Search

Diarrheal disease accounts for more than one million deaths annually in patients over 5 years of age. Although most patients can be managed with oral rehydration solution, patients with severe dehydration require resuscitation with intravenous fluids. Scoring systems to assess dehydration have been empirically derived and validated in children under 5 years, but none have been validated for patients over 5 years. In this study, a prospective cohort of 2,172 patients over 5 years presenting with acute diarrhea to International Centre for Diarrhoeal Disease Research, Dhaka Hospital, Bangladesh, were assessed for clinical signs of dehydration. The percent difference between presentation and posthydration stable weight determined severe (≥ 9%), some (3–9%), or no (

Objectives Few studies have evaluated determinants of multidrug-resistant (MDR) Vibrio cholerae O1 in older children and adults. This study aimed to characterize the prevalence of MDR V. cholerae O1 and associated risk factors among patients over five years of age in Bangladesh. Methods Stool culture and antimicrobial susceptibility testing were performed as a part of a larger study at Dhaka Hospital in Bangladesh from March 2019–March 2020. Univariate statistics and multiple logistic regression were used to assess the association between a range of variables and MDR V. cholerae O1. Results MDR was found in 175 of 623 (28.1%) V. cholerae O1 isolates. High levels of resistance were found to erythromycin (99.2%), trimethoprim-sulfamethoxazole (99.7%), and ampicillin (88.9%), while susceptibility was high to tetracyclines (99.7%), azithromycin (99.2%), ciprofloxacin (99.8%), and cephalosporins (98.6%). MDR was associated with prior antibiotic use, longer transport time to hospital, higher income, non-flush toilet use, greater stool frequency, lower blood pressure, lower mid-upper arm circumference, and lower percent dehydration. Conclusions MDR V. cholerae O1 was common among patients over five in an urban hospital in Bangladesh. Significant factors associated with MDR may be actionable in identifying patients with a high likelihood of MDR.

In 2016, diarrheal disease was the eighth leading cause of mortality globally accounting for over 1.6 million deaths with the majority of deaths in adults and children over 5 years. This study aims to investigate the clinical, sociodemographic, and environmental risk factors associated with common bacterial acute diarrhea among adults and children over 5. Data were collected from March 2019 to March 2020 in patients over 5 years presenting with acute gastroenteritis at icddr,b. Stool samples were collected from each patient for culture and polymerase chain reaction (PCR) testing. Bivariate associations between independent variables and stool-testing indicating bacterial etiology were calculated. This analysis included 2,133 diarrheal patients of whom a bacterial enteropathogen was identified in 1,537 (72%). Detection of bacteria was associated with: younger age (OR 0.92; 95% CI: 0.88–0.96), lower mean arterial pressure (OR 0.84; 95% CI: 0.79–0.89), heart rate (OR 1.06; 95% CI: 1.01–1.10), percentage dehydration (OR 1.33; 95% CI: 1.13–1.55), respiration rate (OR 1.23; 95% CI: 1.04–1.46), lower mid-upper arm circumference (OR 0.97; 95% CI: 0.94–0.99), confused/lethargic mental status (OR 1.85; 95% CI: 1.11–3.25), rice watery stool (OR 1.92; 95% CI: 1.54–2.41), and vomiting more than three times in the past 24 hours (OR 1.30; 95% CI: 1.06–1.58). Higher monthly income (OR 0.92; 95% CI: 0.86–0.98), > 8 years of education (OR 0.79; 95% CI: 0.63–1.00), and having more than five people living at home (OR 0.80; 95% CI: 0.66–0.98) were associated with lower odds of bacterial diarrhea. These findings may help guide the development of predictive tools to aid in identifying patients with bacterial diarrhea for timely and appropriate use of antibiotics.

Objectives We propose a one-shot, privacy-preserving distributed algorithm to perform logistic regression (ODAL) across multiple clinical sites. Materials and Methods ODAL effectively utilizes the information from the local site (where the patient-level data are accessible) and incorporates the first-order (ODAL1) and second-order (ODAL2) gradients of the likelihood function from other sites to construct an estimator without requiring iterative communication across sites or transferring patient-level data. We evaluated ODAL via extensive simulation studies and an application to a dataset from the University of Pennsylvania Health System. The estimation accuracy was evaluated by comparing it with the estimator based on the combined individual participant data or pooled data (ie, gold standard). Results Our simulation studies revealed that the relative estimation bias of ODAL1 compared with the pooled estimates was Conclusions This study demonstrates that ODAL is privacy-preserving and communication-efficient with small bias and high statistical efficiency.

Personalized nutrition (PN) approaches have been shown to help drive behavior change and positively influence health outcomes. This has led to an increase in the development of commercially available PN programs, which utilize various forms of individual-level information to provide services and products for consumers. The lack of a well-accepted definition of PN or an established set of guiding principles for the implementation of PN creates barriers for establishing credibility and efficacy. To address these points, the North American Branch of the International Life Sciences Institute convened a multidisciplinary panel. In this article, a definition for PN is proposed: "Personalized nutrition uses individual-specific information, founded in evidence-based science, to promote dietary behavior change that may result in measurable health benefits." In addition, 10 guiding principles for PN approaches are proposed: 1) define potential users and beneficiaries; 2) use validated diagnostic methods and measures; 3) maintain data quality and relevance; 4) derive data-driven recommendations from validated models and algorithms; 5) design PN studies around validated individual health or function needs and outcomes; 6) provide rigorous scientific evidence for an effect on health or function; 7) deliver user-friendly tools; 8) for healthy individuals, align with population-based recommendations; 9) communicate transparently about potential effects; and 10) protect individual data privacy and act responsibly. These principles are intended to establish a basis for responsible approaches to the evidence-based research and practice of PN and serve as an invitation for further public dialog. Several challenges were identified for PN to continue gaining acceptance, including defining the health–disease continuum, identification of biomarkers, changing regulatory landscapes, accessibility, and measuring success. Although PN approaches hold promise for public health in the future, further research is needed on the accuracy of dietary intake measurement, utilization and standardization of systems approaches, and application and communication of evidence.

Objective To evaluate diagnostic tests, analysts use meta-analyses to provide inputs to parameters in decision models. Choosing parameter estimands from meta-analyses requires understanding the meta-analytic and decision-making contexts. Study Design and Setting We expand on an analysis comparing positron emission tomography (PET), PET with computed tomography (PET/CT), and conventional workup (CW) in women with suspected recurrent breast cancer. We discuss Bayesian meta-analytic summaries (posterior mean over a set of existing studies, posterior estimate in an existing study, posterior predictive mean in a new study) used to estimate diagnostic test parameters (prevalence, sensitivity, specificity) needed to calculate quality-adjusted life years in a decision model contextualizing PET, PET/CT, and CW. Results The mean and predictive mean give similar estimates, but the latter displays greater uncertainty. Namely, PET/CT outperforms CW on average but may not do better than CW when implemented in future settings. Conclusion Selecting estimands for decision model parameters from meta-analyses requires understanding the relationship between decision settings and meta-analysis studies' settings, specifically whether the former resemble one or all study settings or represents new settings. We provide an algorithm recommending appropriate estimands as input parameters in decision models for diagnostic tests to obtain output parameters consistent with the decision context.

Diarrheal diseases lead to an estimated 1.3 million deaths each year, with the majority of those deaths occurring in patients over five years of age. As the severity of diarrheal disease can vary widely, accurately assessing dehydration status remains the most critical step in acute diarrhea management. The objective of this study is to empirically derive clinical diagnostic models for assessing dehydration severity in patients over five years with acute diarrhea in low resource settings. We enrolled a random sample of patients over five years with acute diarrhea presenting to the icddr,b Dhaka Hospital. Two blinded nurses independently assessed patients for symptoms/signs of dehydration on arrival. Afterward, consecutive weights were obtained to determine the percent weight change with rehydration, our criterion standard for dehydration severity. Full and simplified ordinal logistic regression models were derived to predict the outcome of none (9%) dehydration. The reliability and accuracy of each model were assessed. Bootstrapping was used to correct for over-optimism and compare each model’s performance to the current World Health Organization (WHO) algorithm. 2,172 patients were enrolled, of which 2,139 (98.5%) had complete data for analysis. The Inter-Class Correlation Coefficient (reliability) was 0.90 (95% CI = 0.87, 0.91) for the full model and 0.82 (95% CI = 0.77, 0.86) for the simplified model. The area under the Receiver-Operator Characteristic curve (accuracy) for severe dehydration was 0.79 (95% CI: 0.76–0.82) for the full model and 0.73 (95% CI: 0.70, 0.76) for the simplified model. The accuracy for both the full and simplified models were significantly better than the WHO algorithm (p, Author summary More than a million adults and older children die each year from diarrhea, with the vast majority living in low- and middle-income countries. Accurately assessing hydration status remains the most critical step in caring for these patients. While most patients with diarrhea can be managed safely at home, a small proportion will have severe dehydration and require intravenous fluid in a hospital setting to prevent organ damage and death. Despite dramatic improvements in diarrhea care around the world over the past several decades, there are still no evidence-based tools that doctors and nurses in low resource settings can use to determine an adult patient’s hydration status. Our study collected data on more than two thousand patients with acute diarrhea over the age of five years at Dhaka Hospital in Bangladesh. Using artificial intelligence techniques, we developed two new clinical diagnostic tools that can accurately and reliably predict the severity of dehydration in patients with diarrhea, which we will incorporate into a simple mobile phone application for use by doctors and nurses in low resource settings. Once validated, these new tools could improve care for patients with acute diarrhea worldwide.

