Comparison of spouse and patient personality change judgments following MS onset.

OBJECTIVES: This is the first study to estimate the prevalence and predictors of spouse and patient perceptions of global/overall personality change (PC) in patients with multiple sclerosis (MS). METHODS: 69 clinic patients and their spouses completed parallel measures of perceived PC and semantic differential scales measuring pre-MS and current specific behaviours. We correlated perceived personality changes with the following measures of perceived physical, cognitive, emotional, and social functioning: MS Impact Scale, MS Neuropsychological Questionnaire, Beck Depression Inventory-FastScreen; Hospital Anxiety and Depression Scale; Family Questionnaire, McMaster Assessment Device; and Social Provisions Scale. RESULTS: Spouses and patients reported comparable levels of substantial change. Both associated PC with patient distress, perceived cognitive impairment, spouse distress, and poorer family functioning. Spouse, but not patient, PC ratings predicted severity of physical symptoms and social support. Principal component analysis of semantic differential ratings yielded a Compassionate Empathy component correlating with PC within spouse, but not patient, data. CONCLUSIONS: These partially overlapping potential triggers for spouse and patient PC judgments raise questions about the extent they overlap with clinicians' criteria for PC, since spouses did not link impulsivity with PC. It is also suggested that the initial focus of treatment of PC should focus on partner-agreed changes.

Piezo1 acts upstream of TRPV4 to induce pathological changes in endothelial cells due to shear stress.

The ion channels Piezo1 and TRPV4 have both, independently, been implicated in high venous pressure- and fluid shear stress-induced vascular hyperpermeability in endothelial cells. However, the mechanism by which Piezo1 and TRPV4 channels execute the same function is poorly understood. Here we demonstrate that Piezo1 regulates TRPV4 channel activation in endothelial cells and that Piezo1-mediated TRPV4 channel opening is a function of the strength and duration of fluid shear stress. We first confirmed that either fluid shear stress or the Piezo1 agonist, Yoda1, led to an elevation in intracellular calcium ([Ca2+]i) and that application of the Piezo1 antagonist, GsMTx4, completely blocked this change. We discovered that high and prolonged shear stress caused sustained [Ca2+]i elevation that was blocked by inhibition of TRPV4 channel opening. Moreover, Piezo1 stimulated TRPV4 opening through activation of phospholipase A2. TRPV4-dependent sustained [Ca2+]i elevation was responsible for fluid shear stress-mediated and Piezo1-mediated disruption of adherens junctions and actin remodeling. Blockade of TRPV4 channels with the selective TRPV4 blocker, HC067047, prevented the loss of endothelial cell integrity and actin disruption induced by Yoda1 or shear stress and prevented Piezo1-induced monocyte adhesion to endothelial cell monolayers. These findings demonstrate that Piezo1 activation by fluid shear stress initiates a calcium signal that causes TRPV4 opening, which in turn is responsible for the sustained phase calcium elevation that triggers pathological events in endothelial cells. Thus, deleterious effects of shear stress are initiated by Piezo1 but require TRPV4.

Nicotinic stimulation of splenic T cells is protective in endoscopic retrograde cholangiopancreatography-induced acute pancreatitis in mice.

It has previously been shown that current smoking is protective against endoscopic retrograde cholangiopancreatography (ERCP)-induced acute pancreatitis, but the mechanism of this effect was not identified. We tested the hypothesis that nicotine is the active factor in this protection in a mouse model of ERCP. Pretreatment with nicotine dose dependently inhibited acute pancreatitis caused by infusion of ERCP contrast solution into the main pancreatic duct in mice. 3-2,4-Dimethoxybenzylidene anabaseine (GTS-21), a specific partial agonist of the α7 nicotinic cholinergic receptor (α7nAChR), also protected the pancreas against ERCP-induced acute pancreatitis. The effects of GTS-21 were abolished by pretreatment with the nicotinic receptor antagonist mecamylamine. Surgical splenectomy performed 7 days before ERCP-induced pancreatitis blocked the protective effects of GTS-21. Intravenous injection of a crude preparation of total splenocytes prepared from mice pretreated with GTS-21 inhibited ERCP-induced pancreatitis; splenocytes from mice treated with vehicle had no effect. When T cells were removed from the crude GTS-21-treated splenocyte preparation by immunomagnetic separation, the remaining non-T-cell splenocytes did not protect against ERCP-induced acute pancreatitis. We conclude that nicotine protects against ERCP-induced acute pancreatitis and that splenic T cells are required for this effect. Stimulation of α7 nicotinic cholinergic receptors may protect against ERCP-induced acute pancreatitis and may also be a novel approach to therapeutic reversal of ongoing acute pancreatitis.NEW & NOTEWORTHY Epidemiological evidence indicated that acute smoking reduced the risk of endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis, but the mechanism has remained elusive. The current findings indicate the nicotine reduces the severity of ERCP-induced pancreatitis by stimulating a population of splenic T cells that exert a protective effect on the pancreas. These findings raise the possibility that nicotinic agonists might be useful in treating pancreatitis.

