by
Werner F. Blum;
Jurgen Klammt;
Serge Amselem;
Heike M. Pfaeffle;
Marie Legendre;
Marie-Laure Sobrier;
Marie-Pierre Luton;
Christopher J. Child;
Christine Jones;
Alan G. Zimmermann;
Charmian A. Quigley;
Gordon B. Cutler;
Cheri L. Deal;
Jan Lebl;
Ron G. Rosenfeld;
John Parks;
Roland W. Pfaeffle
Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods: The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS; Clinical Trial Registry Number: NCT01088412) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. Findings: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3-6 μg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean ± SD 3.4 ± 1.4) was greater than in non-carriers (2.0 ± 1.4; P <.001) and in patients with non-GHD short stature. Interpretation: DNA testing for mutations in children with severe GHD shows a positive finding in approximately 10%. Phenotypes of mutation carriers can be variable. The benefit for clinical practice justifies DNA testing as an important component in the diagnostic work-up of patients with severe GHD. Fund: Eli Lilly and Company, Indianapolis, IN, USA. ClinicalTrials.com registration: NCT01088412.
OBJECTIVES::
Measurements of extravascular lung water (EVLW) correlate to the degree of pulmonary edema and have substantial prognostic information in critically ill patients. Prior studies using single indicator thermodilution have reported that 21% to 35% of patients with clinical acute respiratory distress syndrome (ARDS) have normal EVLW (<10 mL/kg). Given that lung size is independent of actual body weight, we sought to determine whether indexing EVLW to predicted or adjusted body weight affects the frequency of increased EVLW in patients with ARDS. DESIGN:: Prospective, observational cohort study. SETTING:: Medical and surgical intensive care units at two academic hospitals. PATIENTS:: Thirty patients within 72 hrs of meeting American-European Consensus Conference definition of ARDS and 14 severe sepsis patients without ARDS. INTERVENTIONS:: None. MEASUREMENT AND MAIN RESULTS:: EVLW was measured for 7 days by PiCCO transpulmonary thermodilution; 225 measurements of EVLW indexed to actual body weight (ActBW) were compared with EVLW indexed to predicted body weight (PBW) and adjusted body weight (AdjBW). Mean EVLW indexed to ActBW was 12.7 mg/kg for ARDS patients and 7.8 mg/kg for non-ARDS sepsis patients (p < .0001). In all patients, EVLW increased an average of 1.1 ± 2.1 mL/kg when indexed to AdjBW and 2.0 ± 4.1 mL/kg when indexed to PBW. Indexing EVLW to PBW or AdjBW increased the proportion of ARDS patients with elevated EVLW (each p < .05) without increasing the frequency of elevated EVLW in non-ARDS patients. EVLW indexed to PBW had a stronger correlation to Lung Injury Score (r = .39 vs. r = .17) and Pao2/Fio2 ratio (r = .25 vs. r = .10) than did EVLW indexed to ActBW. CONCLUSIONS:: Indexing EVLW to PBW or AdjBW reduces the number of ARDS patients with normal EVLW and correlates better to Lung Injury Score and oxygenation than using ActBW. Studies are needed to confirm the presumed superiority of this method for diagnosing ARDS and to determine the clinical treatment implications.
by
Robert Ward;
Shiva Ponamgi;
Christopher DeSimone;
Stephen English;
David O Hodge;
Joshua P Slusser;
Jonathan Graff-Radford;
Alejandro A Rabinstein;
Sameul J Asirvatham;
David Holmes
Objective: To determine the utility of the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly) and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age, Diabetes, previous Stroke/transient ischemic attack–VAScular disease) scores among patients on anticoagulation (AC) therapy for atrial fibrillation (AF) who have evidence of cerebral amyloid angiopathy (CAA). Patients and Methods: Patients older than 55 years with a diagnosis of AF who had a nontraumatic intracerebral hemorrhage (ICH) while on AC therapy between 1995 and 2016 were identified using the Rochester Epidemiology Project Database. Medical records were reviewed, including imaging of the brain, to identify baseline characteristics, AC use, and outcomes. Results: A total of 65 patients were identified (mean age, 81.3 years); 35 (53.8%) had evidence of possible/probable CAA. Mean HAS-BLED score in the CAA group was significantly lower (2.1) than that of the non-CAA group (2.9; P<.001). Mortality after ICH, adjusted for HAS-BLED scores, was not significantly different among patients with and without CAA. Sixteen patients restarted on AC therapy after ICH; CHA2DS2-VASc scores were no different between this group and those who were not restarted. Among patients with CAA, the overall rate of ICH recurrence was 8.6% over 93.5 person-years of follow-up. Among patients with CAA, the rate of ICH recurrence was 3.2 per 100 patient-years, higher than their HAS-BLED scores would predict (1.9 bleeds/100 patient-years). Conclusion: HAS-BLED scores were lower in patients who had evidence of CAA compared with those without, suggesting underestimation of ICH risk in patients with CAA. CHA2DS2-VASc scores did not affect resumption of AC therapy. ICH recurrence was higher in patients with CAA than their HAS-BLED scores predicted. Current risk assessment scoring systems do not accurately account for CAA in patients with AF on AC.
