Lifestyle Intervention and Medical Management With vs Without Roux-en-Y Gastric Bypass and Control of Hemoglobin A1c, LDL Cholesterol, and Systolic Blood Pressure at 5 Years in the Diabetes Surgery Study.

Importance: The Roux-en-Y gastric bypass is effective in achieving established diabetes treatment targets, but durability is unknown. Objective: To compare durability of Roux-en-Y gastric bypass added to intensive lifestyle and medical management in achieving diabetes control targets. Design, Setting, and Participants: Observational follow-up of a randomized clinical trial at 4 sites in the United States and Taiwan, involving 120 participants who had a hemoglobin A1c (HbA1c) level of 8.0% or higher and a body mass index between 30.0 and 39.9 (enrolled between April 2008 and December 2011) were followed up for 5 years, ending in November 2016. Interventions: Lifestyle-intensive medical management intervention based on the Diabetes Prevention Program and LookAHEAD trials for 2 years, with and without (60 participants each) Roux-en-Y gastric bypass surgery followed by observation to year 5. Main Outcomes and Measures: The American Diabetes Association composite triple end point of hemoglobin A1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg at 5 years. Results: Of 120 participants who were initially randomized (mean age, 49 years [SD, 8 years], 72 women [60%]), 98 (82%) completed 5 years of follow-up. Baseline characteristics were similar between groups: mean (SD) body mass index 34.4 (3.2) for the lifestyle-medical management group and 34.9 (3.0) for the gastric bypass group and had hemoglobin A1c levels of 9.6% (1.2) and 9.6% (1.0), respectively. At 5 years, 13 participants (23%) in the gastric bypass group and 2 (4%) in the lifestyle-intensive medical management group had achieved the composite triple end point (difference, 19%; 95% CI, 4%-34%; P = .01). In the fifth year, 31 patients (55%) in the gastric bypass group vs 8 (14%) in the lifestyle-medical management group achieved an HbA1c level of less than 7.0% (difference, 41%; 95% CI, 19%-63%; P = .002). Gastric bypass had more serious adverse events than did the lifestyle-medical management intervention, 66 events vs 38 events, most frequently gastrointestinal events and surgical complications such as strictures, small bowel obstructions, and leaks. Gastric bypass had more parathyroid hormone elevation but no difference in B12 deficiency. Conclusions and Relevance: In extended follow-up of obese adults with type 2 diabetes randomized to adding gastric bypass compared with lifestyle and intensive medical management alone, there remained a significantly better composite triple end point in the surgical group at 5 years. However, because the effect size diminished over 5 years, further follow-up is needed to understand the durability of the improvement. Trial Registration: clinicaltrials.gov Identifier: NCT00641251.

Serum and Wound Vancomycin Levels After Intrawound Administration in Primary Total Joint Arthroplasty.

BACKGROUND: Periprosthetic joint infection is the most common cause of readmissions after total joint arthroplasty (TJA). Intrawound vancomycin powder (VP) has reduced infection rates in spine surgery; however, there are no data regarding VP in primary TJA. METHODS: Thirty-four TJA patients received 2 g of VP intraoperatively to investigate VP's pharmacokinetics. Serum and wound concentrations were measured at multiple intervals over 24 hours after closure. RESULTS: All serum concentrations were subtherapeutic (<15µg/mL) and peaked 12 hours after closure (4.7µg/mL; standard deviation [SD], 3.2). Wound concentrations were 922 µg/mL (SD, 523) 3 hours after closure and 207 µg/mL (SD, 317) at 24 hours. VP had a half-life of 7.2 hours (95% confidence interval, 7.0-9.3) in TJA wounds. CONCLUSIONS: VP produced highly therapeutic intrawound concentrations while yielding low systemic levels in TJA. VP may serve as a safe adjunct in the prevention of periprosthetic joint infection.

Normalization of Left Ventricular Ejection Fraction and Incidence of Appropriate Antitachycardia Therapy in Patients With Implantable Cardioverter Defibrillator for Primary Prevention of Sudden Death.