Initiation and severity of experimental pancreatitis are modified by phosphate.

Proper mitochondrial function and adequate cellular ATP are necessary for normal pancreatic protein synthesis and sorting, maintenance of intracellular organelles and enzyme secretion. Inorganic phosphate is required for generating ATP and its limited availability may lead to reduced ATP production causing impaired Ca2+ handling, defective autophagy, zymogen activation, and necrosis, which are all features of acute pancreatitis. We hypothesized that reduced dietary phosphate leads to hypophosphatemia and exacerbates pancreatitis severity of multiple causes. We observed that mice fed a low-phosphate diet before the induction of pancreatitis by either repeated caerulein administration or pancreatic duct injection as a model of pressure-induced pancreatitis developed hypophosphatemia and exhibited more severe pancreatitis than normophosphatemic mice. Pancreatitis severity was significantly reduced in mice treated with phosphate. In vitro modeling of secretagogue- and pressure-induced pancreatic injury was evaluated in isolated pancreatic acini using cholecystokinin and the mechanoreceptor Piezo1 agonist, Yoda1, under low and normal phosphate conditions. Isolated pancreatic acini were more sensitive to cholecystokinin- and Yoda1-induced acinar cell damage and mitochondrial dysfunction under low-phosphate conditions and improved following phosphate supplementation. Importantly, even mice on a normal phosphate diet exhibited less severe pancreatitis when treated with supplemental phosphate. Thus, hypophosphatemia sensitizes animals to pancreatitis and phosphate supplementation reduces pancreatitis severity. These appear to be direct effects of phosphate on acinar cells through restoration of mitochondrial function. We propose that phosphate administration may be useful in the treatment of acute pancreatitis.NEW & NOTEWORTHY Impaired ATP synthesis disrupts acinar cell homeostasis and is an early step in pancreatitis. We report that reduced phosphate availability impairs mitochondrial function and worsens pancreatic injury. Phosphate supplementation improves mitochondrial function and protects against experimental pancreatitis, raising the possibility that phosphate supplementation may be useful in treating pancreatitis.

The Role of Phosphate in Alcohol-Induced Experimental Pancreatitis.

BACKGROUND & AIMS: Heavy alcohol consumption is a common cause of acute pancreatitis; however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals, it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia, and hypophosphatemia has been observed in some patients with acute pancreatitis. Because of abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit adenosine triphosphate synthesis and thereby contribute to alcohol-induced pancreatitis. METHODS: Mice were fed a low-phosphate diet (LPD) before orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini. RESULTS: LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on an LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low-phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular adenosine triphosphate and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury. CONCLUSIONS: Phosphate status plays a critical role in predisposition to and protection from alcohol-induced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, an LPD plus ethanol provides a new model for studying alcohol-associated pancreatic injury.

An evaluation of a pilot of daily testing of SARS-CoV-2 contacts in acute hospital and ambulance trusts in England.

