Role of darunavir in the management of HIV infection

There is an ongoing need for potent antiretroviral therapies to deal with the increasing pool of treatment-experienced patients with multiple drug resistance. The last few years have seen the arrival of 2 new and very potent protease inhibitors – darunavir and tipranavir – alongside 2 whole new classes of anti-HIV agents – the integrase inhibitors and chemokine receptor CCR5 antagonists. This review focuses on the role of darunavir in managing HIV infection, with an emphasis on darunavir’s exceptional resistance profile and related clinical effectiveness, pharmacokinetics, tolerability and toxicity data. Darunavir in combination with the pharmacokinetic booster ritonavir has proved to be very effective in the treatment of highly treatment-experienced HIV patients with multiple drug resistance. The favorable tolerability and toxicity profile alongside the drug’s high genetic barrier to the development of resistance prompted approval of darunavir for HIV-treatment naïve patients. Furthermore, the paradigm of treating HIV with a combination of anti-HIV agents is currently being challenged by ongoing darunavir monotherapy trials and these preliminary data will be discussed

Complete characterization of ultrashort pulse sources at 1550 nm

This paper reviews the use of frequency-resolved optical gating (FROG) to characterize mode-locked lasers producing ultrashort pulses suitable for high-capacity optical communications systems at wavelengths around 1550 nm, Second harmonic generation (SHG) FROG is used to characterize pulses from a passively mode-locked erbium-doped fiber laser, and both single-mode and dual-mode gain-switched semiconductor lasers. The compression of gain-switched pulses in dispersion compensating fiber is also studied using SHG-FROG, allowing optimal compression conditions to be determined without a priori assumptions about pulse characteristics. We also describe a fiber-based FROG geometry exploiting cross-phase modulation and show that it is ideally suited to pulse characterization at optical communications wavelengths. This technique has been used to characterize picosecond pulses with energy as low as 24 pJ, giving results in excellent agreement with SHG-FROG characterization, and without any temporal ambiguity in the retrieved puls

Impact of Implementing Antenatal Syphilis Point-of-Care Testing on Maternal Mortality in KwaZulu-Natal, South Africa: An Interrupted Time Series Analysis.

BACKGROUND: Syphilis infection has been associated with an increased risk of HIV infection during pregnancy which poses greater risk for maternal mortality, and antenatal syphilis point-of-care (POC) testing has been introduced to improve maternal and child health outcomes. There is limited evidence on the impact of syphilis POC testing on maternal outcomes in high HIV prevalent settings. We used syphilis POC testing as a model to evaluate the impact of POC diagnostics on the improvement of maternal mortality in KwaZulu-Natal, South Africa. METHODS: We extracted 132 monthly data points on the number of maternal deaths in facilities and number of live births in facilities for 12 tertiary healthcare facilities in KwaZulu-Natal (KZN), South Africa from 2004 to 2014 from District Health Information System (DHIS) health facility archived. We employed segmented Poisson regression analysis of interrupted time series to assess the impact of the exposure on maternal mortality ratio (MMR) before and after the implementation of antenatal syphilis POC testing. We processed and analyzed data using Stata Statistical Software: Release 13. (Stata, Corp LP, College Station, TX, USA). RESULTS: The provincial average annual maternal mortality ratio (MMR) was estimated at 176.09 ± 43.92 ranging from a minimum of 68.48 to maximum of 225.49 per 100,000 live births. The data comprised 36 temporal points before the introduction of syphilis POC test exposure and 84 after the introduction in primary health care clinics in KZN. The average annual MMR for KZN from 2004 to 2014 was estimated at 176.09 ± 43.92. A decrease in MMR level was observed during 2008 after syphilis POC test implementation, followed by a rise during 2009. Analysis of the MMR trend estimates a significant 1.5% increase in MMR trends during the period before implementation and 1.3% increase after implementation of syphilis POC testing (p < 0.001). CONCLUSION: Although our finding suggests a brief reduction in the MMR trend after the implementation of antenatal syphilis POC testing, a continued increase in syphilis rates is seen in KwaZulu-Natal, South Africa. The study used one of the most powerful quasi-experimental research methods, segmented Poisson regression analysis of interrupted time series to model the impact of syphilis POC on maternal outcome. The study finding requires confirmation by use of more rigorous primary study design