BACKGROUND: Patients with severely depressed left ventricular ejection fractions (LVEFs) receive implantable cardioverter-defibrillators (ICDs) for the primary prevention of sudden death. In some patients, however, LVEF may improve or even normalize over time. Limited data are available on the incidence of appropriate antitachycardia therapy, including pacing and shock, in these patients. METHODS AND RESULTS: We retrospectively identified consecutive patients at our institution with an ICD for primary prevention who had LVEF measurement available at initial implantation and at the time of generator replacement. None of these patients had ever received appropriate antitachycardia therapy before generator replacement. The incidence of appropriate antitachycardia therapy after generator replacement was assessed. Of the 125 patients who received generator replacement, 53 (42%) received an ICD and 72 (58%) a cardiac resynchronization therapy-defibrillator (CRT-D). Among them, 30 (21%) had LVEF normalized to ≥50%, 25 (17%) had LVEF partially improved to 36%-49%, and 70 (63%) had LVEF that remained depressed at ≤35%. During an overall follow-up period of 25 ± 18 months, none of the individuals with normalized LVEF experienced appropriate antitachycardia therapy regardless of ICD or CRT-D. Meanwhile, 20% of patients with LVEF at 36%-49% and 14% of patients with LVEF at ≤35% received appropriate ICD therapy. The omnibus P value for any differences among the 3 LVEF groups was 0.046 for the entire cohort, 0.01 for ICD, and 0.15 for CRT-D patients. CONCLUSIONS: These preliminary data suggest that patients with reduced LVEF and primary-prevention ICDs who normalize their LVEF over time may be at lower risk of appropriate antitachycardia therapy.

Why do families enrol in paediatric weight management? A parental perspective of reasons and facilitators.

BACKGROUND: Few children with obesity who are referred for weight management end up enroled in treatment. Factors enabling enrolment are poorly understood. Our purpose was to explore reasons for and facilitators of enrolment in paediatric weight management from the parental perspective. METHODS: Semi-structured interviews were conducted with parents of 10- to 17-year-olds who were referred to one of four Canadian weight management clinics and enroled in treatment. Interviews were audio-recorded and transcribed verbatim. Manifest/inductive content analysis was used to analyse the data, which included the frequency with which parents referred to reasons for and facilitators of enrolment. RESULTS: In total, 65 parents were interviewed. Most had a child with a BMI ≥95th percentile (n = 59; 91%), were mothers (n = 55; 85%) and had completed some post-secondary education (n = 43; 66%). Reasons for enrolment were related to concerns about the child, recommended care and expected benefits. Most common reasons included weight concern, weight loss expectation, lifestyle improvement, health concern and need for external support. Facilitators concerned the referral initiator, treatment motivation and barrier control. Most common facilitators included the absence of major barriers, parental control over the decision to enrol, referring physicians stressing the need for specialized care and parents' ability to overcome enrolment challenges. CONCLUSIONS: Healthcare providers might optimize enrolment in paediatric weight management by being proactive in referring families, discussing the advantages of the recommended care to meet treatment expectations and providing support to overcome enrolment barriers.

Effect of Hispanic ethnicity and language barriers on appendiceal perforation rates and imaging in children.

OBJECTIVE: To determine the association between Hispanic ethnicity and limited English proficiency (LEP) and the rates of appendiceal perforation and advanced radiologic imaging (computed tomography and ultrasound) in children with abdominal pain. STUDY DESIGN: We performed a secondary analysis of a prospective, cross-sectional, multicenter study of children aged 3-18 years presenting with abdominal pain concerning for appendicitis between March 2009 and April 2010 at 10 tertiary care pediatric emergency departments in the US. Appendiceal perforation and advanced imaging rates were compared between ethnic and language proficiency groups using simple and multivariate regression models. RESULTS: Of 2590 patients enrolled, 1001 (38%) had appendicitis, including 36% of non-Hispanics and 44% of Hispanics. In multivariate modeling, Hispanics with LEP had a significantly greater odds of appendiceal perforation (OR, 1.44; 95% CI, 1.20-1.74). Hispanics with LEP with appendiceal perforation of moderate clinical severity were less likely to undergo advanced imaging compared with English-speaking non-Hispanics (OR, 0.64; 95% CI, 0.43-0.95). CONCLUSION: Hispanic ethnicity with LEP is an important risk factor for appendiceal perforation in pediatric patients brought to the emergency department with possible appendicitis. Among patients with moderate clinical severity, Hispanic ethnicity with LEP appears to be associated with lower imaging rates. This effect of English proficiency and Hispanic ethnicity warrants further investigation to understand and overcome barriers, which may lead to increased appendiceal perforation rates and differential diagnostic evaluation.

Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial.

IMPORTANCE: Controlling glycemia, blood pressure, and cholesterol is important for patients with diabetes. How best to achieve this goal is unknown. OBJECTIVE: To compare Roux-en-Y gastric bypass with lifestyle and intensive medical management to achieve control of comorbid risk factors. DESIGN, SETTING, AND PARTICIPANTS: A 12-month, 2-group unblinded randomized trial at 4 teaching hospitals in the United States and Taiwan involving 120 participants who had a hemoglobin A1c (HbA1c) level of 8.0% or higher, body mass index (BMI) between 30.0 and 39.9, C peptide level of more than 1.0 ng/mL, and type 2 diabetes for at least 6 months. The study began in April 2008. INTERVENTIONS: Lifestyle-intensive medical management intervention and Roux-en-Y gastric bypass surgery. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol and surgical techniques that were standardized. MAIN OUTCOMES AND MEASURES: Composite goal of HbA1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg. RESULTS: All 120 patients received the intensive lifestyle-medical management protocol and 60 were randomly assigned to undergo Roux-en-Y gastric bypass. After 12-months, 28 participants (49%; 95% CI, 36%-63%) in the gastric bypass group and 11 (19%; 95% CI, 10%-32%) in the lifestyle-medical management group achieved the primary end points (odds ratio [OR], 4.8; 95% CI, 1.9-11.7). Participants in the gastric bypass group required 3.0 fewer medications (mean, 1.7 vs 4.8; 95% CI for the difference, 2.3-3.6) and lost 26.1% vs 7.9% of their initial body weigh compared with the lifestyle-medical management group (difference, 17.5%; 95% CI, 14.2%-20.7%). Regression analyses indicated that achieving the composite end point was primarily attributable to weight loss. There were 22 serious adverse events in the gastric bypass group, including 1 cardiovascular event, and 15 in the lifestyle-medical management group. There were 4 perioperative complications and 6 late postoperative complications. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group. CONCLUSIONS AND RELEVANCE: In mild to moderately obese patients with type 2 diabetes, adding gastric bypass surgery to lifestyle and medical management was associated with a greater likelihood of achieving the composite goal. Potential benefits of adding gastric bypass surgery to the best lifestyle and medical management strategies of diabetes must be weighed against the risk of serious adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00641251.

The RNP domain: a sequence-specific RNA-binding domain involved in processing and transport of RNA.

The RNP domain is found in a number of proteins involved in processing and transport of mRNA precursors. The crystal structure of a complex between the U1A spliceosomal protein and its cognate RNA hairpin at 1.92 A resolution reveals the molecular basis of sequence-specific RNA recognition by the RNP domain.

Serum FABP4 concentrations decrease after Roux-en-Y gastric bypass but not after intensive medical management.