OBJECTIVES: Healthcare worker (HCW) SARS-CoV-2 contacts in England have been required to quarantine, creating staff shortages. We piloted daily contact testing (DCT) to assess its feasibility as an alternative. STUDY DESIGN: Observational service evaluation. METHODS: We conducted an observational service evaluation of 7-day DCT using antigen lateral flow devices (LFDs) at four acute hospital trusts and one ambulance trust in England. Mixed methods were used, using aggregate and individual-level test monitoring data, semi-structured interviews, and a survey of eligible contacts. RESULTS: In total, 138 HCWs were identified as contacts of a confirmed SARS-CoV-2 case. Of these, 111 (80%) consented to daily LFD testing, of whom 82 (74%) completed the required programme without interruption and 12 (11%) completed with interruption. Fifty-eight participants (52%) and two non-participants (7.4%) completed the survey. In total, 28 interviews were conducted with participants, site and infection control leads, and union representatives. One participant tested positive on LFD and polymerase chain reaction (PCR) test. Three participants tested positive on PCR but not LFD. DCT was well-accepted by trusts and staff. Participants reported no relaxation of their infection prevention and control behaviours. No incidents of transmission were detected. An estimated 729 potential days of work absence were averted. CONCLUSIONS: DCT can be acceptably operated in a healthcare setting, averting quarantine-related work absences in HCW SARS-CoV-2 contacts.

Heterogeneity in α-synuclein fibril activity correlates to disease phenotypes in Lewy body dementia.

α-Synuclein aggregation underlies pathological changes in Lewy body dementia. Recent studies highlight structural variabilities associated with α-synuclein aggregates in patient populations. Here, we develop a quantitative real-time quaking-induced conversion (qRT-QuIC) assay to measure permissive α-synuclein fibril-templating activity in tissues and cerebrospinal fluid (CSF). The assay is anchored through reference panels of stabilized ultra-short fibril particles. In humanized α-synuclein transgenic mice, qRT-QuIC identifies differential levels of fibril activity across the brain months before the deposition of phosphorylated α-synuclein in susceptible neurons. α-Synuclein fibril activity in cortical brain extracts from dementia with Lewy bodies (DLB) correlates with activity in matched ventricular CSF. Elevated α-synuclein fibril activity in CSF corresponds to reduced survival in DLB. α-Synuclein fibril particles amplified from cases with high fibril activity show superior templating in the formation of new inclusions in neurons relative to the same number of fibril particles amplified from DLB cases with low fibril activity. Our results highlight a previously unknown broad heterogeneity of fibril-templating activities in DLB that may contribute to disease phenotypes. We predict that quantitative assessments of fibril activities in CSF that correlate to fibril activities in brain tissue will help stratify patient populations as well as measure therapeutic responses to facilitate the development of α-synuclein-targeted therapeutics.

Sexual risk and HIV testing disconnect in men who have sex with men (MSM) recruited to an online HIV self-testing trial.

OBJECTIVES: We report the frequency of previous HIV testing at baseline in men who have sex with men (MSM) who enrolled in an HIV self-testing (HIVST) randomized controlled trial [an HIV self-testing public health intervention (SELPHI)]. METHODS: Criteria for enrolment were age ≥ 16 years, being a man (including trans men) who ever had anal intercourse (AI) with a man, not being known to be HIV positive and having consented to national HIV database linkage. Using online survey baseline data (2017-2018), we assessed associations with never having tested for HIV and not testing in the previous 6 months, among men who reported at least two recent condomless AI (CAI) partners. RESULTS: A total of 10 111 men were randomized; the median age was 33 years [interquartile range (IQR) 26-44 years], 89% were white, 20% were born outside the UK, 0.8% were trans men, 47% were degree educated, and 8% and 4% had ever used and were currently using pre-exposure prophylaxis (PrEP), respectively. In the previous 3 months, 89% reported AI and 72% reported CAI with at least one male partner. Overall, 17%, 33%, 54%, and 72% had tested for HIV in the last 3 months, 6 months, 12 months and 2 years, respectively; 13% had tested more than 2 years ago and 15% had never tested. Among 3972 men reporting at least two recent CAI partners, only 22% had tested in the previous 3 months. Region of residence and education level were independently associated with recent HIV testing. Among current PrEP users, 15% had not tested in the previous 6 months. CONCLUSIONS: Most men in SELPHI, particularly those reporting at least two CAI partners and current PrEP users, were not testing in line with current UK recommendations. The results of the trial will inform whether online promotion of HIVST addresses ongoing testing barriers.