Objective To examine pain treatment preferences before and after participation in an N-of-1 trial. Study Design and Setting In this observational study nested within a randomized trial, we examined chronic pain patients’ preferences before and after treatment in relation to N-of-1 trial results; assessed the influence of different schemes for defining comparative “superiority” on potential conclusions; and generated classification trees illustrating the relationship between pre-treatment preferences, N-of-1 trial results, and post-treatment preferences. Results Treatment preferences differed pre- and post-trial for 40% of participants. The proportion of patients whose N-of-1 trials demonstrated “superiority” of one treatment regimen over the other varied depending on how superiority was defined and ranged from 24% (using criteria that required statistically significant differences between regimens) to 62% (when relying only on differences in point estimates). Regardless of criteria for declaring treatment superiority, nearly three-fourths of patients with equivocal N-of-1 trial results nevertheless expressed definite preferences post-trial. Conclusion A large segment of patients undergoing N-of-1 trials for chronic pain altered their treatment preferences. However, the direction of preference change did not necessarily correspond to the N-of-1 results. More research is needed to understand how patients use N-of-1 trial results, why preferences are “sticky” even in the face of personalized data, and how patients and clinicians might be educated to use N-of-1 trial results more informatively.

Key Points Question What is the effect of using nicotine salt pod system (NSPS) electronic cigarettes (e-cigarettes) for replacing cigarettes (ie, switching) on biomarkers of tobacco exposure and potential harm among cigarette smokers? Findings In this randomized clinical trial including 186 African American and Latinx adult smokers, those randomized to the e-cigarette condition maintained their cotinine levels and significantly reduced urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and carbon monoxide levels and respiratory symptoms compared with controls smoking as usual at week 6. Lung function and blood pressure remained unchanged. Meaning This randomized clinical trial found that switching to NSPS e-cigarettes among adult smokers did not increase nicotine exposure and led to short-term reduction in the major pulmonary carcinogen, NNAL, compared with continued smoking., This randomized clinical trial examines biomarkers of carcinogen exposure in African American and Latinx smokers who switch to electronic cigarettes vs smoking as usual., Importance Fourth-generation nicotine salt pod system (NSPS) electronic cigarettes (e-cigarettes) are the leading class of e-cigarettes. They contain high nicotine concentrations, which may facilitate switching among smokers, but could also lead to increased exposure to nicotine and biomarkers of potential harm. African American and Latinx smokers experience significant tobacco-related health disparities. The potential of NSPS e-cigarettes to reduce smoking-related harm among these groups is unknown. Objective To compare the harm reduction potential of NSPS e-cigarette vs combustible cigarettes. Design, Setting, and Participants This unblinded randomized clinical trial compared 6 weeks of e-cigarette use vs cigarettes as usual from to 2018 to 2019 among smokers in the San Diego, California, and Kansas City, Missouri, areas. Participants included African American and Latinx adult combustible cigarette smokers who smoked at least 5 cigarettes/d on at least 25 of the past 30 days for at least 6 months and were interested in switching to e-cigarettes. Data were analyzed from September 18, 2019, to September 4, 2020. Interventions 6 weeks of e-cigarette use in a choice of pod flavors (5% nicotine) along with brief education, training, and action planning to completely switch to e-cigarettes from combustible cigarettes. The control group smoked combustible cigarettes as usual. Main Outcomes and Measures The primary outcome was reduction in urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentration at week 6. Secondary outcomes were change in urinary cotinine, expired carbon monoxide (CO), respiratory symptoms, lung function, blood pressure, past 7-day consumption of combustible cigarettes, and switching rates (e-cigarette group only) at weeks 2 and 6. Results This study included 186 participants, including 92 African American participants and 94 Latinx participants. The mean (SD) age was 43.3 (12.5) years, and 75 (40.3%) were women. Participants smoked a mean (SD) of 12.1 (7.2) cigarettes/d on 6.8 (0.6) d/wk at baseline. A total of 125 participants were randomized to the e-cigarette group and 61 were randomized to the control group. At baseline, median (interquartile range) NNAL was 124 (45-197) pg/mL in the e-cigarette group and 88 (58-197) pg/mL in the control group. At week 6, the e-cigarette group had significantly greater reductions in NNAL (relative risk [RR], 0.36 [95% CI, 0.23-0.54]; P

IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia. Although patients have reported that various exposures determine when and if an AF event will occur, a prospective evaluation of patient-selected triggers has not been conducted, and the utility of characterizing presumed AF-related triggers for individual patients remains unknown. OBJECTIVE: To test the hypothesis that n-of-1 trials of self-selected AF triggers would enhance AF-related quality of life. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial lasting a minimum of 10 weeks tested a smartphone mobile application used by symptomatic patients with paroxysmal AF who owned a smartphone and were interested in testing a presumed AF trigger. Participants were screened between December 22, 2018, and March 29, 2020. INTERVENTIONS: n-of-1 Participants received instructions to expose or avoid self-selected triggers in random 1-week blocks for 6 weeks, and the probability their trigger influenced AF risk was then communicated. Controls monitored their AF over the same time period. MAIN OUTCOMES AND MEASURES: AF was assessed daily by self-report and using a smartphone-based electrocardiogram recording device. The primary outcome comparing n-of-1 and control groups was the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) score at 10 weeks. All participants could subsequently opt for additional trigger testing. RESULTS: Of 446 participants who initiated (mean [SD] age, 58 [14] years; 289 men [58%]; 461 White [92%]), 320 (72%) completed all study activities. Self-selected triggers included caffeine (n = 53), alcohol (n = 43), reduced sleep (n = 31), exercise (n = 30), lying on left side (n = 17), dehydration (n = 10), large meals (n = 7), cold food or drink (n = 5), specific diets (n = 6), and other customized triggers (n = 4). No significant differences in AFEQT scores were observed between the n-of-1 vs AF monitoring-only groups. In the 4-week postintervention follow-up period, significantly fewer daily AF episodes were reported after trigger testing compared with controls over the same time period (adjusted relative risk, 0.60; 95% CI, 0.43- 0.83; P

Although group-level evidence supports the use of behavioral interventions to enhance cognitive and emotional well-being, different interventions may be more acceptable or effective for different people. N-of-1 trials are single-patient crossover trials designed to estimate treatment effectiveness in a single patient. We designed a mobile health (mHealth) supported N-of-1 trial platform permitting US adult volunteers to conduct their own 30-day self-experiments testing a behavioral intervention of their choice (deep breathing/meditation, gratitude journaling, physical activity, or helpful acts) on daily measurements of stress, focus, and happiness. We assessed uptake of the study, perceived usability of the N-of-1 trial system, and influence of results (both reported and perceived) on enthusiasm for the chosen intervention (defined as perceived helpfulness of the chosen intervention and intent to continue performing the intervention in the future). Following a social media and public radio campaign, 447 adults enrolled in the study and 259 completed the post-study survey. Most were highly educated. Perceived system usability was high (mean scale score 4.35/5.0, SD 0.57). Enthusiasm for the chosen intervention was greater among those with higher pre-study expectations that the activity would be beneficial for them (p < 0.001), those who obtained more positive N-of-1 results (as directly reported to participants) (p < 0.001), and those who interpreted their N-of-1 study results more positively (p < 0.001). However, reported results did not significantly influence enthusiasm after controlling for participants' interpretations. The interaction between pre-study expectation of benefit and N-of-1 results interpretation was significant (p < 0.001), such that those with the lowest starting pre-study expectations reported greater intervention enthusiasm when provided with results they interpreted as positive. We conclude that N-of-1 behavioral trials can be appealing to a broad albeit highly educated and mostly female audience, that usability was acceptable, and that N-of-1 behavioral trials may have the greatest utility among those most skeptical of the intervention to begin with.

