Questions to and answers from the International AIDS Society-USA Resistance Testing Guidelines Panel

In 1996 the International AIDS Society-USA convened an international panel of experts in HIV drug resistance and clinical management to develop guidelines for the clinical use and limitations of resistance testing. Since then the International AIDS Society-USA Resistance Testing Guidelines Panel has developed and regularly published its recommendations. The latest panel recommendations appear in the July 1 issue of Clinical Infectious Diseases. We periodically pose questions to the panel relating to clinical elements of resistance testing that have been collected from HIV practitioners across the nation. We are happy to feature the latest edition in this issue of Topics in HIV Medicine. It is our hope that addressing these issues will help guide your treatment strategy decisions regarding resistance testing.     

Sex steroid metabolism in human peripheral blood mononuclear cells changes with aging

CONTEXT: Dehydroepiandrosterone (DHEA) mainly exerts indirect action via downstream conversion toward sex steroids within peripheral target cells including immune cells. In vitro DHEA has been shown to enhance IL-2 release from T lymphocytes, whereas it inhibits IL-6 secretion. Conversely, aging is associated with a decline in both DHEA and IL-2, whereas IL-6 increases. OBJECTIVE: The objective of the study was to investigate age-related differences in expression and functional activity of steroidogenic enzymes involved in downstream conversion of DHEA in peripheral blood mononuclear cells (PBMCs). DESIGN: This study was cross-sectional. PARTICIPANTS/SETTING: Healthy young men (n = 8; age range, 23-29 yr) and healthy middle-aged men (n = 8; age range, 52-66 yr) were studied in an academic setting. MEASURES: mRNA expression of steroidogenic enzymes in PBMCs was measured by qualitative and quantitative RT-PCR analysis and enzyme activity assays after incubation of PBMCs with radiolabeled DHEA, 4-androstene-3,17-dione (androstenedione), and testosterone. RESULTS: RT-PCR analysis showed expression of all enzymes required for DHEA conversion toward active androgens and to the immune-stimulatory metabolite androstenediol. Steroid conversion patterns indicated a particularly increased activity of 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5) in the older men, demonstrated by significantly higher conversion rates of DHEA to androstenediol and of androstenedione to testosterone (all P < 0.05). By contrast, conversion of DHEA to androstenedione via 3beta-HSD occurred at a similar rate. Quantitative RT-PCR analysis revealed increased expression of 17beta-HSD 5 mRNA in PBMCs from the older men. CONCLUSIONS: Our results provide evidence for significant changes in sex steroid metabolism by human PBMCs with aging, which may represent an endocrine link to immune senescence.     

Recommendations for Responsible Development and Application of Neurotechnologies

Advancements in novel neurotechnologies, such as brain computer interfaces (BCI) and neuromodulatory devices such as deep brain stimulators (DBS), will have profound implications for society and human rights. While these technologies are improving the diagnosis and treatment of mental and neurological diseases, they can also alter individual agency and estrange those using neurotechnologies from their sense of self, challenging basic notions of what it means to be human. As an international coalition of interdisciplinary scholars and practitioners, we examine these challenges and make recommendations to mitigate negative consequences that could arise from the unregulated development or application of novel neurotechnologies. We explore potential ethical challenges in four key areas: identity and agency, privacy, bias, and enhancement. To address them, we propose (1) democratic and inclusive summits to establish globally-coordinated ethical and societal guidelines for neurotechnology development and application, (2) new measures, including “Neurorights,” for data privacy, security, and consent to empower neurotechnology users’ control over their data, (3) new methods of identifying and preventing bias, and (4) the adoption of public guidelines for safe and equitable distribution of neurotechnological devices.