HIV self-testing intervention experiences and kit usability: results from a qualitative study among men who have sex with men in the SELPHI (Self-Testing Public Health Intervention) randomized controlled trial in England and Wales.

OBJECTIVES: SELPHI (HIV Self-Testing Public Health Intervention) is the largest randomized controlled trial (RCT) of HIV self-testing (HIVST) in a high-income setting to date, and has recruited 10 000 men who have sex with men (cis- and transgender) and transgender women who have sex with men. This qualitative substudy aimed to explore how those utilizing self-tests experience HIVST and the implications for further intervention development and scale-up. This is the first qualitative study in Europe investigating experiences of HIVST among intervention users, and the first globally examining the experience of using blood-based HIVST. METHODS: Thirty-seven cisgender MSM SELPHI participants from across England and Wales were purposively recruited to the substudy, in which semi-structured interviews were used to explore testing history, HIVST experiences and intervention preferences. Interviews were audio-recorded, transcribed and analysed through a framework analysis. RESULTS: Men accessed the intervention because HIVST reduced barriers related to convenience, stigma and privacy concerns. Emotional responses had direct links to acceptability. Supportive intervention components increased engagement with testing and addressed supportive concerns. HIVST facilitated more frequent testing, with the potential to reduce sexually transmitted infection (STI) screening frequency. Substudy participants with an HIV-positive result (n = 2) linked to care promptly and reported very high acceptability. Minor adverse outcomes (n = 2; relationship discord and fainting) did not reduce acceptability. Ease of use difficulties were with the lancet and the test processing stage. CONCLUSIONS: Intervention components shaped acceptability, particularly in relation to overcoming a perceived lack of support. The intervention was broadly acceptable and usable; participants expressed an unexpected degree of enthusiasm for HIVST, including those with HIV-positive results and individuals with minor adverse outcomes.

Investigating Conceptual Models for the Relationship Between Depression and Condomless Sex Among Gay, Bisexual, and Other Men Who have Sex with Men: Using Structural Equation Modelling to Assess Mediation.

The aim of this study is to investigate five hypothesized mechanisms of causation between depression and condomless sex with ≥ 2 partners (CLS2+) among gay, bisexual, and other men who have sex with men (GBMSM), involving alternative roles of self-efficacy for sexual safety and recreational drug use. Data were from the AURAH cross-sectional study of 1340 GBMSM attending genitourinary medicine clinics in England (2013-2014). Structural equation modelling (SEM) was used to investigate which conceptual model was more consistent with the data. Twelve percent of men reported depression (PHQ-9 ≥ 10) and 32% reported CLS2+ in the past 3 months. AURAH data were more consistent with the model in which depression was considered to lead to CLS2+ indirectly via low self-efficacy for sexual safety (indirect Beta = 0.158; p < 0.001) as well as indirectly via higher levels of recreational drug use (indirect Beta = 0.158; p < 0.001). SEM assists in understanding the relationship between depression and CLS among GBMSM.

Fungal endophthalmitis: A 20-year experience at a tertiary referral centre.

IMPORTANCE: Fungal endophthalmitis is an uncommon and serious intraocular infection, often with poor outcomes. This study examines the trend in this disease over 20 years, to inform clinician decision-making and optimize patient outcomes. BACKGROUND: Due to infrequent presentation of fungal endophthalmitis, there is limited understanding to formulate a standardized approach to management. DESIGN: A prospective case series over the period January 1, 1999 to December 31, 2018. PARTICIPANTS: Patients with clinically diagnosed fungal endophthalmitis managed at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. METHODS: Review of the Victorian Endophthalmitis Registry for endophthalmitis episode of each patient. MAIN OUTCOME MEASURES: Patient demographics, co-morbidities, visual acuity (VA) at presentation, aetiology, treatment, microbiology results and final VA outcome. RESULTS: Eighty-four cases of fungal endophthalmitis were identified over the study period with a median age of 43.5 years [IQR 30.8-63.0]. Then, 65.5% (n = 55) of patients were male; 81.0% (n = 68) of these cases were secondary to endogenous causes, of which 55.9% were associated with intravenous drug use (IVDU). Among the exogenous causes, penetrating eye injury (56.3%) was the most common aetiological factor. Thirty-nine patients (46.4%) grew Candida species from ocular fluid specimens, all of which were sensitive to fluconazole. CONCLUSION AND RELEVANCE: Our case series provides important insights into fungal endophthalmitis-a high degree of suspicion for fungal endophthalmitis in patients with history of IVDU, and relatively good outlook for vision when Candida is the causative organism. This should allow institutions to implement a standardized management strategy based on evidence.

Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome.

BACKGROUND: The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjögren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS. METHODS AND RESULTS: Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib. CONCLUSION: These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition.

Seroprevalence of HCV, HBV and HIV in two inner-city London emergency departments.

SUMMARY: In this paper we build on work investigating the feasibility of human immunodeficiency virus (HIV) testing in emergency departments (EDs), estimating the prevalence of hepatitis B, C and HIV infections among persons attending two inner-London EDs, identifying factors associated with testing positive in an ED. We also undertook molecular characterisation to look at the diversity of the viruses circulating in these individuals, and the presence of clinically significant mutations which impact on treatment and control.Blood-borne virus (BBV) testing in non-traditional settings is feasible, with emergency departments (ED) potentially effective at reaching vulnerable and underserved populations. We investigated the feasibility of BBV testing within two inner-London EDs. Residual samples from biochemistry for adults (⩾18 years) attending The Royal Free London Hospital (RFLH) or the University College London Hospital (UCLH) ED between January and June 2015 were tested for human immunodeficiency virus (HIV)Ag/Ab, anti-hepatitis C (HCV) and HBsAg. PCR and sequence analysis were conducted on reactive samples. Sero-prevalence among persons attending RFH and UCLH with residual samples (1287 and 1546), respectively, were 1.1% and 1.0% for HBsAg, 1.6% and 2.3% for anti-HCV, 0.9% and 1.6% for HCV RNA, and 1.3% and 2.2% for HIV. For RFH, HBsAg positivity was more likely among persons of black vs. white ethnicity (odds ratio 9.08; 95% confidence interval 2.72-30), with anti-HCV positivity less likely among females (0.15, 95% CI 0.04-0.50). For UCLH, HBsAg positivity was more likely among non-white ethnicity (13.34, 95% CI 2.20-80.86 (Asian); 8.03, 95% CI 1.12-57.61 (black); and 8.11, 95% CI 1.13-58.18 (other/mixed)). Anti-HCV positivity was more likely among 36-55 year olds vs. ⩾56 years (7.69, 95% CI 2.24-26.41), and less likely among females (0.24, 95% CI 0.09-0.65). Persons positive for HIV-markers were more likely to be of black vs. white ethnicity (4.51, 95% CI 1.63-12.45), and less likely to have one ED attendance (0.39, 95% CI 0.17-0.88), or female (0.12, 95% CI 0.04-0.42). These results indicate that BBV-testing in EDs is feasible, providing a basis for further studies to explore provider and patient acceptability, referral into care and cost-effectiveness.

Fluorescence detected linear dichroism of small molecules oriented on polyethylene film.

We have previously reported a novel method for measuring the spectral properties and orientation of fluorescent probes in solution, which we denoted fluorescence-detected linear dichroism (FDLD). In this work, we expand the scope of the technique by recording the FDLD spectra of the small organic fluorophores: anthracene, 4',6-diamidino-2-phenylindole (DAPI), 1,6-diphenylhexatriene (DPH), and 4-methylphenyl benzoate (MPB), oriented on stretched oxidised polyethylene film. Much like what was observed in solution, we found that the FDLD produced a large signal enhancement compared with absorbance LD, which lowers the sample requirement for measurement. We also found that FDLD has an increased sensitivity towards the immediate environment of the chromophore, revealing oligomeric structures on the film. We believe that FDLD has the potential to reveal important properties of molecules that are obscured or unattainable when using other methods.

Perceived personality change after traumatic brain injury II: comparing participant and informant perspectives.

