Clinician compliance with laboratory monitoring and prescribing guidelines in HIV 1-infected patients receiving tenofovir

Background. Tenofovir is part of the preferred first-line regimen for HIV-infected patients in South Africa (SA), but is associated with kidney toxicity. SA antiretroviral therapy (ART) guidelines recommend creatinine monitoring at baseline (ART start) and at 3, 6 and 12 months, and substituting tenofovir with zidovudine, stavudine or abacavir should creatinine clearance (CrCl) decrease to <50 mL/min.Objective. To assess clinician compliance with tenofovir monitoring and prescribing guidelines.Methods. We described the proportion of adult patients on tenofovir-based first-line ART who were screened for baseline renal impairment, were monitored according to the SA antiretroviral treatment guidelines, and were switched from tenofovir if renal function declined.Results. We included 13 168 patients who started ART from 2010 to 2012. Creatinine concentrations were recorded in 11 712 (88.9%) patients on tenofovir at baseline, 9 135/11 657 (78.4%) at 3 months, 5 426/10 554 (51.4%) at 6 months, and 5 949/ 8 421 (70.6%) at 12 months. At baseline, 227 (1.9%) started tenofovir despite a CrCl <50 mL/min. While on tenofovir, 525 patients had at least one CrCl of <50 mL/min. Of 382 patients with ≥3 months’ follow-up after a CrCl <50 mL/min, 114 (29.8%) stopped tenofovir within 3 months. Clinicians were more likely to stop tenofovir in patients with lower CrCl and CD4 count. Of 226 patients who continued to receive tenofovir and had further CrCls available, 156 (69.0%) had a CrCl ≥50 mL/min at their next visit.Conclusions. Creatinine monitoring is feasible where access to laboratory services is good. Kidney function recovered in most patients who continued to receive tenofovir despite a CrCl <50 mL/min. Further research is needed to determine how best to monitor renal function with tenofovir in resource-limited settings

Has the phasing out of stavudine in accordance with changes in WHO guidelines led to a decrease in single-drug substitutions in first-line antiretroviral therapy for HIV in sub-Saharan Africa?

This version is the Accepted Manuscript and is published in final edited form as: AIDS. 2017 January 02; 31(1): 147–157. doi:10.1097/QAD.0000000000001307OBJECTIVE: We assessed the relationship between phasing out stavudine in first-line antiretroviral therapy (ART) in accordance with WHO 2010 policy and single-drug substitutions (SDS) (substituting the nucleoside reverse transcriptase inhibitor in first-line ART) in sub-Saharan Africa. DESIGN: Prospective cohort analysis (International epidemiological Databases to Evaluate AIDS-Multiregional) including ART-naive, HIV-infected patients aged at least 16 years, initiating ART between January 2005 and December 2012. Before April 2010 (July 2007 in Zambia) national guidelines called for patients to initiate stavudine-based or zidovudine-based regimen, whereas thereafter tenofovir or zidovudine replaced stavudine in first-line ART. METHODS: We evaluated the frequency of stavudine use and SDS by calendar year 2004-2014. Competing risk regression was used to assess the association between nucleoside reverse transcriptase inhibitor use and SDS in the first 24 months on ART. RESULTS: In all, 33 441 (8.9%; 95% confience interval 8.7-8.9%) SDS occurred among 377 656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in SDS corresponded with the phasing out of stavudine. Competing risks regression models showed that patients on tenofovir were 20-95% less likely to require a SDS than patients on stavudine, whereas patients on zidovudine had a 75-85% decrease in the hazards of SDS when compared to stavudine. CONCLUSION: The decline in SDS in the first 24 months on treatment appears to be associated with phasing out stavudine for zidovudine or tenofovir in first-line ART in our study. Further efforts to decrease the cost of tenofovir and zidovudine for use in this setting is warranted to substitute all patients still receiving stavudine

Alternative splicing in the fragile X gene <i>FMR1</i>

Human Molecular Genetics 2 pp. 399-404 (1993)The authors wish to note a mistake which was incorporated in figure 3 where both Asp and Asn were given the letter code N. A correct version of the figure and its legend is printed below.</p

Alternative splicing in the fragile X gene <i>FMR1</i>

Human Molecular Genetics 2 pp. 399-404 (1993)The authors wish to note a mistake which was incorporated in figure 3 where both Asp and Asn were given the letter code N. A correct version of the figure and its legend is printed below.</p

Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function

Room temperature chiral magnetic skyrmion in ultrathin magnetic nanostructures

Magnetic skyrmions are chiral spin structures with a whirling configuration. Their topological properties, nanometer size and the fact that they can be moved by small current densities have opened a new paradigm for the manipulation of magnetisation at the nanoscale. To date, chiral skyrmion structures have been experimentally demonstrated only in bulk materials and in epitaxial ultrathin films and under external magnetic field or at low temperature. Here, we report on the observation of stable skyrmions in sputtered ultrathin Pt/Co/MgO nanostructures, at room temperature and zero applied magnetic field. We use high lateral resolution X-ray magnetic circular dichroism microscopy to image their chiral N\'eel internal structure which we explain as due to the large strength of the Dzyaloshinskii-Moriya interaction as revealed by spin wave spectroscopy measurements. Our results are substantiated by micromagnetic simulations and numerical models, which allow the identification of the physical mechanisms governing the size and stability of the skyrmions.Comment: Submitted version. Extended version to appear in Nature Nanotechnolog

Scaling Up ART Adherence Clubs in the Public Sector Health System in the Western Cape, South Africa: a Study of the Institutionalisation of a Pilot Innovation

In 2011, a decision was made to scale up a pilot innovation involving ‘adherence clubs’ as a form of differentiated care for HIV positive people in the public sector antiretroviral therapy programme in the Western Cape Province of South Africa. In 2016 we were involved in the qualitative aspect of an evaluation of the adherence club model, the overall objective of which was to assess the health outcomes for patients accessing clubs through epidemiological analysis, and to conduct a health systems analysis to evaluate how the model of care performed at scale. In this paper we adopt a complex adaptive systems lens to analyse planned organisational change through intervention in a state health system. We explore the challenges associated with taking to scale a pilot that began as a relatively simple innovation by a non-governmental organisation

Core Verbal Autopsy Procedures with Comparative Validation Results from Two Countries

BACKGROUND: Cause-specific mortality statistics remain scarce for the majority of low-income countries, where the highest disease burdens are experienced. Neither facility-based information systems nor vital registration provide adequate or representative data. The expansion of sample vital registration with verbal autopsy procedures represents the most promising interim solution for this problem. The development and validation of core verbal autopsy forms and suitable coding and tabulation procedures are an essential first step to extending the benefits of this method. METHODS AND FINDINGS: Core forms for peri- and neonatal, child, and adult deaths were developed and revised over 12 y through a project of the Tanzanian Ministry of Health and were applied to over 50,000 deaths. The contents of the core forms draw upon and are generally comparable with previously proposed verbal autopsy procedures. The core forms and coding procedures based on the International Statistical Classification of Diseases (ICD) were further adapted for use in China. These forms, the ICD tabulation list, the summary validation protocol, and the summary validation results from Tanzania and China are presented here. CONCLUSIONS: The procedures are capable of providing reasonable mortality estimates as adjudged against stated performance criteria for several common causes of death in two countries with radically different cause structures of mortality. However, the specific causes for which the procedures perform well varied between the two settings because of differences in the underlying prevalence of the main causes of death. These differences serve to emphasize the need to undertake validation studies of verbal autopsy procedures when they are applied in new epidemiological settings

Fetal growth and the risk of childhood non-CNS solid tumours in Western Australia

Using population-based linked health data, we investigated whether the risk of certain childhood non-CNS solid tumours (n=186) was associated with intra-uterine growth. The risk of retinoblastoma and rhabdomyosarcoma, but not other tumour types, was positively associated with increased growth, suggesting a possible role of fetal growth factors. Larger studies are needed

Circadian Rhythm-Dependent Alterations of Gene Expression in Drosophila Brain Lacking Fragile X Mental Retardation Protein

Fragile X syndrome is caused by the loss of the FMR1 gene product, fragile X mental retardation protein (FMRP). The loss of FMRP leads to altered circadian rhythm behaviors in both mouse and Drosophila; however, the molecular mechanism behind this phenomenon remains elusive. Here we performed a series of gene expression analyses, including of both mRNAs and microRNAs (miRNAs), and identified a number of mRNAs and miRNAs (miRNA-1 and miRNA-281) with circadian rhythm-dependent altered expression in dfmr1 mutant flies. Identification of these RNAs lays the foundation for future investigations of the molecular pathway(s) underlying the altered circadian rhythms associated with loss of dFmr1