Autoimmune Thyroiditis (AIT) is the most common autoimmune disease, which is characterized by cellular and humoral immunity leading to thyroid destruction. The impact of the humoral immunity on the risk to develop hypothyroidism has not exactly been defined yet. The aim of the present study was to investigate the association between thyroid antibody levels and the risk for developing hypothyroidism. In this retrospective study, 335 untreated AIT patients were enrolled. Anti-thyroperoxidase (TPO) antibodies, anti-thyroglobulin (Tg) antibodies (Abs), and the TSH level were measured. Patients with TPO-Ab levels500 IU/ml showed a moderately increased risk of having elevated TSH levels [p=0.0023; relative risk (95% confidence interval): 1.343 (1.108-1.627)] compared to those below this threshold. AIT patients with TPO- or Tg-Abs100 IU/ml and between 100-500 IU/ml had no significantly different TSH levels. Presence of Tg-Abs alone or in combination with TPO-Abs did not help to increase the sensitivity to identify patients at risk. Long term follow-up of AIT patients with high TPO-Abs level (500 IU/ml) showed an increase of TSH levels (mean: 0.5 mIU/l; range: 2.52±2.73 to 3.02±3.05 mIU/l; p=0.0420). Still, these patients remained euthyroid. Our data indicate largely elevated levels of TPO-Abs being associated with a moderately increased risk of developing hypothyroidism.

Objectives To determine the effectiveness of tai chi interventions compared with aerobic exercise, a current core standard treatment in patients with fibromyalgia, and to test whether the effectiveness of tai chi depends on its dosage or duration. Design Prospective, randomized, 52 week, single blind comparative effectiveness trial. Setting Urban tertiary care academic hospital in the United States between March 2012 and September 2016. Participants 226 adults with fibromyalgia (as defined by the American College of Rheumatology 1990 and 2010 criteria) were included in the intention to treat analyses: 151 were assigned to one of four tai chi groups and 75 to an aerobic exercise group. Interventions Participants were randomly assigned to either supervised aerobic exercise (24 weeks, twice weekly) or one of four classic Yang style supervised tai chi interventions (12 or 24 weeks, once or twice weekly). Participants were followed for 52 weeks. Adherence was rigorously encouraged in person and by telephone. Main outcome measures The primary outcome was change in the revised fibromyalgia impact questionnaire (FIQR) scores at 24 weeks compared with baseline. Secondary outcomes included changes of scores in patient’s global assessment, anxiety, depression, self efficacy, coping strategies, physical functional performance, functional limitation, sleep, and health related quality of life. Results FIQR scores improved in all five treatment groups, but the combined tai chi groups improved statistically significantly more than the aerobic exercise group in FIQR scores at 24 weeks (difference between groups=5.5 points, 95% confidence interval 0.6 to 10.4, P=0.03) and several secondary outcomes (patient’s global assessment=0.9 points, 0.3 to 1.4, P=0.005; anxiety=1.2 points, 0.3 to 2.1, P=0.006; self efficacy=1.0 points, 0.5 to 1.6, P=0.0004; and coping strategies, 2.6 points, 0.8 to 4.3, P=0.005). Tai chi treatment compared with aerobic exercise administered with the same intensity and duration (24 weeks, twice weekly) had greater benefit (between group difference in FIQR scores=16.2 points, 8.7 to 23.6, P

The DHAKA Dehydration Score and the DHAKA Dehydration Tree are the first empirically derived and internally validated diagnostic models for assessing dehydration in children with acute diarrhea for use by general practice nurses in a resource-limited setting. Frontline providers can use these new tools to better classify and manage dehydration in children., Introduction: Diarrhea remains one of the most common and most deadly conditions affecting children worldwide. Accurately assessing dehydration status is critical to determining treatment course, yet no clinical diagnostic models for dehydration have been empirically derived and validated for use in resource-limited settings. Methods: In the Dehydration: Assessing Kids Accurately (DHAKA) prospective cohort study, a random sample of children under 5 with acute diarrhea was enrolled between February and June 2014 in Bangladesh. Local nurses assessed children for clinical signs of dehydration on arrival, and then serial weights were obtained as subjects were rehydrated. For each child, the percent weight change with rehydration was used to classify subjects with severe dehydration (>9% weight change), some dehydration (3–9%), or no dehydration (

Until recently, stimulating TSH receptor autoantibodies (sTRAbs) could only be measured by bioassays. A new assay system, which directly detects sTRAb in sera by applying bridge technology, has been established and is now available as automated chemiluminescence (bridge) immunoassay. We evaluated the automated bridge assay in clinical routine and compared it with a conventional automated TRAb assay (competition assay). Altogether, 226 Graves’ disease (GD), 57 autoimmune thyroiditis, 74 non-autoimmune nodular goiter and 49 thyroid cancer patients, as well as 41 healthy controls were retrospectively evaluated. ROC plot analysis based on sera of newly diagnosed GD patients revealed an area under curve of 0.99 (95% CI: 0.99–1.0) indicating a high assay sensitivity and specificity. The highest sensitivity (100%) and specificity (99%) were seen at a cut-off level of 0.55 IU/l. The calculated positive predictive value was 94%, whereas the negative was 100%. Applying a ROC plot-derived cut-off of≥0.30 IU/l, derived from sera of GD patients already receiving antithyroid drug therapy for≤6 months, the sensitivity was 99% whereas the specificity was 98%. Detailed comparison of both assay systems used revealed a slightly different distribution of sTRAb and TRAb. Measurement of sTRAb during follow-up revealed a steady decline over one year of follow-up. In summary, our results demonstrate that the new automated bridge assay system for detecting sTRAb has a high sensitivity and specificity for diagnosing GD and to discriminate from other thyroid diseases, respectively. Our study, however, does not provide full evidence that the bridge assay is specific for sTRAb only.

Summary Background Dehydration due to diarrhoea is a leading cause of child death worldwide, yet no clinical tools for assessing dehydration have been validated in resource-limited settings. The Dehydration: Assessing Kids Accurately (DHAKA) score was derived for assessing dehydration in children with diarrhoea in a low-income country setting. In this study, we aimed to externally validate the DHAKA score in a new population of children and compare its accuracy and reliability to the current Integrated Management of Childhood Illness (IMCI) algorithm. Methods DHAKA was a prospective cohort study done in children younger than 60 months presenting to the International Centre for Diarrhoeal Disease Research, Bangladesh, with acute diarrhoea (defined by WHO as three or more loose stools per day for less than 14 days). Local nurses assessed children and classified their dehydration status using both the DHAKA score and the IMCI algorithm. Serial weights were obtained and dehydration status was established by percentage weight change with rehydration. We did regression analyses to validate the DHAKA score and compared the accuracy and reliability of the DHAKA score and IMCI algorithm with receiver operator characteristic (ROC) curves and the weighted κ statistic. This study was registered with ClinicalTrials.gov, number NCT02007733. Findings Between March 22, 2015, and May 15, 2015, 496 patients were included in our primary analyses. On the basis of our criterion standard, 242 (49%) of 496 children had no dehydration, 184 (37%) of 496 had some dehydration, and 70 (14%) of 496 had severe dehydration. In multivariable regression analyses, each 1-point increase in the DHAKA score predicted an increase of 0·6% in the percentage dehydration of the child and increased the odds of both some and severe dehydration by a factor of 1·4. Both the accuracy and reliability of the DHAKA score were significantly greater than those of the IMCI algorithm. Interpretation The DHAKA score is the first clinical tool for assessing dehydration in children with acute diarrhoea to be externally validated in a low-income country. Further validation studies in a diverse range of settings and paediatric populations are warranted. Funding National Institutes of Health Fogarty International Center.

Few remedies effectively treat long-term pain and disability from knee osteoarthritis. Studies suggest that Tai Chi alleviates symptoms, but no trials have directly compared Tai Chi with standard therapies for osteoarthritis.To compare Tai Chi with standard physical therapy for patients with knee osteoarthritis.Randomized, 52-week, single-blind comparative effectiveness trial. (ClinicalTrials.gov: NCT01258985).An urban tertiary care academic hospital.204 participants with symptomatic knee osteoarthritis (mean age, 60 years; 70% women; 53% white).Tai Chi (2 times per week for 12 weeks) or standard physical therapy (2 times per week for 6 weeks, followed by 6 weeks of monitored home exercise).The primary outcome was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 12 weeks. Secondary outcomes included physical function, depression, medication use, and quality of life.At 12 weeks, the WOMAC score was substantially reduced in both groups (Tai Chi, 167 points [95% CI, 145 to 190 points]; physical therapy, 143 points [CI, 119 to 167 points]). The between-group difference was not significant (24 points [CI, -10 to 58 points]). Both groups also showed similar clinically significant improvement in most secondary outcomes, and the benefits were maintained up to 52 weeks. Of note, the Tai Chi group had significantly greater improvements in depression and the physical component of quality of life. The benefit of Tai Chi was consistent across instructors. No serious adverse events occurred.Patients were aware of their treatment group assignment, and the generalizability of the findings to other settings remains undetermined.Tai Chi produced beneficial effects similar to those of a standard course of physical therapy in the treatment of knee osteoarthritis.National Center for Complementary and Integrative Health of the National Institutes of Health.

