A prospective longitudinal study of risk factors for abdominal aortic aneurysm.

The aim of this study was to identify risk factors for abdominal aortic aneurysm (AAA) from the largest Welsh screening cohort to date. Patients were recruited from 1993 (to 2015) as part of the South East Wales AAA screening programme through general practitioners. Demographic data and risk factors were collected by means of a self-report questionnaire. Statistical tests were performed to determine whether associations could be observed between AAA and potential risk factors. Odds ratios (OR) were also calculated for each of the risk factors identified. A total of 6879 patients were included in the study. Two hundred and seventy-five patients (4.0%) presented with AAA, of which 16% were female and 84% were male. Patients with AAA were older than the (no AAA) control group (p < 0.0001). The following risk factors were identified for AAA: family history of AAA (p < 0.0001); history of vascular surgery (p < 0.0001), cerebrovascular accident (p < 0.0001), coronary heart disease (p < 0.0001), diabetes (p < 0.0001), medication (p = 0.0018), claudication (p < 0.0001), smoking history (p = 0.0001) and chronic obstructive pulmonary disorder (p = 0.0007). AAA is associated with classical vascular risk factors, in addition to other less-well-documented risk factors including previous vascular surgery. These findings have practical implications with the potential to improve future clinical screening of patients in order to reduce AAA mortality.

Dalzanemdor (SAGE-718), a novel, investigational N-methyl-D-aspartate receptor positive allosteric modulator: Safety, tolerability, and clinical pharmacology in randomized dose-finding studies in healthy participants and an open-label study in participants with Huntington's disease.

N-methyl-D-aspartate receptor (NMDAR)-positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE-718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first-in-human, phase I, double-blind, dose-finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single-ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple-ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open-label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once-daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 8-118 h, and the median time to reach maximum plasma concentration was 4-7 h. Exposures were dose-proportional after single dose (6-46 ng/mL) and more than dose-proportional after multiple doses (6-41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.

Comparing the effectiveness and cost-effectiveness of text-message reminders and telephone patient navigation to improve the uptake of faecal immunochemical test screening among non-responders in London: a randomised controlled trial protocol.

INTRODUCTION: Participation in bowel cancer screening is lower in regions where there is high ethnic diversity and/or socioeconomic deprivation. Interventions, such as text message reminders and patient navigation (PN), have the potential to increase participation in these areas. As such, there is interest in the comparative effectiveness of these interventions to increase bowel cancer screening participation, as well as their relative cost-effectiveness. METHODS AND ANALYSIS: This study will use a three-arm randomised controlled trial design to compare the effectiveness and cost-effectiveness of text message reminders and PN to increase the uptake of bowel cancer screening in London. Participants will be individuals who have not returned a completed faecal immunochemical test kit within 13 weeks of receiving a routine invitation from the London bowel cancer screening hub. Participants will be randomised (in a 1:1:1 ratio) to receive either (1) usual care (ie, 'no intervention'), (2) a text message reminder at 13 weeks, followed by repeated text message reminders at 15, 17 and 19 weeks (in the event of non-response) or (3) a text message reminder at 13 weeks, followed by PN telephone calls at 15, 17 and 19 weeks in the event of non-response. The primary endpoint will be participation in bowel cancer screening, defined as 'the return of a completed kit by week 24'. Statistical analysis will use multivariate logistic regression and will incorporate pairwise comparisons of all three groups, adjusted for multiple testing. ETHICS AND DISSEMINATION: Approvals to conduct the research have been obtained from University College London's Joint Research Office (Ref: 150666), the Screening Research, Innovation and Development Advisory Committee ('RIDAC', Ref: 2223 014 BCSP Kerrison), the Health Research Authority (Ref: 22/WM/0212) and the Confidentiality Advisory Group (Ref: 22/CAG/0140). Results will be conveyed to stakeholders, notably those managing the screening programme and published in peer-reviewed journals/presented at academic conferences. TRIAL REGISTRATION NUMBER: ISRCTN17245519.

Dynamics of Trypanosoma cruzi infection in hamsters and novel association with progressive motor dysfunction.

