Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Evaluation of a real-time virtual intervention to empower persons living with HIV to use therapy self-management: study protocol for an online randomized controlled trial

Background: Living with HIV makes considerable demands on a person in terms of self-management, especially as regards adherence to treatment and coping with adverse side-effects. The online HIV Treatment, Virtual Nursing Assistance and Education (Virus de I'immunodeficience Humaine-Traitement Assistance Virtuelle Infirmiere et Enseignement; VIH-TAVIE (TM)) intervention was developed to provide persons living with HIV (PLHIV) with personalized follow-up and real-time support in managing their medication intake on a daily basis. An online randomized controlled trial (RCT) will be conducted to evaluate the efficacy of this intervention primarily in optimizing adherence to combination anti-retroviral therapy (ART) among PLHIV.Methods/design: A convenience sample of 232 PLHIV will be split evenly and randomly between an experimental group that will use the web application, and a control group that will be handed a list of websites of interest. Participants must be aged 18 years or older, have been on ART for at least 6 months, and have internet access. The intervention is composed of four interactive computer sessions of 20 to 30 minutes hosted by a virtual nurse who engages the PLHIV in a skills-learning process aimed at improving self-management of medication intake. Adherence constitutes the principal outcome, and is defined as the intake of at least 95% of the prescribed tablets. The following intermediary measures will be assessed: self-efficacy and attitude towards antiretroviral medication, symptom-related discomfort, and emotional support. There will be three measurement times: baseline (T0), after 3 months (T3) and 6 months (T6) of baseline measurement. The principal analyses will focus on comparing the two groups in terms of treatment adherence at the end of follow-up at T6. An intention-to-treat (ITT) analysis will be carried out to evaluate the true value of the intervention in a real context.Discussion: Carrying out this online RCT poses various challenges in terms of recruitment, ethics, and data collection, including participant follow-up over an extended period. Collaboration between researchers from clinical disciplines (nursing, medicine), and experts in behavioral sciences information technology and media will be crucial to the development of innovative solutions to supplying and delivering health services

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29–39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Acetabuloplasty at the Anatomic Centre for Treating Crowe Class III and IV Developmental HIP Dysplasia: A Case Series

Introduction: Total hip replacement in patients with developmental dysplasia of the hip (DDH) is a difficult technical procedure for surgeons to perform because of the potential for these patients to have severe anomalies in their bones and soft tissues

Long-term results of cemented total hip arthroplasty in patients younger than 30 years and the outcome of subsequent revisions

Contains fulltext : 118748.pdf (publisher's version ) (Open Access)BACKGROUND: The number of total hip arthroplasties in patients under 30 years is increasing over the years. Almost all of them will face at least one or more future revisions in their life. Therefore, the implant used should have a high survival rate, and needs to be easily revisable resulting in a low re-revision rate. Several studies have evaluated the outcome of total hip arthroplasties in patients under 30 years. However, only a few reported on the follow-up outcome of 10 years or more. In addition, none of these reports published data of the subsequent revisions of these implants within their original report. METHODS: We studied historically prospective collected data of 48 consecutive patients (69 hips) younger than 30 years, treated with a cemented primary total hip prosthesis between 1988 and 2004. Since the last evaluation of this cohort, two patients were lost to follow-up. For all hip revisions in this cohort, again cemented implants were used, mostly in combination with bone impaction grafting. Kaplan-Meier survival curves at 10- and 15 years for the primary total hip arthroplasties and revisions were determined. RESULTS: The mean age at time of primary surgery was 25 years (range, 16 to 29 years). Mean follow-up of the primary hips was 11.5 years (range, 7 to 23 years). During follow-up 13 revisions were performed; in 3 cases a two-stage total revision was performed for septic loosening and 9 cups were revised for aseptic loosening. There were no aseptic stem revisions. The 10 and 15-year survival rates with endpoint revision for aseptic loosening of the primary total hip were 90% (95% CI: 79 to 96) and 82% (95% CI: 65 to 92) respectively. None of our 13 subsequent revisions needed a re-revision within 10 years after re-implantation. CONCLUSIONS: Cemented total hip implants in patients under 30 years have an encouraging outcome at 10 and 15 years after surgery in these young patients. The 13 revised hips, treated with bone grafting and the third generation cement technique, were performing well with no re-revisions within ten years after surgery

High failure rate of a modern, proximally roughened, cemented stem for total hip arthroplasty

The role of surface finish on the survivorship of cemented femoral stems continues to be debated. A total of 34 proximally roughened cemented stems were implanted in 33 consecutive patients undergoing total hip arthroplasty by a single surgeon. An alarmingly high failure rate was observed, prompting a retrospective chart review, analysis of radiographs, and evaluation of retrieved stems and pathological specimens. Nineteen patients were available with more than two years follow-up. Of these 19 patients, nine stems had failed (47%) due to severe osteolysis and stem loosening. Failures were significantly more common in the male gender (p<0.005), and young (p=0.05), tall (p<0.002), and heavy patients (p<0.004). All failed revised hips showed severe metallosis, with both gross and microscopic evidence of metallic shedding from the stems. Our findings suggest that this proximally roughened stem is susceptible to early failure. Failure is characterized by stem debonding, subsidence within the cement mantle, shedding of metallic and cement particles due to fretting, and rapidly progressive osteolysis. These findings have been observed with other rough surface finish cemented stems