Evaluation of care and treatment clinics using a four-year retrospective cohort of patients receiving anti-retroviral therapy in Mbeya Region, Tanzania

Evaluations of sub-national anti-retroviral therapy (ART) programmes’ performance are important to support regional programme planning and epidemic response. We constructed a four-year retrospective cohort of clients from 10 care and treatment clinics (CTC) in the Mbeya region of Tanzania using routinely collected data from patients initiating ART between January 1, 2008 and March 31, 2012. Our primary outcomes were mortality rate and lost to follow up. We calculated ART coverage based on regional prevalence estimates and used medical cards, drug registers and quarterly reports to assess data quality. We enrolled 17,813 participants into the cohort. More patients initiated ART at WHO stages 3 (58.9%), and at CD4 cell counts between 50-199 cells/µl (56%). The proportion of patients initiating ARTs at a CD4 counts <50 cells/µl decreased from 40.7% in 2008 to 33.8% in 2012 (p-value <0.001). A total of 10,155 (57.0%) patients were lost to follow up (LTFU) during the 4 years of follow up; 59.2% were female. The overall mortality rate was 17.8 per 1000 person years; the six-month mortality was 6.2 per 1000 person years. The risk of mortality for patients at WHO stage III and IV was more than twice as high (hazard ratio [HR] 2.15; 95% confidence interval [CI], 1.05-4.39 and HR 2.29; 95% CI, 1.39-6.37, respectively) as compared to stage I and II. Those patients initiating ART with CD4 cell count between 50 and 199 cells/µl had significantly lower hazard of death compared to those initiating ART with CD4 cells counts <50 cells/µl (HR 0.51, 95% CI 0.34-0.78). In conclusion, during the study, a high proportion of patients were lost to follow up, and the majority of them were female. Most patients initiated ARTs at lower CD4 count (<200 cells/mm3) and at WHO stages III and IV, and they had higher risk of mortality compared to those initiated at higher CD4 counts and WHO stage I and II. Emphasis needs to be placed on strategies of early diagnosis of HIV infection, prompt initiation of ART, and support for ART adherence to minimise lost to follow up

Control of Canalization and Evolvability by Hsp90

Partial reduction of Hsp90 increases expression of morphological novelty in qualitative traits of Drosophila and Arabidopsis, but the extent to which the Hsp90 chaperone also controls smaller and more likely adaptive changes in natural quantitative traits has been unclear. To determine the effect of Hsp90 on quantitative trait variability we deconstructed genetic, stochastic and environmental components of variation in Drosophila wing and bristle traits of genetically matched flies, differing only by Hsp90 loss-of-function or wild-type alleles. Unexpectedly, Hsp90 buffering was remarkably specific to certain normally invariant and highly discrete quantitative traits. Like the qualitative trait phenotypes controlled by Hsp90, highly discrete quantitative traits such as scutellor and thoracic bristle number are threshold traits. When tested across genotypes sampled from a wild population or in laboratory strains, the sensitivity of these traits to many types of variation was coordinately controlled, while continuously variable bristle types and wing size, and critically invariant left-right wing asymmetry, remained relatively unaffected. Although increased environmental variation and developmental noise would impede many types of selection response, in replicate populations in which Hsp90 was specifically impaired, heritability and ‘extrinsic evolvability’, the expected response to selection, were also markedly increased. However, despite the overall buffering effect of Hsp90 on variation in populations, for any particular individual or genotype in which Hsp90 was impaired, the size and direction of its effects were unpredictable. The trait and genetic-background dependence of Hsp90 effects and its remarkable bias toward invariant or canalized traits support the idea that traits evolve independent and trait-specific mechanisms of canalization and evolvability through their evolution of non-linearity and thresholds. Highly non-linear responses would buffer variation in Hsp90-dependent signaling over a wide range, while over a narrow range of signaling near trait thresholds become more variable with increasing probability of triggering all-or-none developmental responses

