Search

Reports on a study of the influence of the indium tin oxide electrode surface acido basicity on organic electroluminescent device characteristics. Experimental details; Results and discussion; Conclusions.

Study design:Literature review and a qualitative study.Objective:This article reviews literature examining the sexual rehabilitation of women following spinal cord injury (SCI). It includes recommendations for improvements in initial clinical rehabilitation efforts and counselling services.Setting:United Kingdom, Denmark and Sweden.Methods:Articles concerning sexual rehabilitation following SCI from the last two decades have been reviewed and critiqued. Qualitative results from discussions with women with SCI in Denmark and Sweden are presented.Results:The literature focuses on the effect of neurological change on women's ability to achieve sexual arousal and orgasm. Urinary and bowel incontinence, spasticity, vaginal lubrication and autonomic dysreflexia are the physical consequences of SCI that appear to have most impact on sexual activity. More recent studies have acknowledged that psychosocial factors such as age and partnership status may also affect the successful sexual rehabilitation. Discussions with women with SCI in Denmark and Sweden on their reactions to information and counselling offered during rehabilitation revealed an overwhelming need for the exchange of information and experience with other women with SCI, and a desire for opportunities for counselling after initial rehabilitation.Conclusion:Successful sexual rehabilitation of women with SCI demands a holistic approach that considers individual neurological, physical and psychosocial circumstances. Peer-counselling could make a significant contribution to the sexual rehabilitation of women with SCI.Spinal Cord (2006) 44, 234–241. doi:10.1038/sj.sc.3101844; published online 20 September 2005 [ABSTRACT FROM AUTHOR]

The infiltration of three-dimensional opal structures has been investigated by atomic layer deposition. Demonstrations using ZnS:Mn show that filling fractions >95% can be achieved and that the infiltrated material is of high-quality crystalline material as assessed by photoluminescence measurements. These results demonstrate a flexible and practical pathway to attaining high-performance photonic crystal structures and optical microcavities. © 2003 American Institute of Physics. [ABSTRACT FROM AUTHOR]

SrS:Cu thin films were evaluated using thermally stimulated luminescence (TSL), photoluminescence (PL), electroluminescence (EL), and charge transfer over a temperature range of 10-850 K. The trap states were measured with and without a BaTa[sub 2]O[sub 6] (BTO) overlayer film. From TSL results, the trap state energies were measured in the range of 0.4 eV, with differences due the BTO overlayer. From the PL, EL, and charge transfer measurements, the light emission and charge transfer decrease at a temperature consistent with the 0.4 eV trap level, demonstrating the importance of the trap states to EL devices. © 2001 American Institute of Physics. [ABSTRACT FROM AUTHOR]

It has been claimed that the variation of current I with voltage V in an organic light emitting diode (LED), based on either metal chelate complexes or conducting polymers, is explained by shallow traps that trap carriers propagating in the conduction or valence band. However, because these are disordered materials all states are localized. We show that it is possible to fit the dependence of I on V and on film thickness without explicitly introducing traps, but taking their effect into account by including the mobility variation with the electric field that arises from the distribution in energy of the localized levels. © 1998 American Institute of Physics. [ABSTRACT FROM AUTHOR]