BACKGROUND: Serum concentrations of fatty acid binding protein 4, an adipose tissue fatty acid chaperone, have been correlated with insulin resistance and cardiovascular risk factors. The objective of this study were to assess relationships among Roux-en-Y gastric bypass, intensive lifestyle modification and medical management protocol, fatty acid binding protein 4, and metabolic parameters in obese patients with severe type 2 diabetes mellitus; and to evaluate the relative contribution of abdominal subcutaneous adipose and visceral adipose to the secretion of fatty acid binding protein 4. METHODS: Participants were randomly assigned to intensive lifestyle modification and medical management protocol (n = 29) or to intensive lifestyle modification and medical management protocol augmented with Roux-en-Y gastric bypass (n = 34). Relationships among fatty acid binding protein 4 and demographic characteristics, metabolic parameters, and 12-month changes in these values were examined. Visceral and subcutaneous adipose tissue explants from obese nondiabetic patients (n = 5) were obtained and treated with forskolin to evaluate relative secretion of fatty acid binding protein 4 in the different adipose tissue depots. RESULTS: The intensive lifestyle modification and medical management protocol and Roux-en-Y gastric bypass cohorts had similar fasting serum fatty acid binding protein 4 concentrations at baseline. At 1 year, mean serum fatty acid binding protein 4 decreased by 42% in Roux-en-Y gastric bypass participants (P = .002) but did not change significantly in the intensive lifestyle modification and medical management protocol cohort. Percentage of weight change was not a significant predictor of 12-month fatty acid binding protein 4 within treatment arm or in multivariate models adjusted for treatment arm. In adipose tissue explants, fatty acid binding protein 4 was secreted similarly between visceral and subcutaneous adipose tissue. CONCLUSION: After Roux-en-Y gastric bypass, fatty acid binding protein 4 is reduced 12 months after surgery but not after intensive lifestyle modification and medical management protocol in patients with type 2 diabetes mellitus. Fatty acid binding protein 4 was secreted similarly between subcutaneous and visceral adipose tissue explants.

Reduced-intensity allogeneic transplant in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor.

The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. Unrelated umbilical cord blood (UCB) has been investigated as an alternative stem cell source to suitably HLA matched related (MRD) and adult volunteer unrelated donors. We hypothesized that RIC HCT using UCB would be safe and efficacious in older patients, and compared the treatment-related mortality (TRM) and overall survival (OS) of RIC HCT in patients older than 55 years using either MRD (n = 47) or, in patients with no 5 of 6 or 6 of 6 HLA compatible related donors, UCB (n = 43). RIC regimen consisted of total-body irradiation (TBI; 200 cGy) and either cyclophosphamide and fludarabine (n = 69), or busulfan and fludarabine (n = 16) or busulfan and cladribine (n = 5). The median age of MRD and UCB cohorts was 58 (range, 55-70) and 59 (range, 55-69) years, respectively. acute myelogenous leukemia/myelodysplastic syndrome (AML/MDS) (50%) was the most common diagnosis. All MRD grafts were 6 of 6 HLA matched to the recipient. Among patients undergoing UCB HCT, 88% received 2 UCB units to optimize cell dose and 93% received 1-2 HLA mismatched grafts. The median follow-up for survivors was 27 (range: 12-61) months. The 3-year probabilities of progression-free survival (PFS; 30% versus 34%, P = .98) and OS (43% versus 34%, P = .57) were similar for recipients of MRD and UCB. The cumulative incidence of grade II-IV acute graft-versus-host (aGVHD) disease (42% versus 49%, P = .20) and TRM at 180-days (23% versus 28%, P = .36) were comparable. However, UCB recipients had a lower incidence of chronic graft-versus-host disease (cGVHD) at 1 year (40% versus 17%, P = .02). On multivariate analysis, graft type had no impact on TRM or survival, and the HCT comorbidity index score was the only factor independently predictive for these endpoints. Our study supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have an MRD. The use of RIC and UCB extends the availability of transplant therapy to older patients previously excluded on the basis of age and lack of a suitable MRD. A careful review of existing comorbidities is necessary when considering older patients for HCT.

Allogeneic hematopoietic cell transplantation in children with relapsed acute lymphoblastic leukemia isolated to the central nervous system.

Allogeneic hematopoietic cell transplantation (HCT) is the standard of care for pediatric patients with early medullary relapse of acute lymphoblastic leukemia (ALL). Most patients with isolated central nervous system (CNS) relapse have good outcomes when treated with intrathecal and systemic chemotherapy followed by irradiation to the neuroaxis. However, the role of HCT remains unclear for those patients with early isolated CNS relapse (<18 months) or who had high risk disease at diagnosis. We therefore compared the HCT outcomes of 116 children treated at the University of Minnesota from 1991 to 2006 with relapsed ALL involving the CNS alone (CNS, n = 14), the bone marrow alone (BM, n = 85), or both bone marrow and CNS (BM + CNS, n = 17). There were no significant differences among groups in age at diagnosis or transplant, length of first complete remission (CR1), remission status (CR2 versus >or=CR3), graft source, or preparative regimen. The incidence of acute GVHD was similar between groups. Patients with isolated CNS relapse had the lowest cumulative incidence of mortality following transplant (CNS: 0%, BM: 19%, BM + CNS: 29%, P = .03) and relapse (CNS: 0% BM: 30%, BM + CNS: 12%, at 2 years, P = .01) and highest leukemia-free survival (CNS: 91%, BM: 35%, BM + CNS: 46%, P < .01) at 5 years. Risk factors for poor survival were: T cell leukemia or BCR-ABL gene rearrangement, history of marrow relapse, and receipt of HLA-mismatched marrow. These data support the use of allogeneic HCT in the treatment of children with poor prognosis isolated CNS relapse.