Background Change in glomerular filtration rate (GFR) is important for clinical decision making. GFR estimates from serum creatinine level provide an unbiased but imprecise estimate of GFR at single time points. However, the accuracy of estimated GFR over time is not well known. Study Design Longitudinal study of diagnostic test accuracy. Settings & Participants 4 clinical trials with longitudinal measurements of GFR and serum creatinine on the same day, including individuals with and without kidney disease with a wide range of kidney function, diverse racial backgrounds, and varied clinical characteristics. Index Test GFR estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Reference Test GFR measured using urinary clearance of 125 I-iothalamate. Results Data included 19,735 GFR measurements in 3,531 participants during a mean follow-up of 2.6 years. Mean values at baseline for measured and estimated GFR and error (measured GFR – estimated GFR) were 73.1 (95% CI, 71.6 to 74.5), 72.7 (95% CI, 71.5 to 74.0), and 0.14 (95% CI, −0.35 to 0.63) mL/min/1.73 m 2 , respectively. Mean rates of change in measured and estimated GFR and error were −2.3 (95% CI, −2.4 to −2.1), −2.2 (95% CI, −2.4 to −2.1), and −0.09 (95% CI, −0.24 to 0.05) mL/min/1.73 m 2 per year ( P P P = 0.2, respectively). Variability (ie, standard deviation) among participants in rate of change in measured GFR, estimated GFR, and error was 4.3, 3.4, and 3.3 mL/min/1.73 m 2 per year, respectively. Only 15% of participants had a rate of change in error >3 mL/min/1.73 m 2 per year, and only 2% had a rate of change in error >5% per year. Limitations Participants' characteristics were not available over time. Conclusion The accuracy of GFR estimates did not change over time. Clinicians should interpret changes in estimated GFR over time as reflecting changes in measured GFR rather than changes in errors in the GFR estimates in most individuals.

Summary Background and objectives Interferon (IFN) and pegylated-IFN treatment of hepatitis C virus (HCV) infection in hemodialysis patients result in sustained virological response (SVR) rates of 45% and 37%, respectively. Although most nonhemodialysis patients who achieve SVR remain persistently viral negative, the durability of SVR in hemodialysis patients is unknown. We analyzed the rate of long-term virological negativity in hemodialysis patients who achieved SVR after IFN or pegylated-IFN through analysis of patient-level data. Design, setting, participants, & measurements After performing a systematic literature review for IFN-based treatment of hemodialysis patients with chronic HCV infection, we extracted patient-level data on patients who achieved SVR. We performed life table analysis to estimate long-term virological negativity rates after SVR in patients who continued on hemodialysis or subsequently underwent kidney transplantation. Results Long-term HCV RNA outcomes following SVR were available for 121 hemodialysis patients (20 studies) and 45 patients who subsequently underwent transplantation (11 studies). The probability of remaining HCV RNA negative was 86% (95% confidence interval, 77% to 96%) for patients followed on hemodialysis 48 months after SVR and 95% (95% confidence interval, 89% to 100%) for kidney recipients followed 48 months after transplant. Conclusions Viral negativity from IFN-based HCV treatment in hemodialysis patient appears durable during extended follow-up, including after kidney transplantation. The certainty of the viral negativity estimate is limited by the small number with follow-up beyond 48 months or longer. Transplantation does not confer an increased risk of relapse. Future research should investigate whether IFN-based treatment improves clinical outcomes for hemodialysis patients.

Kidney disease alters the pharmacokinetic disposition of many medications, requiring dosage adjustment to maintain therapeutic serum concentrations. The Cockcroft-Gault (CG) equation is used for pharmacokinetic studies and drug dosage adjustments, but the Modification of Diet in Renal Disease (MDRD) Study equation is more accurate and more often reported by clinical laboratories than the CG equation.Diagnostic test study.Pooled data set for 5,504 participants from 6 research studies and 4 clinical populations with measured glomerular filtration rate (GFR).Estimated kidney function using the MDRD Study and CG equations incorporating actual (CG) or ideal body weight (CG(IBW)) and standardized serum creatinine concentrations.Measured GFR assessed by using iodine-125-iothalamate urinary clearance.Concordance of assigned kidney function categories designated by the Food and Drug Administration (FDA) Guidance for Industry for pharmacokinetic studies and recommended dosages of 15 medications cleared by the kidneys.Concordance of kidney function estimates with measured GFR for FDA-assigned kidney function categories was 78% for the MDRD Study equation compared with 73% for the CG equation (P0.001) and 66% for the CG(IBW) equation (P0.001). Concordance between the MDRD Study equation and CG and CG(IBW) equations was 78% and 75%, respectively (P0.001). Concordance of kidney function estimates with measured GFR for recommended drug dosages was 88% for MDRD Study equation compared with 85% for the CG equation (P0.001) and 82% for the CG(IBW) equation (P0.001), with lower concordance when dosing recommendations for drugs included narrow GFR ranges. Concordance rates between the CG and CG(IBW) equations and MDRD Study equation were 89% and 88%, respectively (P0.05).Results based on simulation rather than pharmacokinetic studies. Outcome was drug dosage recommendations, rather than observed drug efficacy and safety.The MDRD Study equation can also be used for pharmacokinetic studies and drug dosage adjustments. As more accurate GFR-estimating equations are developed, they should be used for these purposes.

Background Proteinuria may be an early marker of chronic kidney disease in human immunodeficiency virus (HIV)-infected patients with coexisting chronic hepatitis and/or drug use. Minorities are at greater risk of chronic kidney disease. Data are limited about risk factors for proteinuria in Hispanic drug users with and without HIV infection. Study Design A cross-sectional study. Setting & Participants A community-recruited Hispanic cohort to study the role of drug use in HIV-associated malnutrition composed of 4 groups (106 HIV-infected drug users, 96 HIV-uninfected drug users, 38 HIV-infected non–drug users, and 47 healthy controls). Patients on renal replacement therapy were excluded. Predictors HIV infection, chronic hepatitis, history of hypertension or diabetes, and intravenous drug use (never, prior, or current). Outcomes & Measurements The presence of proteinuria was defined as urine dipstick result of 1+ or greater. Multivariable logistic regression was used to identify independent risk factors for proteinuria. Results Of 287 patients with available data, 24 (8.4%) had proteinuria. In univariate analyses, those with HIV infection; prior, but not current, intravenous drug use; and a history of hypertension or diabetes were more likely to have proteinuria. In multivariate analyses, significant risk factors for proteinuria were HIV infection (odds ratio, 9.2; 95% confidence interval, 1.9 to 45.8; P = 0.007); prior, but not current, intravenous drug use (odds ratio, 4.7; 95% confidence interval, 1.4 to 15.3; P = 0.01); and history of hypertension or diabetes (odds ratio, 8.2; 95% confidence interval, 3.1 to 21.7; P Limitations The cross-sectional study design makes it difficult to establish the temporal relationship. The number of outcomes in relation to the number of predictors is small. Conclusions HIV and prior intravenous drug use, but not chronic hepatitis or current intravenous drug use, were independently associated with proteinuria in this Hispanic population. Longitudinal studies to assess the development of proteinuria and chronic kidney disease in this high-risk population are warranted.

Objective.To determine whether total and antianaerobic antibiotic exposure increases the risk of room contamination among vancomycin-resistant enterococci (VRE)–colonized patients.Design And Setting.A 14-month study in 2 intensive care units at an academic tertiary care hospital in Boston, Massachusetts.Patients.All patients who acquired VRE or were VRE-colonized on admission and who had environmental cultures performed.Methods.We performed weekly environmental cultures (2 sites per room) and considered a room to be contaminated if there was a VRE-positive environmental culture during the patient's stay. We determined risk factors for room contamination by use of the Cox proportional hazards model.Results.Of 142 VRE-colonized patients, 35 (25%) had an associated VRE-positive environmental culture. Patients who contaminated their rooms were more likely to have diarrhea than those who did not contaminate their rooms (23 [66%] of 35 vs 41 [38%] of 107;P= .005) and more likely to have received antibiotics while VRE colonized (33 [94%] of 35 vs 86 [80%] of 107;P= .02). There was no significant difference in room contamination rates between patients exposed to antianaerobic regimens and patients exposed to nonantianaerobic regimens or between patients with and patients without diarrhea, but patients without any antibiotic exposure were unlikely to contaminate their rooms. Diarrhea and antibiotic use were strongly confounded; although two-thirds of room contamination occurred in rooms of patients with diarrhea, nearly all of these patients received antibiotics. In multivariable analysis, higher mean colonization pressure in the ICU increased the risk of room contamination (adjusted hazard ratio per 10% increase, 1.44 [95% confidence interval, 1.04–2.04]), whereas no antibiotic use during VRE colonization was protective (adjusted hazard ratio, 0.21 [95% confidence interval, 0.05–0.89]).Conclusions.Room contamination with VRE was associated with increased mean colonization pressure in the ICU and diarrhea in the VRE-colonized patient, whereas no use of any antibiotics during VRE colonization was protective.