Introduction: Patients with distributive shock who require high dose vasopressors have a high mortality. Angiotensin II (ATII) may prove useful in patients who remain hypotensive despite catecholamine and vasopressin therapy. The appropriate dose of parenteral angiotensin II for shock is unknown. Methods: In total, 20 patients with distributive shock and a cardiovascular Sequential Organ Failure Assessment score of 4 were randomized to either ATII infusion (N =10) or placebo (N =10) plus standard of care. ATII was started at a dose of 20 ng/kg/min, and titrated for a goal of maintaining a mean arterial pressure (MAP) of 65 mmHg. The infusion (either ATII or placebo) was continued for 6 hours then titrated off. The primary endpoint was the effect of ATII on the standing dose of norepinephrine required to maintain a MAP of 65 mmHg. Results: ATII resulted in marked reduction in norepinephrine dosing in all patients. The mean hour 1 norepinephrine dose for the placebo cohort was 27.6 ± 29.3 mcg/min versus 7.4 ± 12.4 mcg/min for the ATII cohort (P =0.06). The most common adverse event attributable to ATII was hypertension, which occurred in 20% of patients receiving ATII. 30-day mortality for the ATII cohort and the placebo cohort was similar (50% versus 60%, P =1.00). Conclusion: Angiotensin II is an effective rescue vasopressor agent in patients with distributive shock requiring multiple vasopressors. The initial dose range of ATII that appears to be appropriate for patients with distributive shock is 2 to 10 ng/kg/min. Trial registration: Clinicaltrials.gov NCT01393782. Registered 12 July 2011.
Objective: This report describes three patients with Ebola virus disease who were treated in the United States and developed for severe critical illness and multiple organ failure secondary to Ebola virus infection. The patients received mechanical ventilation, renal replacement therapy, invasive monitoring, vasopressor support, and investigational therapies for Ebola virus disease.
Data Sources: Patient medical records from three tertiary care centers (Emory University Hospital, University of Nebraska Medical Center, and Texas Health Presbyterian Dallas Hospital).
Study Selection: Not applicable.
Data Extraction: Not applicable.
Data Synthesis: Not applicable.
Conclusion: In the severe form, patients with Ebola virus disease may require life-sustaining therapy, including mechanical ventilation and renal replacement therapy. In conjunction with other reported cases, this series suggests that respiratory and renal failure may occur in severe Ebola virus disease, especially in patients burdened with high viral loads. Ebola virus disease complicated by multiple organ failure can be survivable with the application of advanced life support measures. This collective, multicenter experience is presented with the hope that it may inform future treatment of patients with Ebola virus disease requiring critical care treatment.