A preliminary study of the effect of closed incision management with negative pressure wound therapy over high-risk incisions

Background Certain postoperative wounds are recognised to be associated with more complications than others and may be termed high-risk. Wound healing can be particularly challenging following high-energy trauma where wound necrosis and infection rates are high. Surgical incision for joint arthrodesis can also be considered high-risk as it requires extensive and invasive surgery and postoperative distal limb swelling and wound dehiscence are common. Recent human literature has investigated the use of negative pressure wound therapy (NPWT) over high-risk closed surgical incisions and beneficial effects have been noted including decreased drainage, decreased dehiscence and decreased infection rates. In a randomised, controlled study twenty cases undergoing distal limb high-energy fracture stabilisation or arthrodesis were randomised to NPWT or control groups. All cases had a modified Robert-Jones dressing applied for 72 h postoperatively and NPWT was applied for 24 h in the NPWT group. Morphometric assessment of limb circumference was performed at six sites preoperatively, 24 and 72 h postoperatively. Wound discharge was assessed at 24 and 72 h. Postoperative analgesia protocol was standardised and a Glasgow Composite Measure Pain Score (GCPS) carried out at 24, 48 and 72 h. Complications were noted and differences between groups were assessed. Results Percentage change in limb circumference between preoperative and 24 and 72 h postoperative measurements was significantly less at all sites for the NPWT group with exception of the joint proximal to the surgical site and the centre of the operated bone at 72 h. Median discharge score was lower in the NPWT group than the control group at 24 h. No significant differences in GCPS or complication rates were noted. Conclusions Digital swelling and wound discharge were reduced when NPWT was employed for closed incision management. Larger studies are required to evaluate whether this will result in reduced discomfort and complication rates postoperatively

Atypical disengagement from faces and its modulation by the control of eye fixation in children with Autism Spectrum Disorder

By using the gap overlap task, we investigated disengagement from faces and objects in children (9–17 years old) with and without autism spectrum disorder (ASD) and its neurophysiological correlates. In typically developing (TD) children, faces elicited larger gap effect, an index of attentional engagement, and larger saccade-related event-related potentials (ERPs), compared to objects. In children with ASD, by contrast, neither gap effect nor ERPs differ between faces and objects. Follow-up experiments demonstrated that instructed fixation on the eyes induces larger gap effect for faces in children with ASD, whereas instructed fixation on the mouth can disrupt larger gap effect in TD children. These results suggest a critical role of eye fixation on attentional engagement to faces in both groups

A developing country response to Lavery et al. "In global health research, is it legitimate to stop clinical trials early on account of their opportunity costs?"

<p>Abstract</p> <p>Background</p> <p>A recent paper presents an argument and mechanism for the possible stopping of clinical trials early based on opportunity costs.</p> <p>Discussion</p> <p>Although we agree that the costs and opportunity costs of clinical trials need to be reduced wherever possible, we raise concerns about the motivation and mechanism for stopping clinical trials early raised by Lavery <it>et al</it>.</p> <p>Summary</p> <p>We argue that there are already enough acceptable criteria and actors in the clinical trials arena to justify early stoppage of clinical trials, and argue that factors other than efficacy need to be carefully considered, especially in developing country contexts.</p

Assessment of BED HIV-1 Incidence Assay in Seroconverter Cohorts: Effect of Individuals with Long-Term Infection and Importance of Stable Incidence