A systematic study of the size dependence of the photoluminescence spectra of Si quantum nanocrystals in the SiO2 matrix has been performed. The results have been fitted to a quantum-confinement model that includes the nanocrystal size dispersion rather than a specific size of the nanocrystal. This, in conjunction with the results [Z. H. Lu, D. J. Lockwood, and J.-M. Baribeau, Nature 378, 258 (1995)] for amorphous Si layers serves as a strong confirmation of the confinement-induced nature of the photoluminescence. © 1996 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The formation of the interface between a thin film of a ladder-type poly(para-phenylene) m-LPPP and aluminum was investigated with x-ray and ultraviolet photoemission spectroscopy. The physical properties of this interface are of actual interest as m-LPPP is successfully applied as active material in organic light emitting devices (LED). Almost no changes in the core-level and valence electronic structure of the polymer upon increasing coverage with aluminum (in situ) are found. This gives indication for a weak interaction of Al with m-LPPP, ruling out the formation of chemical bonds between the two materials. The rapid occurrence of metallic aluminum at rather low coverage in the presented experiment is an important finding for the understanding of charge injection and the interfacial electronic structure in organic LEDs. © 2000 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The bulk trap state properties of a naphthyl-substituted benzidine derivative (NPB) and tris-8-(hydroxyquinoline) aluminum (Alq[sub 3]) have been measured using thermally stimulated luminescence (TSL). The TSL spectra for both organic materials show significant trap distributions over the temperature range from 8 to 300 K. Using a general order TSL expression, the four peaks in NPB were modeled with trap states centered from 0.20 to 0.05 eV. Alq[sub 3] has three TSL peaks over the temperature range, with the peak at 156 K modeled as a distribution of trap states from 0.25 to 0.13 eV. For both materials, the trapping mechanism involves a combination of first and second order emission. NPB and Alq[sub 3] have trap states sufficiently deep to influence the carrier transport and recombination process in bilayer organic based light emitting. © 1998 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Efficient organic light emitting devices (OLEDs) using methyl substituted ladder-type poly (paraphenylene) (m-LPPP) and tris(8-hydroxy) quinoline aluminum (Alq[sub 3]) as active materials are presented. For bilayer OLEDs the emissive region is found to be in both layers adjacent to the m-LPPP/Alq[sub 3] interface. The performance of these hybrid devices with constant m-LPPP thickness and varying Alq[sub 3] thickness is compared to that of a single layer m-LPPP device by investigating the relative spatial distribution of the light emission. The relation between the intensity of the light emitted from each layer and the distance to the cathode metal is discussed. Furthermore, the m-LPPP emission is also affected by the internal electric field at the interface. © 1998 American Institute of Physics. [ABSTRACT FROM AUTHOR]

A dual BN/AlN capping layer has been developed for annealing implanted SiC up to a temperature of at least 1700 °C. The AlN is used as a protective layer on SiC because it is chemically inert on the material and can be removed selectively with a warm KOH etch, while the BN layer prevents the AlN from evaporating at temperatures above 1600 °C. Prior to etching off the AlN film, the BN film is ion milled off. The BN film appears to be an excellent cap as the hexagonal phases present, hexagonal (hBN) and turbostratic (tBN), are stable to temperatures in excess of 2000 °C. After annealing, the BN forms a tight seal on top of the AlN in a dense epitaxial h-BN phase, with a t-BN layer forming above the hBN. The tBN layer should be able to accommodate strains caused by lattice mismatch and differences in the thermal coefficients of expansion because it, like graphite, forms strong sp2 bonds in the basal plane, but contains loosely bonded basal planes that easily slip over each other. [Copyright &y& Elsevier]

Background: Signs and symptoms of Bardet-Biedl syndrome (BBS) occur during early childhood, progress over time, and place substantial, multifaceted burden on patients and their caregivers. Hyperphagia may be a contributing factor to early-onset obesity in BBS; however, there are limited insights into its impacts on patients and caregivers. We quantified disease burden as it relates to the physical and emotional impacts of hyperphagia in BBS., Methods: The CAREgiver Burden in BBS (CARE-BBS) study was a multicountry, cross-sectional survey of adult caregivers of patients with BBS who have had hyperphagia and obesity. The survey consisted of questionnaires including Symptoms of Hyperphagia, Impacts of Hyperphagia, Impact of Weight on Quality of Life (IWQOL)-Kids Parent Proxy, and Patient-Reported Outcome Measurement Information System (PROMIS) v1.0-Global Health 7. In addition, clinical characteristics, medical history, and weight management questions were included. Outcomes were scored and summarized descriptively in aggregate and by country, age, and obesity severity according to weight class., Results: There were 242 caregivers of patients with BBS who completed the survey. Caregivers observed hyperphagic behaviors throughout the day, with negotiating for food (90%) and waking up and asking or looking for food during the night (88%) being the most frequent. Hyperphagia had at least a moderate negative impact on most patients' mood/emotions (56%), sleep (54%), school (57%), leisure (62%), and familial relationships (51%). Hyperphagia affected concentration at school (78%), and symptoms of BBS contributed to patients missing ≥ 1 day of school a week (82%). Responses from the IWQOL-Kids Parent Proxy suggested obesity most greatly negatively affected physical comfort (mean [standard deviation (SD)], 41.7 [17.2]), body esteem (41.0 [17.8]), and social life (41.7 [18.0]). On the PROMIS questionnaire, mean (SD) global health score for pediatric patients with BBS and overweight or obesity (36.8 [10.6]) was lower than the general population (mean, 50)., Conclusions: Evidence from this study suggests that hyperphagia and obesity may have broad negative impacts on the lives of patients with BBS, including physical health, emotional well-being, school performance, and personal relationships. Therapies that target hyperphagia may alleviate the extensive clinical and nonclinical impacts experienced by patients with BBS and their caregivers., (© 2023. © Rhythm Pharmaceuticals 2023.)

