Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study.

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.

Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses.

BACKGROUND: Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). METHODS AND FINDINGS: Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86-0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34-0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90-1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40-0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. CONCLUSIONS: In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon.

Can components of the plasminogen activation system predict the outcome of kidney transplants?

Proteolytic and antiproteolytic enzymes play a critical role in the physiology and pathology of different stages of human life. One of the important members of the proteolytic family is the plasminogen activation system (PAS), which includes several elements crucial for this review: the 50 kDa glycoprotein plasminogen activator inhibitor 1 (PAI-1) that inhibits tissue-type (tPA) and urokinase-type plasminogen activator (uPA). These two convert plasminogen into its active form named plasmin that can lyse a broad spectrum of proteins. Urokinase receptor (uPAR) is the binding site of uPA. This glycoprotein on the cell surface facilitates urokinase activation of plasminogen, creating high proteolytic activity close to the cell surface. PAS activities have been reported to predict the outcome of kidney transplants. However, reports on expression of PAS in kidney transplants seem to be controversial. On the one hand there are reports that impaired proteolytic activity leads to induction of chronic allograft nephropathy, while on the other hand treatment with uPA and tPA can restore function of acute renal transplants. In this comprehensive review we describe the complexity of the PAS as well as biological effects of the PAS on renal allografts, and provide a possible explanation of the reported controversy.

Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.

Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.

A penal problem: the increasing incidence of implantation of penile foreign bodies.

Our objective is to describe a novel presentation of subcutaneous penile insertion of foreign bodies. This is a practice performed globally and mostly has been reported outside of the United States. We present three cases of incarcerated males that implanted sculpted dominos into the penile subcutaneous tissue. The patients presented with erosion of the foreign bodies through the skin without evidence of infection. We believe that insertion of foreign bodies into penile subcutaneous tissue by incarcerated American males for sexual enhancement is more widespread than previously reported. Erosion is a novel presentation.

Advancing maternal survival in the global context: are our strategies working?

There have been significant gains in improving maternal mortality over the last two decades. Researchers have suggested a variety of interventions and mechanisms to explain these improvements. While it is likely that much of what has been done in research and programs has contributed to this decline, the evidence regarding what works in the settings in which women deliver continues to face many challenges. We review the evidence for these improvements and suggest that there remain areas to focus on, particularly the births which currently take place in an unsupervised or substandard environments. We highlight the main areas where more evidence is needed, and end with a call to determine which of our interventions seem to have the most benefit; which do not; and where to invest future resources.

Global health education in U.S. medical schools.

Interest in global health (GH) among medical students worldwide is measurably increasing. There is a concomitant emphasis on emphasizing globally-relevant health professions education. Through a structured literature review, expert consensus recommendations, and contact with relevant professional organizations, we review the existing state of GH education in US medical schools for which data were available. Several recommendations from professional societies have been developed, along with a renewed emphasis on competencies in global health. The implementation of these recommendations was not observed as being uniform across medical schools, with variation noted in the presence of global health curricula. Recommendations for including GH in medical education are suggested, as well as ways to formalize GH curricula, while providing flexibility for innovation and adaptation.

Medicolegal Cases in Bariatric Surgery in the United Kingdom.

PURPOSE OF REVIEW: To evaluate the current state of bariatric medicolegal activity and explore the reasons of litigation in bariatric surgery. The underlying legal principles in bariatric medicolegal cases and most frequent pitfalls will also be discussed. RECENT FINDINGS: There is a growing number of litigations in bariatric surgery, particularly relating to complications and long waiting lists for bariatric surgery within the public-funded health systems. The main issues are related to consent, lack of follow-up, delayed identification of complications and lack of appropriate emergency management of complications, involving bariatric surgeons, clinicians, general practitioners and multidisciplinary team members. Appropriate multidisciplinary involvement pre- and postoperatively and robust follow-up protocols can help to mitigate the risks. Bariatric surgery requires a unique paradigm with a multidisciplinary approach both pre- and postoperatively to improve the long-term functional outcomes of patients. There is a rising incidence of medicolegal claims following bariatric surgery. The underlying reasons for this are multifactorial including an increase in the volume of surgery, high patient expectations, the incidence of long-term postoperative complications and the requirement of long-term follow-up.

