Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic ...variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D‐bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease‐causing genes remain unidentified. We have expanded the spectrum of disease‐causing variants associated with Perrault syndrome.
The development of novel nanomaterials with unique physico-chemical properties is increasing at a rapid rate, with potential applications across a broad range of manufacturing industries and consumer ...products. Nanomaterial safety is therefore becoming an increasingly contentious issue that has intensified over the past 4 years, and in response, a steady stream of studies focusing on nanotoxicology are emerging. However, it is becoming increasingly evident that nanomaterials cannot be treated in the same manner as chemical compounds with regards to their safety assessment, as their unique physico-chemical properties are also responsible for unexpected interactions with experimental components that generate misleading data-sets. In this report, we focus on nanomaterial interactions with colorimetric and fluorometric dyes, components of cell culture growth medium and genotoxicity assay components, and the resultant consequences on test systems are demonstrated. Thus, highlighting some of the potential confounding factors that need to be considered in order to ensure that in vitro genotoxicity assays report true biological impacts in response to nanomaterial exposure.
We present time-delay measurements for the new quadruple imaged quasar DES J0408−5354, the first quadruple imaged quasar found in the Dark Energy Survey (DES). Our result is made possible by ...implementing a new observational strategy using almost daily observations with the MPIA 2.2 m telescope at La Silla observatory and deep exposures reaching a signal-to-noise ratio of about 1000 per quasar image. This data qualityallows us to catch small photometric variations (a few mmag rms) of the quasar, acting on temporal scales much shorter than microlensing, and hence making the time delay measurement very robust against microlensing. In only seven months we very accurately measured one of the time delays in DES J0408−5354: Δt(AB) = −112.1 ± 2.1 days (1.8%) using only the MPIA 2.2 m data. In combination with data taken with the 1.2 m Euler Swiss telescope, we also measured two delays involving the D component of the system Δt(AD) = −155.5 ± 12.8 days (8.2%) and Δt(BD) = −42.4 ± 17.6 days (41%), where all the error bars include systematics. Turning these time delays into cosmological constraints will require deep Hubble Space Telescope (HST) imaging or ground-based adaptive optics (AO), and information on the velocity field of the lensing galaxy.
We examined PrEP use, condomless anal sex (CAS), and PrEP adherence among men who have sex with men (MSM) attending sexual health clinics in Wales, UK. In addition, we explored the association ...between the introduction of measures to control transmission of SARS-CoV-2 on these outcomes. We conducted an ecological momentary assessment study of individuals in receipt of PrEP in Wales. Participants used an electronic medication cap to record PrEP use and completed weekly sexual behaviour surveys. We defined adherence to daily PrEP as the percentage of CAS episodes covered by daily PrEP (preceded by ≥ 3 days of PrEP and followed by ≥ 2 days). Sixty participants were recruited between September 2019 and January 2020. PrEP use data prior to the introduction of control measures were available over 5785 person-days (88%) and following their introduction 7537 person-days (80%). Data on CAS episodes were available for 5559 (85%) and 7354 (78%) person-days prior to and following control measures respectively. Prior to the introduction of control measures, PrEP was taken on 3791/5785 (66%) days, there were CAS episodes on 506/5559 (9%) days, and 207/406 (51%) of CAS episodes were covered by an adequate amount of daily PrEP. The introduction of pandemic-related control measures was associated with a reduction in PrEP use (OR 0.44, 95%CI 0.20–0.95), CAS (OR 0.35, 95%CI 0.17–0.69), and PrEP adherence (RR = 0.55, 95%CI 0.34–0.89) and this may have implications for the health and wellbeing of PrEP users and, in addition to disruption across sexual health services, may contribute to wider threats across the HIV prevention cascade.
Cerebral small vessel disease (SVD) is common in aged brains and causes lacunar stroke, diffuse white matter lesions (leukoaraiosis), and vascular cognitive impairment. The pathogenesis is unknown. ...Endothelial dysfunction is a possible causal factor, and circulating markers of endothelial activation (intercellular adhesion molecule-1, thrombomodulin) and inflammation (interleukin IL-6) are elevated in patients with SVD. In this case-control study, we tested whether brain endothelial ICAM1, thrombomodulin, and IL-6 are altered in SVD.
We examined small penetrating cerebral arteries of pathologically diagnosed SVD cases, aged controls without SVD, young control cases with no brain pathology, and cases with early-onset hereditary SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL). All tissues had minimal cerebral amyloid angiopathy or other Alzheimer pathology.
Thrombomodulin immunoreactivity was present in all aged SVD, aged control, and CADASIL cases, primarily in small artery endothelium. Thrombomodulin was augmented in aged SVD cases compared with aged controls (p = 0.012) and in vessels with higher sclerotic index (an indicator of SVD severity; p < 0.01). Thrombomodulin was sparse/absent in young controls. Endothelial ICAM1 and IL-6 were rarely seen, and were not related to SVD.
