A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial.

AIM: We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. METHODS AND RESULTS: We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference -1.37 (95% confidence interval: -2.63 to -0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. CONCLUSION: Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.

Using matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling in order to predict clinical outcomes of patients with heart failure.

BACKGROUND: Current risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF. METHODS: A cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs. 50 patients who did not have an event). The peptide extraction from plasma samples was performed using reversed phase C18. Then samples were analysed using MALDI-MS. A multiple peptide biomarker model was discovered that was able to predict clinical outcomes for patients with HF. Finally, this model was validated in an independent cohort with 100 patients with HF. RESULTS: After normalisation and alignment of all the processed spectra, a total of 11,389 peptides (m/z) were detected using MALDI-MS. A multiple biomarker model was developed from 14 plasma peptides that was able to predict clinical outcomes in HF patients with an area under the receiver operating characteristic curve (AUC) of 1.000 (p = 0.0005). This model was validated in an independent cohort with 100 HF patients that yielded an AUC of 0.817 (p = 0.0005) in the biomarker validation phase. Addition of this model to the BIOSTAT risk prediction model increased the predictive probability for clinical outcomes of HF from an AUC value of 0.643 to an AUC of 0.823 (p = 0.0021). Moreover, using the prediction model of fourteen peptides and the composite model of the multiple biomarker of fourteen peptides with the BIOSTAT risk prediction model achieved a better predictive probability of time-to-event in prediction of clinical events in patients with HF (p = 0.0005). CONCLUSIONS: The results obtained in this study suggest that a cluster of plasma peptides using MALDI-MS can reliably predict clinical outcomes in HF that may help enable precision medicine in HF.

Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status.

RATIONALE: The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood. OBJECTIVE: Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties. METHODS AND RESULTS: In primary hepatocytes from healthy animals, metformin and the IKKß (inhibitor of kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-α-dependent IκB degradation and expression of proinflammatory mediators interleukin-6, interleukin-1ß, and CXCL1/2 (C-X-C motif ligand 1/2). Metformin suppressed IKKα/ß activation, an effect that could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production, and AMP-activated protein kinase activation. Equally AMP-activated protein kinase was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages, metformin specifically blunted secretion of proinflammatory cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naive diabetes mellitus population cohort, we observed differences in the systemic inflammation marker, neutrophil to lymphocyte ratio, after incident treatment with either metformin or sulfonylurea monotherapy. Compared with sulfonylurea exposure, metformin reduced the mean log-transformed neutrophil to lymphocyte ratio after 8 to 16 months by 0.09 U (95% confidence interval, 0.02-0.17; P=0.013) and increased the likelihood that neutrophil to lymphocyte ratio would be lower than baseline after 8 to 16 months (odds ratio, 1.83; 95% confidence interval, 1.22-2.75; P=0.00364). Following up these findings in a double-blind placebo controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin suppressed plasma cytokines including the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). CONCLUSION: We conclude that anti-inflammatory properties of metformin are exerted irrespective of diabetes mellitus status. This may accelerate investigation of drug utility in nondiabetic cardiovascular disease groups. CLINICAL TRIAL REGISTRATION: Name of the trial registry: TAYSIDE trial (Metformin in Insulin Resistant Left Ventricular [LV] Dysfunction). URL: https://www.clinicaltrials.gov. Unique identifier: NCT00473876.

Identification of novel biomarkers in plasma for prediction of treatment response in patients with heart failure.

