Vitamin D Deficiency (VDD) and Benefits of Supplementation in Veterans with IBS-D.

Many veterans deployed to Gulf War areas suffer from persistent chronic diarrhea that is disabling and affects their quality of life. The causes for this condition have eluded investigators until recently and recent literature has shed light on the effect of vitamin D on the brain-gut axis. This study focused on determining clinical causes contributing to diarrhea and assessed whether reversing the identified causes, specifically vitamin D deficiency (VDD), could reduce the incidence of diarrhea in Gulf War veterans (GWVs). All patients completed a workup that included serologies (IBD, celiac), routine laboratory tests (CBC, chemistry panels, TSH, T4, CRP), cultures for enteric pathogens (C diff, bacteria, viruses, small intestinal bacterial overgrowth (SIBO)), and upper and lower endoscopies with histology and a trial of cholestyramine to exclude choleretic diarrhea and rifaximin for dysbiosis. A total of 4221 veterans were screened for chronic diarrhea, yielding 105 GWVs, of which 69 GWVs had irritable bowel syndrome with diarrhea (IBS-D). Paired t-tests demonstrated that all GWVs had VDD (t-11.62, df68 and sig(2-tailed) 0.0001) (defined as a vitamin D level less than 30 ng/mL with normal ranges of 30-100 ng/mL) but no positive serologies, inflammatory markers, abnormal endoscopies, cultures, or histology to explain their persistent diarrhea. There was no correlation with age, BMI, or inflammation. Some zip codes had a higher frequency of GWVs with VDD, but the number of deployments had no impact. Treatment with vitamin D supplementation (3000-5000 units), given in the morning, based on weight, reduced the number of bowel movements per day (p < 0.0001) without causing hypercalcemia. We suggest that VDD is important in the etiology of IBS-D in GWVs and that vitamin D supplementation significantly reduces diarrhea.

RAD-140 Drug-Induced Liver Injury.

Background: RAD-140, one of the novel selective androgen receptor modulators (SARMs), has potent anabolic effects on bones and muscles with little androgenic effect. Despite the lack of approval for its clinical use, RAD-140 is readily accessible on the consumer market. Hepatotoxicity associated with the use of SARMs has only rarely been reported in the literature. Case Report: A 24-year-old male presented with a 2-week history of diffuse abdominal pain, scleral icterus, pruritus, and jaundice. Prior to presentation, he had been taking the health supplement RAD-140 for muscle growth for 5 weeks. He had a cholestatic pattern of liver injury, with a peak total bilirubin of 38.5 mg/dL. Liver biopsy was supportive of a diagnosis of RAD-140-associated liver injury characterized pathologically by intracytoplasmic and canalicular cholestasis with minimal portal inflammation. Symptoms and liver injury resolved after cessation of the offending agent. Conclusion: To date, only select descriptions of the potential hepatoxicity associated with the use of SARMs, including RAD-140, have been published. Given their potential hepatoxicity and ready availability on the consumer market, RAD-140 and other SARMs should be used judiciously and under close clinical supervision until further hepatic safety data become available.

Case Report: Nivolumab-Induced Autoimmune Pancreatitis.

Nivolumab is an anti-programmed cell death protein 1 monoclonal antibody. While an effective treatment for a variety of tumors, immune checkpoint inhibitors (ICI) can cause immune-related adverse events such as ICI-pancreatic injury (ICI-PI). Here we present a case of a 60-year-old man with metastatic acral melanoma treated with nivolumab and ipilimumab who developed ICI-PI. Changes in positron emission tomography images preceded symptom onset. However, this case is unique in that the patient presented with cholestatic liver disease. Magnetic resonance cholangiopancreatography showed a dilated extrahepatic bile duct that resolved with steroid therapy, similar to the clinical course of autoimmune pancreatitis. ICI-PI has variable presentations including obstructive jaundice with a clinical course mimicking autoimmune pancreatitis and prompt awareness and treatment of ICI-PI is clinically significant given increasing use of ICIs.

Model system identification of novel congenital heart disease gene candidates: focus on RPL13.

Genetics is a significant factor contributing to congenital heart disease (CHD), but our understanding of the genetic players and networks involved in CHD pathogenesis is limited. Here, we searched for de novo copy number variations (CNVs) in a cohort of 167 CHD patients to identify DNA segments containing potential pathogenic genes. Our search focused on new candidate disease genes within 19 deleted de novo CNVs, which did not cover known CHD genes. For this study, we developed an integrated high-throughput phenotypical platform to probe for defects in cardiogenesis and cardiac output in human induced pluripotent stem cell (iPSC)-derived multipotent cardiac progenitor (MCPs) cells and, in parallel, in the Drosophila in vivo heart model. Notably, knockdown (KD) in MCPs of RPL13, a ribosomal gene and SON, an RNA splicing cofactor, reduced proliferation and differentiation of cardiomyocytes, while increasing fibroblasts. In the fly, heart-specific RpL13 KD, predominantly at embryonic stages, resulted in a striking 'no heart' phenotype. KD of Son and Pdss2, among others, caused structural and functional defects, including reduced or abolished contractility, respectively. In summary, using a combination of human genetics and cardiac model systems, we identified new genes as candidates for causing human CHD, with particular emphasis on ribosomal genes, such as RPL13. This powerful, novel approach of combining cardiac phenotyping in human MCPs and in the in vivo Drosophila heart at high throughput will allow for testing large numbers of CHD candidates, based on patient genomic data, and for building upon existing genetic networks involved in heart development and disease.

