On the proportion of patients who experience a prodrome prior to psychosis onset: A systematic review and meta-analysis.

BACKGROUND: Preventing or delaying the onset of psychosis requires identification of those at risk for developing psychosis. For predictive purposes, the prodrome - a constellation of symptoms which may occur before the onset of psychosis - has been increasingly recognized as having utility. However, it is unclear what proportion of patients experience a prodrome or how this varies based on the multiple definitions used. METHODS: We conducted a systematic review and meta-analysis of studies of patients with psychosis with the objective of determining the proportion of patients who experienced a prodrome prior to psychosis onset. Inclusion criteria included a consistent prodrome definition and reporting the proportion of patients who experienced a prodrome. We excluded studies of only patients with a prodrome or solely substance-induced psychosis, qualitative studies without prevalence data, conference abstracts, and case reports/case series. We searched Ovid MEDLINE, Embase (Ovid), APA PsycInfo (Ovid), Web of Science Core Collection (Clarivate), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, APA PsycBooks (Ovid), ProQuest Dissertation & Thesis, on March 3, 2021. Studies were assessed for quality using the Critical Appraisal Checklist for Prevalence Studies. Narrative synthesis and proportion meta-analysis were used to estimate prodrome prevalence. I2 and predictive interval were used to assess heterogeneity. Subgroup analyses were used to probe sources of heterogeneity. (PROSPERO ID: CRD42021239797). RESULTS: Seventy-one articles were included, representing 13,774 patients. Studies varied significantly in terms of methodology and prodrome definition used. The random effects proportion meta-analysis estimate for prodrome prevalence was 78.3% (95% CI = 72.8-83.2); heterogeneity was high (I2 97.98% [95% CI = 97.71-98.22]); and the prediction interval was wide (95% PI = 0.411-0.936). There were no meaningful differences in prevalence between grouped prodrome definitions, and subgroup analyses failed to reveal a consistent source of heterogeneity. CONCLUSIONS: This is the first meta-analysis on the prevalence of a prodrome prior to the onset of first episode psychosis. The majority of patients (78.3%) were found to have experienced a prodrome prior to psychosis onset. However, findings are highly heterogenous across study and no definitive source of heterogeneity was found despite extensive subgroup analyses. As most studies were retrospective in nature, recall bias likely affects these results. While the large majority of patients with psychosis experience a prodrome in some form, it is unclear if the remainder of patients experience no prodrome, or if ascertainment methods employed in the studies were not sensitive to their experiences. Given widespread investment in indicated prevention of psychosis through prospective identification and intervention during the prodrome, a resolution of this question as well as a consensus definition of the prodrome is much needed in order to effectively direct and organize services, and may be accomplished through novel, densely sampled and phenotyped prospective cohort studies that aim for representative sampling across multiple settings.

Antipsychotic drugs in first-episode psychosis: A target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in First Episode Psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts to emulate a target trial comparing antipsychotics with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from EUFEST, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone (95% CI) were: 61.5% (52.5-70.6), 73.5% (60.5-84.9), 76.8% (67.2-85.3), 58.4% (40.4-77.4), 76.5% (62.1-88.5), and 74.4% (67.0-81.2) respectively. Compared with aripiprazole, the 12-month risk differences (95% CI) were -15.3% (-30.0, 0.0) for olanzapine, -12.8% (-25.7, -1.0) for risperidone, and 3.0% (-21.5, 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration data sufficed to approximately remove confounding for these clinical questions.

Sex differences in schizophrenia-spectrum diagnoses: results from a 30-year health record registry.