We conducted a metaanalysis of published evidence on the relationship between maternal obesity and the risk of neural tube defects (NTDs). Eligible studies were identified from 3 sources: (1) PubMed search of articles that were published from January 1980 through January 2007, (2) reference lists of publications that were selected from the PubMed search, and (3) reference lists of review articles on obesity and maternal outcomes that were published from January 2000 through January 2007. Twelve studies met inclusion criteria. A Bayesian random effects model was used for the metaanalysis and metaregression. Unadjusted odds ratios for an NTD-affected pregnancy were 1.22 (95% CI, 0.99-1.49), 1.70 (95% CI, 1.34-2.15), and 3.11 (95% CI, 1.75-5.46) among overweight, obese, and severely obese women, respectively, compared with normal-weight women. None of the study characteristics included in the metaregression analysis affected the results significantly. Maternal obesity is associated with an increased risk of an NTD-affected pregnancy.

Background Patients colonized with vancomycin-resistant enterococci (VRE) frequently contaminate their environment, but the environmental role of VRE transmission remains controversial. Methods During a 14-month study in 2 intensive care units, weekly environmental and twice-weekly patient surveillance cultures were obtained. VRE acquisition was defined as a positive culture result >48 h after admission. To determine risk factors for VRE acquisition, Cox proportional hazards models using time-dependent covariates for colonization pressure and antibiotic exposure were examined. Results Of 1330 intensive care unit admissions, 638 patients were at risk for acquisition, and 50 patients (8%) acquired VRE. Factors associated with VRE acquisition included average colonization pressure (hazard ratio [HR], 1.4 per 10% increase; 95% confidence interval [CI], 1.2-1.8), mean number of antibiotics (HR, 1.7 per additional antibiotic; 95% CI, 1.2-2.5), leukemia (HR, 3.1; 95% CI, 1.2-7.8), a VRE-colonized prior room occupant (HR, 3.1; 95% CI, 1.6-5.8), any VRE-colonized room occupants within the previous 2 weeks (HR, 2.5; 95% CI, 1.3-4.8), and previous positive room culture results (HR, 3.4; 95% CI, 1.2-9.6). In separate multivariable analyses, a VRE-colonized prior room occupant (HR, 3.8; 95% CI, 2.0-7.4), any VRE-colonized room occupants within the previous 2 weeks (HR, 2.7; 95% CI, 1.4-5.3), and previous positive room culture results (HR, 4.4; 95% CI, 1.5-12.8) remained independent predictors of VRE acquisition, adjusted for colonization pressure and antibiotic exposure. Conclusions We found that prior room contamination, whether measured via environmental cultures or prior room occupancy by VRE-colonized patients, was highly predictive of VRE acquisition. Increased attention to environmental disinfection is warranted.

Background Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables. Study Design Test of diagnostic accuracy. Setting & Participants Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438). Reference Test Measured GFR (mGFR). Index Test Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study. Measurements GFR was measured by using urinary clearance of iodine-125–iothalamate in the US studies and chromium-51–EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used. Results Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m 2 (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables. Limitations Study population composed mainly of patients with CKD. Conclusions Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.

Glomerular filtration rate (GFR) estimates facilitate detection of chronic kidney disease. Performance of the Modification of Diet in Renal Disease (MDRD) Study equation varies substantially among populations. To describe the performance of the equation in a large, diverse population, estimated GFR (eGFR) was compared to measured GFR (mGFR) in a cross-sectional analysis of 5504 participants in 10 studies that included measurements of standardized serum creatinine and urinary clearance of iothalamate. At eGFR60 ml/min per 1.73 m(2), the MDRD Study equation had lower bias and higher precision than at eGFRor =60 ml/min per 1.73 m(2). The accuracy of the equation, measured by the percent of estimates that fell within 30% of mGFR, was similar for eGFR values above or below 60 ml/min per 1.73 m(2) (82% and 84%, respectively). Differences in performance among subgroups defined by age, sex, race, diabetes, transplant status, and body mass index were small when eGFR was60 ml/min per 1.73 m(2). The MDRD Study equation therefore provides unbiased and reasonably accurate estimates across a wide range of subgroups when eGFR is60 ml/min per 1.73 m(2). In individual patients, interpretation of GFR estimates near 60 ml/min per 1.73 m(2) should be interpreted with caution to avoid misclassification of chronic kidney disease in the context of the clinical setting.

We conducted this metaanalysis to summarize the available epidemiologic evidence on the relationship between maternal overweight and obesity and the risk of stillbirth. We identified studies from 3 sources: (1) a PubMed search of relevant articles that were published between January 1980 and September 2005, (2) reference lists of publications that were selected from the PubMed search, and (3) reference lists of review articles on obesity and maternal outcomes that were published between 2000 and 2005. We used a Bayesian random effects model to perform the metaanalysis and metaregression. Nine studies were included in the metaanalysis. The unadjusted odds ratios of a stillbirth were 1.47 (95% CI, 1.08-1.94) and 2.07 (95% CI, 1.59-2.74) among overweight and obese pregnant women, respectively, compared with normal-weight pregnant women. The metaregression analysis found no evidence that these estimates were affected by selected study characteristics. Maternal obesity is associated with an increased risk of stillbirth, although the mechanisms to explain this association are not clear.

Background/Aims: In a cohort of hemodialysis patients, we evaluated the hypothesis that weekly administration of intravenous (IV) darbepoetin-α (DA) was associated with lower total erythropoiesis-stimulating agent (ESA) requirements as compared to a regimen of multiple subcutaneous (SC) doses per week of epoetin-β (EB). Methods: We studied 1,159 hemodialysis patients who were treated exclusively with either IV DA or SC EB across a network of Portuguese clinics during 2004. Linear regression was used to assess the adjusted relationship between the ESA regimen and weekly ESA requirements over the period of observation. Generalized estimating equations were applied in order to model the population average effects of the correlated mean weekly ESA dose for each individual. We also calculated propensity scores for the receipt of DA and assessed the relationship between ESA type and dose requirement within each quintile of the score. Results: The adjusted dose of IV DA, when expressed as a proportion of the dose used in EB-treated patients, did not differ from the dose administered to EB recipients (0.961, 95% CI 0.904, 1.021). A similar relationship was observed within each propensity score quintile. Conclusions: Hemodialysis patients who received IV DA had dose requirements that were similar to their counterparts who were treated with SC EB. A once-weekly dosing regimen and avoidance of SC administration enhance the attractiveness of DA as an alternative to traditional ESAs. The potential for unmeasured confounding, restriction to a population that was treated with a single ESA preparation and application of a 200 IU:1 µg EB:DA dose conversion are important limitations of this study.

Left ventricular (LV) mass and other LV measures have been shown to be heritable. In this study we hypothesized that functional variation in the gene coding for estrogen receptor-α ( ESR1 ), known for mediating the effect of estrogens on myocardium, is associated with age-related changes in LV structure. Four genetic markers ( ESR1 TA repeat; rs2077647 , or + 30T > C ; rs2234693 , or Pvu II; and rs9340799 , or Xba I) were genotyped in 847 unrelated individuals (488 women) from the Framingham Offspring Study, who attended 2 examination cycles 16 years apart (mean ages at first examination: 43±9 years; at follow-up: 59±9 years). ANCOVA was used to assess the association of polymorphisms and their haplotypes with cross-sectional measurements and longitudinal changes in LV mass, wall thickness, end-diastolic and end-systolic internal diameter, and fractional shortening after adjustment for factors known to influence these variables. Changes over time were detected for all of the LV measurements ( P ranging from SS genotype of the ESR1 TA repeat polymorphism in the promoter region was associated with longitudinal changes in LV mass and LV wall thickness ( P ranging from 0.0006 to 0.01). Moreover, the TA [ S ]– +30 [ T ]– Pvu II[ T ]– Xba I[ A ] haplotype (frequency: 47.5%) was associated with greater LV changes as compared with the TA [ L ] –+30 [ C ]– Pvu II[ C ]– Xba I[ G ] haplotype (frequency: 31.8%). Our results are consistent with the hypothesis that common ESR1 polymorphisms are significantly associated with age-related changes in LV structure. Understanding the mechanisms predisposing to unfavorable LV remodeling of the heart with advancing age may aid in the discovery of new therapeutic targets for the prevention of heart failure.

