Murad, M. Hassan

Abstract Background: Myelodysplastic syndromes (MDS) are clonal hematological diseases which present with cytopenias. Hematopoietic cell transplantation is usually limited to fit patients with higher risk MDS and donor availability. Hypomethylating agents (azacitidine and decitabine) have been the mainstay option for the management of MDS with different clinical efficacy in low versus high risk MDS trials. No trials have compared the two agents. Aim: To conduct a systematic review and network analysis comparing the efficacy of azacitidine to decitabine. Methods: The protocol of the systematic review was developed a priori. A comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus) was conducted from each database's earliest inception through November 20th, 2014 without language restrictions. Trials enrolling adults diagnosed with MDS who received hypomethylating agents (azacitidine or decitabine) therapy were included. Studies were screened by two independent reviewers and differences were resolved by consensus. The Cochrane Risk of bias tool was used to appraise the trials. Random effects model was used to pool relative risks (RR) of outcomes (overall survival, overall response rate, hematologic improvement and grade 3 or 4 toxicity). Adjusted indirect comparisons were used to estimate RR for indirect comparisons (Glenny AM, et al. Health Technol Assess. 2005). All statistical analyses were conducted using STATA, version 13 (StataCorp LP, College Station, TX). Results: Only four trials met the eligibility criteria (Figure 1). Two trials compared Azacitidine (75mg/m²/day SC x 7 days) to the best suppurative care (BSC) and included 549 patients (278 azacitidine and 271 BSC, age average: 69; range: 31-92), and the other 2 compared decitabine (15 mg/m² IV q 8 hours x9) to BSC and included 403 patients (208 Decitabine and 195 BSC, age average: 69.7; range: 60-90) (Table 1). The proportion of patients with intermediate-2 and high-risk myelodysplastic syndrome (based on International Prognostic Scoring System (IPSS)) in trials comparing decitabine to BSC was 82.21% and 83.08%; respectively, and in trials comparing azacitidine to BSC was 62.59% and 61.26%; respectively. The risk of bias was moderate overall. Compared to BSC, azacitidine was significantly associated with lower risk of death (RR=0.83, 95% CI: 0.74-0.94, p=0.002) whereas the effect of decitabine did not reach statistical significance (RR=0.88, 95% CI: 0.77-1.001, p=0.053). Both drugs were superior to BSC in terms of partial and complete response. Head to head comparisons were not statistically significant (except for the outcome of complete response where low certainty evidence suggested that azacitidine treated patients were less likely to have complete response compared to decitabine (RR=0.11, 95% CI= 0.01, 0.86, p=0.04). (Table 2). Conclusion: Azacitidine and decitabine are both superior to BSC. The available indirect evidence comparing the two agents warrants low certainty and cannot reliably confirm superiority of either agent. Head-to-head trials are needed. In the meantime, the choice of agent should be driven by patients' preferences, drug availability and cost. Table 2. Results of meta-analysis Outcome Azacitidine VS. Decitabine Azacitidine VS. BSC Decitabine VS. BSC RR LCI HCI P value RR LCI HCI P value RR LCI HCI P value Death 0.95 0.79 1.13 0.54 0.83 0.74 0.94 0.002 0.88 0.77 1.001 0.05 Complete response 0.11 0.01 0.86 0.04* 2.56 1.44 4.58 0.001 23.46 3.22 170.84 0.002 Partial response 0.35 0.04 3.03 0.34 4.91 2.27 10.63 <0.0001 14.02 1.87 105.08 0.01 Major erythroid improvement 0.47 0.03 8.37 0.60 6.37 3.93 10.33 <0.0001 13.67 0.79 235.57 0.07 Major platelet improvement 1.51 0.30 7.56 0.62 4.80 2.98 7.70 <0.0001 3.19 0.68 14.89 0.14 Major neutrophil improvement 2.89 0.56 14.82 0.20 2.63 1.68 4.12 <0.0001 0.91 0.19 4.38 0.907 Hematologic improvement 0.25 0.06 1.09 0.07 2.18 1.67 2.85 <0.0001 8.62 2.05 36.32 0.003 Anemia 1.18 0.53 2.63 0.69 0.89 0.75 1.06 0.198 0.76 0.35 1.66 0.49 Neutropenia 0.99 0.75 1.30 0.92 1.87 1.63 2.14 <0.0001 1.90 1.49 2.42 <0.0001 Thrombocytopenia 0.87 0.64 1.18 0.37 1.63 1.43 1.86 <0.0001 1.87 1.43 2.45 <0.0001 Infection 1.13 0.52 2.43 0.76 1.25 0.60 2.60 0.55 1.11 0.87 1.42 0.41 *These results warrant low certainty due to imprecision (very small number of events) and are driven by 14 patients achieving complete response in BSC arm in one trial. Disclosures Al-Kali: Celgene: Research Funding.