This study investigated sociodemographic and clinical differences between the sexes in individuals affected by schizophrenia-spectrum disorders (SSD) who accessed outpatient mental health services. Within a retrospective cohort of 45,361 outpatients receiving care in Ferrara (Italy) from 1991 to 2021, those with a SSD diagnosis were compared between the sexes for sociodemographic and clinical characteristics before and after the index date (when the ICD-9: 295.*diagnosis was first recorded) to assess early trajectory, age and type of diagnosis, and severity of illness indicated by medication use, hospitalization, and duration of psychiatric care. Predictors of discharge were also investigated. Among 2439 patients, 1191 were women (48.8%). Compared to men, women were significantly older at first visit (43.7 vs. 36.8 years) and at index date (47.8 vs. 40.6) with peak frequency at age 48 (vs. 30). The most frequent last diagnosis recorded before the index date was delusional disorder (27.7%) or personality disorder (24.3%) in men and depression (24%) and delusional disorder (30.1%) in women. After the index date, long-acting antipsychotics and clozapine were more frequently prescribed to men (46.5% vs. 36.3%; 13.2% vs. 9.4%, p < 0.05) and mood stabilizers and antidepressants to women (24.3% vs. 21.1%; 50.1% vs. 35.5%; p < 0.05). Women had fewer involuntary admissions (10.1% vs. 13.6%) and were more likely to be discharged as the time under care increased (p = 0.009). After adjusting for covariates, sex was not a significant predictor of discharge. Our study confirmed that sex differences exist in clinical and sociodemographic characteristics of outpatients with SSD and that gender considerations might influence the rapidity of diagnosis and medications prescribed. These findings highlight the need to implement a women-tailored approach in specialist care programs for psychoses.

Trust matters: The Addressing Vaccine Hesitancy in Europe Study.

This article presents the design of a seven-country study focusing on childhood vaccines, Addressing Vaccine Hesitancy in Europe (VAX-TRUST), developed during the COVID-19 pandemic. The study consists of (a) situation analysis of vaccine hesitancy (examination of individual, socio-demographic and macro-level factors of vaccine hesitancy and analysis of media coverage on vaccines and vaccination and (b) participant observation and in-depth interviews of healthcare professionals and vaccine-hesitant parents. These analyses were used to design interventions aimed at increasing awareness on the complexity of vaccine hesitancy among healthcare professionals involved in discussing childhood vaccines with parents. We present the selection of countries and regions, the conceptual basis of the study, details of the data collection and the process of designing and evaluating the interventions, as well as the potential impact of the study. Laying out our research design serves as an example of how to translate complex public health issues into social scientific study and methods.

Application of Raman spectroscopy to the evaluation of F-actin changes in sea urchin eggs at fertilization.

The actin filaments on the surface of echinoderm oocytes and eggs readily undergo massive reorganization during meiotic maturation and fertilization. In sea urchin eggs, the actin cytoskeletal response to the fertilizing sperm is fast enough to accompany Ca2+ signals and to guide sperm's entry into the egg. Although recent work using live cell imaging technology confirmed changes in the actin polymerization status in fertilized eggs, as was previously shown using light and electron microscopy, it failed to provide experimental evidence of F-actin depolymerization a few seconds after insemination, which is concurrent with the sperm-induced Ca2+ release. In the present study, we applied Raman microspectroscopy to tackle this issue by examining the spectral profiles of the egg's subplasmalemmal regions before and after treating the eggs with actin drugs or fertilizing sperm. At both early (15 s) and late (15 min) time points after fertilization, specific peak shifts in the Raman spectra revealed change in the actin structure, and Raman imaging detected the cytoskeletal changes corresponding to the F-actin reorganization visualized with LifeAct-GFP in confocal microscopy. Our observation suggests that the application of Raman spectroscopy, which does not require microinjection of fluorescent probes and exogenous gene expression, may serve as an alternative or even advantageous method in disclosing rapid subtle changes in the subplasmalemmal actin cytoskeleton that are difficult to resolve.