Background: Bardet-Biedl syndrome (BBS) is a rare, genetically heterogeneous obesity syndrome associated with hyperphagia. Given the early onset of BBS symptoms in childhood and multifaceted complications, this study aimed to quantify the caregiver burden associated with BBS., Methods: A cross-sectional, multi-country survey of caregivers from the United States (US), United Kingdom (UK), Canada, and Germany was designed to quantify the extent of caregiver burden associated with obesity and hyperphagia symptoms (i.e., uncontrollable hunger) among patients with BBS., Results: A total of 242 caregivers across the four countries met the inclusion criteria and completed the survey. The mean (standard deviation [SD]) age of the caregivers was 41.9 (6.7) years, and the mean (SD) age of individuals with BBS in their care was 12.0 (3.7) years. Hyperphagia contributed to a BBS diagnosis in 230 of 242 individuals (95.0%). On average, caregivers used eight different weight management approaches for those in their care and expressed a strong desire for more effective weight management methods. Based on the Impacts of Hyperphagia: Caregiver version, patients' hyperphagia had a moderate-to-severe impact on caregiver mood (56.6%), sleep (46.6%), and relationships (48.0%). Caregivers reported experiencing a high level of personal strain (mean [SD], 17.1 [2.9]) and family impact (mean [SD] score, 26.0 [3.8]) due to BBS, as measured by the Revised Impact on Family Scale. Among caregivers in the workforce, there also was high impairment in total work productivity (mean [SD], 60.9% [21.4%]) due to caring for patients with BBS according to the Work Productivity and Activity Impairment. More than half (53%) of the caregivers reported spending over 5,000 out-of-pocket in local currency for medical expenses for the patient with BBS in their care., Conclusions: Obesity and hyperphagia have negative impacts on the lives of caregivers of patients with BBS. The burden is demonstrated to be multifaceted, with various components that may interact with and confound each other, including intensive weight management efforts, productivity loses, impaired family dynamics and out-of-pocket medical expenses., (© 2023. Rhythm Pharmaceuticals.)

Using data from the Current Population Survey, we investigate the distributional consequences of the Covid-19 pandemic and the associated public policy response on labor earnings and unemployment benefits in the United States up until February 2021. We find that year-on-year changes in labor earnings for employed individuals were not atypical during the pandemic months, regardless of their initial position in the earnings distribution. The incidence of job loss, however, was substantially higher among low earners, leading to a dramatic increase in labor income inequality among the set of individuals who were employed prior to the onset of the pandemic. By providing very high replacement rates for individuals displaced from low-paying jobs, the initial public policy response was successful in reversing the regressive nature of the pandemic's impacts. We estimate, however, that recipiency rates for displaced low earners were lower than for higher earners. Moreover, from September 2020 onwards, when policy changes led to a decline in benefit levels, earnings changes became less progressive., Supplementary Information: The online version contains supplementary material available at 10.1007/s10888-022-09552-8., Competing Interests: Conflicts of interestNone, (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Bardet-Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity. There is limited evidence on how hyperphagia and obesity affect health-related quality of life in patients with Bardet-Biedl syndrome, and on how management of these symptoms may influence disease burden. This analysis evaluated changes in health-related quality of life in adults and children with Bardet-Biedl syndrome in a Phase 3 trial following 1 year of setmelanotide treatment (ClinicalTrials.gov identifier: NCT03746522)., Methods: Patients with Bardet-Biedl syndrome and obesity received 52 weeks of treatment with setmelanotide and completed various self-reported health-related quality of life measures. Patients aged < 18 years or their caregiver completed the Pediatric Quality of Life Inventory (PedsQL; meaningful improvement, 4.4-point change); adults aged ≥ 18 years completed the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-Lite; meaningful improvement range, 7.7-12-point change). Descriptive outcomes were reported in patients with data both at active treatment baseline and after 52 weeks of treatment., Results: Twenty patients (< 18 years, n = 9; ≥ 18 years, n = 11) reported health-related quality of life at baseline and 52 weeks. For children and adolescents, PedsQL score mean change from baseline after 52 weeks was + 11.2; all patients with PedsQL impairment at baseline (n = 4) experienced clinically meaningful improvement. In adults, IWQOL-Lite score mean change from baseline was + 12.0. Of adults with IWQOL-Lite impairment at baseline (n = 8), 62.5% experienced clinically meaningful improvement. In adults, IWQOL-Lite score was significantly correlated with changes in percent body weight (P = 0.0037) and body mass index (P = 0.0098)., Conclusions: After 1 year of setmelanotide, patients reported clinically meaningful improvements across multiple health-related quality of life measures. This study highlights the need to address the impaired health-related quality of life in Bardet-Biedl syndrome, and supports utility of setmelanotide for reducing this burden. Trial Registration NCT03746522. Registered November 19, 2018, https://clinicaltrials.gov/ct2/show/NCT03746522 ., (© 2023. Rhythm Pharmaceuticals.)