BACKGROUND: Heart failure is a complex clinical syndrome that occurs at the end stage of heart disease. Despite advances in therapy for heart failure, improvement of clinical outcomes remains a challenge for physicians. The identification of treatment response early in the course of disease would be useful to improve management of these patients. The aim of this study was to identify novel biomarkers in plasma that could predict treatment response in patients with heart failure. METHODS: Patients with heart failure who met inclusion and exclusion criteria according to the guidelines of the European Society of Cardiology were recruited. Uptitration of angiotensin-converting enzyme inhibitors and ß blockers was performed over 6 months. Patients were followed up for clinical events within the next 24 months. Plasma proteins in patients who responded to standard treatment (responders) were compared with patients who died or were re-admitted for heart failure (non-responders). Plasma samples were depleted of 14 high abundance proteins with a multiple affinity removal system column (MARS). Then plasma samples were analysed on two-dimensional liquid chromatography coupled to a tandem mass spectrometry (2D LC-ESI-MS/MS) in high definition mode (HDMS(E)) to identify and quantify the different expression of proteins in plasma. Finally, ELISA was used to verify candidate biomarkers. FINDINGS: Participants were 100 patients with heart failure matched for sex and age (50 responders [25 women], 50 non-responders [25 women], mean age 76·6 years [SD 8·1]). Of the non-responders, 18 died and 32 were re-admitted to hospital. 2D LC-ESI-MS/MS showed that the expression of neurotrimin (NTM) was highly upregulated, by 26·5 times (p<0·0001), in the responder group compared with the non-responder group. ELISA in the verification phase showed that the concentrations of NTM in plasma were significantly higher in the responders and lower in the non-responders (mean 4·73 log10 relative light units [SD 0·07] vs 4·70 [0·08], p=0·036). When ANOVA with Bonferroni post-hoc comparisons was used in three outcome subgroups (responders, patients re-admitted to hospital, and deaths), NTM concentrations were significantly different between death and the other groups (higher in responder vs death group, p<0·0001; higher in re-admission vs death group, p=0·001). INTERPRETATION: Our findings suggest that NTM as a novel biomarker in heart failure will not only add information to understand the pathophysiological mechanisms of heart failure better, but also might provide a more accurate prediction of treatment response to guide medical therapy. In addition, a novel therapeutic target could be identified for design of drugs to improve outcomes. Futher work is required in larger populations to confirm this biomarker. FUNDING: European Union's Seventh Framework Programme (BIOSTAT-CHF), John and Lucille van Geest Foundation.

Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design.

BACKGROUND: Heart failure (HF) and diabetes (DM) are a lethal combination. The current armamentarium of anti-diabetic agents has been shown to be less efficacious and sometimes even harmful in diabetic patients with concomitant cardiovascular disease, especially HF. Sodium glucose linked co-transporter type 2 (SGLT2) inhibitors are a new class of anti-diabetic agent that has shown potentially beneficial cardiovascular effects such as pre-load and after load reduction through osmotic diuresis, blood pressure reduction, reduced arterial stiffness and weight loss. This has been supported by the recently published EMPA-REG trial which showed a striking 38 and 35 % reduction in cardiovascular death and HF hospitalisation respectively. METHODS: The REFORM trial is a novel, phase IV randomised, double blind, placebo controlled clinical trial that has been ongoing since March 2015. It is designed specifically to test the safety and efficacy of the SLGT2 inhibitor, dapagliflozin, on diabetic patients with known HF. We utilise cardiac-MRI, cardio-pulmonary exercise testing, body composition analysis and other tests to quantify the cardiovascular and systemic effects of dapagliflozin 10 mg once daily against standard of care over a 1 year observation period. The primary outcome is to detect the change in left ventricular (LV) end systolic and LV end diastolic volumes. The secondary outcome measures include LV ejection fraction, LV mass index, exercise tolerance, fluid status, quality of life measures and others. CONCLUSIONS: This trial will be able to determine if SGLT2 inhibitor therapy produces potentially beneficial effects in patients with DM and HF, thereby replacing current medications as the drug of choice when treating patients with both DM and HF. Trial registration Clinical Trials.gov: NCT02397421. Registered 12th March 2015.

Pilot study to test the feasibility and clinical efficacy of a psychosocial care programme for patients with psychosis in low-resource settings.

