How low can you go? The lower limits of platinum loading, in the sub‐monolayer to monolayer range, have been explored for the hydrogen evolution reaction (HER). A low‐cost substrate material, ...tungsten monocarbide (see picture; W blue, C small gray spheres) is capable of supporting monolayer amounts of platinum (large blue‐gray spheres) to produce an electrocatalyst with the same HER activity as bulk platinum.
To assess the spectrum and reversibility of the cardiotoxicity observed in the adjuvant trastuzumab trials.
The design and efficacy of the major adjuvant trastuzumab trials was assessed, including ...the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group N9831, Herceptin Adjuvant, Breast Cancer International Research Group 006, and Finland Herceptin trials. The cardiotoxicity data were evaluated with a focus on the follow-up cardiac evaluations of women who were diagnosed with cardiotoxicity. Proposed mechanisms of trastuzumab-related cardiotoxicity were considered. The natural history of congestive heart failure (CHF) was reviewed with the goal of placing the trastuzumab experience in context.
Up to 4% of patients enrolled onto the adjuvant trastuzumab trials experienced severe CHF during treatment. In these trials, early stopping rules that identified an unacceptable level of cardiotoxicity were never reached. Despite this, a large number of patients on these trials experienced some form of cardiotoxicity that ultimately required discontinuation of trastuzumab. Approximately 14% of patients in the NSABP B-31 trial discontinued trastuzumab because of asymptomatic decreases in left ventricular ejection fraction (LVEF). Results of follow-up cardiac evaluations of patients diagnosed with any degree of cardiotoxicity in the NSABP B-31 trial document that a clinically significant proportion of patients have sustained decrements in their LVEF to less than 50%.
Adjuvant trastuzumab provides substantial benefits to patients with human epidermal growth factor receptor 2-positive breast cancer, however, competing immediate and long-term cardiovascular risks are a great concern. Continued cardiac follow-up of these women is of critical importance.
Haemonchus contortus is one of the most pathogenic gastrointestinal nematodes in small ruminants. To understand molecular mechanisms underlying host resistance to this parasite, we used ...RNA-sequencing technology to compare the transcriptomic response of the abomasal tissue, the site of the host-parasite interaction, of Merino sheep bred to be either genetically resistant or susceptible to H. contortus infection. Two different selection flocks, the Haemonchus selection flock (HSF) and the Trichostrongylus selection flock (TSF), and each contains a resistant and susceptible line, were studied. The TSF flock was seemingly more responsive to both primary and repeated infections than HSF. A total of 127 and 726 genes displayed a significant difference in abundance between resistant and susceptible animals in response to a primary infection in HSF and TSF, respectively. Among them, 38 genes were significantly affected by infection in both flocks. Gene ontology (GO) enrichment of the differentially expressed genes identified in this study predicted the likely involvement of extracellular exosomes in the immune response to H. contortus infection. While the resistant lines in HSF and TSF relied on different mechanisms for the development of host resistance, adhesion and diapedesis of both agranulocytes and granulocytes, coagulation and complement cascades, and multiple pathways related to tissue repair likely played critical roles in the process. Our results offered a quantitative snapshot of changes in the host transcriptome induced by H. contortus infection and provided novel insights into molecular mechanisms of host resistance.
•Non-metric traits and minor anatomical variants may be mistaken for skeletal trauma.•Knowledge of common non-metric traits is important in medico-legal cases.•Indicators of healing can help ...distinguish trauma from non-metric traits.
This paper presents some of the more commonly encountered non-metric traits and minor anatomical variants in the adult human skeleton that can mimic or be mistaken for trauma. Distinguishing non-metric traits is contingent upon both a knowledge of potential non-metric traits as well as the normal developmental timing, location, and anatomy of maturational markers in the human skeleton. Distinguishing non-metric traits from trauma in dry bone is an essential component in establishing an accurate and thorough forensic analysis of human remains, especially as it deals with antemortem and perimortem trauma, and postmortem damage.
A statewide investigation of urban creek sediment toxicity was conducted in California in recognition of increased incidences of toxicity linked to pyrethroid pesticides. The goals were to examine ...the spatial occurrence and magnitude of sediment toxicity in California urban creeks, and to examine the role of pyrethroids in toxic urban creek sediment samples. After a preliminary screening of 90 sites, 30 creeks were sampled in eight geographical regions. Sediment toxicity was assessed using 10 day bioassays with the resident amphipod Hyalella azteca. Bioassays were conducted at two test temperatures of 23 °C and at 15 °C to provide evidence of the cause of toxicity, and to more accurately reflect ambient environmental temperatures. Twenty-five of 30 samples were toxic when tested at 23 °C, and all 30 samples were toxic when tested at 15 °C. The magnitude of toxicity increased in samples tested at 15 °C suggesting the influence of pyrethroids, which are more toxic at colder temperatures. Pyrethroids were present in all sediment samples and were the only compounds detected at concentrations toxic to H. azteca. Bifenthrin was the pyrethroid of greatest toxicological concern, occurring in all 30 samples at concentrations up to 219 ng/g. Pyrethroid contamination of urban creeks was most severe in the Los Angeles, Central Valley, and San Diego regions, respectively. However, pyrethroids were also linked to urban creek aquatic toxicity in all regions sampled, including the less urbanized areas of the North Coast and Lake Tahoe.
Small unmanned aircraft vehicles (UAV) are potential remote sensing platforms for precision agriculture. However, to be useful for in-season management, nitrogen status needs to be estimated ...sufficiently early in the growing season. To determine when differences in nitrogen status of irrigated potatoes could be detected, an experiment was established in 2013 with a randomized block design with four N fertilization rates and three replicates. Over the growing season, a small parafoil-wing UAV was used to acquire color-infrared images with pixel sizes between 20 and 25 mm. Two normalized difference spectral indices were determined from image digital numbers, the normalized difference vegetation index (NDVI) and the green normalized difference vegetation index (GNDVI), which were then calibrated using reflectance-based NDVI and GNDVI. Unexpectedly, there were decreases in the NDVI and GNDVI calibrations with increased camera exposure time. After calibration, both NDVI and GNDVI were about equal to indices calculated using reflectances from high-altitude aerial photography and the WorldView-2 satellite. During tuber initiation and early tuber bulking, differences in measured leaf area index (LAI), chlorophyll meter values and spectral indices were only detectable at the lowest N fertilization rate. Later in the growing season, all N treatments could be distinguished in the imagery, but too late to mitigate yield losses from N deficiency. Linear relationships between plot GNDVI and NDVI were hypothesized to differ among N treatments because there would be less chlorophyll content per leaf area. Contrary to the hypothesis, there were no differences among fertilization rates on either of the two sampling dates. Compared with alternative technologies, small UAV platforms and sensors may not provide value to farmers for in-season nitrogen management.
Abstract
Background
Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system.
...Methods
A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48.
Results
Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10).
Conclusions
This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.
A5324 assessed whether ART intensification with dolutegravir and maraviroc compared with placebo would benefit persons with human immunodeficiency virus and neurocognitive impairment. Neurocognitive performance, depressive symptoms, and daily functioning improved over 96 weeks but did not differ by treatment arm.
Clinical Trials Registration
. NCT02519777.
Graphical abstract
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/challenges-in-the-long-term-management-of-patients-with-coccidioidal-meningitis-a-retrospective-analysis-of-treatment-and-outcomes
MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of deoxynucleoside triphosphate (dNTP) ...pools are a recognized cause of mitochondrial genomic instability; therefore, we determined DNA copy number and dNTP levels in mitochondria of two models of MPV17 deficiency. In Mpv17 ablated mice, liver mitochondria showed substantial decreases in the levels of dGTP and dTTP and severe mitochondrial DNA depletion, whereas the dNTP pool was not significantly altered in kidney and brain mitochondria that had near normal levels of DNA. The shortage of mitochondrial dNTPs in Mpv17-/- liver slows the DNA replication in the organelle, as evidenced by the elevated level of replication intermediates. Quiescent fibroblasts of MPV17-mutant patients recapitulate key features of the primary affected tissue of the Mpv17-/- mice, displaying virtual absence of the protein, decreased dNTP levels and mitochondrial DNA depletion. Notably, the mitochondrial DNA loss in the patients' quiescent fibroblasts was prevented and rescued by deoxynucleoside supplementation. Thus, our study establishes dNTP insufficiency in the mitochondria as the cause of mitochondrial DNA depletion in MPV17 deficiency, and identifies deoxynucleoside supplementation as a potential therapeutic strategy for MPV17-related disease. Moreover, changes in the expression of factors involved in mitochondrial deoxynucleotide homeostasis indicate a remodeling of nucleotide metabolism in MPV17 disease models, which suggests mitochondria lacking functional MPV17 have a restricted purine mitochondrial salvage pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background HIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of ...first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART. Methods We retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs. Findings Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60·5 cells per μL IQR 21·0–128·0 in patients with TAMS vs 95·0 cells per μL 37·0–177·0 in patients without TAMs; p=0·007) and were more likely to have tenofovir resistance (93 81% of 115 patients with TAMs vs 352 59% of 597 patients without TAMs; p<0·0001), NNRTI resistance (107 93% vs 462 77%; p<0·0001), and cytosine analogue resistance (100 87% vs 378 63%; p=0·0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0·64 (p<0·0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1·29 (1·13–1·47; p<0·0001) Interpretation TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains. Funding The Wellcome Trust.
Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil ...fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase ( RT ) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 57%). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio OR 1·50, 95% CI 1·27–1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20–1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL SE 12 480 versus 133 900 copies per mL SE 16 650; p=0·626). Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.
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