The authors study the distributional consequences of the COVID-19 pandemic's impact on employment, both during the onset of the pandemic and over subsequent months. Using cross-sectional and matched longitudinal data from the Current Population Survey, they show that the pandemic has exacerbated pre-existing inequalities. Although employment losses have been widespread, they have been substantially larger-and more persistent-in lower-paying occupations and industries. Hispanics and non-White workers suffered larger increases in job losses, not only because of their over-representation in lower-paying jobs but also because of a disproportionate increase in their job displacement probability relative to non-Hispanic White workers with the same job background. Gaps in year-on-year job displacement probabilities between Black and White workers have widened over the course of the pandemic recession, both overall and conditional on pre-displacement occupation and industry. These gaps are not explained by state-level differences in the severity of the pandemic nor by the associated response in terms of mitigation policies. In addition, evidence suggests that older workers have been retiring at faster rates., (© The Author(s) 2022.)

Background: Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients., Methods: This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m 2 for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522., Findings: Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment., Interpretation: Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome., Funding: Rhythm Pharmaceuticals., Competing Interests: Declaration of interests RMH received study medication, grant support for clinical trials of setmelanotide, payments for lectures and expert testimony, and support for attending meetings from Rhythm Pharmaceuticals; consulting fees from Rhythm Pharmaceuticals and Axovia Therapeutics; participated in the data safety monitoring board for Rhythm Pharmaceuticals; and is a stockholder in Rhythm Pharmaceuticals. AMH received grants from the Weston Family Microbiome Initiative and Canadian Institutes of Health Research, payment as a speaker for Pfizer Canada, is a member of the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals and the 2021 Somatrogon advisory board for Pfizer, and head of the scientific advisory board for the Prader-Willi Syndrome Association USA. WKC received study funding, consulting fees, and payment for speaker bureaus from Rhythm Pharmaceuticals. HD received consulting fees and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals. GÁM-M received payment for lectures and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals. CP received support for attending meetings and grant funding for clinical trials of setmelanotide from Rhythm Pharmaceuticals; clinical trials of Prader-Willi syndrome from Millendo; and clinical trials of obesity from Novo Nordisk. JAY received grant support for clinical trials of setmelanotide from Rhythm Pharmaceuticals, grant support for clinical trials of diazoxide choline-controlled release in Prader-Willi syndrome from Soleno Therapeutics, and study medication for clinical trials from Hikma Pharmaceuticals and Versanis Bio. RSM and GY are employees and stockholders of Rhythm Pharmaceuticals. EF received consulting fees and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals and is a clinical investigator for clinical trials of setmelanotide in Bardet-Biedl syndrome for Rhythm Pharmaceuticals. KC received grant funding from Ysopia, Integrative Phenomics, and Confo Therapeutics; and is a clinical investigator for clinical trials of setmelanotide in Bardet-Biedl syndrome for Rhythm Pharmaceuticals. JA received payment for lectures and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Functional autoantibodies directed to the M2 muscarinic acetylcholine receptor (M2R) could affect the heart rate directly by altering cardiac M2R activity and/or indirectly by changing vagal-mediated cardiac M2R activity. We measured M2R autoantibody activity in sera from 10 subjects with postural tachycardia syndrome (POTS) and 5 healthy control