BACKGROUND: Performance of the BED assay in estimating HIV-1 incidence has previously been evaluated by using longitudinal specimens from persons with incident HIV infections, but questions remain about its accuracy. We sought to assess its performance in three longitudinal cohorts from Thailand where HIV-1 CRF01_AE and subtype B' dominate the epidemic. DESIGN: BED testing was conducted in two longitudinal cohorts with only incident infections (a military conscript cohort and an injection drug user cohort) and in one longitudinal cohort (an HIV-1 vaccine efficacy trial cohort) that also included long-term infections. METHODS: Incidence estimates were generated conventionally (based on the number of annual serocoversions) and by using BED test results in the three cohorts. Adjusted incidence was calculated where appropriate. RESULTS: For each longitudinal cohort the BED incidence estimates and the conventional incidence estimates were similar when only newly infected persons were tested, whether infected with CRF01_AE or subtype B'. When the analysis included persons with long-term infections (to mimic a true cross-sectional cohort), BED incidence estimates were higher, although not significantly, than the conventional incidence estimates. After adjustment, the BED incidence estimates were closer to the conventional incidence estimates. When the conventional incidence varied over time, as in the early phase of the injection drug user cohort, the difference between the two estimates increased, but not significantly. CONCLUSIONS: Evaluation of the performance of incidence assays requires the inclusion of a substantial number of cohort-derived specimens from individuals with long-term HIV infection and, ideally, the use of cohorts in which incidence remained stable. Appropriate adjustments of the BED incidence estimates generate estimates similar to those generated conventionally

Dual Testing Algorithm of BED-CEIA and AxSYM Avidity Index Assays Performs Best in Identifying Recent HIV Infection in a Sample of Rwandan Sex Workers

To assess the performance of BED-CEIA (BED) and AxSYM Avidity Index (Ax-AI) assays in estimating HIV incidence among female sex workers (FSW) in Kigali, Rwanda. Eight hundred FSW of unknown HIV status were HIV tested; HIV-positive women had BED and Ax-AI testing at baseline and ≥12 months later to estimate assay false-recent rates (FRR). STARHS-based HIV incidence was estimated using the McWalter/Welte formula, and adjusted with locally derived FRR and CD4 results. HIV incidence and local assay window periods were estimated from a prospective cohort of FSW. At baseline, 190 HIV-positive women were BED and Ax-AI tested; 23 were classified as recent infection (RI). Assay FRR with 95% confidence intervals were: 3.6% (1.2-8.1) (BED); 10.6% (6.1-17.0) (Ax-AI); and 2.1% (0.4-6.1) (BED/Ax-AI combined). After FRR-adjustment, incidence estimates by BED, Ax-AI, and BED/Ax-AI were: 5.5/100 person-years (95% CI 2.2-8.7); 7.7 (3.2-12.3); and 4.4 (1.4-7.3). After CD4-adjustment, BED, Ax-AI, and BED/Ax-AI incidence estimates were: 5.6 (2.6-8.6); 9.7 (5.0-14.4); and 4.7 (2.0-7.5). HIV incidence rates in the first and second 6 months of the cohort were 4.6 (1.6-7.7) and 2.2 (0.1-4.4). Adjusted incidence estimates by BED/Ax-AI combined were similar to incidence in the first 6 months of the cohort. Furthermore, false-recent rate on the combined BED/Ax-AI algorithm was low and substantially lower than for either assay alone. Improved assay specificity with time since seroconversion suggests that specificity would be higher in population-based testing where more individuals have long-term infectio

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

A Nitrile Hydratase in the Eukaryote Monosiga brevicollis

Bacterial nitrile hydratase (NHases) are important industrial catalysts and waste water remediation tools. In a global computational screening of conventional and metagenomic sequence data for NHases, we detected the two usually separated NHase subunits fused in one protein of the choanoflagellate Monosiga brevicollis, a recently sequenced unicellular model organism from the closest sister group of Metazoa. This is the first time that an NHase is found in eukaryotes and the first time it is observed as a fusion protein. The presence of an intron, subunit fusion and expressed sequence tags covering parts of the gene exclude contamination and suggest a functional gene. Phylogenetic analyses and genomic context imply a probable ancient horizontal gene transfer (HGT) from proteobacteria. The newly discovered NHase might open biotechnological routes due to its unconventional structure, its new type of host and its apparent integration into eukaryotic protein networks