A corrector design using active vase mirrors that allows a fixed telescope to access a large region of the sky

We investigate whether a three-mirror system, having secondary and the tertiary mirrors with surfaces warped by Zernike polynomials generated by active vase mirrors, is suitable to do the corrections of a fixed parabolic mirror observing at large angles from the zenith. We obtain designs of correctors with remarkable images and control of the distortion of the field of the view contained within a field greater than 15 Deg.Comment: Postscript file no figures included, 0.08 Megs, Complete paper can be obtained upon request from authors or from http://athene.as.arizona.edu:8000/~moretto/PUB.html Additional info on LMs at:http://astrosun.phy.ulaval.ca/lmt/lmt-home.html To appear in Applied Optic

A map of white matter tracts in a lesser ape, the lar gibbon

The recent development of methods for constructing directly comparable white matter atlases in primate brains from diffusion MRI allows us to probe specializations unique to humans, great apes, and other primate taxa. Here, we constructed the first white matter atlas of a lesser ape using an ex vivo diffusion-weighted scan of a brain from a young adult (5.5 years) male lar gibbon. We find that white matter architecture of the gibbon temporal lobe suggests specializations that are reminiscent of those previously reported for great apes, specifically, the expansion of the arcuate fasciculus and the inferior longitudinal fasciculus in the temporal lobe. Our findings suggest these white matter expansions into the temporal lobe were present in the last common ancestor to hominoids approximately 16 million years ago and were further modified in the great ape and human lineages. White matter atlases provide a useful resource for identifying neuroanatomical differences and similarities between humans and other primate species and provide insight into the evolutionary variation and stasis of brain organization

The uncertain role of substandard and falsified medicines in the emergence and spread of antimicrobial resistance

Approximately 10% of antimicrobials used by humans in low- and middle-income countries are estimated to be substandard or falsified. In addition to their negative impact on morbidity and mortality, they may also be important drivers of antimicrobial resistance. Despite such concerns, our understanding of this relationship remains rudimentary. Substandard and falsified medicines have the potential to either increase or decrease levels of resistance, and here we discuss a range of mechanisms that could drive these changes. Understanding these effects and their relative importance will require an improved understanding of how different drug exposures affect the emergence and spread of resistance and of how the percentage of active pharmaceutical ingredients in substandard and falsified medicines is temporally and spatially distributed

Evaluation of antenatal rapid human immunodeficiency virus testing in rural South Africa

Introduction: South African guidelines recommend two rapid tests for diagnosing human immunodeficiency virus (HIV) using the serial HIV testing algorithm, but the accuracy and compliance to this algorithm is unknown in rural clinics. We evaluated the accuracy of HIV rapid testing and the time to receiving test results among pregnant women in rural KwaZulu-Natal (KZN).Method: We observed the accuracy of rapid HIV testing algorithms for 208 consenting antenatal patients accessing voluntary HIV testing services in nine rural primary healthcare (PHC) clinics in KZN. A PHC-based HIV counsellor obtained finger-prick whole blood from each participant to perform rapid testing using the Advanced Quality™ One Step anti-HIV (1&amp;2) and/or ABON™ HIV 1/2/O Tri-Line HIV test. A research nurse obtained venous blood for an enzyme-linked immunosorbent assay (ELISA) HIV test, which is the gold standard diagnostic test. We recorded the time of receipt of HIV test results for each test.Results: Among 208 pregnant women with a mean age of 26 years, 72 women from nine rural PHC clinics were identified as HIV-positive by two rapid tests with an HIV-prevalence of 35% (95% Bayesian credibility intervals [BCI]: 28% – 41%). Of the 208 patients, 135 patients from six clinics were tested with the serial HIV testing algorithm. The estimated sensitivity and specificity for the 135 participants were 100% (95% confidence interval [CI]: 93% – 100%) and 99% (CI: 95% – 100%), respectively. The positive predictive value and negative predictive value were estimated at 98% (CI: 94% – 100%) and 95% (CI: 88% – 99%), respectively. All women received their HIV rapid test results within 20 min of testing. Test stock-out resulted in poor test availability at point-of-care, preventing performance of a second HIV test in three out of nine PHC clinics in rural KZN.Conclusion: Despite the poor compliance with national guidelines for HIV rapid testing services, HIV rapid test results provided to pregnant women in rural PHC clinics in KZN were generally accurate and timely. Test stock-out was shown to be one of the barriers to test availability in rural PHC clinics, resulting in poor compliance with guidelines. We recommend a compulsory confirmation HIV rapid test for all HIV-negative test results obtained from pregnant patients in rural and resource-limited settings

SAHA Decreases HDAC 2 and 4 Levels In Vivo and Improves Molecular Phenotypes in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a progressive neurological disorder for which there are no disease-modifying treatments. Transcriptional dysregulation is a major molecular feature of HD, which significantly contributes to disease progression. Therefore, the development of histone deacetylase (HDAC) inhibitors as therapeutics for HD has been energetically pursued. Suberoylanilide hydroxamic acid (SAHA) – a class I HDAC as well an HDAC6 inhibitor, improved motor impairment in the R6/2 mouse model of HD. Recently it has been found that SAHA can also promote the degradation of HDAC4 and possibly other class IIa HDACs at the protein level in various cancer cell lines. To elucidate whether SAHA is a potent modifier of HDAC protein levels in vivo, we performed two independent mouse trials. Both WT and R6/2 mice were chronically treated with SAHA and vehicle. We found that prolonged SAHA treatment causes the degradation of HDAC4 in cortex and brain stem, but not hippocampus, without affecting its transcript levels in vivo. Similarly, SAHA also decreased HDAC2 levels without modifying the expression of its mRNA. Consistent with our previous data, SAHA treatment diminishes Hdac7 transcript levels in both wild type and R6/2 brains and unexpectedly was found to decrease Hdac11 in R6/2 but not wild type. We investigated the effects of SAHA administration on well-characterised molecular readouts of disease progression. We found that SAHA reduces SDS-insoluble aggregate load in the cortex and brain stem but not in the hippocampus of the R6/2 brains, and that this was accompanied by restoration of Bdnf cortical transcript levels

"I feel dumb, embarrassed, and frustrated”: A qualitative exploration of the lived experience of acalculia.

Introduction: Acalculia is an acquired disability following stroke or brain injury, which involves difficulty processing numerical information (e.g. phone numbers, measurements) or problems with calculations and understanding quantities. Acalculia is not routinely screened for as part of standard post-stroke assessment. As a result, there is a lack of understanding of the nature and prevalence of poststroke acalculia, and the impact it has on stroke survivors. This qualitative study aimed to explore stroke survivors’ experiences of acalculia. Stroke survivors with a strong interest in acalculia and its rehabilitation initiated the study and contributed to its design. Methods: We explored the impact of acalculia on the lives of 16 stroke/brain injury survivors with acalculia and 7 carers using semi-structured online interviews. Participants ranged in age, gender, time post onset, lesion localisation, country of residence and numeracy level prior to brain injury. Data were analysed using thematic analysis. Results: Three main themes were identified: Awareness and Diagnosis, Emotional and Physical Impact, and Coping Strategies and Independence. Participants and carers repeatedly referred to the lack of awareness and treatment for acalculia and the devastating impact acalculia has had on their lives and independence. Practical impacts included managing money, making appointments, using timetables, organising social activities and employment, and managing medication. Conclusions: Our results highlight the urgent need to develop suitable assessments and interventions for acalculia and the scope for this to be PCPI-led. The data also reveal useful strategies and suggestions regarding effective timing and approaches for intervention

Using a complete spectroscopic survey to find red quasars and test the KX method

We present an investigation of quasar colour-redshift parameter space in order to search for radio-quiet red quasars and to test the ability of a variant of the KX quasar selection method to detect quasars over a full range of colour without bias. This is achieved by combining IRIS2 imaging with the complete Fornax Cluster Spectroscopic Survey to probe parameter space unavailable to other surveys. We construct a new sample of 69 quasars with measured bJ - K colours. We show that the colour distribution of these quasars is significantly different from that of the Large Bright Quasar Survey's quasars at a 99.9% confidence level. We find 11 of our sample of 69 quasars have signifcantly red colours (bJ - K >= 3.5) and from this, we estimate the red quasar fraction of the K <= 18.4 quasar population to be 31%, and robustly constrain it to be at least 22%. We show that the KX method variant used here is more effective than the UVX selection method, and has less colour bias than optical colour-colour selection methods.Comment: 11 pages, 14 figures, accepted for publication in MNRA