Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is an immune-mediated reaction that can occur after hematopoietic stem cell transplantation in which donor T cells recognize the host antigens as foreign, destroying host tissues. Establishment of a tolerogenic immune environment while preserving the immune response to infectious agents is required for successful bone marrow transplantation. Pregnancy-specific glycoprotein 1 (PSG1), which is secreted by the human placenta into the maternal circulation throughout pregnancy, likely plays a role in maintaining immunotolerance to prevent rejection of the fetus by the maternal immune system. We have previously shown that PSG1 activates the latent form of transforming growth factor ß1 (TGF-ß), a cytokine essential for the differentiation of tolerance-inducing CD4+FoxP3+ regulatory T cells (Tregs). Consistent with this observation, treatment of naïve murine T cells with PSG1 resulted in a significant increase in FoxP3+ cells that was blocked by a TGF-ß receptor I inhibitor. We also show here that PSG1 can increase the availability of active TGF-ß in vivo. As the role of CD4+FoxP3+ cells in the prevention of aGVHD is well established, we tested whether PSG1 has beneficial effects in a murine aGHVD transplantation model. PSG1-treated mice had reduced numbers of tissue-infiltrating inflammatory CD3+ T cells and had increased expression of FoxP3 in T cells compared with vehicle-treated mice. In addition, administration of PSG1 significantly inhibited aGVHD-associated weight loss and mortality. On the other hand, administration of PSG1 was less effective in managing aGVHD in the presence of an alloimmune reaction against a malignancy in a graft-versus-leukemia experimental model. Combined, this data strongly suggests that PSG1 could be a promising treatment option for patients with aGVHD following bone marrow transplantation for a nonmalignant condition, such as an autoimmune disorder or a genetic immunodeficiency.

Sex specific retinoic acid signaling is required for the initiation of urogenital sinus bud development.

The mammalian urogenital sinus (UGS) develops in a sex specific manner, giving rise to the prostate in the male and the sinus vagina in the embryonic female. Androgens, produced by the embryonic testis, have been shown to be crucial to this process. In this study we show that retinoic acid signaling is required for the initial stages of bud development from the male UGS. Enzymes involved in retinoic acid synthesis are expressed in the UGS mesenchyme in a sex specific manner and addition of ligand to female tissue is able to induce prostate-like bud formation in the absence of androgens, albeit at reduced potency. Functional studies in mouse organ cultures that faithfully reproduce the initiation of prostate development indicate that one of the roles of retinoic acid signaling in the male is to inhibit the expression of Inhba, which encodes the ßA subunit of Activin, in the UGS mesenchyme. Through in vivo genetic analysis and culture studies we show that inhibition of Activin signaling in the female UGS leads to a similar phenotype to that of retinoic acid treatment, namely bud formation in the absence of androgens. Our data also reveals that both androgens and retinoic acid have extra independent roles to that of repressing Activin signaling in the development of the prostate during fetal stages. This study identifies a novel role for retinoic acid as a mesenchymal factor that acts together with androgens to determine the position and initiation of bud development in the male UGS epithelia.

Non-tuberculous mycobacterial pulmonary disease (NTM-PD): Epidemiology, diagnosis and multidisciplinary management.

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause significant disease in both immunocompromised and immunocompetent individuals. The incidence of NTM pulmonary disease (NTM-PD) is rising globally. Diagnostic challenges persist and treatment efficacy is variable. This article provides an overview of NTM-PD for clinicians. We discuss how common it is, who is at risk, how it is diagnosed and the multidisciplinary approach to its clinical management.

Amblyopia Treatment Outcomes Re-Audit, Comparing Current Outcomes to Those from the 2011-12 Audit.