subjects using a cell-based bioassay. Half of the POTS subjects demonstrated presence of elevated M2R autoantibody activity, while no significant M2R autoantibody activity was found in the healthy subjects. Serum-derived immunoglobulin G (IgG) from antibody-positive POTS patients induced a dose-dependent activation of M2R, which was blocked by the muscarinic antagonist atropine. Moreover, antibody-positive POTS IgG decreased the responsiveness to oxotremorine, an orthosteric muscarinic agonist, indicating an indirect inhibitory effect. These data suggest that M2R autoantibodies may contribute to the pathophysiology of POTS by increasing the normal vagal withdrawal during upright posture through its negative allosteric modulation of M2R activity. M2 muscarinic receptor-activating autoantibodies are present in a subgroup of patients with POTS and act as a negative allosteric modulator of the orthosteric ligand response., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Development of therapeutic approaches for rare respiratory diseases is hampered by the lack of systems that allow medium-to-high-throughput screening of fully differentiated respiratory epithelium from affected patients. This is a particular problem for primary ciliary dyskinesia (PCD), a rare genetic disease caused by mutations in genes that adversely affect ciliary movement and consequently mucociliary transport. Primary cell culture of basal epithelial cells from nasal brush biopsies followed by ciliated differentiation at the air-liquid interface (ALI) has proven to be a useful tool in PCD diagnostics but the technique's broader utility, including in pre-clinical PCD research, has been restricted by the limited number of basal cells that can be expanded from such biopsies., Methods: We describe an immunofluorescence screening method, enabled by extensive expansion of basal cells from PCD patients and the directed differentiation of these cells into ciliated epithelium in miniaturised 96-well transwell format ALI cultures. As proof-of-principle, we performed a personalised investigation in a patient with a rare and severe form of PCD (reduced generation of motile cilia), in this case caused by a homozygous nonsense mutation in the MCIDAS gene., Results: Initial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures. The screening system in our proof-of-principal investigation allowed drugs that induce translational readthrough to be evaluated alone or in combination with nonsense-mediated decay inhibitors. We observed restoration of basal body formation but not the generation of cilia in the patient's nasal epithelial cells in vitro. CONCLUSION: Our study provides a platform for higher throughput analyses of airway epithelia that is applicable in a range of settings and suggests novel avenues for drug evaluation and development in PCD caused by nonsense mutations., Competing Interests: Conflict of interest: D.D.H. Lee has nothing to disclose. Conflict of interest: D. Cardinale has nothing to disclose. Conflict of interest: E. Nigro has nothing to disclose. Conflict of interest: C.R. Butler has nothing to disclose. Conflict of interest: A. Rutman has nothing to disclose. Conflict of interest: M.R. Fassad has nothing to disclose. Conflict of interest: R.A. Hirst has nothing to disclose. Conflict of interest: D. Moulding has nothing to disclose. Conflict of interest: A. Agrotis has nothing to disclose. Conflict of interest: E. Forsythe has nothing to disclose. Conflict of interest: D. Peckham has nothing to disclose. Conflict of interest: E. Robson has nothing to disclose. Conflict of interest: C.M. Smith has nothing to disclose. Conflict of interest: S. Somavarapu has nothing to disclose. Conflict of interest: P.L. Beales has nothing to disclose. Conflict of interest: S.L. Hart has nothing to disclose. Conflict of interest: S.M. Janes has nothing to disclose. Conflict of interest: H.M. Mitchison has nothing to disclose. Conflict of interest: R. Ketteler has nothing to disclose. Conflict of interest: R.E. Hynds has nothing to disclose. Conflict of interest: C. O'Callaghan has nothing to disclose., (Copyright ©The authors 2021.)

