Incidence and Outcome of Progressive Multifocal Leukoencephalopathy over 20 Years of the Swiss HIV Cohort Study

Background. We investigated the incidence and outcome of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected individuals before and after the introduction of combination antiretroviral therapy (cART) in 1996. Methods. From 1988 through 2007, 226 cases of PML were reported to the Swiss HIV Cohort Study. By chart review, we confirmed 186 cases and recorded all-cause and PML-attributable mortality. For the survival analysis, 25 patients with postmortem diagnosis and 2 without CD4+ T cell counts were excluded, leaving a total of 159 patients (89 before 1996 and 70 during 1996-2007). Results. The incidence rate of PML decreased from 0.24 cases per 100 patient-years (PY; 95% confidence interval [CI], 0.20-0.29 cases per 100 PY) before 1996 to 0.06 cases per 100 PY (95% CI, 0.04-0.10 cases per 100 PY) from 1996 onward. Patients who received a diagnosis before 1996 had a higher frequency of prior acquired immunodeficiency syndrome-defining conditions (P=.007) but similar CD4+ T cell counts (60 vs. 71 cells/µL; P=.25), compared with patients who received a diagnosis during 1996 or thereafter. The median time to PML-attributable death was 71 days (interquartile range, 44-140 days), compared with 90 days (interquartile range, 54-313 days) for all-cause mortality. The PML-attributable 1-year mortality rate decreased from 82.3 cases per 100 PY (95% CI, 58.8-115.1 cases per 100 PY) during the pre-cART era to 37.6 cases per 100 PY (95% CI, 23.4.-60.5 cases per 100 PY) during the cART era. In multivariate models, cART was the only factor associated with lower PML-attributable mortality (hazard ratio, 0.18; 95% CI, 0.07-0.50; P<.001), whereas all-cause mortality was associated with baseline CD4+ T cell count (hazard ratio per increase of 100 cells/µL, 0.52; 95% CI, 0.32-0.85; P=.010) and cART use (hazard ratio, 0.37; 95% CI, 0.19-0.75; P=.006). Conclusions. cART reduced the incidence and PML-attributable 1-year mortality, regardless of baseline CD4+ T cell count, whereas overall mortality was dependant on cART use and baseline CD4+ T cell coun

Hexagonal Si-Ge Class of Semiconducting Alloys Prepared Using Pressure and Temperature

Multi-anvil and laser-heated diamond anvil methods have been used to subject Ge and Si mixtures to pressures and temperatures of between 12 and 17 GPa and 1500–1800 K, respectively. Synchrotron angle dispersive X-ray diffraction, precession electron diffraction and chemical analysis using electron microscopy, reveal recovery atambient pressure of hexagonal Ge-Si solid solutions (P6$_3$/mmc). Taken together, the multi-anvil and diamond anvil results reveal that hexagonal solid solutions can be preparedfor all Ge-Si compositions. This hexagonal class of solid solutions constitutes a significant expansion of the bulk Ge-Sisolid solution family, and is of interest for optoelectronic applications

Overcoming the clinical challenges of traditional ayahuasca: a first-in-human trial exploring novel routes of administration of N,N-Dimethyltryptamine and harmine

Recently, the Amazonian plant medicine “ayahuasca”—containing the psychedelic compound N,N-dimethyltryptamine (DMT) and numerous β-carboline alkaloids, such as harmine—has been suggested to exhibit beneficial effects in patients with affective and other mental health disorders. Although ayahuasca ingestion is considered safe, its pharmacokinetics/pharmacodynamics and tolerability profile pose some challenges and may limit the clinical applicability in vulnerable patient populations. While overdosing and the admixture of intolerable plant constituents may explain some of the common adverse reactions, the peroral route of administration may represent another relevant source of gastro-intestinal intolerabilities and unpredictable pharmacokinetics across users. To overcome these challenges, the present work aimed at creating ayahuasca-analogue formulations with improved pharmacokinetics and tolerability profiles. To this end, we developed peroral formulas and compared them with parenteral formulas specifically designed to circumvent the gastro-intestinal tract. In more detail, peroral administration of a capsule (containing purified DMT and harmine) was tested against a combined administration of an oromucosal harmine tablet and an intranasal DMT spray at two dose levels in an open-label within-subject study in 10 healthy male subjects. Pharmacokinetic and pharmacodynamic profiles were assessed by means of continuous blood sampling, vital sign monitoring, and psychometric assessments. Common side effects induced by traditional herbal ayahuasca such as nausea, vomiting, and diarrhea were significantly attenuated by our DMT/harmine formulations. While all preparations were well tolerated, the combined buccal/intranasal administration of harmine and DMT yielded substantially improved pharmacokinetic profiles, indicated by significantly reduced variations in systemic exposure. In conclusion, the combined buccal/intranasal administration of harmine and DMT is an innovative approach that may pave the way towards a safe, rapid-acting, and patient-oriented administration of DMT/harmine for the treatment of affective disorders.Clinical Trial Registration:clinicaltrials.gov, identifier NCT0471633

Maximal oxygen uptake and fatty acid oxidation in athletic older men and women and healthy control

Introduction: Cardiopulmonary and musculoskeletal systems deteriorate through middle and into older age. This has a negative impact on physical capability and energy metabolism. The purpose of the present study was to determine the effects of ageing and exercise on peak rates of oxygen uptake (VO2peak) and fatty acid oxidation (PFO).Methods: All participants provided written, informed consent. Masters Athletes (MA: n=40, aged 37-90) specialised in endurance (n=10) or sprint running (n=30) were recruited during the 2012 European MA Championships in Zittau, Germany. Untrained (n=42, aged 18-67; 23 men and 16 women) were recruited from the general Manchester population (UK). The untrained participants also completed 12 weeks very high intensity sprint cycle training (4* 20s at 170% VO2max, 3/wk). VO2max and PFO were assessed using indirect calorimetry and incremental cycle ergometry. Statistical significance was gained by independent samples t-tests using IBM SPSS v.20.Results: The endurance and sprint trained MA were a similar age and had similar VO2max (Endurance MA: 47.22 ml/kg/min (±4.15) vs Sprint MA: 43.52 ml/kg/min (±2.21) p=0.416). Both MA groups were significantly higher than untrained people (38.86 ml/kg/min). MA sprinters and endurance runners had a VO2max similar to 19 years younger untrained, healthy people. Regression analysis showed that VO2max decreased by around 11% per decade after the age of 40 yrs in the MA group and 5% per decade after the age of 40 yrs in the untrained group. PFO was similar in endurance and sprint trained MA (Endurance: 8.09 mg/kg/min (±0.95) vs Sprint: 6.91 mg/kg/min (±0.53) p=0.284). In the untrained group, PFO was significantly lower than MA (p=0.006). Regression showed that PFO of MAs was similar to that of an untrained, healthy person 19 years younger. The sprint-training programme caused VO2max to increase by 10% (Pre: 38.86 ml/kg/min (±1.31) vs Post: 42.84 ml/kg/min (±1.24) p&lt;0.001) and PFO to increase by 18% (Pre: 5.57 mg/kg/min (±0.33) vs Post: 6.58 mg/kg/min (±0.41) p=0.050).Conclusion: These results show that MAs have a cardiopulmonary and metabolic fitness at levels equivalent to someone almost 20 yrs younger. Previously untrained middle-aged people can achieve substantial gains in fitness by completing relatively short duration, but high intensity sprint training and reach levels similar to those observed in the master athletes