Gastrojejunostomy Closure Technique and Risk of Leak: an Evaluation in Ex Vivo Porcine Models.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed bariatric operations worldwide. Leaks following RYGB are rare, but the consequences can be devastating. Although most leaks occur at the gastrojejunostomy (GJ) anastomosis, there is a lack of data on modifiable technical factors that can reduce the risk of leaks. Therefore, we evaluated whether the leak pressure of a GJ linear stapled anastomosis is dependent on the closure technique. METHODS: Two expert surgeons constructed gastric pouches and GJ anastomoses on ex vivo porcine models in a laparoscopic simulator using 30-mm and 45-mm endoscopic staplers. The GJ anastomosis was closed using either a single layer suture, double layer suture or stapler. The endpoints were leak pressure to air insufflation, measured by two independent observers, site of leak and internal circumference of the GJ anastomosis. RESULTS: In total, 30 GJ anastomoses were constructed (30 mm, n = 15; 45 mm, n = 15). The GJ anastomosis was closed using single layer (n = 9), double layer (n = 9) and stapled techniques (n = 12). Inter-observer agreement was high. Stapled and double layer closures were more resilient than a single layer closure, with 75% (9/12) stapled closures remaining intact at < 70 mmHg. GJ stoma circumference was lower using a 30-mm stapler (64.8 mm vs 80.2 mm; p < 0.05) but independent of closure technique. The most common leak site was the corner of the closure (67%). CONCLUSION: In summary, the GJ anastomosis closure technique may be a modifiable factor to prevent anastomotic leak.

Bariatric surgery provision in response to the COVID-19 pandemic: retrospective cohort study of a national registry.

BACKGROUND: When surgery resumed following the outbreak of the COVID-19 pandemic, guidelines recommended the prioritization of patients with greater obesity-related co-morbidities and/or higher body mass index. OBJECTIVE: The aim of this study was to record the effect of the pandemic on total number, patient demographics, and perioperative outcomes of elective bariatric surgery patients in the United Kingdom. SETTING AND METHODS: The United Kingdom National Bariatric Surgical Registry was used to identify patients who underwent elective bariatric surgery during the pandemic (1 yr from April 1, 2020). Characteristics of this group were compared with those of a pre-pandemic cohort. Primary outcomes were case volume, case mix, and providers. National Health Service cases were analyzed for baseline health status and perioperative outcomes. Fisher exact, χ2, and Student t tests were used as appropriate. RESULTS: The total number of cases decreased to one third of pre-pandemic volume (8615 to 2930). The decrease in operating volume varied, with 36 hospitals (45%) experiencing a 75%-100% reduction. Cases performed in the National Health Service fell from 74% to 53% (P < .0001). There was no change in baseline body mass index (45.2 ± 8.3 kg/m2 from 45.5 ± 8.3 kg/m2; P = .23) or prevalence of type 2 diabetes (26% from 26%; P = .99). Length of stay (median 2 d) and surgical complication rate (1.4% from 2.0%; relative risk = .71; 95% CI .45-1.12; P = .13) were unchanged. CONCLUSIONS: In the context of a dramatic reduction in elective bariatric surgery due to the COVID-19 pandemic, patients with more severe co-morbidities were not prioritized for surgery. These findings should inform preparation for future crises.

Clinical characteristics of patients undergoing primary bariatric surgery in the United Kingdom based on the National Bariatric Surgery Registry.

Baseline demographic characteristics and operations undertaken for patients having bariatric surgery in the United Kingdom are largely unknown. This study aimed to describe the profile of patients having primary bariatric surgery in the National Health Service (NHS) or by self-pay, and associated operations performed for both pathways. The National Bariatric Surgery Registry dataset for 5 years between January 2015 and December 2019 was used. 34 580 patients underwent primary bariatric surgery, of which 75.9% were NHS patients. Mean patient age and initial body mass index were significantly higher for NHS compared to self-pay patients (mean age 45.8 ± 11.3 [SD] vs. 43.0 ± 12.0 years and initial body mass index 48.0 ± 7.9 vs. 42.9 ± 7.3 kg/m2 , p < .001). NHS patients were more likely to have obesity-related complications compared to self-pay patients: prevalence of Type 2 diabetes mellitus 27.7% versus 8.3%, hypertension 37.1% versus 20.1%, obstructive sleep apnoea 27.4% versus 8.9%, severely impaired functional status 19.3% versus 13.9%, musculoskeletal pain 32.5% versus 20.1% and being on medication for depression 31.0% versus 25.9%, respectively (all p < .001). Gastric bypass was the most commonly performed primary NHS bariatric operation 57.2%, but sleeve gastrectomy predominated in self-pay patients 48.7% (both p < .001). In contrast to self-pay patients, NHS patients are receiving bariatric surgery only once they are older and at a much more advanced stage of obesity-related disease complications.

Impact of Moderate Aortic Stenosis in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Afterload from moderate aortic stenosis (AS) may contribute to adverse outcomes in patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: The authors evaluated clinical outcomes in patients with HFrEF and moderate AS relative to those without AS and with severe AS. METHODS: Patients with HFrEF, defined by left ventricular ejection fraction (LVEF) <50% and no, moderate, or severe AS were retrospectively identified. The primary endpoint, defined as a composite of all-cause mortality and heart failure (HF) hospitalization, was compared across groups and within a propensity score-matched cohort. RESULTS: We included 9,133 patients with HFrEF, of whom 374 and 362 had moderate and severe AS, respectively. Over a median follow-up time of 3.1 years, the primary outcome occurred in 62.7% of patients with moderate AS vs 45.9% with no AS (P < 0.0001); rates were similar with severe and moderate AS (62.0% vs 62.7%; P = 0.68). Patients with severe AS had a lower incidence of HF hospitalization (36.2% vs 43.6%; P < 0.05) and were more likely to undergo AVR within the follow-up period. Within a propensity score-matched cohort, moderate AS was associated with an increased risk of HF hospitalization and mortality (HR: 1.24; 95% CI: 1.04-1.49; P = 0.01) and fewer days alive outside of the hospital (P < 0.0001). Aortic valve replacement (AVR) was associated with improved survival (HR: 0.60; CI: 0.36-0.99; P < 0.05). CONCLUSIONS: In patients with HFrEF, moderate AS is associated with increased rates of HF hospitalization and mortality. Further investigation is warranted to determine whether AVR in this population improves clinical outcomes.

Refining the association of MHC with multiple sclerosis in African Americans.

Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system mediated by autoimmune and neurodegenerative pathogenic mechanisms. Multiple genes account for its moderate heritability, but the only genetic region shown to have a large replicable effect on MS susceptibility is the major histocompatibility complex (MHC). Strong linkage disequilibrium (LD) across the MHC has made it difficult to fully characterize individual genetic contributions of this region to MS risk in previous studies. African Americans are at a lower risk for MS when compared with northern Europeans and Americans of European descent, but greater haplotypic diversity and distinct patterns of LD suggest that this population may be particularly informative for fine-mapping efforts. To examine the role of the MHC in African American MS, a case-control association study was performed with 499 African American MS patients and 750 African American controls that were genotyped for 6040 MHC region single nucleotide polymorphisms (SNPs). A replication data set consisting of 451 African American patients and 718 African American controls was genotyped for selected SNPs. Two MHC class II SNPs, rs2647040 and rs3135021, were significant in the replication cohort and partially tagged DRB1*15 alleles. Surprisingly, in comparison to similar studies of individuals of European descent, the MHC seems to play a smaller role in MS susceptibility in African Americans, consistent with pervasive genetic heterogeneity across ancestral groups, and may explain the difference in MS susceptibility between African Americans and individuals of European descent.

Long-Term Quality of Life Outcomes After Laparoscopic Sleeve Gastrectomy and Roux-en-Y Gastric Bypass-a Comparative Study.

Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) have been shown to improve metabolic comorbidities as well as quality of life (QoL) in the obese population. The vast majority of previous studies have investigated the metabolic effects of bariatric surgery and there is a dearth of studies examining long-term QoL outcomes post bariatric surgery. The outcomes of 43 patients who underwent bariatric surgery were prospectively assessed, using BAROS questionnaires to quantify QoL and metabolic status pre-operatively, at 1 year and at 8 years. Total weight loss and comorbidity resolution were similar between RYGB and SG. The RYGB cohort experienced greater QoL improvement from baseline and had higher BAROS scores at 8 years. RYGB may provide more substantial and durable long-term benefits as compared to SG.