The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: Ciliary dysfunction underlies a range of genetic disorders collectively termed ciliopathies, for which there are no treatments available. Bardet-Biedl syndrome (BBS) is characterised by multisystemic involvement, including rod-cone dystrophy and renal abnormalities. Together with Alström syndrome (AS), they are known as the 'obesity ciliopathies' due to their common phenotype. Nonsense mutations are responsible for approximately 11% and 40% of BBS and AS cases, respectively. Translational readthrough inducing drugs (TRIDs) can restore full-length protein bypassing in-frame premature termination codons, and are a potential therapeutic approach for nonsense-mediated ciliopathies., Methods: Patient fibroblasts harbouring nonsense mutations from two different ciliopathies (Bardet-Biedl Syndrome and Alström Syndrome) were treated with PTC124 (ataluren) or amlexanox. Following treatment, gene expression, protein levels and ciliogenesis were evaluated. The expression of intraflagellar transport protein IFT88 and G-protein coupled receptor SSTR3 was investigated as a readout of ciliary function., Findings: mRNA expression was significantly increased in amlexanox-treated patient fibroblasts, and full-length BBS2 or ALMS1 protein expression was restored in PTC124- and amlexanox-treated fibroblasts. Treatment with TRIDs significantly improved ciliogenesis defects in BBS2 Y24*/R275* fibroblasts. Treatment recovered IFT88 expression and corrected SSTR3 mislocalisation in BBS2 Y24*/R275* and ALMS1 S1645*/S1645* fibroblasts, suggesting rescue of ciliary function., Interpretation: The recovery of full-length BBS2 and ALMS1 expression and correction of anatomical and functional ciliary defects in BBS2 Y24*/R275* and ALMS1 S1645*/S1645* fibroblasts suggest TRIDs are a potential therapeutic option for the treatment of nonsense-mediated ciliopathies., Funding: Wellcome Trust 205174/Z/16/Z, National Centre for the Replacement, Refinement & Reduction of Animals in Research. Deutsche Forschungsgemeinschaft SPP2127 (DFG Grant MA 6139/3-1)., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest, (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Bardet-Biedl Syndrome (BBS) is a pleiotropic genetic disease caused by the dysfunction of primary cilia. The immune system of patients with ciliopathies has not been investigated. However, there are multiple indications that the impairment of the processes typically associated with cilia may have influence on the hematopoietic compartment and immunity. In this study, we analyze clinical data of BBS patients and corresponding mouse models carrying mutations in Bbs4 or Bbs18. We find that BBS patients have a higher prevalence of certain autoimmune diseases. Both BBS patients and animal models have altered red blood cell and platelet compartments, as well as elevated white blood cell levels. Some of the hematopoietic system alterations are associated with BBS-induced obesity. Moreover, we observe that the development and homeostasis of B cells in mice is regulated by the transport complex BBSome, whose dysfunction is a common cause of BBS. The BBSome limits canonical WNT signaling and increases CXCL12 levels in bone marrow stromal cells. Taken together, our study reveals a connection between a ciliopathy and dysregulated immune and hematopoietic systems., (© 2021 The Authors.)

We use job vacancy data collected in real time by Burning Glass Technologies, as well as unemployment insurance (UI) initial claims and the more traditional Bureau of Labor Statistics (BLS) employment data to study the impact of COVID-19 on the labor market. Our job vacancy data allow us to track the economy at disaggregated geography and by detailed occupation and industry. We find that job vacancies collapsed in the second half of March. By late April, they had fallen by over 40%. To a first approximation, this collapse was broad based, hitting all U.S. states, regardless of the timing of stay-at-home policies. UI claims and BLS employment data also largely match these patterns. Nearly all industries and occupations saw contraction in postings and spikes in UI claims, with little difference depending on whether they are deemed essential and whether they have work-from-home capability. Essential retail, the "front line" job most in-demand during the current crisis, took a much smaller hit, while leisure and hospitality services and non-essential retail saw the biggest collapses. This set of facts suggests the economic collapse was not caused solely by the stay-at-home orders, and is therefore unlikely to be undone simply by lifting them., (© 2020 Elsevier B.V. All rights reserved.)

Objective: Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)?, Design and Methods: We retrospectively screened sera from 40 patients with PCOS and 14 normal controls (NCs) with regular menses using enzyme-linked immunosorbent assay (ELISA) for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified immunoglobulin (Ig)G using a cell-based GnRHR bioassay., Results: The mean ELISA value in the PCOS group was markedly higher than the NC ( P  = .000036) and the OIC ( P  = .0028) groups. IgG from a sample of 5 PCOS subjects, in contrast to a sample of 5 OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. The GnRHR antagonist cetrorelix significantly suppressed ( P  < .01) the elevated GnRHR activity induced by IgG from 7 PCOS patients while the IgG activity level from 7 OIC subjects was unchanged. Five other OIC subjects had relatively high ELISA values at or above the 95% confidence limits. On further study, 3 had normal or low activity while 2 had elevated IgG-induced GnRHR activity. One suppressed with cetrorelix while the other did not. The copresence of PCOS IgG increased the responsiveness to GnRH and shifted the dosage response curve to the left ( P  < .01)., Conclusions: GnRHR-ECL2-AAb are significantly elevated in patients with PCOS compared with NCs. Their presence raises important etiological, diagnostic, and therapeutic implications., (© Endocrine Society 2020.)