Abstract Introduction Steroid refractory chronic graft-versus-host-disease (SR-cGVHD) is the leading cause of late morbidity and mortality in allogeneic transplant patients. Safety of extracorporeal photophoresis (ECP) has led to multiple studies evaluating its role in SR-cGVHD. Overall and organ specific response rates (RR) of SR-cGVHD have varied significantly between studies. We conducted a systemic review and meta-analysis to assess the efficacy of ECP in SR-cGVHD. Methods A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central register of Controlled Trials,, Scopus) for articles published in any language between 1984-2012 was conducted. Unpublished studies using electronic databases from the annual meetings abstracts of hematology/transplant societies were searched. Experts in the field were also contacted for selection of studies and missing data from selected trials. End points included complete response rate (CR), overall RR (ORR), and organ-specific RR's. Results Initial search generated 312 studies, out of which 18 studies (4 prospective) met selection criteria (N=595). Random effects model was used for pooled rates. Pooled CR rate (11 studies) was 29% (CI 19%-42%). Pooled ORR (16 studies) was 64% (CI 65-82%). 1 year overall survival was 49% (CI 29-70%). There was significant heterogeneity between studies (I²=72) likely due to differences in ECP schedules utilized, and a variety of scales used to measure outcomes. Pooled RR's for SR-cGVHD of skin was 74% (CI 60-85%), liver was 68% (CI 57-77%), ocular was 60% (CI 40-78%), oral was 72% (CI 51-86%), lung was 48% (CI 33-63%), gastrointestinal (GI) was 53% (CI 21-83%), and musculoskeletal (MSK) was 64% (CI 18-94%). No significant differences in responses to ECP for pediatric and adult populations were found. Sensitivity analysis could not be done due to limited number of prospective studies. Conclusions ECP is an effective therapy for oral, skin & liver SR-cGVHD, with modest activity in lung and GI SR-cGVHD. Further studies must report standardized outcomes with a uniform schedule of ECP. Disclosures: No relevant conflicts of interest to declare.

Objectives: This systematic review evaluated the accuracy of triaxial and omnidirectional accelerometers for measuring physical activity and sedentary behavior in children. Design: Systematic review of the literature. Methods: We comprehensively searched several databases for studies published from January 1996 through June 2018 that reported diagnostic accuracy measures in children and adolescents (age 3-18 years) and compared accelerometers with energy expenditure using indirect calorimetry. Results: We included 11 studies that enrolled 570 participants. All studies used indirect calorimetry as the reference standard. Across the studies, median sensitivity ranged from 46% to 96% and median specificity ranged from 71% to 96%. Median area under the curve ranged from 69% to 98%. Conclusions: Accuracy measures were greatest when detecting sedentary behavior and lowest when detecting light physical activity. Accuracy was higher when the accelerometer was placed on the hip compared with the wrist. The current evidence suggests that triaxial and omnidirectional accelerometers are accurate in measuring sedentary behavior and physical activity levels in children.

Abstract Background US public health strategy for eliminating tuberculosis (TB) prioritizes treatment of latent TB infection (LTBI). Healthcare personnel (HCP) are less willing to accept treatment than other populations. Little is known about factors associated with HCP LTBI therapy acceptance and completion. Methods We conducted a retrospective chart review to identify all employees with LTBI at time of hire at a large academic medical center during a 10-year period. Personal demographics, occupational factors, and clinic visit variables were correlated with LTBI treatment acceptance and completion rates using multivariate logistic regression. Results Of 470 HCP with LTBI for whom treatment was recommended, 193 (41.1%) accepted treatment, while 137 (29.1%) completed treatment. Treatment adherence was better with 4 months of rifampin than 9 months of isoniazid (95% vs 68%, P &lt; .005). Increased age of the healthcare worker was independently associated with lower rates of treatment acceptance (odds ratio [95% confidence interval]: 0.97 [0.94–0.99] per year), as was having an occupation of clinician (0.47 [0.26–0.85]) or researcher (0.34 [0.19–0.64]). Male gender was associated with higher treatment acceptance (1.90 [1.21–2.99]). Treatment completion was associated with being from a low- (9.49 [2.06–43.73]) or medium- (8.51 [3.93–18.44]) TB-burden country. Conclusions Geographic and occupational factors affect acceptance and completion of LTBI therapy. Short-course regimens may improve adherence. Physicians, researchers, and HCP from high-TB-burden countries have lower treatment rates than other HCP. Improving LTBI treatment in HCP will require attending to cultural and occupational differences.