OBJECTIVE: The objective of this paper was to correlate informant personality change (PC) judgements following moderate-severe traumatic brain injury with quantitative neurobehavioural measures and to contrast the neurobehavioural correlates of informant and participant judgements of PC. PARTICIPANTS: Informant-participant pairs were recruited from a medico-legal clinic passing effort tests (N = 31) and a National Health Service clinic (N = 40). MEASURES: Participants were assessed on Wechsler tests of general ability, tests of executive functioning (Zoo Map and Fluency) and emotional distress (Beck Depression Inventory-FastScreen, Hospital Anxiety and Depression Scale and State-Trait Anger Expression Inventory-II). Informants' expressed emotion towards participants was assessed with the family questionnaire. Both completed the DEX, the Frontal and Social Behavior Questionnaire and PC ratings. RESULTS: The correlates of participant and informant ratings of participant PC partially overlapped. For example, participant self-reported PC was associated with self-reported dysexecutive symptoms and emotional distress. In contrast, informant report of participant PC was associated with lower perceived emotional recognition and empathy, informant report of dysexecutive symptoms and high informant expressed emotion. CONCLUSIONS: It is argued that whilst researchers aim to exhaustively quantify specific neurobehavioural changes and their clusters, partially overlapping subsets of these changes evoke the PC judgements of participants and informants. The clinical implications of this are briefly considered.

ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells.

In the mammalian inner ear, bicellular and tricellular tight junctions (tTJs) seal the paracellular space between epithelial cells. Tricellulin and immunoglobulin-like (Ig-like) domain containing receptor 1 (ILDR1, also referred to as angulin-2) localize to tTJs of the sensory and non-sensory epithelia in the organ of Corti and vestibular end organs. Recessive mutations of TRIC (DFNB49) encoding tricellulin and ILDR1 (DFNB42) cause human nonsyndromic deafness. However, the pathophysiology of DFNB42 deafness remains unknown. ILDR1 was recently reported to be a lipoprotein receptor mediating the secretion of the fat-stimulated cholecystokinin (CCK) hormone in the small intestine, while ILDR1 in EpH4 mouse mammary epithelial cells in vitro was shown to recruit tricellulin to tTJs. Here we show that two different mouse Ildr1 mutant alleles have early-onset severe deafness associated with a rapid degeneration of cochlear hair cells (HCs) but have a normal endocochlear potential. ILDR1 is not required for recruitment of tricellulin to tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in the inner ear sensory epithelia of ILDR1 null mice after the first postnatal week. As revealed by freeze-fracture electron microscopy, ILDR1 contributes to the ultrastructure of inner ear tTJs. Taken together, our data provide insight into the pathophysiology of human DFNB42 deafness and demonstrate that ILDR1 is crucial for normal hearing by maintaining the structural and functional integrity of tTJs, which are critical for the survival of auditory neurosensory HCs.

Seletalisib: Characterization of a Novel, Potent, and Selective Inhibitor of PI3Kδ.

Phosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating cellular survival, development, and function. Expression of the PI3Kδ isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a novel small-molecule inhibitor of PI3Kδ that was evaluated in biochemical assays, cellular assays of adaptive and innate immunity, and an in vivo rat model of inflammation. Our findings show that seletalisib is a potent, ATP-competitive, and selective PI3Kδ inhibitor able to block protein kinase B (AKT) phosphorylation following activation of the B-cell receptor in a B-cell line. Moreover, seletalisib inhibited N-formyl peptide-stimulated but not phorbol myristate acetate-stimulated superoxide release from human neutrophils, consistent with a PI3Kδ-specific activity. No indications of cytotoxicity were observed in peripheral blood mononuclear cells (PBMCs) or other cell types treated with seletalisib. Findings from cellular assays of adaptive immunity demonstrated that seletalisib blocks human T-cell production of several cytokines from activated T-cells. Additionally, seletalisib inhibited B-cell proliferation and cytokine release. In human whole blood assays, seletalisib inhibited CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation. Seletalisib showed dose-dependent inhibition in an in vivo rat model of anti-CD3-antibody-induced interleukin 2 release. Collectively, these data characterize seletalisib as a selective PI3Kδ inhibitor and potential therapeutic candidate for the treatment of B-cell malignancies and autoimmune diseases driven by dysregulated proinflammatory cytokine secretion.