BACKGROUND: Home-based psychosocial care has the potential to improving outcomes in patients with schizophrenia and related disorders (SCZ). There is lack of India data for such care in early psychosis. We developed the "Saksham" programme, a bespoke self-managed home-based psychosocial care model, available in two formats: manual-based and mobile-application based. With the anticipated success of recruitment of early psychosis cases in our setting, we plan to test the such intervention in this population in future trials. AIM: To assess the feasibility of the Saksham programme intervention in people with SCZ and its clinical efficacy as an adjunct to treatment as usual. METHODS: Seventy-five patient-caregiver pairs (total n=150) were recruited. Patients received either: treatment-as-usual (TAU) (n=25), manual-based Saksham intervention+TAU (n=25), or app-based Saksham intervention+TAU (n=25). Feasibility (i.e. acceptability, practicality, demand, implementation and integration) was assessed at three-months. Participants were assessed for psychopathology, illness-severity, cognition, functioning, disability, and caregiver-coping at baseline, one-month, and three-month. The percentage changes over time were compared across three groups. RESULTS: More found the mobile application-based intervention acceptable and easy-to-use than the manual-based intervention (92 % vs 68 %, and 76 % vs 68 %, respectively). Psychopathology and caregiver-burden improved significantly in all three groups (p<0.05). Cognition, disability, functioning, and caregiver burden improved significantly in the two Saksham intervention groups, with greater improvement in the Saksham app group (p<0.05). CONCLUSION: Home-based intervention is feasible and acceptable in a low-resource setting, with preliminary evidence for effectiveness. These findings need corroboration with randomised controlled trials in early psychosis to ameliorate course of illness.

Development and validation of home-based psychosocial self-management interventions in schizophrenia and related disorders in low-resource settings: A mixed methods approach.

Background: Psychosocial interventions, crucial for recovery in patients with schizophrenia, have often been developed and tested in high income countries. We aimed at developing and validating home-based a booklet based psycho-social intervention with inputs from stakeholders: patients, families, and mental health professionals (MHP) for patients with schizophrenia and related disorders in low resource settings. Methods: We developed a preliminary version of psychosocial intervention booklets based on six themes derived from focus group discussions conducted with patients, families, and MHP. Initially, quantitative assessment of content validity was done by MHP on overall and Content Validity Index of individual items of the specific booklets, followed by in-depth interviews about their views. The booklets were modified based on their inputs. Further, pilot testing of manuals was done on the users - nine pairs of patients and caregivers followed by development of a final version of psycho-social intervention. Results: The percentage content validity of individual modules and overall booklets was ≥78.5% indicating good validity. Most MHP reported that the manuals were relevant and easy to use but were text-heavy, and lengthy. On pilot testing of modified manuals with patients and their family caregivers, majority (77.8%) of them found booklets useful and suggested that there should be separate booklets for both patients and caregivers for providing information and entering separate response for the activities, integrating helpful tips. Language should be simple. Finally, two sets of booklets ("info book" and "workbook") named 'Saksham' (meaning empowered) were created with specific modules (viz., 'Medicine adherence', 'Daily routine', 'Eating right', 'Physical activity', 'Physical health monitoring', 'Self-reliance', and 'Psychoeducation') for patients and caregivers each, in two languages (Hindi and English). Conclusion: Booklets with modules for psychosocial interventions for patients with schizophrenia and their caregivers were developed after establishing content validity and pilot testing.

Qualitative study to explore the perspectives and mental health experiences of first episode psychosis patients and their caregivers in North India.

BACKGROUND: The onset of psychosis brings unfamiliar experiences that can be disturbing for patients and their caregivers. Few studies from India (only one from North India) have examined these experiences from the perspective of the patient and caregiver. We explored experiences of first episode psychosis (FEP) patients and their caregivers within a North Indian context. METHOD: Semi-structured interviews were conducted in 2019 with ten FEP patients and their caregivers (total n=20) receiving out-patient care in a tertiary care centre. Topic guides focused on concerns/complaints, symptoms, help-seeking, and barriers and facilitators to treatment. Interviews were audio recorded, transcribed, and analysed using qualitative content analysis. RESULTS: Main categories of responses from patients and caregivers included: initial complaints for seeking help, initial emotional response, barriers to seeking treatment, perceived dysfunction and improvement, experienced stigma, understanding about illness, early follow-up, preventive measures and awareness programs. Caregivers undergo myriad of emotional reactions including anger, anxiety, guilt, and confusion. Symptoms other than psychotic symptoms were the primary complaint upon seeking help, and there was lack of understanding about the psychosocial model of care (role of medications acknowledged with little awareness regarding psychosocial interventions in recovery). Persisting occupational dysfunction despite perceived symptomatic improvement was described by both patients and caregivers. CONCLUSION: North Indian patients with FEP lack awareness of symptoms. Therefore, onus for seeking help often falls on their caregivers. Psychoeducation from first contact with services and increasing awareness about psychotic illness within the community might help address lack of awareness about symptoms, mental health services, early signs of relapse, and importance of psychosocial interventions in achieving functional recovery.

