Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.     

Providing Mental Health Services in the Primary Care Setting: the Experiences and Perceptions of General Practitioners at a New York City Clinic

Mental illness is a significant cause of disability worldwide, including here in the United States. Given the shortage of trained mental health professionals, a significant portion of patients needing care are managed in the primary care setting. Accountable Care Organizations (ACOs), for example, are seeking to improve the quality of care for this vulnerable population, but many are facing significant challenges relating to integration of new services. We sought to elucidate barriers faced by primary care practitioners (PCPs)—physicians, physician trainees and nurse practitioners—at a New York primary care clinic, which impede delivery of optimal care to those suffering from mental illness. The study was conducted with 32 PCPs in 2016–2017 at Mount Sinai Internal Medicine Associates in New York City. For the quantitative component of the study, a 54-item questionnaire was devised to assess their attitude, behavior and confidence in managing psychiatric patients. For the qualitative component, data was obtained from 3 open-ended questions. Responses were coded for salient themes. Analysis revealed a range of difficulties faced by PCPs. Overall, participants felt that the need to integrate mental health care into primary care was important, however they reported significant barriers in terms of lack of time, lack of resources, low confidence in treating more complex mental health conditions and difficulties with referring patient to mental health specialists. Despite a growing body of evidence that integration of mental health services in primary care leads to improved outcomes, addressing barriers to care will be key to ensuring feasibility of integration measures.     

A Qualitative Analysis of Vaccine Safety Perceptions and Concerns Among Caretakers in Uganda

Parents and caretakers of young children often have concerns about vaccine safety and adverse events following immunization (AEFI). Little is known about vaccine safety perceptions in Uganda and their influence on parental decision-making about infant immunization. The study objectives were: to identify community sources of information on immunization, vaccine safety and AEFI; determine caretakers?? knowledge of immunization; identify community concerns/fears about immunization and AEFI and their influence on caretakers?? decisions to vaccinate; and obtain an understanding of knowledge, perceptions, and experience of health care workers (HCWs) and policy administrators on vaccine safety and AEFI. Twelve focus group discussions with 136 caretakers who were very or somewhat concerned about vaccine safety and 25 key informant interviews were conducted in two districts (1 urban and 1 rural) with district authorities and health facility staff as well as national level decision-makers between December and April 2006. Content analysis was used to analyze the results. The main themes identified related to general lack of information among caretakers about immunization, perceived immunization benefits, immunization concerns, and misconceptions. Specific caretaker concerns related to vaccine administration, immunization services and vaccine safety. Experiences with AEFI and concerns about vaccine safety negatively affected caretakers?? decisions to vaccinate their children, notably in rural areas. HCWs demonstrated knowledge about AEFI and their management although incidences reported to facilities were rare. Inadequate communication between HCWs and caretakers was noted. Concerns and misconceptions about vaccination still exist among caretakers in Uganda and influence decisions to vaccinate. Effective inter personal communication initiated by HCWs towards caretakers is needed.     

Laparoscopy following peritoneal entry during transanal endoscopic microsurgery may increase the safety and maximize the benefits of the transanal excision

Background

Peritoneal entry (PE) during transanal endoscopic microsurgery (TEM) for tumors of the upper rectum is not an uncommon complication. The suture line of the rectal defect performed for PE is not devoid of leaks. Diagnostic laparoscopy after PE enables visualization and testing of the suture line. Here, we report the outcome of patients undergoing laparoscopy for PE following TEM.

Methods

Data pertaining to patients undergoing laparoscopy for PE following TEM between 2004 and 2013 were retrospectively collected.

Results

One hundred and forty-one TEM procedures were performed, and 19 (13 %) with PE were included. The mean age was 68.1 ± 10.6 years, mean distance from the anal verge 12.5 ± 2 cm, and mean tumor size 2 cm. Lesions were located in the lateral wall (n = 14), anteriorly (n = 4), and posteriorly (n = 1). Indications for TEM were: adenoma (n = 13), indeterminate margins after polypectomy (n = 4, a submucosal lesion (n = 1), and a T1N0 adenocarcinoma (n = 1). In all patients, the rectal wall defect was closed primarily. Twelve patients underwent additional laparoscopy and suture line leak testing. In one patient, a small leak was detected which was repaired laparoscopically. In another, a hematoma of the suture line was observed and a drain was left in place. The mean operative time was 109 min (range 80–135 min) for TEM and 33 min (range 22–45 min) for laparoscopy. A diverting ileostomy was fashioned in one patient on postoperative day 3 after TEM without laparoscopy. No other major complications were observed.

Conclusions

Laparoscopy after PE during TEM permits visualization and testing of the suture line. It is not associated with increased morbidity, and it may increase the safety of TEM.

     

Response Strategies against Meningitis Epidemics after Elimination of Serogroup A Meningococci,Niger

To inform epidemic response strategies for the African meningitis belt after a meningococcal serogroup A conjugate vaccine was introduced in 2010, we compared the effectiveness and efficiency of meningitis surveillance and vaccine response strategies at district and health area levels using various thresholds of weekly incidence rates. We analyzed reports of suspected cases from 3 regions in Niger during 2002–2012 (154,392 health area weeks), simulating elimination of serogroup A meningitis by excluding health area years with identification of such cases. Effectiveness was highest for health area surveillance and district vaccination (58–366 cases; thresholds 7–20 cases/100,000 doses), whereas efficiency was optimized with health area vaccination (5.6–7.7 cases/100,000 doses). District-level intervention prevented <6 cases (0.2 cases/100,000 doses). Reducing the delay between epidemic signal and vaccine protection by 2 weeks doubled efficiency. Subdistrict surveillance and response might be most appropriate for meningitis epidemic response after elimination of serogroup A meningitis.