Respiratory health status is impaired in UK HIV-positive adults with virologically suppressed HIV infection.

OBJECTIVES: We sought to evaluate whether people living with HIV (PLWH) using effective antiretroviral therapy (ART) have worse respiratory health status than similar HIV-negative individuals. METHODS: We recruited 197 HIV-positive and 93 HIV-negative adults from HIV and sexual health clinics. They completed a questionnaire regarding risk factors for respiratory illness. Respiratory health status was assessed using the St George's Respiratory Questionnaire (SGRQ) and the Medical Research Council (MRC) breathlessness scale. Subjects underwent spirometry without bronchodilation. RESULTS: PLWH had worse respiratory health status: the median SGRQ Total score was 12 [interquartile range (IQR) 6-25] in HIV-positive subjects vs. 6 (IQR 2-14) in HIV-negative subjects (P < 0.001); breathlessness was common in the HIV-positive group, where 47% compared with 24% had an MRC breathlessness score ≥ 2 (P = 0.001). Eighteen (11%) HIV-positive and seven (9%) HIV-negative participants had airflow obstruction. In multivariable analyses (adjusted for age, gender, smoking, body mass index and depression), HIV infection remained associated with higher SGRQ and MRC scores, with an adjusted fold-change in SGRQ Total score of 1.54 [95% confidence interval (CI) 1.14-2.09; P = 0.005] and adjusted odds ratio of having an MRC score of ≥ 2 of 2.45 (95% CI 1.15-5.20; P = 0.02). Similar findings were obtained when analyses were repeated including only HIV-positive participants with a viral load < 40 HIV-1 RNA copies/mL. CONCLUSIONS: Despite effective ART, impaired respiratory health appears more common in HIV-positive adults, and has a significant impact on health-related quality of life.

Age, time living with diagnosed HIV infection, and self-rated health.

OBJECTIVES: An increasing proportion of people living with HIV are older adults, who may require specialized care. Adverse physical and psychological effects of HIV infection may be greatest among older people or those who have lived longer with HIV. METHODS: The ASTRA study is a cross-sectional questionnaire study of 3258 HIV-diagnosed adults (2248 men who have sex with men, 373 heterosexual men and 637 women) recruited from UK clinics in 2011-2012. Associations of age group with physical symptom distress (significant distress for at least one of 26 symptoms), depression and anxiety symptoms (scores ≥ 10 on PHQ-9 and GAD-7, respectively), and health-related functional problems (problems on at least one of three domains of the Euroqol 5D-3L)) were assessed, adjusting for time with diagnosed HIV infection, gender/sexual orientation and ethnicity. RESULTS: The age distribution of participants was: < 30 years, 5%; 30-39 years, 23%; 40-49 years, 43%; 50-59 years, 22%; and ≥ 60 years, 7%. Overall prevalences were: physical symptom distress, 56%; depression symptoms, 27%; anxiety symptoms, 22%; functional problems, 38%. No trend was found in the prevalence of physical symptom distress with age [adjusted odds ratio (OR) for trend across age groups, 0.96; 95% confidence interval (CI) 0.89, 1.04; P = 0.36]. The prevalence of depression and anxiety symptoms decreased with age [adjusted OR 0.86 (95% CI 0.79, 0.94; P = 0.001) and adjusted OR 0.85 (95% CI 0.77, 0.94; P = 0.001), respectively], while that of functional problems increased (adjusted OR 1.28; 95% CI 1.17, 1.39; P < 0.001). In contrast, a longer time with diagnosed HIV infection was strongly and independently associated with a higher prevalence of symptom distress, depression symptoms, anxiety symptoms, and functional problems (P < 0.001 for trends, adjusted analysis). CONCLUSIONS: Among people living with HIV, although health-related functional problems were more common with older age, physical symptom distress was not, and mental health was more favourable. These results suggest that a longer time with diagnosed HIV infection, rather than age, is the dominating factor contributing to psychological morbidity and lower quality of life.