Protocol-based assessment and management of first episode psychosis: Comparison of short and medium-term outcomes in psychopathology, quality of life, functioning and family burden across two sites in India.

BACKGROUND: Standard assessment and management protocols exist for first episode psychosis (FEP) in high income countries. Due to cultural and resource differences, these need to be modified for application in low-and middle-income countries. AIMS: To assess the applicability of standard assessment and management protocols across two cohorts of FEP patients in North and South India by examining trajectories of psychopathology, functioning, quality of life and family burden in both. METHOD: FEP patients at two sites (108 at AIIMS, North India, and 115 at SCARF, South India) were assessed using structured instruments at baseline, 3, 6 and 12 months. Standard management protocols consisted of treatment with antipsychotics and psychoeducation for patients and their families. Generalised estimating equation (GEE) modelling was carried out to test for changes in outcomes both across and between sites at follow-up. RESULTS: There was an overall significant improvement in both cohorts for psychopathology and other outcome measures. The trajectories of improvement differed between the two sites with steeper improvement in non-affective psychosis in the first three months at SCARF, and affective symptoms in the first three months at AIIMS. The reduction in family burden and improvement in quality of life were greater at AIIMS than at SCARF during the first three months. CONCLUSIONS: Despite variations in cultural contexts and norms, it is possible to implement FEP standard assessment and management protocols in North and South India. Preliminary findings indicate that FEP services lead to significant improvements in psychopathology, functioning, quality of life, and family burden within these contexts.

Designing and implementing a physical exercise intervention for people with first episode psychosis using experience-based co-design: A pilot study from Chennai, India.

BACKGROUND: Physical exercise can improve outcomes for people with first-episode psychosis (FEP). Co-designing physical exercise interventions with end users has the potential to enhance their acceptability, feasibility, and long-term viability. This study's objective was to use experience-based co-design (EBCD) methodology to develop a physical exercise intervention for FEP, and pilot test it. METHODS: The study was conducted at the Schizophrenia Research Foundation's FEP program in Chennai, India. Participants(N=36) were individuals with FEP and their caregivers, mental health professionals (MHPs, and physical training experts. EBCD methodology included one-to-one interviews, focus group discussions, joint conferences, and co-design workshops. Two instructional videos were developed. Twelve FEP patients engaged in physical exercise with help of the videos over three months. They were followed up through weekly phone calls and in-person interviews to capture data on regularity, frequency, location of exercise, and comfort levels. RESULTS: Several touch points emerged from the interviews, focus groups, and joint meetings including lack of motivation, knowledge about physical exercise; differing perspectives about physical exercise; limited resource, and time constraints. Two instructional videos demonstrating activities for participants incorporated strategies that addressed these touch points. Pilot data indicated that participants engaged with the physical exercise intervention over 3 months. CONCLUSION: This was the first study to use co-design methodology to design a physical exercise intervention for first-episode psychosis. The intervention may have therefore been responsive to stakeholder needs and preferences. Results of this study highlight the potential of co-design in designing and adapting interventions. There is need for rigorous testing with larger samples.

Effectiveness of a mental health literacy module on stigma related mental health knowledge and behaviour among youth in two educational settings in Chennai, South India: A quasi-experimental study.