Obstructive sleep apnea remission following bariatric surgery: a national registry cohort study.

BACKGROUND: Obstructive sleep apnea (OSA) is strongly associated with metabolic syndrome. Bariatric surgery is an effective available treatment for OSA; however, limited research predicts which patients undergoing bariatric surgery will undergo OSA resolution. OBJECTIVES: To determine perioperative predictors for OSA resolution following bariatric surgery using a national database. SETTING: United Kingdom national bariatric surgery database. METHODS: The UK National Bariatric Surgery Registry (NBSR) was interrogated to identify all patients with OSA that underwent primary bariatric surgery between January 2009 and June 2017. Those with at least 1 follow-up recording postoperative OSA status were selected for further analysis. Demographic, pre- and postoperative outcomes were collected and analyzed. Poisson multivariate regression was conducted to identify predictors of OSA remission. RESULTS: A total of 4015 bariatric cases were eligible for inclusion: 2482 (61.8%) patients underwent laparoscopic Roux-en-Y gastric bypass (LRYGB), 1196 (29.8%) sleeve gastrectomy (LSG), and 337 (8.4%) adjustable gastric banding (LAGB). Overall, the mean excess weight loss (EWL) % for the whole group was 61.2 (SD ± 27.2). OSA resolution was recorded in 2377 (59.2%) patients. Following Poisson regression, LRYGB (risk ratio [RR], 1.49 confidence interval [CI] 1.25-1.78) and LSG (RR, 1.46 [CI 1.22-1.75] were associated with approximately 50% increased likelihood of OSA remission compared with LAGB. Greater weight loss following intervention was associated with greater likelihood of OSA remission, while both greater age and greater preoperative body mass index (BMI) were associated with reduced likelihood of OSA remission (P < .001). CONCLUSION: This study demonstrated that metabolic surgery results in OSA remission in the majority of patients with obesity. Younger age, lower BMI preprocedure, greater %EWL and the use of LSG or LRYGB positively predicted OSA remission.

Global health education: international collaboration at ICDDR,B.

The purpose of this commentary is to provide an overview of the growing interest in global health education at ICDDR,B and to review examples of how this has grown from public-health research and education to include clinical education (medical and nursing) as well. This parallels the growth of the institution, with an increased focus on educational linkages within and beyond Bangladesh and the rise in interest in global health at western medical schools. Specific collaborations, their setup and structure are described. This is presented as a model for other centres of excellence in developing countries to engage their partners in the South and North on matters of education and research for mutual cooperation and benefit.

Pediatric-onset multiple sclerosis in African-American black and European-origin white patients.

Pediatric-onset multiple sclerosis is now recognized, but the association with ethnicity has not been well studied. In a retrospective review at a major teaching facility, 46 pediatric-onset multiple sclerosis patients were identified; of these, 24 were African-American black and 19 were European-origin white. Both groups were similar in mean age at onset (black, 13.6 +/- 3.36 years; white, 13.68 +/- 3.42 years) and total duration of follow-up (black, 42.7 +/- 43.5 months; white, 38.2 +/- 35.3 months), with no significant difference in time to onset of disease-modifying therapy (black, 11.2 +/- 4.7 months; white, 12.4 +/- 5.1 months). The percentage of females was higher in the black than in the white group (83% vs 47%; P = 0.014). The annualized relapse rate was significantly higher in the black than in the white group (1.80 +/- 1.14 vs 1.13 +/- 0.50; P < 0.001). These findings are consistent with data suggesting a more aggressive disease phenotype among African-American blacks with adult-onset multiple sclerosis. Larger multicenter studies are warranted to confirm the findings.

No more Doritos and lobster tails: a case report of life-threatening sublingual hematoma.

This case report highlights a life-threatening complication of mild hemophilia A. We report the onset of airway compromise through a massive sublingual hematoma in a 67-year-old male suffering from the mild form of hemophilia A. This case emphasizes the need for prompt medical attention and recognition of potentially serious complications of the disease in patients suffering with even mild form of this bleeding diathesis.

The myths of obesity.

Despite an epidemic of obesity, the availability of bariatric surgery is limited. Negative beliefs about obesity and bariatric surgery are one of the barriers to access. In this article, we address and dispel some of the common myths surrounding obesity and bariatric surgery.