Vitamin D Levels Do Not Predict Risk of Metatarsal Fractures.

INTRODUCTION: In the literature, there is conflicting data regarding the relationship between vitamin D and fractures. Reports on the effects of vitamin D levels on pathologies of the foot and ankle are limited. The purpose of this study is to assess the prevalence of vitamin D insufficiency in patients who have sustained low-energy metatarsal fractures compared to foot or ankle sprains without osseous involvement. METHODS: Between May 2012 and August 2014, vitamin D levels and demographic data were collected prospectively in a total of 99 patients; 71 with metatarsal fractures and 28 with sprains, both from a low-energy mechanism of injury. Data between the metatarsal fracture group and sprain group were compared through univariate and multivariate analyses. RESULTS: Mean vitamin D in the fracture group was 26.9 ng/mL (range = 78.0-4.3), and in the sprain group it was 27.1 ng/mL (range = 64.1-8.3; P = .93). Vitamin D insufficiency (<30 ng/mL) was present in 47 (66%) of fracture patients and 20 (71%) of sprain patients ( P = .81). CONCLUSION: A high incidence of hypovitaminosis D was seen in all foot and ankle patients. There was no difference in mean vitamin D level or incidence of vitamin D insufficiency between patients with metatarsal fractures or sprains resulting from similar low-energy mechanisms. LEVELS OF EVIDENCE: Level III: Prospective, case-control study.

Opioid Use During Pregnancy, Observations of Opioid Use, and Secular Trend From 2006 to 2014 at HealthPartners Medical Group.

OBJECTIVES: To determine the prevalence of opioid use before, during, and after pregnancy and describe its use based on patient-specific characteristics. Determine secular trend of opioid use 2006 to 2014. MATERIALS AND METHODS: Retrospective cohort study. A large Upper Midwest integrated health care system and insurer. Female individuals age 10 to 50 years with a delivery diagnosis from July 1, 2006 through June 30, 2014. MAIN OUTCOME MEASURE: prevalence of opioid use before, during, and after pregnancy; description of opioid use during these time periods. RESULTS: From 11,565 deliveries among 9690 unique women, 862 (7.5%) deliveries were associated with significant opioid use. Significant opioid use was associated with single marital status, Cesarean section, Medicaid coverage, tobacco use, depression, anxiety, bipolar disorder, substance use disorder, nonopioid analgesic use, and referral to physical therapy, psychotherapy, or pain specialists. From 2006 to 2014 opioid use decreased from 9% to 6% before, during, and after pregnancy with a rate of change per year of -0.2%. DISCUSSION: Known risk factors including tobacco and alcohol use, mental health diagnoses, substance use disorder, or Medicaid enrollment may enable enhanced assessments and targeted interventions to reduce unnecessary prescribing and use of opioids among pregnant women and those who might become pregnant. Strategies to decrease opioid use during pregnancy should be considered by health care systems and health plans to reduce opioid prescribing in this patient population.

Factors affecting exhaled nitric oxide measurements: the effect of sex.

BACKGROUND: Exhaled nitric oxide (F(E)NO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect F(E)NO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting F(E)NO in a well characterised adult population. METHODS: Data were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on F(E)NO were explored by unadjusted and adjusted linear regression analyses. RESULTS: The effect of sex on F(E)NO was both statistically and clinically significant, with F(E)NO levels approximately 25% less in females. Overall, current smoking reduced F(E)NO up to 50%, but this effect occurred predominantly in those who smoked on the day of the F(E)NO measurement. Atopy increased F(E)NO by 60%. The sex-related differences in F(E)NO remained significant (p < 0.001) after controlling for all other significant factors affecting F(E)NO. CONCLUSION: Even after adjustment, F(E)NO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.