BACKGROUND: Improving mental health literacy (MHL) can reduce stigma towards mental illness, decreasing delays in help-seeking for mental disorders such as psychosis. We aimed to develop and assess the impact of an interactive MHL intervention on stigma related mental health knowledge and behaviour (SRMHKB) among youth in two urban colleges in South India. METHODS: Incorporating input from stakeholders (students, teachers, and mental health professionals), we developed a mental health literacy module to address SRMHKB. The module was delivered as an interactive session lasting 90 min. We recruited 600 (300 males; 300 females; mean age 19.6) participants from two city colleges in Chennai from Jan-Dec 2019 to test the MHL module. We assessed SRMHKB before the delivery of the MHL intervention, immediately after, and at 3 and 6 months after the intervention using the Mental Health Knowledge Schedule (MAKS) and Reported and Intended Behaviour Scale (RIBS). We used generalised estimating equations (GEE) to assess the impact of the intervention over time. RESULTS: Compared to baseline, there was a statistically significant increase in stigma related knowledge and behaviour immediately after the intervention (coefficient=3.8; 95% CI: 3.5,4.1) and during the 3-month (coefficient=3.4; 95% CI: 3.0,3.7) and 6-month (coefficient=2.4; 95% CI: 2.0,2.7) follow-up. CONCLUSION: Preliminary findings suggest that a single 90-minute MHL interactive session could lead to improvements in SRMHKB among youth in India. Future research might utilise randomised controlled trials to corroborate findings, and explore how improvements can be sustained over the longer-term.

Development of adolescent mental health services in Sri Lanka.

Sri Lanka has faced two major catastrophes in recent history: the civil war (1983-2009) and the tsunami (2004). Furthermore, there is a continuously changing socioeconomic situation which is becoming ever more challenging. Nearly a quarter of the Sri Lankan population is a youth or adolescent, and this age group is particularly vulnerable to adversity. Over the past decade Sri Lanka has acknowledged the need to support these young people and embarked on developing adolescent mental health services, but they require further expansion. This article provides a critical review of the state of current adolescent mental health services in our country and makes suggestions for improvement.

Pathways to care in first-episode psychosis in low-resource settings: Implications for policy and practice.

OBJECTIVE: Developing countries such as India face a major mental health care gap. Delayed or inadequate care can have a profound impact on treatment outcomes. We compared pathways to care in first episode psychosis (FEP) between North and South India to inform solutions to bridge the treatment gap. METHODS: Cross-sectional observation study of 'untreated' FEP patients (n = 177) visiting a psychiatry department in two sites in India (AIIMS, New Delhi and SCARF, Chennai). We compared duration of untreated psychosis (DUP), first service encounters, illness attributions and socio-demographic factors between patients from North and South India. Correlates of DUP were explored using logistic regression analysis (DUP ≥ 6 months) and generalised linear models (DUP in weeks). RESULTS: Patients in North India had experienced longer DUP than patients in South India (ß = 17.68, p < 0.05). The most common first encounter in North India was with a faith healer (45.7%), however, this contact was not significantly associated with longer DUP. Visiting a faith healer was the second most common first contact in South India (23.6%) and was significantly associated with longer DUP (Odds Ratio: 6.84; 95% Confidence Interval: 1.77, 26.49). Being in paid employment was significantly associated with shorter DUP across both sites. CONCLUSIONS: Implementing early intervention strategies in a diverse country like India requires careful attention to local population demographics; one size may not fit all. A collaborative relationship between faith healers and mental health professionals could help with educational initiatives and to provide more accessible care.

Amino acid homeostasis is a target of metformin therapy.

OBJECTIVE: Unexplained changes in regulation of branched chain amino acids (BCAA) during diabetes therapy with metformin have been known for years. Here we have investigated mechanisms underlying this effect. METHODS: We used cellular approaches, including single gene/protein measurements, as well as systems-level proteomics. Findings were then cross-validated with electronic health records and other data from human material. RESULTS: In cell studies, we observed diminished uptake/incorporation of amino acids following metformin treatment of liver cells and cardiac myocytes. Supplementation of media with amino acids attenuated known effects of the drug, including on glucose production, providing a possible explanation for discrepancies between effective doses in vivo and in vitro observed in most studies. Data-Independent Acquisition proteomics identified that SNAT2, which mediates tertiary control of BCAA uptake, was the most strongly suppressed amino acid transporter in liver cells following metformin treatment. Other transporters were affected to a lesser extent. In humans, metformin attenuated increased risk of left ventricular hypertrophy due to the AA allele of KLF15, which is an inducer of BCAA catabolism. In plasma from a double-blind placebo-controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin caused selective accumulation of plasma BCAA and glutamine, consistent with the effects in cells. CONCLUSIONS: Metformin restricts tertiary control of BCAA cellular uptake. We conclude that modulation of amino acid homeostasis contributes to therapeutic actions of the drug.

Suicidality Treatment Occurring in Paediatrics (STOP) Medication Suicidality Side Effects Scale in young people in two cohorts across Europe.

OBJECTIVES: As part of the 'Suicidality: Treatment Occurring in Paediatrics (STOP)' study, we developed and performed psychometric validation of an electronic-clinical-outcome-assessment (eCOA), which included a patient-reported-outcome (ePRO), an observer-rated-outcome (eObsRO) for parents/carers and a clinician-reported-outcome (eClinRO) that allows identification and monitoring of medication-related suicidality (MRS) in adolescents. DESIGN: STOP: Prospective study: A two phase validation study to assess the impact of medication on suicidal ideations. SETTING: Six participating countries: Netherlands, UK, Germany, France, Spain and Italy that were part of the Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261411. PARTICIPANTS: Cohort 1 consisted of 41 adolescent-completions, 50 parent-completions and 56 clinician-completions. Cohort 2 consisted of 244 adolescent-completions, 198 parent-completions and 240 clinician-completions from across the six countries. The scale was administered only to participants who have screened positive for the STOP-Suicidality Assessment Scale (STOP-SAS). RESULTS: A total of 24 items for the development of the STOP-Medication Suicidality Side Effects Scale (STOP-MS3) were identified and three versions (for patients, parents and clinicians) of the STOP-MS3 were developed and validated in two separate study cohorts comprising of adolescents, their parents and clinicians. Cronbach's α coefficients were above 0.85 for all domains. The inter-rater reliability of the STOP-MS3 was good and significant for the adolescent (ePRO), clinician (eClinRO) (r=0.613), parent (eObsRO) versions of the scale (r=0.394) and parent and clinician (r=0.347). Exploratory factor analysis identified a 3-factor model across 24 items for the adolescent and parent version of the scale: (1) Emotional Dysregulation, (2) Somatic Dysregulation and (3) Behavioural Dysregulation. For the clinician version, a 4-factor model defined the scale structure: (1) Somatic Dysregulation, (2) Emotional Dysregulation, (3) Behavioural Dysregulation and (4) Mood Dysregulation. CONCLUSION: These findings suggest that the STOP-MS3 scale, a web-based eCOA, allows identification and monitoring of MRS in the adolescent population and shows good reliability and validity.

Understanding needs of stakeholders and outcomes desired from a home-based intervention program for "difficult to treat" schizophrenia and related disorders: A qualitative study.

Background: We aimed to understand the needs of service users - families and patients with schizophrenia and related disorders, and mental health professionals (MHPs) and expectations from a home-based psychosocial intervention program in Indian setting. Materials and Methods: We conducted four focus group discussions (FGDs) with families, patients with schizophrenia and related disorders and MHPs. Two FGDs were conducted with families and one each with the patients and MHPs. Participants in families and MHP group were asked about their primary concerns in caring for the patients, perceived needs of patients and the areas that can be targeted through a home-based psychosocial intervention program. All FGDs were audio-recorded and verbatim transcribed. Content analysis of the data was done to obtain a final list of needs and expected outcomes from a psychosocial intervention supported by families. Results: Six key priority needs were identified for intervention: medication adherence, activities of daily living, promoting physical health, engagement in meaningful work, building of social and support networks and information about all aspects of illness. Priority outcomes identified by MHPs were mostly clinical like symptom reduction, fewer rehospitalisation while families and patients focused more on psychosocial outcomes, such as improvement of wellbeing, having relationships, engagement in meaningful activities, better organization of the day, increased self-respect, reduced stress, lesser interference, and critical comments. All groups suggested that book or mobile app or video could be used. Conclusion: This qualitative study shows that while both clinicians and service users consider recovery from schizophrenia and related disorders to be important, they differ on what they prioritise.