Effects of electroconvulsive therapy on cortical thickness in depression: a systematic review.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most studied and validated available treatments for severe or treatment-resistant depression. However, little is known about the neural mechanisms underlying ECT. This systematic review aims to critically review all structural magnetic resonance imaging studies investigating longitudinal cortical thickness (CT) changes after ECT in patients with unipolar or bipolar depression. METHODS: We performed a search on PubMed, Medline, and Embase to identify all available studies published before April 20, 2023. A total of 10 studies were included. RESULTS: The investigations showed widespread increases in CT after ECT in depressed patients, involving mainly the temporal, insular, and frontal regions. In five studies, CT increases in a non-overlapping set of brain areas correlated with the clinical efficacy of ECT. The small sample size, heterogeneity in terms of populations, comorbidities, and ECT protocols, and the lack of a control group in some investigations limit the generalisability of the results. CONCLUSIONS: Our findings support the idea that ECT can increase CT in patients with unipolar and bipolar depression. It remains unclear whether these changes are related to the clinical response. Future larger studies with longer follow-up are warranted to thoroughly address the potential role of CT as a biomarker of clinical response after ECT.

Sustained improvement of intrinsic capacity in community-dwelling older adults: The +AGIL Barcelona multidomain program.

BACKGROUND: Different programs promote healthy ageing through the optimization of intrinsic capacity. However, a major challenge is to assess their sustained effects over time. +AGIL Barcelona, a consolidated multidomain program, aims to optimize older adults' intrinsic capacity through a coordinated approach among primary care, geriatrics and community resources, in agreement with the integrated care for older people (ICOPE) guidelines. We aimed to evaluate the +AGIL Barcelona longitudinal effect on older adults' physical performance. METHODS: All +AGIL Barcelona consecutive participants since 2016 were enrolled. After a comprehensive geriatric assessment, a tailored, multidisciplinary intervention aligned with the ICOPE guidelines is offered. It includes a 10-week boost multicomponent exercise program, nutritional and sleep-hygiene counselling, revision and optimization of pharmacological treatments and screening for cognitive impairment, depression and loneliness. Changes in physical performance after 3 and 6 months were assessed using mixed models including baseline frailty degree, time and all potential significant confounders. RESULTS: We included 194 participants in the analysis (mean age = 81.6 [standard deviation = 5.8], 68% women). An independent, clinically and statistically significant improvement in physical performance (Short Physical Performance Battery [SPPB] test, combining gait speed, strength and balance) was found at 3 months (SPPB mean change: 1.4; 95% CI: 1.1-1.6) and 6 months (SPPB mean change: 1.1; 95% CI 0.8-1.5). Equivalent results were observed for all the SPPB sub-tests. CONCLUSIONS: A coordinated, multidisciplinary and integrated program can benefit older adults' intrinsic capacity. The participants' empowerment and the connection with the available community resources are critical points for a successful intervention.

Poor sleep quality may contribute to dysfunctional illness perception, physical and emotional distress in hospitalised patients: results of a national survey of the Italian Society of Consultation-Liaison Psychiatry.

Distress associated with physical illness is a well-known risk factor for adverse illness course in general hospitals. Understanding the factors contributing to it should be a priority and among them dysfunctional illness perception and poor sleep quality may contribute to it. As poor sleep quality is recognised as a major risk factor for health problems, we aimed to study its association with illness perception and levels of distress during hospitalisation. This cross-sectional study included a consecutive series of 409 individuals who were hospitalised in medical and surgical units of different hospitals located throughout the Italian national territory and required an assessment for psychopathological conditions. Sleep quality was assessed with the Pittsburgh (Sleep Quality Index), emotional and physical distress with the Edmonton Symptom Assessment System (ESAS), and illness perception with the Brief Illness Perception Questionnaire (BIPQ). Differences between groups, correlations and mediations analyses were computed. Patients with poor sleep quality were more frequently females, with psychiatric comorbidity, with higher scores in the ESAS and BIPQ. Poor sleep quality was related to dysfunctional illness perception, and to both emotional and physical distress. In particular, by affecting cognitive components of illness perception, poor sleep quality may, directly and indirectly, predict high levels of distress during hospitalisation. Poor sleep quality may affect >70% of hospitalised patients and may favour dysfunctional illness perception and emotional/physical distress.Assessing and treating sleep problems in hospitalised patients should be included in the routine of hospitalised patients.

Countering vaccine hesitancy: a systematic review of interventions to strengthen healthcare professionals' action.

