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Abstract Background: Sickle cell disorder (SCD) and transfusion dependent beta-thalassemia (TDT) are inherited disorders of β-globin genes leading to ineffective erythropoiesis, hemolysis and multi-organ damage. Though allogenic hematopoietic cell transplantation (allo-HCT) in the only potentially curative therapy, lack of full HLA-matched donor, increased risk of myeloablative conditioning (MAC) regimen related toxicity, poor prognosis in older age groups (>14 years), and a high risk of infections and graft versus host disease (GVHD) culminating into a high transplant related mortality (TRM) preclude HCT as a treatment option for many patients. Gene therapy has been proposed as a relatively new treatment option for these monogenic disorders. It involves transfection of harvested CD34+ hematopoietic stem cells (HSC) with viral vector to transfer a normal beta globin gene, which are then transplanted back to the autologous donor. However, the available data on gene therapy is extremely variable. The purpose of this review is to evaluate the risks and outcomes of SCD and TDT patients undergoing gene therapy. Methods: A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on with no restrictions of language or time period. A total of 4312 articles were identified and after duplicates removal, 3508 articles were screened for relevance. Clinical studies reporting the most recent follow up results about the efficacy and safety of gene therapy in patients with hemoglobinopathies were considered for inclusion. Their quality assessment was done using the Cochrane tool, and bias was evaluated regarding the study selection, performance, detection, attrition and the reporting of the clinical trials. RESULTS (table-1): Only 7 articles qualified for the strict selection criteria with an N of 47: six studies were phase I trials (Cavazzana, M. et al 2010, Boulad, F. et al 2013, Marktel, S. et al 2017, Kwiatkowski, J. et al 2017, Cavazzana, M. et al 2017, Kanter, J. et al 2017) and one was a phase III trial (Walters, M. et al 2017). Thirty five patients (74.4%) had TDT while 12 patients (25.5%) had SCD. All these patients did not have a suitable HLA-matched HCT donor. The length of follow up was heterogeneous owing to the step wise enrollment of participants and ranged from 2-36 months. Except for 4 cases, the age of included population was >13 years. Lentivirus BB305 encoding the HbAT87Q globin gene was used for gene delivery in 81% patients (n=38). The normal beta globin gene was transduced in remaining 9 TDT cases and it involved transduction using TNS 9.3.55 vector in two cases and with GLOBE lentivirus in 7 cases. MAC with busulfan was used in 81% cases (n=38), while treosulfan+thiotepa was used in 7 cases. The non-myeloablative (NMA) conditioning with busulfan was used in only 2 cases (both TDT). Bone marrow harvest was the source of HSCs in all SCD cases. Except for 3 SCD cases in HGB-204 trial and 3 TDT cases in HGB-207 which measured the potential improvement in outcome by an increase in DP-VCN, the range of drug vector copy number (DP-VCN) was 0.3-1.5 copies per diploid genome. The total hemoglobin (HB) level at last follow up was reported for 62% cases (n=29) and it was >8.8 g/dl in all cases. Twenty-one (60%) thalassemia cases were in a transfusion (Tx) free state at last follow up, including the 7 cases (20%) who developed a complete independence from transfusions. No such Tx-free state was noted in SCD cases although they developed a reduction in the Tx-requirement and 75% SCD cases (n=9) had a 30-100% reduction in the frequency of VOCs. All the cases were alive at their recent follow up with manageable toxicity form conditioning. Acceptable safety until the median follow-up from the 7 trials was established in all cases, with no reported development of post-treatment leukemia or new malignancy in these trials. DISCUSSION: In this largest series of gene therapy for the treatment of hemoglobinopathies (to our knowledge), we find it to be clinically effective in terms of reduction in transfusion needs; data to suggest an improved OS and disease free survival is promising, however long term data is awaited. Gene therapy appears to bypass the limitations faced by allo-HCT especially a high early TRM. Randomized trials reporting the efficacy and safety outcomes with longer follow ups are urgently required. Disclosures No relevant conflicts of interest to declare.

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.

Loss of muscle mass and function, or sarcopenia, is a common feature of cirrhosis and contributes significantly to morbidity and mortality in this population. Sarcopenia is a main indicator of adverse outcomes in this population, including poor quality of life, hepatic decompensation, mortality in patients with cirrhosis evaluated for liver transplantation (LT), longer hospital and intensive care unit stay, higher incidence of infection following LT, and higher overall health care cost. Although it is clear that muscle mass is an important predictor of LT outcomes, many questions remain, including the best modality for assessing muscle mass, the optimal cut‐off values for sarcopenia, the ideal timing and frequency of muscle mass assessment, and how to best incorporate the concept of sarcopenia into clinical decision making. For these reasons, we assembled a group of experts to form the North American Working Group on Sarcopenia in Liver Transplantation to use evidence from the medical literature to address these outstanding questions regarding sarcopenia in LT. We believe sarcopenia assessment should be considered in all patients with cirrhosis evaluated for liver transplantation. Skeletal muscle index (SMI) assessed by computed tomography constitutes the best‐studied technique for assessing sarcopenia in patients with cirrhosis. Cut‐off values for sarcopenia, defined as SMI < 50 cm 2 /m 2 in male and < 39 cm 2 /m 2 in female patients, constitute the validated definition for sarcopenia in patients with cirrhosis. Conclusion: The management of sarcopenia requires a multipronged approach including nutrition, exercise, and additional pharmacological therapy as deemed necessary. Future studies should evaluate whether recovery of sarcopenia with nutritional management in combination with an exercise program is sustainable as well as how improvement in muscle mass might be associated with improvement in clinical outcomes.

Abstract Aim A previous study showed significantly greater reductions in number of cigarettes smoked and biomarkers of toxicant and carcinogen exposure in smokers assigned to immediate reduction of nicotine in cigarettes to very low levels versus gradually over time or continued smoking of normal nicotine content cigarettes. This study examines the effects of these approaches on selected biomarkers associated with harmful biological effects. Design Three‐arm, randomized controlled trial. Setting Ten United States academic institutional sites. Participants Daily smokers uninterested in quitting smoking with a mean age of 45.1 [standard deviation (SD) = 13.4)] years and smoking 17.1 (SD = 8.5) cigarettes/day; 43.9% (549 of 1250) female; 60.6% (758 of 1250) white ethnicity. Interventions (1) Smoking cigarettes where nicotine content was immediately reduced to very low levels ( n = 503); (2) smoking cigarettes where nicotine content was gradually reduced, with dose changes occurring monthly ( n = 498); and (3) continued smoking with normal nicotine content cigarettes ( n = 249). Measurements Smokers were assessed at baseline while smoking their usual brand cigarettes, and again at 4, 8, 12, 16 and 20 weeks. Outcomes were areas under the concentration time curve (AUC) for the period of study of biomarkers of inflammation, oxidative stress and hematological parameters. Findings No consistent significant differences were observed across groups (Bayes factors showing data to be insensitive), with the only exception being red blood cell size variability, which was observed to be lower in the immediate versus gradual nicotine reduction [mean difference = −0.11; 95% confidence interval (CI) = –0.18, −0.04, P = 0.004] and normal nicotine control groups (mean difference = − 0.15, 95% CI = –0.23, −0.06, P = 0.001). Conclusion It remains unclear whether switching to very low nicotine cigarettes leads to a short‐term reduction in biomarkers of tobacco‐related harm.

ABSTRACT Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com ) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published ( GA questions ). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to $150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty‐eight questions (23% of all GA questions) achieved the requisite > 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable.