Many direct‐acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C‐ISLE study assessed the efficacy and safety of ...elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open‐label study. Treatment‐naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment‐experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks SVR12). Among treatment‐naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment‐experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12‐week arm, with and without RBV, respectively, and 94% (17/18) in the 16‐week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8‐week arm), 1 discontinued due to vomiting/cellulitis (16‐week arm), and 2 discontinued (consent withdrawn/lost to follow‐up). SVR12 was not affected by the presence of resistance‐associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. Conclusion: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment‐naive and peginterferon/RBV–experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113‐2126)
Background
Screening for skin cancer can be cost‐effective if focused on high‐risk groups. Risk prediction tools have been developed for keratinocyte cancers and melanoma to optimize advice and ...management. However, few have been validated in a clinical setting over the past few years.
Objectives
To assess the clinical utility of risk assessment tools to identify individuals with prevalent skin cancers in a volunteer‐based screening clinic.
Methods
Participants were adults presenting for a skin check at a volunteer‐based skin cancer screening facility. We used previously published tools, based on questionnaire responses, to predict melanoma and keratinocyte cancers KCs; basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) and classified each participant into one of five risk categories. Participants subsequently underwent a full skin examination by a dermatologist. All suspicious lesions were biopsied, and all cancers were histopathologically confirmed.
Results
Of 789 people who presented to the clinic, 507 (64%) consented to the study. Twenty‐two BCCs, 19 SCCs and eight melanomas were diagnosed. The proportion of keratinocyte cancers diagnosed increased according to risk category from <1% in the lowest to 24% in the highest risk category (P < 0.001). Subtype analysis revealed similar proportionate increases in BCC or SCC prevalence according to risk category. However, a similar proportion of melanoma cases were detected in the low‐risk and high‐risk groups.
Conclusion
The risk prediction model for keratinocyte cancers can reliably identify individuals with a significant skin cancer burden prior to a skin examination in the community setting. The prediction tool for melanoma needs to be tested in a larger sample exposed to a wider range of environmental risk factors.
Objective To assess whether adding liothyronine (LT3) to levothyroxine (LT4) monotherapy normalizes serum thyrotropin (TSH) and thyroxine (T4) concentrations in children with congenital ...hypothyroidism and central resistance to thyroid hormone. Study design We retrospectively studied 12 patients with congenital hypothyroidism and central resistance to thyroid hormone (6 treated with LT3+LT4 combined therapy and 6 treated with LT4 monotherapy). In patients receiving combined therapy, we compared serum concentrations of TSH, T4, and triiodothyronine before and after addition of LT3. We used repeated measures analysis to compare thyroid function in participants receiving combined therapy vs monotherapy, while accounting for age and intrasubject correlation. Results In patients receiving combined therapy, the addition of LT3 was associated with normalization of mean TSH (9.2 vs 4.5 mIU/L, P = .002), a lower proportion of TSH values greater than 10 mIU/L (35% vs 8%, P = .03), and a decrease in mean serum T4 by 23 ± 9% ( P < .001). Compared with patients receiving LT4 monotherapy, patients receiving combined therapy had lower mean TSH (8.5 ± 0.9 vs 4.3 ± 0.4, P < .001), lower odds of TSH elevation greater than 10 mIU/L (OR 0.20, 95% CI 0.10-0.41, P < .001), and lower odds of T4 elevation (OR 0.21, 95% CI 0.04-1.09, P = .06). LT3 treatment did not increase serum T3 levels significantly. Conclusion The addition of LT3 to LT4 monotherapy facilitates normalization of both serum TSH and T4 in patients with congenital hypothyroidism and central resistance to thyroid hormone. Larger prospective studies are needed to confirm these findings and to determine the effect of combined therapy on neurodevelopmental outcomes.
Biogeochemical changes in marine sediments during coastal water hypoxia are well described, but less is known about underlying changes in microbial communities. Bacterial and archaeal communities in ...Louisiana continental shelf (LCS) hypoxic zone sediments were characterized by pyrosequencing 16S rRNA V4‐region gene fragments obtained by PCR amplification of community genomic DNA with bacterial‐ or archaeal‐specific primers. Duplicate LCS sediment cores collected during hypoxia had higher concentrations of Fe(II), and dissolved inorganic carbon, phosphate, and ammonium than cores collected when overlying water oxygen concentrations were normal. Pyrosequencing yielded 158 686 bacterial and 225 591 archaeal sequences from 20 sediment samples, representing five 2‐cm depth intervals in the duplicate cores. Bacterial communities grouped by sampling date and sediment depth in a neighbor‐joining analysis using Chao–Jaccard shared species values. Redundancy analysis indicated that variance in bacterial communities was mainly associated with differences in sediment chemistry between oxic and hypoxic water column conditions. Gammaproteobacteria (26.5%) were most prominent among bacterial sequences, followed by Firmicutes (9.6%), and Alphaproteobacteria (5.6%). Crenarchaeotal, thaumarchaeotal, and euryarchaeotal lineages accounted for 57%, 27%, and 16% of archaeal sequences, respectively. In Thaumarchaeota Marine Group I, sequences were 96–99% identical to the Nitrosopumilus maritimus SCM1 sequence, were highest in surficial sediments, and accounted for 31% of archaeal sequences when waters were normoxic vs. 13% of archaeal sequences when waters were hypoxic. Redundancy analysis showed Nitrosopumilus‐related sequence abundance was correlated with high solid‐phase Fe(III) concentrations, whereas most of the remaining archaeal clusters were not. In contrast, crenarchaeotal sequences were from phylogenetically diverse lineages, differed little in relative abundance between sampling times, and increased to high relative abundance with sediment depth. These results provide further evidence that marine sediment microbial community composition can be structured according to sediment chemistry and suggest the expansion of hypoxia in coastal waters may alter sediment microbial communities involved in carbon and nitrogen cycling.
Traumatic brain injury (TBI) is a pervasive public health crisis that severely impacts the quality of life of affected individuals. Like peripheral forms of trauma, TBI results from extraordinarily ...heterogeneous environmental forces being imparted on the cranial space, resulting in heterogeneous disease pathologies. This has made therapies for TBI notoriously difficult to develop, and currently, there are no FDA-approved pharmacotherapies specifically for the acute or chronic treatment of TBI. TBI is associated with changes in cognition and can precipitate the onset of debilitating psychiatric disorders like major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Complicating these effects of TBI, FDA-approved pharmacotherapies utilized to treat these disorders often fail to reach the desired level of efficacy in the context of neurotrauma. Although a complicated association, decades of work have linked central serotonin (5-HT) neurotransmission as being involved in the etiology of a myriad of neuropsychiatric disorders, including MDD and GAD. 5-HT is a biogenic monoamine neurotransmitter that is highly conserved across scales of biology. Though the majority of 5-HT is isolated to peripheral sites such as the gastrointestinal (GI) tract, 5-HT neurotransmission within the CNS exerts exquisite control over diverse biological functions, including sleep, appetite and respiration, while simultaneously establishing normal mood, perception, and attention. Although several key studies have begun to elucidate how various forms of neurotrauma impact central 5-HT neurotransmission, a full determination of precisely how TBI disrupts the highly regulated dynamics of 5-HT neuron function and/or 5-HT neurotransmission has yet to be conceptually or experimentally resolved. The purpose of the current review is, therefore, to integrate the disparate bodies of 5-HT and TBI research and synthesize insight into how new combinatorial research regarding 5-HT neurotransmission and TBI may offer an informed perspective into the nature of TBI-induced neuropsychiatric complications.
Aims/hypothesis The aim of this meta-analysis was to integrate the results of primary research testing the effect of diabetes self-management interventions that included recommendations to increase ...exercise on metabolic outcomes among adults with type 2 diabetes. Materials and methods Extensive literature searching strategies were used to identify published and unpublished intervention studies that measured glycated haemoglobin outcomes. Primary study results were coded. Fixed- and random-effects meta-analytic procedures included moderator analyses. Results Data were synthesised across 10,455 subjects from 103 research reports. The overall mean weighted effect size for two-group comparisons was 0.29 (higher mean for treatment than control). This effect size is consistent with a difference in HbA₁c means of 0.45% (e.g. 7.38% for treatment subjects vs 7.83% for control subjects). For single-group studies, the overall mean weighted effect size was 0.32-0.34. Control group subjects experienced no improvement in metabolic control during participation in the studies. Interventions that targeted multiple health behaviours resulted in smaller effect size estimates (0.22) than interventions that focused only on exercise behaviours (0.45). Funded studies reported greater improvements in metabolic controls. Studies with a greater proportion of female subjects reported lower effect sizes. Baseline HbA₁c and BMI were unrelated to metabolic outcomes. Conclusions/interpretation These findings suggest that self-management interventions that include exercise recommendations improve metabolic control, despite considerable heterogeneity in the magnitude of the intervention effect. Interventions that emphasise exercise may be especially effective in improving metabolic control. Primary research testing interventions in randomised trials to confirm causal relationships would be constructive.
Evolutionarily enlightened management ASHLEY, Mary V; WILLSON, Mary F; PERGAMS, Oliver R. W ...
Biological conservation,
06/2003, Letnik:
111, Številka:
2
Journal Article
Recenzirano
Here we review growing evidence that microevolutionary changes may often be rapid and, in many cases, occur on time frames comparable to human disturbance and anthropogenic change. Contemporary ...evolutionary change has been documented in relatively pristine habitats, in disturbed populations, under captive management, and in association with both intentional and inadvertent introductions. We argue that evolutionary thinking is thus relevant to conservation biology and resource management but has received insufficient consideration. Ignoring evolution may have a variety of consequences, including unpredicted evolutionary responses to disturbance and naive or inappropriate management decisions. Philosophically, we must also grapple with the issue of whether the evolution of adaptations to disturbance and degraded habitats is sometimes beneficial or something to be rigorously avoided. We advocate promoting evolutionarily enlightened management Lecture Notes in Biomathematics 99 (1994) 248, in which both the ecological and evolutionary consequences of resource management decisions are considered.
Sterol accumulation in membranes blocks the exit of SCAP from the ER, preventing SREBP cleavage and reducing cholesterol synthesis. Sterols act through SCAP's sterol-sensing domain by an obscure ...mechanism. Here, we show that addition of cholesterol to ER membranes in vitro causes a conformational change in SCAP, detected by the unmasking of closely spaced trypsin cleavage sites. Two mutant forms of SCAP (Y298C and D443N) that are refractory to sterol regulation in vivo are also refractory to sterol-induced conformational change in vitro. 25-hydroxycholesterol, a potent regulator of SCAP in vivo, fails to change SCAP's conformation in vitro, suggesting that oxysterols act in intact cells by translocating cholesterol from plasma membrane to ER. These studies demonstrate an in vitro effect of cholesterol on the sterol regulatory machinery.
Provision of ancillary services is one of the key sources of revenue for energy storage. Hence, in order to understand the economic viability of a given technology it is important to assess its ...potential profitability and performance through provision of such services. Firm Frequency Response (FFR) is a type of ancillary service used for balancing grid frequency; this work uses grid frequency data to determine the real-time usage of lithium ion and lead acid batteries providing FFR. Battery capacity is balanced in real-time using several different proposed strategies; degradation and lifetime are then calculated, along with Net Present Value (NPV) for the different battery types, to ascertain their profitability. Lead acid batteries are found to not be worthwhile investments for this usage. On the other hand, lithium ion batteries are found to be suitable. In particular, battery chemistries providing high power density are economically preferable to those with high energy densities. It is found that the highest NPV (of the order £105) can be achieved when the batteries are used in a way that reduces degradation and increases lifetime; practically, this equates to a high level of capacity balancing in order to maintain battery capacity close to its mid-point, even if this is more costly in the short-term.
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