BACKGROUND: Vaccine hesitancy is relevant for healthcare professionals (HCPs) who face challenges in building trusting relationships with patients. Accordingly, the VAX-TRUST project has been developed to improve experiences of HCPs and patients dealing with vaccinations. To support VAX-TRUST, this work aimed to identify latest interventions targeted at HCPs to address hesitancy and increase vaccine uptake. METHODS: A systematic review was conducted according to PRISMA by searching PubMed, Scopus and Embase. The protocol was registered on PROSPERO. Articles were eligible if evaluated interventions directly targeted at HCPs/healthcare students. The search was run on 26 January 2022. Articles published in 2016 or after were included. RESULTS: A total of 17 492 records were identified; 139 articles were selected. Most articles were set in USA (n = 110). Over half had a pre-post design without a control group (n = 78). A total of 41 articles focused on single-component interventions, 60 on multi-component interventions involving only HCPs and/or students and 38 on multi-component interventions involving also other professionals. Main components were in-person education (n = 76), synchronous (n = 10) and asynchronous (n = 23) online learning, educational materials (n = 26), performance assessment and feedback (n = 33), electronic record changes (n = 30), role play/simulation (n = 21) and online games/apps (n = 5). Educational sessions were mainly about scientific update or communication. Outcomes of interventions were grouped in: vaccination rates (n = 69), knowledge (n = 32), attitudes (n = 26), confidence in counselling (n = 30) and acceptability (n = 16). CONCLUSIONS: Apps, gaming, role play/simulations could represent innovative interventions. This review highlighted the need of delving into communication strategies and using more robust evaluations, longer follow-up and standardized measurements.

Frailty and post-operative delirium influence on functional status in patients with hip fracture: the GIOG 2.0 study.

BACKGROUND: This study analyzes the effect of frailty and Post-Operative Delirium (POD) on the functional status at hospital discharge and at 4-month follow-up in patients with hip fracture (HF). METHODS: Multicenter prospective observational study of older patients with HF admitted to 12 Italian Orthogeriatric centers (July 2019-August 2022). POD was assessed using the 4AT. A 26-item Frailty Index (FI) was created using data collected on admission. The outcome measures were Cumulated Ambulation Score (CAS) ≤ 2 at discharge and a telephone-administered CAS ≤ 2 after 4 months. Poisson regression models were used to assess the effect of frailty and POD on outcomes. RESULTS: 984 patients (median age 84 years, IQR = 79-89) were recruited: 480 (48.7%) were frail at admission, 311 (31.6%) developed POD, and 158 (15.6%) had both frailty and POD. In a robust Poisson regression, frailty alone (Relative Risk, RR = 1.56, 95% Confidence Intervals, CI 1.19-2.04, p = 0.001) and its combination with POD (RR = 2.57, 95% CI 2.02-3.26, p < 0.001) were associated with poor functional status at discharge. At 4-month follow-up, the combination of frailty with POD (RR 3.65, 95% CI 1.85-7.2, p < 0.001) increased the risk of poor outcome more than frailty alone (RR 2.38, 95% CI 1.21-4.66, p < 0.001). CONCLUSIONS: POD development exacerbates the negative effect that frailty exerts on functional outcomes in HF patients.

Frailty and long-COVID: is COVID-19 responsible for a transition in frailty status among older adults who survived hospitalization for COVID-19?

BACKGROUND: There is a paucity of knowledge about the effects of COronaVIrus Disease-19 (COVID-19) on long-term frailty development or progression over time. AIM: This study aims to assess transitions in frailty status in older adults who survived hospitalization for COVID-19. METHODS: This is a longitudinal panel study. A multidisciplinary outpatient follow-up service was established since summer 2020, for the evaluation of individuals discharged alive, after hospitalization due to COVID-19. Frailty status was assessed in-hospital and at follow-up using the clinical frailty scale (CFS). Main patients' characteristics, including health, functional, cognitive, and psychological status were collected. RESULTS: A total of 177 patients aged 65 years and older were evaluated until June 2022. They were predominantly male, with a median age of 70 (Q1-Q3 67-75) years and a median body mass index of 27.5 (Q1-Q3 24.9-30.6) kg/m2 at hospital admission. The median follow-up time was 6.3 (Q1-Q3 3.7-10.9) months. Sixty-one patients (34.5%) scored worse at CFS follow-up compared to hospital admission, and twenty-two patients (12.4%) became frail. DISCUSSION AND CONCLUSION: This study shows that one out of three older patients previously hospitalized for COVID-19 had an unfavorable transition in CFS score during a median follow-up of nearly 6 months. Specific interventions to prevent frailty development or progression should be considered for patients at risk. Further studies are required to confirm our findings.

Neural cell-derived plasma exosome protein abnormalities implicate mitochondrial impairment in first episodes of psychosis.

Neuroprotective and other functional proteins of mitochondria were quantified in extracts of plasma neural-derived exosomes from ten first-episode psychosis (FP) patients and ten matched psychiatrically normal controls (ctls). Astrocyte-derived extracellular vesicles (ADEVs) and neuron-derived extracellular vesicles (NDEVs) were immunoabsorbed separately from physically precipitated plasma total EVs. Extracted mitochondrial ATP synthase was specifically immunofixed to plastic wells for quantification of catalytic activity based on conversion of NADH to NAD+ . Other extracted mitochondrial functional proteins were quantified by ELISAs. All protein levels were normalized with EV content of the CD81 exosome marker. FP patient ADEV level but not NDEV level of mitochondrial ATP synthase activity was significantly lower than that of ctls. FP patient ADEV and NDEV levels of the functionally critical mitochondrial proteins mitofusin 2 and cyclophilin D, but not of transcription factor A of mitochondria, and of the mitochondrial short open-reading frame neuroprotective and metabolic regulatory peptides humanin and MOTS-c were significantly lower than those of ctls. In contrast, FP patient NDEV, but not ADEV, level of the mitochondrial-tethering protein syntaphilin, but not of myosin VI, was significantly higher than that of ctls. The distinctively different neural levels of some mitochondrial proteins in FP patients than ctls now should be correlated with diverse clinical characteristics. Drugs that increase depressed levels of proteins and mimetics of deficient short open-reading frame peptides may be of therapeutic value in early phases of schizophrenia.

Debating Euthanasia and Physician-Assisted Death in People with Psychiatric Disorders.

PURPOSE OF REVIEW: Over the last 30 years, medical assistance in dying (MAiD) including euthanasia (EU) and physician-assisted death (or suicide, PAS) has become the center of a large debate, particularly when these practices have involved people with psychiatric illness, including resistant depression, schizophrenia, personality, or other severe psychiatric disorders. We performed a review utilizing several databases, and by including the most relevant studies in full journal articles investigating the problem of MAiD in patients with psychiatric disorders but not in physical terminal conditions (non-terminal, MAiD-NT). RECENT FINDINGS: Literature has shown that a small percentage of people with psychiatric disorders died by MAiD-NT in comparison with patients with somatic diseases in terminal clinical conditions (e.g., cancer, AIDS). However, the problem in the field is complex and not solved yet as confirmed by the fact that only a few countries (e.g., the Netherlands, Belgium, Luxemburg) have legalized MAiD-NT for patients with psychiatric disorders, while most have maintained the practices accessible only to people with somatic disease in a terminal phase. Also, how to make objective the criterion of irremediability of a mental disorder; how to balance suicide prevention with assisted suicide; how to avoid the risk of progressively including in requests for MAiD-NT vulnerable segments of the population, such as minors, elderly, or people with dementia, in a productive-oriented society, are some of the critical points to be discussed. The application of MAiD-NT in people with psychiatric disorders should be further explored to prevent end-of-life rights from contradicting the principles of recovery-oriented care.

Machine Learning and Non-Affective Psychosis: Identification, Differential Diagnosis, and Treatment.

PURPOSE OF REVIEW: This review will cover the most relevant findings on the use of machine learning (ML) techniques in the field of non-affective psychosis, by summarizing the studies published in the last three years focusing on illness detection and treatment. RECENT FINDINGS: Multiple ML tools that include mostly supervised approaches such as support vector machine, gradient boosting, and random forest showed promising results by applying these algorithms to various sources of data: socio-demographic information, EEG, language, digital content, blood biomarkers, neuroimaging, and electronic health records. However, the overall performance, in the binary classification case, varied from 0.49, which is to be considered very low (i.e., noise), to over 0.90. These results are fully justified by different factors, some of which may be attributable to the preprocessing of the data, the wide variety of the data, and the a-priori setting of hyperparameters. One of the main limitations of the field is the lack of stratification of results based on biological sex, given that psychosis presents differently in men and women; hence, the necessity to tailor identification tools and data analytic strategies. Timely identification and appropriate treatment are key factors in reducing the consequences of psychotic disorders. In recent years, the emergence of new analytical tools based on artificial intelligence such as supervised ML approaches showed promises as a potential breakthrough in this field. However, ML applications in everyday practice are still in its infancy.

Mortality from cancer in people with severe mental disorders in Emilia Romagna Region, Italy.

OBJECTIVE: To examine cancer-related mortality in patients with severe mental disorders (SMI) in the Emilia Romagna (ER) Region, Northern Italy, during the period 2008-2017 and compare it with the regional population. METHODS: We used the ER Regional Mental Health Registry identifying all patients aged ≥18 years who had received an ICD-9CM system diagnosis of SMI (i.e., schizophrenia or other functional psychosis, mania, or bipolar affective disorders) during a 10-year period (2008-2017). Information on deaths (date and causes of death) were retrieved through the Regional Cause of Death Registry. Comparisons were made with the deaths and cause of deaths of the regional population over the same period. RESULTS: Amongst 12,385 patients suffering from SMI (64.1% schizophrenia spectrum and 36.9% bipolar spectrum disorders), 24% (range 21%-29%) died of cancer. In comparison with the general regional population, the mortality for cancer was about 50% higher among patients with SMI, irrespective if affected by schizophrenia or bipolar disorders. As for the site-specific cancers, significant excesses were reported for stomach, central nervous system, respiratory, and pancreas cancer with a variability according to psychiatric diagnosis and gender. CONCLUSIONS: Patients suffering from SMI had higher mortality risk than the regional population with some differences according to cancer type, gender, and psychiatric diagnosis. Proper cancer preventive and treatment interventions, including more effective risk modification strategies (e.g., smoking cessation, dietary habits) and screening for cancer, should be part of the agenda of all mental health departments in conjunction with other health care organizations, including psycho-oncology.

Frailty, post-operative delirium and functional status at discharge in patients with hip fracture.

OBJECTIVE: To explore the effect of frailty, alone and in combination with post-operative delirium (POD), on the risk of poor function at discharge in patients with hip fracture (HF). METHODS: This is a prospective cohort study of patients with HF admitted to an Orthogeriatric Unit (OGU) between October 1, 2011 and March 15, 2019. POD was assessed using the 4AT and the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5-edition criteria. A 22-items Frailty Index (FI) was created using the data collected on admission. The outcome measure was the Cumulated Ambulation Score (CAS) score at discharge. A log-binomial regression model was used to assess the effect of frailty and POD on CAS. RESULTS: A total of 988 patients (median age = 84.9 years, Interquartile range = 80.6-89.2) were included: 360 patients (36.4%) were frail and 411 (42%) developed POD. Poor functional status at discharge (CAS score ≤2) was more common in frail than non-frail patients (68.3% vs. 53.8%, p < 0.001) In a regression adjusted for confounders, frailty alone (Relative Risk, RR = 1.33, 95% Confidence Intervals, CI = 1.14-1.55) and POD alone (RR 1.38, 95% CI = 1.2-1.59) were associated with poor functional status at discharge; when combined, frailty and POD had an interaction, yielding a mild increase in the risk of poor outcome (RR 1.47, 95% CI = 1.28-1.69). CONCLUSIONS: In older patients undergoing HF surgery, frailty, POD and their combination, are associated with poor functional status at discharge.

First help-seeking attempt before and after psychosis onset: measures of delay and aversive pathways to care.

PURPOSE: Delay in receiving effective treatment for psychosis adversely impacts outcomes. We investigated the timing of the first help-seeking attempt in individuals with recent onset non-affective psychosis by comparing those who sought help during the prodrome to those who sought help after psychosis onset across sociodemographic and clinical characteristics, overall functioning, and occurrence of aversive events during their pathways to care. METHODS: Patients were admitted from February 1st, 2014 to January 31st, 2019 to the Program for Specialized Treatment Early in Psychosis (STEP) in New Haven, CT. Psychosis-onset date was ascertained using the Structured Interview for Psychosis-risk Syndromes. Key dates before and after psychosis onset, along with initiators and aversive events, were collected via semi-structured interview. RESULTS: Within 168 individuals, 82% had their first help-seeking episode after psychosis onset and did not differ in terms of sociodemographic characteristics from prodrome help seekers. When the first help-seeking episode started before (i.e., during prodrome) vs after psychosis onset it was mostly initiated by patients vs family members (Cramer's V = 0.23, p = 0.031) and led to a faster prescription of an antipsychotic once full-blown psychosis emerged (time to antipsychotic since psychosis onset = 21 vs 56 days, p = 0.03). No difference in aversive events before STEP enrollment was detected across groups. CONCLUSION: Help seeking during the prodrome is associated with faster initiation of antipsychotic treatment and is more likely to be self-initiated, compared to help seeking after psychosis onset. Early detection efforts that target prodromal samples may improve the length and experience of pathways to care.

Carnitine is a pharmacological allosteric chaperone of the human lysosomal α-glucosidase.

Pompe disease is an inherited metabolic disorder due to the deficiency of the lysosomal acid α-glucosidase (GAA). The only approved treatment is enzyme replacement therapy with the recombinant enzyme (rhGAA). Further approaches like pharmacological chaperone therapy, based on the stabilising effect induced by small molecules on the target enzyme, could be a promising strategy. However, most known chaperones could be limited by their potential inhibitory effects on patient's enzymes. Here we report on the discovery of novel chaperones for rhGAA, L- and D-carnitine, and the related compound acetyl-D-carnitine. These drugs stabilise the enzyme at pH and temperature without inhibiting the activity and acted synergistically with active-site directed pharmacological chaperones. Remarkably, they enhanced by 4-fold the acid α-glucosidase activity in fibroblasts from three Pompe patients with added rhGAA. This synergistic effect of L-carnitine and rhGAA has the potential to be translated into improved therapeutic efficacy of ERT in Pompe disease.

ASP-Enzymosomes with Saccharomyces cerevisiae Asparaginase II Expressed in Pichia pastoris: Formulation Design and In Vitro Studies of a Potential Antileukemic Drug.

The bacterial enzyme asparaginase is the main treatment option for acute lymphoblastic leukemia. However, it causes side effects, such as immunological reactions, and presents undesirable glutaminase activity. As an alternative, we have been studying asparaginase II from Saccharomyces cerevisiae, coded by ASP3 gene, which was cloned and expressed in Pichia pastoris. The recombinant asparaginase (ASP) presented antileukemic activity and a glutaminase activity 100 times lower in comparison to its asparaginase activity. In this work, we describe the development of a delivery system for ASP via its covalent attachment to functionalized polyethylene glycol (PEG) polymer chains in the outer surface of liposomes (ASP-enzymosomes). This new delivery system demonstrated antiproliferative activity against K562 (chronic myeloid leukemia) and Jurkat (acute lymphocytic leukemia) cell lines similar to that of ASP. The antiproliferative response of the ASP-enzymosomes against the Jurkat cells suggests equivalence to that of the free Escherichia coli commercial asparaginase (Aginasa®). Moreover, the ASP-enzymosomes were stable at 4 °C with no significant loss of activity within 4 days and retained 82% activity up to 37 days. Therefore, ASP-enzymosomes are a promising antileukemic drug.