Aim: An audit of the effectiveness of amblyopia treatment in the Newcastle Eye Centre (NEC) to determine how current visual acuity (VA) outcomes compare to those found in the 2011-12 audit. Methods: A retrospective database review. VA outcomes of patients who had undergone treatment for anisometropic, strabismic and mixed amblyopia; discharged between 31.08.2016 - 01.09.19, were compared with VA outcomes found in the previous audit. The previous audit reviewed patients commencing amblyopia treatment during 1.1.11-31.12.12.An unpaired T-test was used to assess if results were statistically significantly different to those found previously. Proportion of visual change from commencement to completion of treatment was calculated. The duration of episode from first visit to discharge, adverse events and percentage of patients who achieved acceptable visual outcomes following only six to eight weeks of occlusion, were also analysed. Results: Between 31.8.16 and 01.09.19, 1,100 patients were discharged, of which 174 had completed amblyopia treatment and fit the inclusion criteria for the audit. Results show no statistically significant difference between current and previous VA outcomes for each type of amblyopia. The majority of patients (60%) achieve a VA outcome of ≤0.250 (logMAR) in the amblyopic eye. This is comparable to the previous audit where 59% of patients achieved a VA outcome of ≤0.250. Most patients still achieve a level of VA which is equal or almost equal to the fellow eye following amblyopia treatment. Treatment is still completed within a two-year period for the majority of patients (62%). There was only one adverse event and this related to atropine occlusion. Only 18 out of the 174 (10%) patients showed that occlusion could be discontinued following just six to eight weeks of treatment. Conclusions: The treatment of amblyopia in the NEC is as successful as found in the previous audit and the current amblyopia treatment protocol remains effective. Only 10% of patients achieved the appropriate VA for amblyopia treatment to be ceased on their first return visit. This indicates that the follow-up length for patients undergoing amblyopia treatment could be extended beyond six to eight weeks without causing a detriment to VA outcome.

COVID-19 and Fidelity to the Sobriety Treatment and Recovery Teams Model.

OBJECTIVE: Quick access to substance use treatment is associated with better outcomes, but little is known about COVID-19's impact on access and retention. This study examined the relationship between COVID-19-related practice changes and quick access fidelity outcomes of the Sobriety Treatment and Recovery Teams (START) program, which serves families with co-occurring substance use and child abuse/neglect. METHOD: This study was a retrospective cohort comparison. On March 23, 2020, most START child welfare and treatment services were shifted to a virtual format because of the COVID-19 pandemic. Families referred to the program between that date and March 23, 2021, were compared with families served the year before (i.e., March 23, 2019, to March 22, 2020). Cohorts were compared across nine fidelity outcomes (e.g., number of days to complete four treatment sessions), with differences assessed using chi-square tests and independent samples t tests. RESULTS: Referrals to START were 14% lower during the first COVID-19 year than in the prior year, with a greater percentage of referred cases being accepted during COVID-19. Transition to virtual service provision was not related to quick access fidelity outcomes; however, adults referred in the year before COVID-19 were more likely to complete four treatment sessions than adults referred during the first COVID-19 year. CONCLUSIONS: In this study, quick access to services and initial engagement did not appear to be negatively affected by virtual service provision resulting from COVID-19. However, during COVID-19, fewer adults completed four treatment sessions. In a largely virtual treatment environment, additional engagement and pre-treatment services may be necessary.

AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG).