IMPORTANCE Diabetes prevention is imperative to slowworldwide growth of diabetes-related morbidity and mortality. Yet the long-term efficacy of prevention strategies remains unknown. OBJECTIVE To estimate aggregate long-term effects of different diabetes prevention strategies on diabetes incidence. DATA SOURCES Systematic searches of MEDLINE, EMBASE, Cochrane Library, andWeb of Science databases. The initial search was conducted on January 14, 2014, and was updated on February 20, 2015. Search terms included prediabetes, primary prevention, and risk reduction. STUDY SELECTION Eligible randomized clinical trials evaluated lifestyle modification (LSM) and medication interventions (>6 months) for diabetes prevention in adults (age ≥18 years) at risk for diabetes, reporting between-group differences in diabetes incidence, published between January 1, 1990, and January 1, 2015. Studies testing alternative therapies and bariatric surgery, as well as those involving participants with gestational diabetes, type 1 or 2 diabetes, and metabolic syndrome, were excluded. DATA EXTRACTION AND SYNTHESIS Reviewers extracted the number of diabetes cases at the end of active intervention in treatment and control groups. Random-effects meta-analyses were used to obtain pooled relative risks (RRs), and reported incidence rates were used to compute pooled risk differences (RDs). MAIN OUTCOMES AND MEASURES The main outcomewas aggregate RRs of diabetes in treatment vs control participants. Treatment subtypes (ie, LSM components, medication classes) were stratified. To estimate sustainability, post-washout and follow-up RRs for medications and LSM interventions, respectively, were examined. RESULTS Forty-three studies were included and pooled in meta-analysis (49 029 participants; mean [SD] age, 57.3 [8.7] years; 48.0% [n = 23 549] men): 19 tested medications; 19 evaluated LSM, and 5 tested combined medications and LSM. At the end of the active intervention (range, 0.5-6.3 years), LSM was associated with an RR reduction of 39% (RR, 0.61; 95% CI, 0.54-0.68), and medications were associated with an RR reduction of 36% (RR, 0.64; 95% CI, 0.54-0.76). The observed RD for LSM and medication studies was 4.0 (95% CI, 1.8-6.3) cases per 100 person-years or a number-needed-to-treat of 25. At the end of the washout or follow-up periods, LSM studies (mean follow-up, 7.2 years; range, 5.7-9.4 years) achieved an RR reduction of 28% (RR, 0.72; 95% CI, 0.60-0.86); medication studies (mean follow-up, 17 weeks; range, 2-52 weeks) showed no sustained RR reduction (RR, 0.95; 95% CI, 0.79-1.14). CONCLUSIONS AND RELEVANCE In adults at risk for diabetes, LSM and medications (weight loss and insulin-sensitizing agents) successfully reduced diabetes incidence. Medication effects were short lived. The LSM interventions were sustained for several years; however, their effects declined with time, suggesting that interventions to preserve effects are needed.
Introduction A substantial share of urban Indians with diagnosed hypertension do not take regular treatment, potentially due to poor knowledge of hypertension consequences and treatment options. We describe hypertension knowledge and beliefs, treatment patterns, and reported reasons for treatment non-use among adults with diagnosed hypertension in Chennai, India. Methods We collected data on 833 adults ages 30+ with physician diagnosed hypertension using a door-to-door household survey within randomly selected wards of Chennai. We described the proportion of individuals who were not taking daily medications and their reported reasons for not doing so. Next, we described individuals' knowledge of hypertension consequences and how to control blood pressure (BP) and assessed the association between knowledge and daily treatment use. Results Over one quarter (28% (95% CI 25% to 31%)) of diagnosed individuals reported not taking daily treatment. The largest proportion (18% (95% CI 16% to 21%)) were individuals who had discontinued prior treatment use. The primary reason individuals reported for non-daily use was that their BP had returned to normal. Just 23% (95% CI 20% to 26%) of individuals listed BP medications as the most effective way to reduce BP; however, these individuals were 11% points (95% CI 4% to 19%) more likely to take daily medications. Conversely, 43% (95% CI 40% to 47%) of individuals believed that BP medications should be stopped from time to time and these individuals were 15% points (95% CI -0.21 to -0.09) less likely to take daily treatment. While awareness of the consequences of hypertension was poor, we found no evidence that it was associated with taking daily medications. Conclusions There were large gaps in consistency of BP medication use which were strongly associated with knowledge about BP medications. Further research is needed to identify whether addressing beliefs can improve daily treatment use among individuals with diagnosed hypertension.
BACKGROUND: Urea transporters (UTs) are important in urine concentration and in urea recycling, and UT-B has been implicated in both. In kidney, UT-B was originally localized to outer medullary descending vasa recta, and more recently detected in inner medullary descending vasa recta. Endogenously produced microRNAs (miRs) bind to the 3'UTR of genes and generally inhibit their translation, thus playing a pivotal role gene regulation. METHODS: Mice were dehydrated for 24 hours then sacrificed. Inner and outer medullas were analyzed by polymerase chain reaction (PCR) and quantitative PCR for miRNA expression and analyzed by western blotting for protein abundance. RESULTS: MiRNA sequencing analysis of mouse inner medullas showed a 40% increase in miRNA-200c in dehydrated mice compared with controls. An in silico analysis of the targets for miR-200c revealed that miRNA-200c could directly target the gene for UT-B. PCR confirmed that miR-200c is up-regulated in the inner medullas of dehydrated mice while western blot showed that UT-B protein abundance was down-regulated in the same portion of the kidney. However, in the outer medulla, miR-200c was reduced and UT-B protein was increased in dehydrated mice. CONCLUSIONS: This is the first indication that UT-B protein and miR-200c may each be differentially regulated by dehydration within the kidney outer and inner medulla. The inverse correlation between the direction of change in miR-200c and UT-B protein abundance in both the inner and outer medulla suggests that miR-200c may be associated with the change in UT-B protein in these 2 portions of the kidney medulla.