     

Prediction of surface area size in orbital floor and medial orbital wall fractures based on topographical subregions

ObjectiveThis retrospective study evaluates the occurrence and frequency of different fracture patterns in a series of computed tomography (CT) scans in terms of the AOCMF Trauma Classification (TC) orbit module and correlates the assigned defects with measurements of the fracture area in order to get an approximate guideline for fracture size predictions on the basis of the classification.Material and methodsCT scans of patients with orbital floor fractures were evaluated using the AOCMFTC to determine the topographical subregions. The coding consisted of: W = orbital wall, 1 = anterior orbit, 2 = midorbit, i = inferior, m = medial. The 3-dimensional surface area size of the fractures was quantified by the “defect body” method (Brainlab, Munich, Germany). The fracture area size and its confidence and prediction interval within each topographical subregion was estimated by regression analysis.ResultsA total of 137 CT scans exhibited 145 orbital floor fractures, which were combined with 34 medial orbital wall fractures in 31 patients. The floor fractures – W1(i)2(i) (n = 86) and W1(i) (n = 19) were the most frequent patterns. Combined floor and medial wall fractures most frequently corresponded to the pattern W1 (im)2 (im) (n = 15) ahead of W1 (im) 2(i) (n = 10). The surface area size ranged from 0.11 cm² to 6.09 cm² for orbital floor and from 0.29 cm² to 5.43 cm² for medial wall fractures.The prediction values of the mean fracture area size within the subregions were computed as follows: W1(i) = 2.25 cm², W2(i) = 1.64 cm², W1(i)2(i) = 3.10 cm², W1(m) = 1.36 cm², W2(m) = 1.65 cm², W1(m)2(m) = 2.98 cm², W1 (im) = 3.35 cm², W1 (im) 2(i) = 4.63 cm², W1 (im)2(m) = 4.06 cm² and W1 (im)2 (im) = 7.16 cm².ConclusionThe AOCMFTC orbital module offers a suitable framework for topographical allocation of fracture patterns inside the infero-medial orbital cavity. The involvement of the subregions is of predictive value providing estimations of the mean 3-D fracture area size.     

FISSURE SEALANT IN A NUTSHELL. EVIDENCE-BASED META-EVALUATION OF SEALANTS’ EFFECTIVENESS IN CARIES PREVENTION AND ARREST

ObjectiveThis meta-evaluation aimed to summarize all available evidence regarding different fissure sealants on occlusal caries prevention, arrest, retention rate, adverse effect, and cost-effectiveness; when compared with no intervention, other preventive or minimally-invasive procedures.Materials and MethodsThe systematic reviews and meta-analyses were identified via four electronic databases and manual searching. Two independent reviewers performed study selection, data extraction, quality assessment with AMSTAR-2.ResultsAmong the 366 records yielded, 38 systematic reviews were identified as eligible 24 of them included meta-analyses. Moderate evidence has supported the efficacies of resin-based sealants (RBS) in occlusal caries prevention, arrest and cost-effectiveness compared to no interventions. Low to very low certainty of evidence suggested similar effectiveness of glass-ionomer cements in caries prevention with RBS and more superior performance of resin infiltration in arresting non-cavitated occlusal lesions.ConclusionThis meta-evaluation supports the use of RBS on permanent molars to reduce occlusal caries occurrence, arrest lesion progression and alleviate oral health inequalities between individuals of different socioeconomic status. This meta-evaluation also advocates further research on glass-ionomer cements and resin infiltration with respect to their efficacies in caries prevention and arrest.     

The effect of spironolactone on diastolic function in haemodialysis patients

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e’. Changes in the frequency of HFpEF were analysed using the comprehensive ‘HFA-PEFF score’. Complete echocardiographic assessment was available in 65 individuals (59.5?±?13.0 years, 21.5% female) with preserved left ventricular ejection fraction (LVEF?>?50%). At baseline, mean E/e’ was 15.2?±?7.8 and 37 (56.9%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e’ between the spironolactone group and the placebo group (+?0.93?±?5.39 vs.?+?1.52?±?5.94, p?=?0.68) or in mean change of left atrial volume index (LAVi) (1.9?±?12.3 ml/m² vs. 1.7?±?14.1 ml/m², p?=?0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+?0.8?±?14.2 g/m² vs.?+?2.7?±?15.9 g/m²; p?=?0.72) or NT-proBNP (p?=?0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p?=?0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients.

The trial has been registered at clinicaltrials.gov (NCT01691053; first posted Sep. 24, 2012).