Predicting neutropenia risk in patients with cancer using electronic data.

OBJECTIVES: Clinical guidelines recommending the use of myeloid growth factors are largely based on the prescribed chemotherapy regimen. The guidelines suggest that oncologists consider patient-specific characteristics when prescribing granulocyte-colony stimulating factor (G-CSF) prophylaxis; however, a mechanism to quantify individual patient risk is lacking. Readily available electronic health record (EHR) data can provide patient-specific information needed for individualized neutropenia risk estimation. An evidence-based, individualized neutropenia risk estimation algorithm has been developed. This study evaluated the automated extraction of EHR chemotherapy treatment data and externally validated the neutropenia risk prediction model. MATERIALS AND METHODS: A retrospective cohort of adult patients with newly diagnosed breast, colorectal, lung, lymphoid, or ovarian cancer who received the first cycle of a cytotoxic chemotherapy regimen from 2008 to 2013 were recruited from a single cancer clinic. Electronically extracted EHR chemotherapy treatment data were validated by chart review. Neutropenia risk stratification was conducted and risk model performance was assessed using calibration and discrimination. RESULTS: Chemotherapy treatment data electronically extracted from the EHR were verified by chart review. The neutropenia risk prediction tool classified 126 patients (57%) as being low risk for febrile neutropenia, 44 (20%) as intermediate risk, and 51 (23%) as high risk. The model was well calibrated (Hosmer-Lemeshow goodness-of-fit test = 0.24). Discrimination was adequate and slightly less than in the original internal validation (c-statistic 0.75 vs 0.81). CONCLUSION: Chemotherapy treatment data were electronically extracted from the EHR successfully. The individualized neutropenia risk prediction model performed well in our retrospective external cohort.

National Differences in Remission of Type 2 Diabetes Mellitus After Roux-en-Y Gastric Bypass Surgery-Subgroup Analysis of 2-Year Results of the Diabetes Surgery Study Comparing Taiwanese with Americans with Mild Obesity (BMI 30-35 kg/m2).

BACKGROUND: The purpose of this study is to compare effects of different nations on Roux-en-Y gastric bypass (RYGB) vs. intensive medical management (IMM) in achieving remission of type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Between April 2008 and December 2011, this randomized, controlled clinical trial was conducted at four teaching hospitals in the United States and Taiwan involving 71 participants with mild obesity (BMI 30-35 kg/m2). Thirty-six of 71 participants were randomly assigned to the RYGB group, and the others were in IMM group. Partial or complete remission of T2DM was defined as blood HbA1c < 6.5 % (48 mmol/mol) or <6 % (42 mmol/mol) without any antihyperglycemic medication for at least 1-year duration, respectively. RESULTS: At baseline, Taiwanese participants had a lower BMI, younger age, and shorter duration of T2DM than American participants. At 24 months, weight loss was greater in the RYGB group in both populations than in the IMM group. No IMM participant of either population had partial or complete remission of T2DM. In the RYGB group, a substantial proportion of the subjects achieved complete or partial remission (57 % in Taiwanese and 27 % in American participants, P = 0.08). Logistic regression revealed stimulated C-peptide (Odds ratio 2.22, P = 0.02) but not nationality as a significant predictor of diabetes remission. CONCLUSION: Adding RYGB to lifestyle and medical management was associated with a greater likelihood of remission of T2DM in both Taiwanese and American subjects with mild obesity with type 2 diabetes. Residual beta-cell function at baseline appears to be the major factor predicting remission of T2DM. Trial registry number: clinicaltrials.gov Identifier: NCT00641251.

Two structurally different RNA molecules are bound by the spliceosomal protein U1A using the same recognition strategy.