Phosphoglucomutase 1 (PGM1) deficiency is recognized as the third most common N-linked congenital disorders of glycosylation (CDG) in humans. Affected individuals present with liver, musculoskeletal, endocrine, and coagulation symptoms; however, the most life-threatening complication is the early onset of dilated cardiomyopathy (DCM). Recently, we discovered that oral D-galactose supplementation improved liver disease, endocrine, and coagulation abnormalities, but does not alleviate the fatal cardiomyopathy and the associated myopathy. Here we report on left ventricular ejection fraction (LVEF) in 6 individuals with PGM1-CDG. LVEF was pathologically low in most of these individuals and varied between 10% and 65%. To study the pathobiology of the cardiac disease observed in PGM1-CDG, we constructed a novel cardiomyocyte-specific conditional Pgm2 gene (mouse ortholog of human PGM1) knockout (Pgm2 cKO) mouse model. Echocardiography studies corroborated a DCM phenotype with significantly reduced ejection fraction and left ventricular dilation similar to those seen in individuals with PGM1-CDG. Histological studies demonstrated excess glycogen accumulation and fibrosis, while ultrastructural analysis revealed Z-disk disarray and swollen/fragmented mitochondria, which was similar to the ultrastructural pathology in the cardiac explant of an individual with PGM1-CDG. In addition, we found decreased mitochondrial function in the heart of KO mice. Transcriptomic analysis of hearts from mutant mice demonstrated a gene signature of DCM. Although proteomics revealed only mild changes in global protein expression in left ventricular tissue of mutant mice, a glycoproteomic analysis unveiled broad glycosylation changes with significant alterations in sarcolemmal proteins including different subunits of laminin-211, which was confirmed by immunoblot analyses. Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement therapy prevented and halted the progression of the DCM phenotype.

Using the multiphase optimization strategy to adapt cognitive processing therapy (CPT MOST): study protocol for a randomized controlled factorial experiment.

BACKGROUND: Approximately ten percent of US military veterans suffer from posttraumatic stress disorder (PTSD). Cognitive processing therapy (CPT) is a highly effective, evidence-based, first-line treatment for PTSD that has been widely adopted by the Department of Veterans Affairs (VA). CPT consists of discrete therapeutic components delivered across 12 sessions, but most veterans (up to 70%) never reach completion, and those who discontinue therapy receive only four sessions on average. Unfortunately, veterans who drop out prematurely may never receive the most effective components of CPT. Thus, there is an urgent need to use empirical approaches to identify the most effective components of CPT so CPT can be adapted into a briefer format. METHODS: The multiphase optimization strategy (MOST) is an innovative, engineering-inspired framework that uses an optimization trial to assess the performance of individual intervention components within a multicomponent intervention such as CPT. Here we use a fractional factorial optimization trial to identify and retain the most effective intervention components to form a refined, abbreviated CPT intervention package. Specifically, we used a 16-condition fractional factorial experiment with 270 veterans (N = 270) at three VA Medical Centers to test the effectiveness of each of the five CPT components and each two-way interaction between components. This factorial design will identify which CPT components contribute meaningfully to a reduction in PTSD symptoms, as measured by PTSD symptom reduction on the Clinician-Administered PTSD Scale for DSM-5, across 6 months of follow-up. It will also identify mediators and moderators of component effectiveness. DISCUSSION: There is an urgent need to adapt CPT into a briefer format using empirical approaches to identify its most effective components. A brief format of CPT may reduce attrition and improve efficiency, enabling providers to treat more patients with PTSD. The refined intervention package will be evaluated in a future large-scale, fully-powered effectiveness trial. Pending demonstration of effectiveness, the refined intervention can be disseminated through the VA CPT training program. TRIAL REGISTRATION: ClinicalTrials.gov NCT05220137. Registration date: January 21, 2022.

Development of an individualized procedure to induce reward-related impulsivity and evaluating its impact on drinking control.

High impulsivity predisposes young adults to engage in hazardous alcohol use. Experimental research has shown that reward-related impulsivity is causally-related to heavier drinking. Correlational studies suggest that positive alcohol outcome expectancies mediate this effect, but causation has yet to be established. This study sought to clarify this relationship by: 1) developing a new, individualized procedure for inducing reward-related impulsivity with high generalizability; 2) experimentally manipulating positive alcohol expectancies to determine its mechanistic role in reward-related impulsivity risk for drinking. Eighty-seven young adults (67% female; Mage = 19.19, SD = 2.01) received either a covert manipulation to reduce positive alcohol expectancies (n = 43) or control (n = 44) after being administered the Individualized Reward-Seeking Induction Schedule (IRIS). The primary outcome was self-reported confidence in the ability to refuse alcohol in cued situations (drinking refusal self-efficacy). Results showed that IRIS increased reward-related impulsivity (p < .001, drm = 0.48) and reduced drinking refusal self-efficacy (p = .029, η2P = .055, ωp2 = .043). Experimentally diminishing positive alcohol expectancies had a marginal effect on the reward-seeking induction when controlling for covariates (p = .057, η2P = .044). Findings provide preliminary validation of IRIS as a new methodology for investigating the causal role of reward-related impulsivity in alcohol-related cognition and youth drinking.