Psychosocial interventions for people with a first episode psychosis: between tradition and innovation.

PURPOSE OF REVIEW: Assessing recent evidence on psychosocial interventions for people with first episode psychosis (FEP). RECENT FINDINGS: Family interventions (FI) reduce relapse rates, whilst cognitive behavioural therapy (CBT) shows a moderate effect in improving positive psychotic symptoms. Vocational interventions (VI) appear to be worthy of implementation within early intervention for psychosis (EIP) teams, but it is still unclear what is the most cost-effective strategy for their delivery. Promising interventions, which need more careful evaluation, focus on substance misuse, physical health comorbidities, improvement of social participation, peer support and the potential of new technologies. SUMMARY: The first five years after the onset of psychotic symptoms are a 'critical period' in which psychosocial interventions can be particularly influential in determining prognosis. Traditional EIP interventions have different effectiveness profiles, i.e., FI reduce relapse rates, CBT has a moderate effectiveness on overall and positive symptoms and VI can improve educational and employment-related functioning. Newer interventions show promise on important targets for FEP treatment but require higher-quality evaluations. Decisions on which interventions to implement within EIP teams should be informed by high-quality evidence, but difficult choices will have to be made based on costs, professionals and technologies available, and local priorities.

COVID-19 in People With Schizophrenia: Potential Mechanisms Linking Schizophrenia to Poor Prognosis.

As the global burden of mortality from COVID-19 continues to rise, an understanding of who is most at risk of adverse outcomes is of paramount importance. Pre-existing cardiometabolic, renal and respiratory diseases as well as old age are well-established risk factors associated with disease severity and mortality among patients with COVID-19. However, mounting evidence also indicates an increased susceptibility to, and risk of adverse outcomes from COVID-19 in people with schizophrenia, independent of age and comorbidity. Therefore, elucidating the underlying pathophysiological mechanisms which may increase the risk of poor outcomes in people with schizophrenia is of crucial importance. Here, we provide a narrative on the current understanding of COVID-19 in patients with schizophrenia and propose potential mechanisms which may link schizophrenia with an increased susceptibility to, and greater risk of adverse outcomes from COVID-19. Given the existing knowledge gaps, robust clinical and biological studies are required to further our understanding of some of these underlying mechanisms, so that effective prevention and treatment strategies for COVID-19 in patients with schizophrenia can be developed.

Left Ventricular Hypertrophy in Diabetic Cardiomyopathy: A Target for Intervention.

Heart failure is an important manifestation of diabetic heart disease. Before the development of symptomatic heart failure, as much as 50% of patients with type 2 diabetes mellitus (T2DM) develop asymptomatic left ventricular dysfunction including left ventricular hypertrophy (LVH). Left ventricular hypertrophy (LVH) is highly prevalent in patients with T2DM and is a strong predictor of adverse cardiovascular outcomes including heart failure. Importantly regression of LVH with antihypertensive treatment especially renin angiotensin system blockers reduces cardiovascular morbidity and mortality. However, this approach is only partially effective since LVH persists in 20% of patients with hypertension who attain target blood pressure, implicating the role of other potential mechanisms in the development of LVH. Moreover, the pathophysiology of LVH in T2DM remains unclear and is not fully explained by the hyperglycemia-associated cellular alterations. There is a growing body of evidence that supports the role of inflammation, oxidative stress, AMP-activated kinase (AMPK) and insulin resistance in mediating the development of LVH. The recognition of asymptomatic LVH may offer an opportune target for intervention with cardio-protective therapy in these at-risk patients. In this article, we provide a review of some of the key clinical studies that evaluated the effects of allopurinol, SGLT2 inhibitor and metformin in regressing LVH in patients with and without T2DM.