Our data suggest that cerebral endothelial activation in deep penetrating arteries is not associated with SVD. Endothelial thrombomodulin increased with SVD severity, and CADASIL data suggest that this may be a cerebral response to SVD. Elevated thrombomodulin may be a protective agent in SVD. Our data confirm endothelial involvement in SVD.
Activated macrophages undergo metabolic reprogramming, which not only supports their energetic demands but also allows for the production of specific metabolites that function as signaling molecules. ...Several Krebs cycles, or Krebs-cycle-derived metabolites, including succinate, α-ketoglutarate, and itaconate, have recently been shown to modulate macrophage function. The accumulation of 2-hydroxyglutarate (2HG) has also been well documented in transformed cells and more recently shown to play a role in T cell and dendritic cell function. Here we have found that the abundance of both enantiomers of 2HG is increased in LPS-activated macrophages. We show that L-2HG, but not D-2HG, can promote the expression of the proinflammatory cytokine IL-1β and the adoption of an inflammatory, highly glycolytic metabolic state. These changes are likely mediated through activation of the transcription factor hypoxia-inducible factor-1α (HIF-1α) by L-2HG, a known inhibitor of the HIF prolyl hydroxylases. Expression of the enzyme responsible for L-2HG degradation, L-2HG dehydrogenase (L-2HGDH), was also found to be decreased in LPS-stimulated macrophages and may therefore also contribute to L-2HG accumulation. Finally, overexpression of L-2HGDH in HEK293 TLR4/MD2/CD14 cells inhibited HIF-1α activation by LPS, while knockdown of L-2HGDH in macrophages boosted the induction of HIF-1α-dependent genes, as well as increasing LPS-induced HIF-1α activity. Taken together, this study therefore identifies L-2HG as a metabolite that can regulate HIF-1α in macrophages.
Texas Air Quality Study field campaigns took place in eastern Texas in August–October of 2000 and 2006. Several flights of NOAA and NCAR research aircraft were dedicated to characterizing ...anthropogenic emissions over Houston. We present results from an inverse modeling technique that uses three atmospheric transport models and these aircraft observations to assess and improve existing emission inventories. We used inverse modeling techniques to improve the spatial and temporal emissions' distribution of CO, NOy, and SO2 predicted by the 4 km resolution U.S. Environmental Protection Agency (EPA) National Emission Inventory (NEI) for 2005. Differences between the prior and posterior inventories are discussed in detail. In September 2006, we found that the prior daytime CO emissions in the Houston urban area have to be reduced by 41% ± 8%. Over the Houston Ship Channel, where industrial emissions are predominant, the prior emissions have to be decreased by 43% ± 5% for CO and 51% ± 5% for NOy. Prior NOy emissions from other major ports around Houston also have to be reduced, probably owing to uncertain nearshore ship emissions in the EPA NEI inventory. Using the measurements from the two field campaigns, we assessed the emissions' variability between August 2000 and September 2006. Daytime CO emissions from the Houston urban area have decreased by 8% ± 3%, while the NOy emissions have increased by 20% ± 6%. In the Houston Ship Channel, daytime NOy emissions have increased by 13% ± 7%. Our results show qualitative consistencies with known changes in Houston emissions' sources.
Key Points
Aircraft observations are used to improve emission inventories in Houston
Three transport models and two inverse modeling methods used to estimate uncertainties
Urban and industrial emission are reduced by 40% and 50% in EPA NEI in Houston
Background
Three medications are FDA-approved and recommended for treating alcohol use disorders (AUD) but they are not offered to most patients with AUD. Primary care (PC) may be an optimal setting ...in which to offer and prescribe AUD medications, but multiple barriers are likely.
Objective
This qualitative study used social marketing theory, a behavior change approach that employs business marketing techniques including “segmenting the market,” to describe (1) barriers and facilitators to prescribing AUD medications in PC, and (2) beliefs of PC providers after they were segmented into groups more and less willing to prescribe AUD medications.
Design
Qualitative, interview-based study.
Participants
Twenty-four providers from five VA PC clinics.
Approach
Providers completed in-person semi-structured interviews, which were recorded, transcribed, and analyzed using social marketing theory and thematic analysis. Providers were divided into two groups based on consensus review.
Key Results
Barriers included lack of knowledge and experience, beliefs that medications cannot replace specialty addiction treatment, and alcohol-related stigma. Facilitators included training, support for prescribing, and behavioral staff to support follow-up. Providers more willing to prescribe viewed prescribing for AUD as part of their role as a PC provider, framed medications as a potentially effective “tool” or “foot in the door” for treating AUD, and believed that providing AUD medications in PC might catalyze change while reducing stigma and addressing other barriers to specialty treatment. Those less willing believed that medications could not effectively treat AUD, and that treating AUD was the role of specialty addiction treatment providers, not PC providers, and would require time and expertise they do not have.
Conclusions
We identified barriers to and facilitators of prescribing AUD medications in PC, which, if addressed and/or capitalized on, may increase provision of AUD medications. Providers more willing to prescribe may be the optimal target of a customized implementation intervention to promote changes in prescribing.
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