Chagas disease is a zoonosis caused by the protozoan parasite Trypanosoma cruzi. Clinical outcomes range from long-term asymptomatic carriage to cardiac, digestive, neurological and composite presentations that can be fatal in both acute and chronic stages of the disease. Studies of T. cruzi in animal models, principally mice, have informed our understanding of the biological basis of this variability and its relationship to infection and host response dynamics. Hamsters have higher translational value for many human infectious diseases, but they have not been well developed as models of Chagas disease. We transposed a real-time bioluminescence imaging system for T. cruzi infection from mice into female Syrian hamsters (Mesocricetus auratus). This enabled us to study chronic tissue pathology in the context of spatiotemporal infection dynamics. Acute infections were widely disseminated, whereas chronic infections were almost entirely restricted to the skin and subcutaneous adipose tissue. Neither cardiac nor digestive tract disease were reproducible features of the model. Skeletal muscle had only sporadic parasitism in the chronic phase, but nevertheless displayed significant inflammation and fibrosis, features also seen in mouse models. Whereas mice had normal locomotion, all chronically infected hamsters developed hindlimb muscle hypertonia and a gait dysfunction resembling spastic diplegia. With further development, this model may therefore prove valuable in studies of peripheral nervous system involvement in Chagas disease.

Phase 2 study of neoadjuvant enzalutamide and paclitaxel for luminal androgen receptor-enriched TNBC: Trial results and insights into "ARness".

Luminal androgen receptor (LAR)-enriched triple-negative breast cancer (TNBC) is a distinct subtype. The efficacy of AR inhibitors and the relevant biomarkers in neoadjuvant therapy (NAT) are yet to be determined. We tested the combination of the AR inhibitor enzalutamide (120 mg daily by mouth) and paclitaxel (80 mg/m2 weekly intravenously) (ZT) for 12 weeks as NAT for LAR-enriched TNBC. Eligibility criteria included a percentage of cells expressing nuclear AR by immunohistochemistry (iAR) of at least 10% and a reduction in sonographic volume of less than 70% after four cycles of doxorubicin and cyclophosphamide. Twenty-four patients were enrolled. Ten achieved a pathologic complete response or residual cancer burden-I. ZT was safe, with no unexpected side effects. An iAR of at least 70% had a positive predictive value of 0.92 and a negative predictive value of 0.97 in predicting LAR-enriched TNBC according to RNA-based assays. Our data support future trials of AR blockade in early-stage LAR-enriched TNBC.

A panel of phenotypically and genotypically diverse bioluminescent:fluorescent Trypanosoma cruzi strains as a resource for Chagas disease research.

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that displays considerable genetic diversity. Infections result in a range of pathological outcomes, and different strains can exhibit a wide spectrum of anti-parasitic drug tolerance. The genetic determinants of infectivity, virulence and therapeutic susceptibility remain largely unknown. As experimental tools to address these issues, we have generated a panel of bioluminescent:fluorescent parasite strains that cover the diversity of the T. cruzi species. These reporters allow spatio-temporal infection dynamics in murine models to be monitored in a non-invasive manner by in vivo imaging, provide a capability to detect rare infection foci at single-cell resolution, and represent a valuable resource for investigating virulence and host:parasite interactions at a mechanistic level. Importantly, these parasite reporter strains can also contribute to the Chagas disease drug screening cascade by ensuring that candidate compounds have pan-species in vivo activity prior to being advanced into clinical testing. The parasite strains described in this paper are available on request.

Enteric nervous system regeneration and functional cure of experimental digestive Chagas disease with trypanocidal chemotherapy.

Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. There is a lack of evidence on the mechanism of pathogenesis and rationales for treatment. We used a female C3H/HeN mouse model that recapitulates key clinical manifestations to study how infection dynamics shape DCD pathology and the impact of treatment with the front-line, anti-parasitic drug benznidazole. Curative treatment 6 weeks post-infection resulted in sustained recovery of gastrointestinal transit function, whereas treatment failure led to infection relapse and gradual return of DCD symptoms. Neuro/immune gene expression patterns shifted from chronic inflammation to a tissue repair profile after cure, accompanied by increased cellular proliferation, glial cell marker expression and recovery of neuronal density in the myenteric plexus. Delaying treatment until 24 weeks post-infection led to partial reversal of DCD, suggesting the accumulation of permanent tissue damage over the course of chronic infection. Our study shows that murine DCD pathogenesis is sustained by chronic T. cruzi infection and is not an inevitable consequence of acute stage denervation. The risk of irreversible enteric neuromuscular tissue damage and dysfunction developing highlights the importance of prompt diagnosis and treatment. These findings support the concept of treating asymptomatic, T. cruzi-infected individuals with benznidazole to prevent DCD development.