Abstract Background Proctocolectomy with ileal pouch–anal anastomosis (IPAA) is the surgical procedure of choice for medically refractory ulcerative colitis and familial adenomatous polyposis. While rare, a pouch volvulus can occur. We aimed to determine the frequency, presentation, and management approach of pouch volvulus in patients with IPAA. Methods A systematic search of published literature was performed by a medical reference librarian on 10 August 2018 and two independent reviewers identified relevant publications, extracted data, and assessed the methodological quality based on a validated tool. A retrospective review of the Mayo Clinic electronic medical records identified one case of pouch volvulus between January 2008 and August 2018. Results The frequency of pouch volvulus from one large published study reporting long-term outcomes of IPAA was 0.18% (3/1,700). A total of 22 patients (18 ulcerative colitis) were included (median age 32 years, 73% females). Median time to volvulus after IPAA was 36 months while median interval to volvulus diagnosis from symptom onset was 24 hours. Abdominal pain was the most commonly reported symptom (76%). The diagnosis was made primarily by abdominal computed tomography (13/17 patients, 76%). Endoscopic treatment was successful in 1 of 11 patients (9%). Surgery was performed in 20 patients and pouch-pexy and pouch excision were the most frequent surgical operations. A redo IPAA was performed in five patients (25%). Conclusion Pouch volvulus is a rare but serious complication of IPAA and should be suspected even in the absence of obstruction symptoms. Endoscopic treatment often fails and surgery is effective when performed early.

Introduction There is a considerable implementation gap in managing early stage chronic kidney disease (CKD) in primary care despite the high prevalence and risk for increased morbidity and mortality associated with CKD. This systematic review aims to synthesise the evidence of efficacy of implementation interventions aimed at primary care practitioners (PCPs) to improve CKD identification and management. We further aim to describe the interventions’ behavioural change components. Methods and analysis We will conduct a systematic review of studies from 2000 to October 2017 that evaluate implementation interventions targeting PCPs and which include at least one clinically meaningful CKD outcome. We will search several electronic data bases and conduct reference mining of related systematic reviews and publications. An interdisciplinary team will independently and in duplicate, screen publications, extract data and assess the risk of bias. Clinical outcomes will include all clinically meaningful medical management outcomes relevant to CKD management in primary care such as blood pressure, chronic heart disease and diabetes target achievements. Quantitative evidence synthesis will be performed, where possible. Planned subgroup analyses include by (1) study design, (2) length of follow-up, (3) type of intervention, (4) type of implementation strategy, (5) whether a behavioural or implementation theory was used to guide study, (6) baseline CKD severity, (7) patient minority status, (8) study location and (9) academic setting or not. Ethics and dissemination Approval by research ethics board is not required since the review will only include published and publicly accessible data. Review findings will inform a future trial of an intervention to promote uptake of CKD diagnosis and treatment guidelines in our primary care setting and the development of complementary tools to support its successful adoption and implementation. We will publish our findings in a peer-reviewed journal and develop accessible summaries of the results. PROSPERO registration number CRD42018102441.

AbstractObjectiveTo develop clinical practice guidelines for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM) in individuals at metabolic risk for developing these conditions.ConclusionsHealth care providers should incorporate regular screening and identification of individuals at metabolic risk (at higher risk for ASCVD and T2DM) with measurement of blood pressure, waist circumference, fasting lipid profile, and blood glucose. Individuals identified at metabolic risk should undergo 10-year global risk assessment for ASCVD or coronary heart disease to determine targets of therapy for reduction of apolipoprotein B–containing lipoproteins. Hypertension should be treated to targets outlined in this guideline. Individuals with prediabetes should be tested at least annually for progression to diabetes and referred to intensive diet and physical activity behavioral counseling programs. For the primary prevention of ASCVD and T2DM, the Writing Committee recommends lifestyle management be the first priority. Behavioral programs should include a heart-healthy dietary pattern and sodium restriction, as well as an active lifestyle with daily walking, limited sedentary time, and a structured program of physical activity, if appropriate. Individuals with excess weight should aim for loss of ≥5% of initial body weight in the first year. Behavior changes should be supported by a comprehensive program led by trained interventionists and reinforced by primary care providers. Pharmacological and medical therapy can be used in addition to lifestyle modification when recommended goals are not achieved.

Abstract Context The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to type 2 diabetes mellitus (T2DM) in at-risk individuals is unclear. Methods We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus through 24 August 2017 for randomized controlled trials evaluating the effect of drugs suspected to modify the risk of biochemical conversion to T2DM. Results We included 43 trials with 192,156 subjects (mean age, 60 years; 56% men; mean body mass index, 30.4 kg/m2). α-Glucosidase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, metformin, orlistat, phentermine/topiramate, and pioglitazone significantly reduced the risk of biochemical conversion to T2DM, whereas statins and nateglinide increased the risk. There was insufficient direct evidence regarding the effects of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Most trials were brief and evaluated this outcome during treatment without a withdrawal or washout period. Conclusions Several drugs modify the risk of biochemical conversation to T2DM, although whether this effect is persistent and clinically relevant is unclear. Future studies need to focus on cardiovascular disease prevention, mortality, and patient-important outcomes instead of biochemical conversion to T2DM.