Background The use of antiretroviral agents in pregnant HIV-infected women has been reported to increase the risk of premature delivery in some studies. We performed a meta-analysis on relevant studies to address this question. Methods We searched Medline, Embase and the Cochrane Controlled Clinical Trials Register for English language articles. Studies that reported premature delivery for HIV-infected women treated with antiretroviral regimens during pregnancy were selected. Meta-analyses were performed using a random effects model. Results Thirteen prospective cohorts and one retrospective study met the inclusion criteria. Antiretroviral therapy during pregnancy did not increase the risk of premature delivery overall [odds ratio (OR) 1.01, 95% confidence interval (CI) 0.76-1.34]. In subgroup analyses, compared with no therapy, monotherapy (mostly zidovudine) conferred an OR of 0.86 (95% CI 0.73-1.01), whereas combination therapy conferred an OR of 1.13 (95% CI 0.79-1.63). The use of protease inhibitor (PI)-containing combinations resulted in an OR for premature delivery of 1.24 (95% CI 0.76-2.02), compared with combinations without PI. The initiation of combination therapy before pregnancy or in the first trimester resulted in an OR of 1.71 (95% CI 1.09-2.67) compared with therapy initiation in the second trimester and beyond. There was a large degree of heterogeneity between studies. Conclusion Evidence indicates that antiretroviral therapy during pregnancy is not associated with an overall increased risk of premature delivery. The use of combination regimens before or early in pregnancy may slightly increase the risk of prematurity. Continued surveillance will be necessary to quantify such a risk accurately.

Objectives To assess how the inclusion of N-of-1 trial data into randomized controlled trial (RCT) meta-analyses impacts the magnitude and precision of yielded treatment effects, using amphetamines and methylphenidate for pediatric attention deficit hyperactivity disorder as a model. Study Design and Setting We combined the N-of-1 and RCT data generated from previously conducted systematic reviews using parent and teacher ratings of hyperactivity and/or impulsivity as the outcome. Data were combined using standardized mean differences assuming a random effects model. The amphetamine and methylphenidate evidence were synthesized separately. Results We found that the inclusion of N-of-1 trial data in the meta-analysis impacted both magnitude and precision. The addition of the N-of-1 trial data narrowed the confidence intervals in three of the four comparisons as compared to the treatment effect yielded by RCT-only data. Furthermore, the addition of N-of-1 trials changed the overall treatment effects yielded by the RCT-only meta-analyses from statistically nonsignificant to statistically significant in one of the four outcomes. Conclusions If the overall goal of a meta-analysis is to synthesize all available evidence on a given topic, then N-of-1 trials should be included. This study shows it is possible to combine N-of-1 trial data with RCT data and the potential merits of this approach.

Meta-analysis of diagnostic test accuracy often involves mixture of case-control and cohort studies. The existing bivariate random-effects models, which jointly model bivariate accuracy indices (e.g., sensitivity and specificity), do not differentiate cohort studies from case-control studies and thus do not utilize the prevalence information contained in the cohort studies. The recently proposed trivariate generalized linear mixed-effects models are only applicable to cohort studies, and more importantly, they assume a common correlation structure across studies and trivariate normality on disease prevalence, test sensitivity, and specificity after transformation by some pre-specified link functions. In practice, very few studies provide justifications of these assumptions, and sometimes these assumptions are violated. In this paper, we evaluate the performance of the commonly used random-effects model under violations of these assumptions and propose a simple and robust method to fully utilize the information contained in case-control and cohort studies. The proposed method avoids making the aforementioned assumptions and can provide valid joint inferences for any functions of overall summary measures of diagnostic accuracy. Through simulation studies, we find that the proposed method is more robust to model misspecifications than the existing methods. We apply the proposed method to a meta-analysis of diagnostic test accuracy for the detection of recurrent ovarian carcinoma. Copyright © 2016 John WileySons, Ltd.

Objectives To evaluate how data from n-of-1 trials may be used in systematic reviews and meta-analyses by examining the effects of amphetamine and methylphenidate for attention-deficit hyperactivity disorder (ADHD). Study Design and Setting Electronic search of MEDLINE, EMBASE, and PsychINFO for English language articles published from 1950 to 2013. N-of-1 trials of pediatric participants with ADHD that assessed either amphetamine or methylphenidate vs. placebo were included. The primary outcome was improvement of core symptoms of ADHD, which was assessed by multiple rating scales. Studies with obtainable individual participant data were included in the meta-analysis. Weighted mean differences were computed using a random-effects model. Results Nine studies were included in the amphetamine-placebo comparison and 10 in the methylphenidate-placebo comparison. Meta-analyses were consistently in favor of amphetamine in 10 of 11 ADHD symptom domains and methylphenidate in 7 of 12 symptom domains. A high degree of heterogeneity across participant treatment response was observed. Conclusions Meta-analysis of n-of-1 trials suggests that amphetamine and methylphenidate are effective treatments for pediatric ADHD. Synthesizing n-of-1 trials enables assessment of individual responses to treatment as well as aggregate summaries across individuals and studies. It offers a promising general approach with applications across diverse treatments and disorders.

Second allogeneic hematopoietic stem cell transplantation (HSCT2) is a frequently used treatment option for relapse of acute leukemia after first allogeneic transplantation. Remission can be induced in selected patients, but data on long-term outcome and finally cure are limited. To estimate the long-term results of HSCT2, we retrospectively analyzed the course of 286 patients receiving myeloablative HSCT2 between 1985 and 2000, with a median follow-up of 11.3 years. Overall survival (OS) and leukemia-free survival (LFS) at 10 years from HSCT2 were 10±2 and 7±2%, respectively. Cumulative 10-year incidence of relapse and non-relapse mortality were 58±3% and 35±3%, respectively. CR at HSCT2, an interval from first transplant to relapse >10 months and TBI as part of the conditioning for HSCT2 favorably influenced LFS and OS. Patients with all three favorable factors had a 10-year OS of 36±10% and LFS of 25±9%, whereas patients showing no favorable factor had all died before year 5. Although retrospective, the long follow-up of this analysis supports the curative potential of alloHSCT2 in selected patients, who might be identified in advance, based on prognostic factors.

OBJECTIVE We report on our experience with the BerlinHeart Excor system in adults and paediatric patients who underwent placement of the mechanical support device under emergency conditions and demonstrate the exceptional advantages and the considerable versatility of the system. METHODS Since 2003, 29 consecutive patients (25 adults and 4 infants) with ages ranging from 10 months to 54 years underwent implantation of an Excor system. Main underlying heart diseases in adults were acute myocardial infarction (n = 9), dilative cardiomyopathy (n = 6), acute myocarditis (n = 6), whereas most of the children suffered from dilative cardiomyopathy. Ten patients had undergone implantation of an extracorporeal membrane oxygenation system. RESULTS In 26 cases, a left ventricular assist device (LVAD) was implanted, while 3 patients had biventricular support. The support interval of all patients surviving the perioperative period lasted from 30 to 412 days, mean period of support until heart transplantation or explantation was 184 +/- 117 days. Severe complications were rare. CONCLUSION The Excor paracorporeal mechanical support system is an excellent and highly versatile device for the support of patients of all ages and different types of underlying heart disease in the mid-term and long-term. The implant procedure and the perioperative management are simple, and complication rates are low.

Plasma lipid profile is affected by endogenous estrogen levels and hormone replacement therapy (HRT). As plasma lipid concentrations have a significant heritable basis and the effects of both endogenous estrogen and use of HRT are mediated by estrogen receptors, we sought to investigate the relationships between polymorphisms in estrogen receptor-α ( ESR1 ) and plasma lipid and lipoprotein concentrations. We analyzed data from 854 women (mean age 52±10 years) from the Framingham Heart Study. A TA repeat in the promoter region, c.30T > C in exon 1, c.454-397T > C , and c.454-351A > G in intron 1, all in linkage disequilibrium (LD), were significantly associated with low-density lipoprotein (LDL) particle size and concentration of small LDL particles. Women with the c.454-397C allele had larger LDL particle size (21.09±0.02nm versus 21.01±0.03nm, p =0.021) concurrent with lower small LDL particle concentration (0.47±0.02mmol/L versus 0.58±0.03mmol/L, p =0.008). Moreover, the TA[L] – c.30C – c.454-397C – c.454-351G haplotype (frequency, 32%) was associated with lower small LDL particle concentrations (−0.06±0.03mmol/L change associated with each copy of this haplotype, p =0.011) when compared to the TA[S] – c.30T – c.454-397T – c.454-351A haplotype (frequency, 46%), where L and S are long and short TA repeats. Our results suggest that common ESR1 polymorphisms have a significant effect on lipoprotein metabolism in women.

Background Left ventricular (LV) hypertrophy is a significant risk factor for cardiovascular disease. Given sex-based differences in cardiac structure and remodeling, we hypothesized that variation in estrogen pathway genes might be associated with alteration of LV structure. Methods We studied 1249 unrelated individuals, 547 men and 702 women (mean age 59 years) from the Framingham Heart Study. Eight single nucleotide polymorphisms in the genes for estrogen receptor α and estrogen receptor β (ESR2) were tested for association with 5 LV measures: LV mass (LVM), LV wall thickness (LVWT), LV internal diameter at end-diastole and end-systole, and fractional shortening. Sex-specific multiple regression analyses were performed adjusting for age, weight, height, systolic and diastolic blood pressure, hypertension treatment, diabetes, and in women, menopausal status. Results In men, there was no evidence of association between the estrogen pathway polymorphisms tested and LV structure or function. In women, however, two polymorphisms, ESR2 rs1256031 and ESR2 rs1256059, in linkage disequilibrium with one another, were associated with LVM and LVWT (P = .0007 to .03); the association was most pronounced in those women with hypertension (P = .0006 to .01). The association did not appear to be explained by variation in blood pressure, plasma lipoprotein levels, or hyperglycemia. Conclusions The ESR2 polymorphisms are associated with LV structural differences in women with hypertension in a community-based population. These data are consistent with the hypothesis that genetic factors may mediate part of the observed sex-based differences in LV structure and remodeling.