Long-term clinical outcomes and cost-effectiveness of catheter vs thoracoscopic surgical ablation in long-standing persistent atrial fibrillation using continuous cardiac monitoring: CASA-AF randomized controlled trial.

BACKGROUND: Long-term clinical outcomes of catheter ablation (CA) compared to thoracoscopic surgical ablation (SA) to treat patients with long-standing persistent atrial fibrillation (LSPAF) are not known. OBJECTIVE: The purpose of this study was to compare the long-term (36-month) clinical efficacy, quality of life, and cost-effectiveness of SA and CA in LSPAF. METHODS: Participants were followed up for 3 years using implantable loop recorders and questionnaires to assess the change in quality of life. Intention-to-treat analyses were used to report the findings. RESULTS: Of the 115 patients with LSPAF treated, 104 (90.4%) completed 36-month follow-up [CA: n = 57 (95%); SA: n = 47 (85%)]. After a single procedure without antiarrhythmic drugs, 7 patients (12%) in the CA arm and 5 (11%) in the SA arm [hazard ratio 1.22; 95% confidence interval (CI) 0.81-1.83; P = .41] were free from atrial fibrillation/tachycardia (AF/AT) ≥30 seconds at 36 months. Thirty-three patients (58%) in the CA arm and 26 (55%) in the SA arm (hazard ratio 1.04; 95% CI 0.57-1.88; P = .91) had their AF/AT burden reduced by ≥75%. The overall impact on health-related quality of life was similar, with mean quality-adjusted life year estimates of 2.45 (95% CI 2.31-2.59) for CA and 2.32 (95% CI 2.13-2.52) for SA. Estimated costs were higher for SA (mean £24,682; 95% CI £21,746-£27,618) than for CA (mean £18,002; 95% CI £15,422-£20,581). CONCLUSION: In symptomatic LSPAF, CA and SA were equally effective at achieving arrhythmia outcomes (freedom from AF/AT ≥30 seconds and ≥75% burden reduction) after a single procedure without antiarrhythmic drugs. However, SA is significantly more costly than CA. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04280042.

Assessment of Patient-Derived Xenograft Growth and Antitumor Activity: The NCI PDXNet Consensus Recommendations.

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification of promising novel therapies and biomarkers for guiding cancer therapy.

Upregulated Matrisomal Proteins and Extracellular Matrix Mechanosignaling Underlie Obesity-Associated Promotion of Pancreatic Ductal Adenocarcinoma.

Diet-induced obesity (DIO) promotes pancreatic ductal adenocarcinoma (PDAC) in mice expressing KRasG12D in the pancreas (KC mice), but the precise mechanisms remain unclear. Here, we performed multiplex quantitative proteomic and phosphoproteomic analysis by liquid chromatography-tandem mass spectrometry and further bioinformatic and spatial analysis of pancreas tissues from control-fed versus DIO KC mice after 3, 6, and 9 months. Normal pancreatic parenchyma and associated proteins were steadily eliminated and the novel proteins, phosphoproteins, and signaling pathways associated with PDAC tumorigenesis increased until 6 months, when most males exhibited cancer, but females did not. Differentially expressed proteins and phosphoproteins induced by DIO revealed the crucial functional role of matrisomal proteins, which implies the roles of upstream regulation by TGFß, extracellular matrix-receptor signaling to downstream PI3K-Akt-mTOR-, MAPK-, and Yap/Taz activation, and crucial effects in the tumor microenvironment such as metabolic alterations and signaling crosstalk between immune cells, cancer-associated fibroblasts (CAFs), and tumor cells. Staining tissues from KC mice localized the expression of several prognostic PDAC biomarkers and elucidated tumorigenic features, such as robust macrophage infiltration, acinar-ductal metaplasia, mucinous PanIN, distinct nonmucinous atypical flat lesions (AFLs) surrounded by smooth muscle actin-positive CAFs, invasive tumors with epithelial-mesenchymal transition arising close to AFLs, and expanding deserted areas by 9 months. We next used Nanostring GeoMX to characterize the early spatial distribution of specific immune cell subtypes in distinct normal, stromal, and PanIN areas. Taken together, these data richly contextualize DIO promotion of Kras-driven PDAC tumorigenesis and provide many novel insights into the signaling pathways and processes involved.

Targeted CQA analytical control strategy for commercial antibody products: Replacing ion-exchange chromatography methods for charge heterogeneity with multi-attribute monitoring.

Peptide mapping with mass spectrometry (MS) is an important tool for protein characterization in the biopharmaceutical industry. Historically, peptide mapping monitors post-translational modifications (PTMs) of protein products and process intermediates during development. Multi-attribute monitoring (MAM) methods have been used previously in commercial release and stability testing panels to ensure control of selected critical quality attributes (CQAs). Our goal is to use MAM methods as part of an overall analytical testing strategy specifically focused on CQAs, while removing or replacing historical separation methods that do not effectively distinguish CQAs from non-CQAs due to co-elution. For example, in this study, we developed a strategy to replace a profile-based ion-exchange chromatography (IEC) method using a MAM method in combination with traditional purity methods to ensure control of charge variant CQAs for a commercial antibody (mAb) drug product (DP). To support this change in commercial testing strategy, the charge variant CQAs were identified and characterized during development by high-resolution LC-MS and LC-MS/MS. The charge variant CQAs included PTMs, high molecular weight species, and low molecular weight species. Thus, removal of the IEC method from the DP specification was achieved using a validated LC-MS MAM method on a QDa system to directly measure the charge variant PTM CQAs in combination with size exclusion chromatography (SE-HPLC) and capillary electrophoresis (CE-SDS) to measure the non-PTM charge variant CQAs. Bridging data between the MAM, IEC, and SE-HPLC methods were included in the commercial marketing application to justify removing IEC from the DP specification. We have also used this MAM method as a test for identity to reduce the number of QC assays. This strategy has received approvals from several health authorities.

Spontaneous Fusion with Transformed Mesenchymal Stromal Cells Results in Complete Heterogeneity in Prostate Cancer Cells.

Tumor cells gain advantages in growth and survival by acquiring genotypic and phenotypic heterogeneity. Interactions with bystander cells in the tumor microenvironment contribute to the progression of heterogeneity. We have shown that fusion between tumor and bystander cells is one form of interaction, and that tumor-bystander cell fusion has contrasting effects. By trapping fusion hybrids in the heterokaryon or synkaryon state, tumor-bystander cell fusion prevents the progression of heterogeneity. However, if trapping fails, fusion hybrids will resume replication to form derivative clones with diverse genomic makeups and behavioral phenotypes. To determine the characteristics of bystander cells that influence the fate of fusion hybrids, we co-cultured prostate mesenchymal stromal cell lines and their spontaneously transformed sublines with LNCaP as well as HPE-15 prostate cancer cells. Subclones derived from cancer-stromal fusion hybrids were examined for genotypic and phenotypic diversifications. Both stromal cell lines were capable of fusing with cancer cells, but only fusion hybrids with the transformed stromal subline generated large numbers of derivative subclones. Each subclone had distinct cell morphologies and growth behaviors and was detected with complete genomic hybridization. The health conditions of the bystander cell compartment play a crucial role in the progression of tumor cell heterogeneity.

Unveiling why race does not affect the mask effect on attractiveness: but gender and expression do.

Studies show that surgical face masks can have both positive and negative effects on attractiveness. Race has been implicated as a moderator of the size of this mask effect. Here, the moderating effects of expression, race and gender are explored. The mask effect was more positive for males than for females, for neutral faces than for smiling faces, and there were differences between the races. Further, the effect of unmasked attractiveness was partialled out for each image, which removed the race effects, but the gender and expression effects remained. It is suggested that racial differences previously observed in the mask effects are a consequence of differences in attractiveness of the faces sampled from those races. Re-analysis of previous research that showed race effects also demonstrates how they are better explained as attractiveness effects rather than race effects. This explanation can provide order to the different findings observed across the literature.

Cancer-related cells and oncosomes in the liquid biopsy of pancreatic cancer patients undergoing surgery.

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of less than 10% due to its late diagnosis, rapid metastasis, and chemotherapeutic resistance. For a small proportion (10-20%) of early-stage patients however, surgical resection of the pancreatic tumor offers the best chance for survival but the effect of surgery on disease dissemination is unknown. The primary objective of this study was to characterize cellular and acellular blood-based analytes in portal and peripheral blood before pancreatic manipulation, during tumor dissection and immediately after surgical resection to determine the effects of the surgery. This study used the non-enriching third generation High-Definition Single Cell Assay (HDSCA3.0) workflow to investigate heterogeneous circulating rare cell population in the blood. Blood from both sites taken before surgical manipulation of the pancreas had significantly greater incidence of total rare cellular and acellular analytes than normal donor samples. Post-surgery portal and peripheral blood had significantly greater incidence of specific cellular and acellular subtypes compared to the matched pre- and during-surgery samples. Our results reveal that in patients with PDAC liquid biopsy analytes are increased in both the portal and peripheral blood; portal blood contains a higher frequency of analytes than in the peripheral blood; total analytes in the portal and peripheral blood samples were significantly associated with the tumor volume and pathological T stage; and the surgical procedure increased the blood levels of circulating cellular and acellular analytes, but not Epi.CTCs or Mes.CTCs. This study demonstrates liquid biopsy's utility in monitoring patients with PDAC with surgically resectable disease.

Overcoming Resistance in Prostate Cancer Therapy Using a DZ-Simvastatin Conjugate.

Prostate cancer (PC), particularly its metastatic castration-resistant form (mCRPC), is a leading cause of cancer-related deaths among men in the Western world. Traditional systemic treatments, including hormonal therapy and chemotherapy, offer limited effectiveness due to tumors' inherent resistance to these therapies. Moreover, they often come with significant side effects. We have developed a delivery method using a tumor-cell-specific heptamethine carbocyanine dye (DZ) designed to transport therapeutic agents directly to tumor cells. This research evaluated simvastatin (SIM) as the antitumor payload because of its demonstrated chemopreventive effects on human cancers and its well-documented safety profile. We designed and synthesized a DZ-SIM conjugate for tumor cell targeting. PC cell lines and xenograft tumor models were used to assess tumor-cell targeting specificity and killing activity and to investigate the corresponding mechanisms. DZ-SIM treatment effectively killed PC cells regardless of their androgen receptor status or inherent therapeutic resistance. The conjugate targeted and suppressed xenograft tumor formation without harming normal cells of the host. In cancer cells, DZ-SIM was enriched in subcellular organelles, including mitochondria, where the conjugate formed adducts with multiple proteins and caused the loss of transmembrane potential, promoting cell death. The DZ-SIM specifically targets PC cells and their mitochondria, resulting in a loss of mitochondrial function and cell death. With a unique subcellular targeting strategy, the conjugate holds the potential to outperform existing chemotherapeutic drugs. It presents a novel strategy to circumvent therapeutic resistance, offering a more potent treatment for mCRPC.

A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma.

BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition. METHODS: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen. RESULTS: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC50 of 0.013-0.059 µM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups. CONCLUSIONS: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB. IMPACT AND IMPLICATIONS: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.

Pharmacological characterization of SAGE-718, a novel positive allosteric modulator of N-methyl-d-aspartate receptors.

BACKGROUND AND PURPOSE: Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC), which is an N-methyl-d-aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction. EXPERIMENTAL APPROACH: Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE-718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile. KEY RESULTS: SAGE-718 potentiated GluN1/GluN2A-D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE-718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine-evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE-718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)-HC depletion caused by 7-dehydrocholesterol reductase inhibition. Finally, SAGE-718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing. CONCLUSIONS AND IMPLICATIONS: These findings provide strong evidence that SAGE-718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction.

Potential Sources of Moral Injury for Healthcare Workers in Forensic and Psychiatric Settings: A Systematic Review and Meta-ethnography.

The current research examines potentially morally injurious events (PMIEs) faced by healthcare professionals working in forensic and psychiatric environments. A systematic literature review was conducted to identify peer-reviewed articles reporting on sources of moral injury or similar concepts (e.g., moral distress) for healthcare workers in such settings. Thirty articles were included and analyzed using a meta-ethnographic approach. Synthesis yielded three third-order factors, each reflecting a moral dichotomy: (a) "between profession and system," (b) "between relations with patients and relations with others," and (c) "between principles and practices." Findings illustrated the hierarchical relationships between dichotomies, with discordance between values of the healthcare profession and features of the healthcare system providing the conditions for PMIEs to occur. The review advances conceptual understandings of PMIEs in forensic and psychiatric settings, illustrating the multilayered dimensions within which morally injurious events are experienced. Theoretical and practical implications are offered that may support the early detection and prevention of moral injury in healthcare professionals.