What are the Risk Factors for Cerebrovascular Accidents After Elective Orthopaedic Surgery?

BACKGROUND: Perioperative cerebrovascular accidents (CVAs) are one of the leading causes of patient morbidity, mortality, and medical costs. However, little is known regarding the rates of these events and risk factors for CVA after elective orthopaedic surgery. QUESTIONS/PURPOSES: Our goals were to (1) establish the national, baseline proportion of patients experiencing a 30-day CVA and the timing of CVA; and (2) determine independent risk factors for 30-day CVA rates after common elective orthopaedic procedures. METHODS: Patients undergoing elective TKA, THA, posterior or posterolateral lumbar fusion, anterior cervical discectomy and fusion, and total shoulder arthroplasty, from 2006 to 2012, were identified from the American College of Surgeons National Surgical Quality Improvement Program(®) database. A total of 42,150 patients met inclusion criteria. Thirty-day CVA rates were recorded for each procedure, and patients were assessed for characteristics associated with CVA through univariate analysis. Multivariate regression models were created to identify independent risk factors for CVA. RESULTS: A total of 55 (0.13%) patients experienced a CVA within 30 days of the procedure, occurring a median of 2 days after surgery (range, 1-30 days) with 0.08% of patients experiencing a CVA after TKA, 0.15% after THA, 0.00% after single-level anterior cervical discectomy and fusion, 0.38% after multilevel anterior cervical discectomy and fusions, 0.20% after single-level posterior or posterolateral lumbar fusion, 0.70% after multilevel posterior or posterolateral lumbar fusion, and 0.22% after total shoulder arthroplasty. Independent risk factors for CVA included age of 75 years or older (odds ratio [OR], 2.50; 95% CI, 1.44-4.35; p = 0.001), insulin-dependent diabetes mellitus (OR, 3.08; CI, 1.47-6.45; p = 0.003), hypertension (OR, 2.71; CI, 1.19-6.13; p = 0.017), history of transient ischemic attack (OR, 2.83; CI, 1.24-6.45; p = 0.013), dyspnea (OR, 2.51; CI, 1.30-4.86; p = 0.006), chronic obstructive pulmonary disease (OR, 2.33; CI, 1.06-5.13; p = 0.036), and operative time of 180 minutes or greater (OR, 3.25; CI 1.60-6.60; p = 0.001). CONCLUSIONS: Numerous nonmodifiable patient comorbidities and increased operative time were associated with CVA after elective orthopaedic procedures. However, the American College of Surgeons National Surgical Quality Improvement Program(®) database does not code for cardiac arrhythmia or atrial fibrillation, which other studies have suggested may be important predictor variables; those may be important risk factors, although we were unable to evaluate them in our study. Surgeons should counsel patients with these risk factors and limit their operative time to reduce the risk of these adverse events, and future studies should examine other patient characteristics such as arrhythmia and noncoronary heart disease and assess the role of pharmacologic prophylaxis in patients with these risk factors. LEVEL OF EVIDENCE: Level III, prognostic study.

Magnetic resonance elastography and acoustic radiation force impulse for staging hepatic fibrosis: a meta-analysis.

PURPOSE: Elastography is a non-invasive method to quantify fibrosis based on tissue mechanical properties. We performed a meta-analysis to assess the diagnostic accuracy of two such techniques: Acoustic Radiation Force Impulse Imaging (ARFI) or Magnetic Resonance Elastography (MRE) for staging hepatic fibrosis. MATERIALS AND METHODS: Literature databases were searched until June 2013. Inclusion criteria were evaluation of MRE or ARFI, liver biopsy, and reported sensitivity and specificity. A random effects model was used to combine sensitivity and specificity, from which positive (LR+) and negative (LR-) likelihood ratios, diagnostic odds ratios, and area under receiver operating characteristics curve (AUROC) were derived. Differences between MRE and ARFI were compared with t tests (P < 0.05 considered significant). RESULTS: Eleven MRE studies including 982 patients and fifteen ARFI studies including 2,128 patients were selected. AUROC for MRE staging fibrosis were 0.94, 0.97, 0.96, and 0.97 for F1-F4, respectively, whereas AUROC for ARFI staging were 0.82, 0.85, 0.94, and 0.94 for F1-F4, respectively. Significance was found in AUROC between MRE and ARFI for the diagnosis of stage 1 and 2 fibrosis. CONCLUSION: MRE is more accurate than ARFI with a higher combination of sensitivity, specificity, LR, and AUROC particularly in diagnosing early stages of hepatic fibrosis.