Alcohol and drug problems among Australian homicide offenders.

BACKGROUND AND AIMS: Most homicide studies focus upon 'acute' situational intoxication as opposed to 'chronic' substance misuse. The aims of the study were to: (1) determine the extent of homicide offenders' alcohol and drug use in the year preceding the homicide; (2) compare the individual characteristics of homicide offenders across levels of problematic substance use; and (3) compare homicide incident characteristics across levels of problematic substance use. DESIGN AND SETTING: Observational study using data collected through face-to-face interviews in custodial and community correctional settings across Australia. Participants were recruited through an opt-in process. PARTICIPANTS: The data consist of 302 individuals convicted of murder or manslaughter. MEASUREMENTS: We used the Alcohol Use Disorder Identification Test and Drug Abuse Screening Test to determine problematic alcohol or drug use. We also used a range of self-report measures to ascertain offender characteristics [socio-demographics, developmental experiences, criminal history, personality] and incident characteristics (who was killed, and situational intoxication). FINDINGS: Of the sample, 38.8% displayed high levels of alcohol problems and 30.8% displayed high levels of drug problems. Those displaying high levels of alcohol and/or drug problems were more likely than those without high levels of alcohol and/or drug problems to report adverse developmental experiences, low education, financial difficulties, extensive criminal histories and high levels of trait anger, impulsivity and risk-seeking. In addition, offenders with problematic substance use were more likely to have killed non-family and to have used substances at the time of the homicide. CONCLUSIONS: High proportions of homicide offenders in Australia appear to have problematic substance use in the year preceding the homicide offence, and such use appears to be associated with a range of other challenging factors, including adverse childhoods, criminal involvement, low socio-economic factors and low self-regulation.

Identification of new genetic risk factors for prostate cancer.

There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Adolescent exposure to cocaine, amphetamine, and methylphenidate cross-sensitizes adults to methamphetamine with drug- and sex-specific effects.

The increasing availability, over-prescription, and misuse and abuse of ADHD psychostimulant medications in adolescent populations necessitates studies investigating the long-term effects of these drugs persisting into adulthood. Male and female C57Bl/6J mice were exposed to amphetamine (AMPH) (1.0 and 10 mg/kg), methylphenidate (MPD) (1.0 and 10 mg/kg), or cocaine (COC) (5.0 mg/kg) from postnatal day 22 to 31, which represents an early adolescent period. After an extended period of drug abstinence, adult mice were challenged with a subacute methamphetamine (METH) dose (0.5 mg/kg), to test the long-term effects of adolescent drug exposures on behavioral cross-sensitization using an open field chamber. There were no sex- or dose-specific effects on motor activity in adolescent, saline-treated controls. However, AMPH, MPD, and COC adolescent exposures induced cross-sensitization to a subacute METH dose in adulthood, which is a hallmark of addiction and a marker of long-lasting plastic changes in the brain. Of additional clinical importance, AMPH-exposed male mice demonstrated increased cross-sensitization to METH in contrast to the female-specific response observed in MPD-treated animals. There were no sex-specific effects after adolescent COC exposures. This study demonstrates differential drug, dose, and sex-specific alterations induced by early adolescent psychostimulant exposure, which leads to behavioral alterations that persist into adulthood.

Multiple newly identified loci associated with prostate cancer susceptibility.

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at