High levels of small low density lipoprotein (LDL) particles are a major risk factor for cardiovascular morbidity and mortality. Both estrogens and smoking, with known anti-estrogenic effects, alter the atherogenic lipid profile. We tested for a role of interaction between smoking and estrogen receptor alpha gene (ESR1) variation in association with plasma concentration of atherogenic small LDL particles and LDL particle size. We studied 1727 unrelated subjects, 854 women and 873 men, mean age 51 years (SD 10), from the population-based Framingham Heart Study. After covariate adjustment, women who smoked and had the common ESR1 c.454-397 TT genotype (in 30% of women, T was present on both chromosomes at position 397 prior to the start of exon 2) had >1.7-fold higher levels of small LDL particles than women with the alternative genotypes (P-value for smoking-genotype interaction was 0.001). Similar results were obtained for three other ESR1 variants including c.454-351A > G, in the same linkage disequilibrium block. A similar substantial gender-specific result was also evident with a fifth variant, in a separate linkage disequilibrium block, in exon 4 (P = 0.003). Women who smoked and had specific, common ESR1 genotypes had a substantially higher plasma concentration of atherogenic small LDL particles. Significant results revealed a dose-dependent effect of smoking and were evident in both pre- and postmenopausal women. The reported association has the potential to explain the risks associated with estrogen use in certain women and a recent report of association between an ESR1 haplotype comprised of c.454-397 T and c.454-351 A alleles with increased myocardial infarction and ischaemic heart disease, independent of the standard, established cardiovascular risk factors.

Objective Two investigations evaluate Bayesian meta-regression for detecting treatment interactions. Study design and setting The first compares analyses of aggregate and individual patient data on 1,860 subjects from 11 trials testing angiotensin converting enzyme (ACE) inhibitors for nondiabetic kidney disease. The second explores meta-regression for detecting treatment interaction on 671 covariates, including the baseline risk, from 232 meta-analyses of binary outcomes compiled from the Cochrane Collaboration and the medical literature. Results In the ACE inhibitor study, treatment effects were homogeneous so meta-regression identified no interactions. Analysis of individual patient data using a multilevel model, however, discovered that treatment reduced glomerular filtration rate (GFR) more among patients with higher baseline proteinuria. The second investigation found meta-regression most effective for detecting treatment interactions with study-level factors in meta-analyses with >10 studies, heterogeneous treatment effects, or significant overall treatment effects. Under all three conditions, 46% of meta-regressions produced strong interactions (posterior probability >0.995) compared with 6% otherwise. Baseline risk was associated with the odds ratio in 6% of meta-analyses, half the rate found using maximum likelihood. Conclusion Meta-regression can detect interactions of treatment with study-level factors when treatment effects are heterogeneous. Individual patient data are needed for patient-level factors and homogeneous effects.

We report on our experience with six patients with malignant sarcoma of the heart and show that long-term survival is possible after radical resection. At presentation, the 6 patients (3 male, 3 female) were 45.8 +/- 20 years old. Three patients are alive without evidence of metastases since 29.6 +/- 36.8 months, three patients died after 38 +/- 50.2 months due to distant metastases. Precise preoperative localization of the tumor by means of imaging techniques is very important. In some cases, radical surgery requires an ex situ procedure (autotransplantation). If necessary, the right heart can be resected almost completely, and reconstructed in the form of a Fontan-type circulation. A heart transplantation, as suggested by others, is not justified from our point of view, since prognosis is not better and donor organs are too rare. The results of radical resection are promising, but new concepts for treatment--in particular chemotherapy concepts--for these mostly middle-aged or young patients are required.

Background. Some studies suggest that progression of renal disease is slower in women than in men. However, other factors that are also associated with progression of renal disease have not always been taken into account. Therefore, we undertook this analysis to explore the independent association of renal disease progression with gender.Methods. We analysed a pooled database of patients with non-diabetic renal disease enrolled in 11 randomized controlled trials evaluating the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) for slowing renal disease progression. The primary end point was the combined outcome of doubling of baseline serum creatinine or onset of end-stage renal disease (ESRD). The secondary end point was the onset of ESRD alone. We performed multivariable Cox proportional hazards analysis to study the independent effect of gender on these end points after adjusting for baseline patient characteristics, and changes from baseline to follow-up systolic blood pressure (SBP) and urine protein (UP) excretion.Results. The total number of patients was 1860: 645 (35%) females and 1215 (65%) males. Mean duration of follow-up was 2.2 years. The proportions randomized to ACEI (51%), mean baseline serum creatinine (2.2 mg/dl) and mean age (52 years) were similar for both genders. Mean baseline SBP was greater in women than in men: 151 vs 147 mmHg (P Conclusions. Our findings suggest that the rate of renal disease progression may not be slower, and may even be faster in women compared with men, after adjusting for other factors associated with a faster rate of progression. We caution that most women in our database were of post-menopausal age, and thus our findings may not extend to younger women.

Transfer of infants between hospitals or their discharge home may bias comparisons of the performance across neonatal intensive care units (NICUs). This study attempts to show the potential size of transfer bias in the context of a large cohort study and describe strategies for minimizing this type of bias.To limit transfer bias in a neonatal growth study of extremely premature infants in six tertiary NICUs, we restricted eligibility to infants30 weeks gestation at birth and substituted matched replacements for early transfers (infants transferred or discharged prior to day of life 16).The restriction strategy was successful, reducing the overall early transfer rate from 16.4 to 3.6% and the range of transfer rates among individual NICUs from 0.6-32.7% to 0-11.0%. Replacement by matched substitutes had a much smaller effect because of the small number of early transfers and our inability to match on all factors distinguishing early transfers.Sampling strategies to minimize infants lost to follow-up were more successful than replacement strategies in limiting transfer bias in a NICU growth study. Although complete elimination of bias is likely impossible, valid studies require efforts to minimize, quantify, and test the effect of transfer bias.

Cardiovascular risks are globally elevated in South Asians, but this masks important ethnic subgroup differences in risk factors, such as hypertension, which have not been fully explored. We conducted this study to explore the variations in hypertension within ethnic subgroups among South Asians.Cross-sectional survey [National Health Survey of Pakistan (NHSP) (1990-1994)].Population based.A total of 9442 individuals aged 15 years or over.Data on sociodemographic and clinical variables were collected. Distinct ethnic subgroups - Muhajir, Punjabi, Sindhi, Pashtun and Baluchi - were defined by mother tongue.Hypertension defined as systolic blood pressureor= 140 mmHg or diastolic blood pressureor= 90 mmHg, or currently receiving antihypertensive therapy.The age-standardized prevalence of hypertension was highest among Baluchis (25.3% in men and 41.4% in women), then Pashtuns (23.7% in men and 28.4% in women), Muhajirs (24.1% in men and 24.6% in women), and lowest among Punjabis (17.3% in men and 16.4% in women) and Sindhis (19.0% in men and 9.9% in women) (P = 0.001). While hypertension was more prevalent in urban (22.7%) versus rural dwellers (18.1%) [odds ratio (OR) 1.34; 95% confidence interval (CI), 1.20, 1.49], this difference was no longer significant after adjusting for body mass and waist circumference (OR 1.03; 95% CI, 0.91, 1.16). However, ethnic differences persisted after adjusting for major sociodemographic, dietary and clinical risk factors (unadjusted OR for Baluchi versus Sindhi, 2.92; 95% CI, 2.20-3.89; adjusted OR, 2.71; 95% CI, 1.97-3.75).A threefold difference in prevalence of hypertension exists between people of South Asian descent, which, unlike the urban/rural difference, cannot be accounted for by measured risk factors. Further study would provide valuable etiological and therapeutic clues.

