulative incidence function analysis revealed that ataxia, gait difficulties, and corticospinal tract abnormalities developed throughout life, while cognitive decline tended to develop later in life. Of the less common neurological abnormalities, seizures, psychiatric changes and speech changes developed throughout life, while parkinsonism and sensory changes tended to develop later in life. Our case series corroborated this temporal pattern of neurological abnormalities.
Conclusion
We provide estimates for the neurological progression of CTX, categorizing neurological abnormalities according to time and probability of development. Our approach may be applicable to other rare disorders.
Physiologic barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic ...priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduced metastasis, and increased both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (i) increase intratumoral drug accumulation by >10-fold, (ii) increase the duration of drug exposure above a critical therapeutic threshold, and (iii) attenuate surges in CD44 and CXCR4 expression, which mediate chemoresistance often observed after multicycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression, and drug resistance and to extend patient survival.
A biophysical priming approach overcomes key treatment barriers, significantly reduces metastases, and prolongs survival in orthotopic models of human pancreatic cancer.
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The Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial is a multicenter, randomized trial designed to assess the efficacy and safety of early neuromuscular blockade in patients with ...moderate to severe acute respiratory distress syndrome. This document provides background for interpretation of the trial results, and highlights unique design approaches that may inform future trials of acute illness. We describe the process by which ROSE was chosen as the inaugural trial of the multidisciplinary Prevention and Early Treatment of Acute Lung Injury Network, provide the trial methodology using the Consolidated Standards of Reporting Trials framework, and discuss key design challenges and their resolution. Four key design issues proved challenging-feasibility, choice of sedation depth in the control group, impact of emphasizing early treatment on enrollment criteria and protocol execution, and choice of positive end-expiratory pressure strategy. We used literature, an iterative consensus model, and internal surveys of current practice to inform design choice. ROSE will provide definitive, Consolidated Standards of Reporting Trials adherent data on early neuromuscular blockade for future patients with acute respiratory distress syndrome. Our multidisciplinary approach to trial design may be of use to other trials of acute illness. Clinical trial registered with www.clinicaltrials.gov (NCT02509078).
Use of a volume- and pressure-limited mechanical ventilation strategy improves clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, the ...extent to which tidal volumes and inspiratory airway pressures should be reduced to optimize clinical outcomes is a controversial topic. This article addresses the question, "Is there a safe upper limit to inspiratory plateau pressure in patients with ALI/ARDS?" We reviewed data from animal models with and without preexisting lung injury, studies of normal human respiratory system mechanics, and the results of five clinical trials of lung-protective mechanical ventilation strategies. We also present an original analysis of data from the largest of the five clinical trials. The available data from each of these assessments do not support the commonly held view that inspiratory plateau pressures of 30 to 35 cm H2O are safe. We could not identify a safe upper limit for plateau pressures in patients with ALI/ARDS.
To characterize the prevalence, onset, and burden of urinary and bowel dysfunction in adult patients with adrenoleukodystrophy (ALD) and to evaluate any sex differences in symptom presentation.
In ...this retrospective and prospective study, we performed medical record review (n = 103), analyzed the results of clinically indicated urodynamic testing (n = 11), and developed and distributed a symptom and quality of life (QOL) survey (n = 59).
Urinary and bowel symptoms are highly prevalent in both males (75.0%) and females (78.8%) in this population, most commonly urinary urgency, often leading to incontinence. Time to onset of first urinary or bowel symptom occurs approximately a decade earlier in males. Seventy-two percent of symptomatic patients report a limitation to QOL. Urodynamic evaluation provides evidence of three distinct mechanisms underlying lower urinary tract dysfunction: involuntary detrusor contractions (indicating uncontrolled neuronal stimulation with or without leakage), motor underactivity of the bladder, and asynergy between detrusor contraction and sphincter relaxation.
Beyond gait and balance difficulties, urinary and bowel symptoms are common in adults with ALD and impair QOL. Males are affected at a younger age but both sexes experience a higher symptom burden with age. As this population also experiences gait and balance impairment, patients with ALD are more vulnerable to urinary urgency leading to incontinence. Urodynamic evaluation may help better elucidate the pathophysiologic mechanisms underlying neurogenic lower urinary tract dysfunction, which can allow more targeted treatment.
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