Design and synthesis of sarolaner, a novel, once-a-month, oral isoxazoline for the control of fleas and ticks on dogs.

Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal health companies in their search for novel pesticides and ectoparasiticides. Herein we report the discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral treatment of flea and tick infestation on dogs.

Evaluation of Xpert MTB/RIF for detection of tuberculosis from blood samples of HIV-infected adults confirms Mycobacterium tuberculosis bacteremia as an indicator of poor prognosis.

Tuberculosis (TB) remains a leading cause of death among HIV-infected adults, in part because of delayed diagnosis and therefore delayed initiation of treatment. Recently, the Gene-Xpert platform, a rapid, PCR-based diagnostic platform, has been validated for the diagnosis of TB with sputum. We have evaluated the Xpert MTB/RIF assay for the diagnosis of Mycobacterium tuberculosis bacteremia and investigated its impact on clinical outcomes. Consecutive HIV-infected adults with fever and cough presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, were recruited and followed up for 2 months. At presentation, three sputum samples were examined by smear, culture, and Xpert MTB/RIF assay for the presence of M. tuberculosis and blood was drawn for PCR with Xpert, for mycobacterial culture (Myco/F Lytic), and for aerobic culture. One hundred four patients were recruited, and 44 (43%) were sputum culture positive for M. tuberculosis. Ten were Xpert blood positive, for a sensitivity of 21% and a specificity of 100%. The 2-week mortality rate was significantly higher among patients who were Xpert blood positive than among those who were negative (40% versus 3%; multivariate odds ratio [OR] for death if positive, 44; 95% confidence interval [CI], 3 to 662). This effect persisted on assessment of the mortality rate at 2 months (40% versus 11%; OR, 5.6; 95% CI, 1.3 to 24.6). When screening uncomplicated patients presenting with a productive cough for pulmonary TB, Xpert blood offers no diagnostic advantage over sputum testing. Despite this, Xpert blood positivity is highly predictive of early death and this test rapidly identifies a group of patients in urgent need of initiation of treatment.

The operating theatre as a classroom: a literature review of medical student learning in the theatre environment.

OBJECTIVES: We set out to review the published literature relating to the educational experiences of medical students in the operating theatre.  In particular, we wished to deduce from the current evidence what challenges are posed to student learning in this environment, and how they may be overcome. METHODS: National Library of Medicine and Google Scholar databases were searched from 1990-2018, using search terms 'Operating Theatre,' OR 'Operating Theater,' OR 'Operating Room' AND 'Medical Students.' Title and abstract review of 679 papers were performed.  Full-text English language papers about the learning or satisfaction of medical students in the theatre environment were included.  Papers exploring the experiences of residents/trainees rather than medical students were excluded.  A total of 36 papers were eligible for inclusion.  Thematic analysis was conducted on these papers. RESULTS: A number of common themes were identified.  Throughout the literature, medical students describe a lack of clear learning objectives, fear, anxiety, feelings of humiliation and intimidation, lack of visualisation and lack of opportunity for participation as barriers to their satisfaction with theatre placements and to their subjective learning. CONCLUSIONS: Obstacles identified by students as deleterious to their experiences in the operating theatre are remarkably reproducible across a number of research studies in different populations.  Areas to address by both individual educators and curriculum designers include fostering a culture of inclusion in theatre, setting explicit, achievable learning goals for students in this environment and making a concerted effort to prepare students for the theatre setting.

Re-exposure to mismatched HLA class I is a significant risk factor for graft loss: multivariable analysis of 259 kidney retransplants.

BACKGROUND: Kidney retransplants carry increased immunologic risk. One possible contributor to this risk may be re-exposure to human leukocyte antigens (HLA) common to a previous donor but foreign to the recipient. Conflicting publications have assessed this risk, so to examine our experience 259 kidney retransplants were analyzed. METHODS: A retrospective cohort of retransplant patients from 1973 to 2005 with minimum 12 months follow up was examined. Using multivariable modeling, important confounders were controlled for identifying factors significantly affecting graft survival. RESULTS: Re-exposure to HLA class I (HLA-A or B) antigens, peak panel reactive antibodies and donor source were the most important determinants of allograft survival, despite a negative conventional or anti-human globulin-augmented T cell crossmatch. We failed to demonstrate that recipient re-exposure to HLA class II (HLA-DR) or positive B cell crossmatch were associated with adverse outcomes. Sample size and molecular versus serologic methods may have influenced the former, while inability to determine antibody specificities may have influenced the latter. Controlling for other variables, the adjusted risk of graft loss associated with re-exposure to HLA class I increased by 71% (P=0.006) and occurred early, consistent with recall of memory cytotoxic T lymphocyte or antibody responses. CONCLUSIONS: Kidney recipients re-exposed to mismatched HLA class I antigens appear to be at heightened risk of early graft loss. Such patients may benefit from pretransplant identification of donor specific antibodies using solid phase methods and heightened vigilance for acute rejection. Future studies may indicate whether more intensive immunosuppression for these patients is warranted.

Risk factors for endoscopic sedation reversal events: a five-year retrospective study.

OBJECTIVE: Conscious sedation is widely used in endoscopic practice but is not without risk. We aimed to determine the frequency of sedation complications requiring reversal, and to identify potential patient and procedural risk factors. DESIGN: A retrospective study of all gastrointestinal endoscopic procedures performed under conscious sedation, in a large three-campus tertiary referral endoscopic centre, between 12 October 2007 and 31 December 2012 (n=52 553). Flumazenil or naloxone administration was used as a marker of sedation complications requiring reversal. Reversal cases were analysed for associations with sedation dose, patient American Society of Anesthesiologists (ASA) grade, age and type of procedure undertaken. RESULTS: In total, 149 sedation reversals occurred, representing 0.28% of all sedated endoscopic procedures carried out. Endoscopic Retrograde Cholangiopancreatography (ERCP) and increasing patient ASA grade were positively associated with sedation reversal (p<0.05). Mean midazolam dose was highest for ERCP (4.9±2.9 mg) and lowest for flexible sigmoidoscopy (1.7±0.6 mg; p<0.01). Mean opioid dose (calculated as pethidine equivalent) was highest for ERCP (62.9±38.7 mg) and lowest for gastroscopy (6.9±13.5 mg; p<0.01). Maximum doses of midazolam or opioid recommended by the British Society of Gastroenterology were exceeded in 7.4% and 14.1% of reversals, respectively. CONCLUSIONS: ERCP procedures and higher patient ASA grade were associated with an increased risk of conscious sedation-related complications requiring reversal. In these high-risk groups, alternative sedation strategies should be considered and tested. Prospective studies are needed to further explore risk factors that may help predict adverse sedation outcomes.