To understand predictors of cardiac arrest early in acute myocardial infarction (AMI), for the Thrombolytic Predictive Instrument, we developed a multivariable regression model predicting primary cardiac arrest using time-dependent variables based on a case-control study of emergency department (ED) patients with AMI: 65 cases with sudden cardiac arrest and 258 without cardiac arrest. Within the first hour of AMI symptom onset, adjusting for age, systolic blood pressure, serum potassium, and infarct size, increased risk of cardiac arrest was associated with electrocardiographic prolonged QTc interval and a greater sum of ST-segment elevation. After 1 hour, the effect of ST-segment elevation was much reduced and the effect of the QTc interval was reversed, so prolonged QTc appeared protective. Accordingly, for patients presenting 30 minutes after chest pain onset, compared with a QTc of 0.44, the risk for cardiac arrest for patients with QTc of 0.50 was more than doubled (odds ratio [OR] 2.20, 95% confidence intervals [CI] 1.17 to 4.13), whereas for those presenting after an hour, it was much lower (e.g., at 1.5 hours, OR 0.21, 95% CI 0.06 to 0.73). Patients presenting 30 minutes after chest pain onset with a sum of ST elevation of 20 mm had a threefold higher risk than patients with a sum of ST elevation of 5 mm (OR 3.37, 95% CI 1.83 to 6.20). However, if presenting 1.5 hours after chest pain onset, the risk was barely elevated (OR 1.18; 95% CI 1.09 to 1.29). Thrombolytic therapy was protective, halving the odds of cardiac arrest (OR 0.51, 95% CI 0.27 to 0.93). Thus, the relation of prolonged QTc interval and substantial ST segment elevation to cardiac arrest in AMI may be obscured because patients with these risks are more likely to die soon after AMI onset, before ED presentation, and are thereby unavailable for study. Those with prolonged QTc or substantial ST elevation who survive the initial 1.5-hour period are those less susceptible to these risks.

Background Knee osteoarthritis (OA) causes pain and long-term disability with annual healthcare costs exceeding $185 billion in the United States. Few medical remedies effectively influence the course of the disease. Finding effective treatments to maintain function and quality of life in patients with knee OA is one of the national priorities identified by the Institute of Medicine. We are currently conducting the first comparative effectiveness and cost-effectiveness randomized trial of Tai Chi versus a physical-therapy regimen in a sample of patients with symptomatic and radiographically confirmed knee OA. This article describes the design and conduct of this trial. Methods/Design A single-center, 52-week, comparative effectiveness randomized controlled trial of Tai Chi versus a standardized physical-therapy regimen is being conducted at an urban tertiary medical center in Boston, Massachusetts. The study population consists of adults ≥ 40 years of age with symptomatic and radiographic knee OA (American College of Rheumatology criteria). Participants are randomly allocated to either 12 weeks of Tai Chi (2x/week) or Physical Therapy (2x/week for 6 weeks, followed by 6 weeks of rigorously monitored home exercise). The primary outcome measure is pain (Western Ontario and McMaster Universities WOMAC) subscale at 12 weeks. Secondary outcomes include WOMAC stkiffness and function domain scores, lower extremity strength and power, functional balance, physical performance tests, psychological and psychosocial functioning, durability effects, health related quality of life, and healthcare utilization at 12, 24 and 52 weeks. Discussion This study will be the first randomized comparative-effectiveness and cost-effectiveness trial of Tai Chi versus Physical Therapy in a large symptomatic knee OA population with long-term follow up. We present here a robust and well-designed randomized comparative-effectiveness trial that also explores multiple outcomes to elucidate the potential mechanisms of mind-body effect for a major disabling disease with substantial health burdens and economic costs. Results of this study are expected to have important public health implications for the large and growing population with knee OA. Trial registration ClinicalTrials.gov identifier: NCT01258985 Electronic supplementary material The online version of this article (doi:10.1186/1472-6882-14-333) contains supplementary material, which is available to authorized users.

It is controversial whether prolonged antibiotic treatment is effective for patients in whom symptoms persist after the recommended antibiotic treatment for acute Lyme disease.We conducted two randomized trials: one in 78 patients who were seropositive for IgG antibodies to Borrelia burgdorferi at the time of enrollment and the other in 51 patients who were seronegative. The patients received either intravenous ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or matching intravenous and oral placebos. Each patient had well-documented, previously treated Lyme disease but had persistent musculoskeletal pain, neurocognitive symptoms, or dysesthesia, often associated with fatigue. The primary outcome measures were improvement on the physical- and mental-health-component summary scales of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36)--a scale measuring the health-related quality of life--on day 180 of the study.After a planned interim analysis, the data and safety monitoring board recommended that the studies be discontinued because data from the first 107 patients indicated that it was highly unlikely that a significant difference in treatment efficacy between the groups would be observed with the planned full enrollment of 260 patients. Base-line assessments documented severe impairment in the patients' health-related quality of life. In intention-to-treat analyses, there were no significant differences in the outcomes with prolonged antibiotic treatment as compared with placebo. Among the seropositive patients who were treated with antibiotics, there was improvement in the score on the physical-component summary scale of the SF-36, the mental-component summary scale, or both in 37 percent, no change in 29 percent, and worsening in 34 percent; among seropositive patients receiving placebo, there was improvement in 40 percent, no change in 26 percent, and worsening in 34 percent (P=0.96 for the comparison between treatment groups). The results were similar for the seronegative patients.There is considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these two trials, treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo.

Proinflammatory cytokines have been implicated in the short- and long-term morbidity experienced by hemodialysis (HD) patients. The present study, which is based on long-term follow-up of a cohort of 37 patients, relates peripheral blood mononuclear cell (PBMC) interleukin-1 receptor antagonist (IL-1Ra) synthesis (a reliable marker of IL-1beta synthesis in HD patients) and plasma levels of an acute phase reactant, lipopolysaccharide binding protein (LBP), to clinical outcomes. In July 1993, predialysis blood samples from these patients were collected and IL-1Ra synthesis by PBMC and plasma LBP was measured. Hospital records were reviewed and patient follow-up data were obtained until December 1997 (54 mo) or death, whichever occurred earlier. The effect of age, diabetes, endotoxin- and IgG-stimulated IL-1Ra synthesis, and plasma LBP levels on mortality was assessed using the Cox proportional hazard regression model. Poisson regression was used to determine potential relationships between the number of outcome events and each continuous risk factor. Twenty-two patients (59%) died during the follow-up period. Mortality was unrelated to IL-1Ra synthesis but did increase with age (relative risk, 1.05/yr; P: = 0.01) and diabetes (relative risk, 3.00/yr; P: = 0.03). Cardiovascular event rates were higher among older individuals and in those with higher endotoxin-stimulated PBMC IL-1Ra synthesis. Cardiovascular events increased with plasma LBP levels in the range of 9,000 to 12,000 pg/ml but then seemed to decrease. In contrast, older age and low IgG-stimulated IL-1Ra synthesis were associated with an increased risk of infectious events. The results of this study demonstrate an interesting link between stimulus-dependent variability in IL-1Ra synthesis by PBMC and clinical outcomes among patients on chronic HD and provide interesting targets for therapeutic interventions in this vulnerable patient population.

Background: Patients suffering from malignant hematological disorders may be at increased risk, when undergoing cardiac surgery. We report on our experiences with ten cardiac procedures in nine patients (3 males, 6 females, 19–85 yr old, mean age 61 yr). Methods and Results: There were two patients with Hodgkin's lymphoma and one patient each with Waldenstrom's syndrome, multiple myeloma, polycythemia, myelodysplasia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma and idiopathic aplastic anemia. Cardiac diseases included coronary artery disease in six, aortic stenosis in two, and mitral insufficiency in one patient. Consecutively, cardiac procedures were coronary artery bypass grafting in six, aortic valve replacement in two, and mitral valve replacement in one patient. No patient died. Postoperatively, one patient suffered from a pericardial tamponade requiring surgical removal and 5 months later from a prosthetic endocarditis necessitating change of the bioprosthesis. One patient developed a superficial wound infection, which was treated conservatively. Four patients received no blood products. Alltogether, we transfused 32 packed red blood cells, seven units of fresh frozen plasma and 16 platelet concentrates. Total drainage loss was 883 ml (250–1510 ml). Conclusions: Cardiac surgery in patients suffering from malignant hematological disorders may be performed, but carries an increased morbidity. Therefore, indications for cardiac procedures must be carefully considered.

Infections remain common life-threatening complications of bone marrow transplantation. To examine clinical factors that affect infection risk, we retrospectively studied patients who received bone marrow transplants (53 autologous and 51 allogeneic). Over a median of 27 hospital days, 44 patients developed documented infections. Both autologous transplantation and hematopoietic growth factor use were associated with less prolonged neutropenia and decreased occurrence of infection (P < or = .05). In a survival regression model, variables independently associated with infection risk were the log10 of the neutrophil count (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.32-0.75), ciprofloxacin prophylaxis (HR, 0.42; 95% CI, 0.19-0.95), empirical intravenous antibiotic use (HR, 0.09; 95% CI, 0.03-0.32), and an interaction between neutrophil count and intravenous antibiotic use (HR, 1.86; 95% CI, 1.06-3.29). In this model, infection risk increases steeply at low neutrophil counts for patients receiving no antibiotic therapy. Ciprofloxacin prophylaxis and particularly intravenous antibiotic therapy provide substantial protection at low neutrophil counts. These results can be used to model management strategies for transplant recipients.