BACKGROUND: Human U1A protein binds to hairpin II of U1 small nuclear RNA (snRNA) and, together with other proteins, forms the U1 snRNP essential in pre-mRNA splicing. U1A protein also binds to the 3' untranslated region (3'UTR) of its own pre-mRNA, inhibiting polyadenylation of the 3'end and thereby downregulating its own expression. The 3'UTR folds into an evolutionarily conserved secondary structure with two internal loops; one loop contains the sequence AUUGCAC and the other its variant AUUGUAC. The sequence AUUGCAC is also found in hairpin II of U1 snRNA; hence, U1A protein recognizes the same heptanucleotide sequence in two different structural contexts. In order to better understand the control mechanism of the polyadenylation process, we have built a model of the U1A protein-3'UTR complex based on the crystal structure of the U1A protein-hairpin II RNA complex which we determined previously. RESULTS: In the crystal structure of the U1A protein-hairpin II RNA complex the AUUGCAC sequence fits tightly into a groove on the surface of U1A protein. The conservation of the heptanucleotide in the 3'UTR strongly suggests that U1A protein forms identical sequence-specific contacts with the heptanucleotide sequence when complexed with the 3'UTR. The crystal structure of the hairpin II complex and the twofold symmetry in the 3'UTR RNA provide sufficient information to restrict the conformation of the 3'UTR RNA and have enabled us to build a model of the 3'UTR complex. CONCLUSIONS: In the U1A-3'UTR complex, sequence-specific interactions are made entirely by the conserved heptanucleotide and the last base pair (C:G) of the stem. The structure is stabilized by protein-protein contacts and by electrostatic interactions between basic amino acids of the protein and the phosphate backbone of the RNA stem regions. The formation of a protein dimer necessary for the inhibition of poly(A) polymerase requires a conformational change of the C termini of the proteins upon RNA binding. This mechanism could prevent the inhibition of poly(A) polymerase by free U1A protein. The model is consistent with biochemical data, and the protein-protein interactions within the 3'UTR complex account for the cooperativity of U1A protein binding to the 3'UTR. The model also serves as an important structural guide for designing further experiments to understand the interaction between the U1A-3'UTR complex and poly(A) polymerase.

Modeled Health and Economic Impact of Team-Based Care for Hypertension.

INTRODUCTION: Team-based interventions for hypertension care have been widely studied and shown effective in improving hypertension outcomes. Few studies have evaluated long-term effects of these interventions; none have assessed broad-scale implementation. This study estimates the prospective health, economic, and budgetary impact of universal adoption of a team-based care intervention model that targets people with treated but uncontrolled hypertension in the U.S. METHODS: Analysis was conducted in 2014-2015 using a microsimulation model, constructed with various data sources from 1948 to 2014, designed to evaluate prospective cardiovascular disease (CVD)-related interventions in the U.S. POPULATION: Ten-year primary outcomes included prevalence of uncontrolled hypertension; incident myocardial infarction, stroke, CVD events, and CVD-related mortality; intervention and net medical costs by payer; productivity; and quality-adjusted life years. RESULTS: About 4.7 million (13%) fewer people with uncontrolled hypertension and 638,000 prevented cardiovascular events would be expected over 10 years. Assuming $525 per enrollee, implementation would cost payers $22.9 billion, but $25.3 billion would be saved in averted medical costs. Estimated net cost savings for Medicare approached $5.8 billion. Net costs were especially sensitive to intervention costs, with break-even thresholds of $300 (private), $450 (Medicaid), and $750 (Medicare). CONCLUSIONS: Nationwide adoption of team-based care for uncontrolled hypertension could have sizable effects in reducing CVD burden. Based on the study's assumptions, the policy would be cost saving from the perspective of Medicare and may prove to be cost effective from other payers' perspectives. Expected net cost savings for Medicare would more than offset expected net costs for all other insurers.

Durability of Addition of Roux-en-Y Gastric Bypass to Lifestyle Intervention and Medical Management in Achieving Primary Treatment Goals for Uncontrolled Type 2 Diabetes in Mild to Moderate Obesity: A Randomized Control Trial.

OBJECTIVE: We compared 3-year achievement of an American Diabetes Association composite treatment goal (HbA1c <7.0%, LDL cholesterol <100 mg/dL, and systolic blood pressure <130 mmHg) after 2 years of intensive lifestyle-medical management intervention, with and without Roux-en-Y gastric bypass, with one additional year of usual care. RESEARCH DESIGN AND METHODS: A total of 120 adult participants, with BMI 30.0-39.9 kg/m(2) and HbA1c ≥8.0%, were randomized 1:1 to two treatment arms at three clinical sites in the U.S. and one in Taiwan. All patients received the lifestyle-medical management intervention for 24 months; half were randomized to also receive gastric bypass. RESULTS: At 36 months, the triple end point goal was met in 9% of lifestyle-medical management patients and 28% of gastric bypass patients (P = 0.01): 10% and 19% lower than at 12 months. Mean (SD) HbA1c values at 3 years were 8.6% (3.5) and 6.7% (2.0) (P < 0.001). No lifestyle-medical management patient had remission of diabetes at 36 months, whereas 17% of gastric bypass patients had full remission and 19% had partial remission. Lifestyle-medical management patients used more medications than gastric bypass patients: mean (SD) 3.8 (3.3) vs. 1.8 (2.4). Percent weight loss was mean (SD) 6.3% (16.1) in lifestyle-medical management vs. 21.0% (14.5) in gastric bypass (P < 0.001). Over 3 years, 24 serious or clinically significant adverse events were observed in lifestyle-medical management vs. 51 with gastric bypass. CONCLUSIONS: Gastric bypass is more effective than lifestyle-medical management intervention in achieving diabetes treatment goals, mainly by improved glycemic control. However, the effect of surgery diminishes with time and is associated with more adverse events.

Crystallization of RNA-protein complexes. I. Methods for the large-scale preparation of RNA suitable for crystallographic studies.

In vitro transcription using bacteriophage RNA polymerases and linearised plasmid or oligodeoxynucleotide templates has been used extensively to produce RNA for biochemical studies. This method is, however, not ideal for generating RNA for crystallisation because efficient synthesis requires the RNA to have a purine rich sequence at the 5' terminus, also the subsequent RNA is heterogenous in length. We have developed two methods for the large scale production of homogeneous RNA of virtually any sequence for crystallization. In the first method RNA is transcribed together with two flanking intramolecularly-, (cis-), acting ribozymes which excise the desired RNA sequence from the primary transcript, eliminating the promoter sequence and heterogeneous 3' end generated by run-off transcription. We use a combination of two hammerhead ribozymes or a hammerhead and a hairpin ribozyme. The RNA-enzyme activity generates few sequence restrictions at the 3' terminus and none at the 5' terminus, a considerable improvement on current methodologies. In the second method the BsmAI restriction endonuclease is used to linearize plasmid template DNA thereby allowing the generation of RNA with any 3' end. In combination with a 5' cis-acting hammerhead ribozyme any sequence of RNA may be generated by in vitro transcription. This has proven to be extremely useful for the synthesis of short RNAs.

Solution structure of the N-terminal RNP domain of U1A protein: the role of C-terminal residues in structure stability and RNA binding.

The solution structure of a fragment of the human U1A spliceosomal protein containing residues 2 to 117 (U1A117) determined using multi-dimensional heteronuclear NMR is presented. The C-terminal region of the molecule is considerably more ordered in the free protein than thought previously and its conformation is different from that seen in the crystal structure of the complex with U1 RNA hairpin II. The residues between Asp90 and Lys98 form an alpha-helix that lies across the beta-sheet, with residues IIe93, IIe94 and Met97 making contacts with Leu44, Phe56 and IIe58. This interaction prevents solvent exposure of hydrophobic residues on the surface of the beta-sheet, thereby stabilising the protein. Upon RNA binding, helix C moves away from this position, changing its orientation by 135 degrees to allow Tyr13, Phe56 and Gln54 to stack with bases of the RNA, and also allowing Leu44 to contact the RNA. The new position of helix C in the complex with RNA is stabilised by hydrophobic interactions from IIe93 and IIe94 to IIe58, Leu 41, Val62 and His 10, as well as a hydrogen bond between Ser91 and Thr11. The movement of helix C mainly involves changes in the main-chain torsion angles of Thr89, Asp90 and Ser91, the helix thereby acting as a "lid" over the RNA binding surface.