A micropeptide encoded by a putative long noncoding RNA regulates muscle performance.

Functional micropeptides can be concealed within RNAs that appear to be noncoding. We discovered a conserved micropeptide, which we named myoregulin (MLN), encoded by a skeletal muscle-specific RNA annotated as a putative long noncoding RNA. MLN shares structural and functional similarity with phospholamban (PLN) and sarcolipin (SLN), which inhibit SERCA, the membrane pump that controls muscle relaxation by regulating Ca(2+) uptake into the sarcoplasmic reticulum (SR). MLN interacts directly with SERCA and impedes Ca(2+) uptake into the SR. In contrast to PLN and SLN, which are expressed in cardiac and slow skeletal muscle in mice, MLN is robustly expressed in all skeletal muscle. Genetic deletion of MLN in mice enhances Ca(2+) handling in skeletal muscle and improves exercise performance. These findings identify MLN as an important regulator of skeletal muscle physiology and highlight the possibility that additional micropeptides are encoded in the many RNAs currently annotated as noncoding.

A myocardin-adjacent lncRNA balances SRF-dependent gene transcription in the heart.

Myocardin, a potent coactivator of serum response factor (SRF), competes with ternary complex factor (TCF) proteins for SRF binding to balance opposing mitogenic and myogenic gene programs in cardiac and smooth muscle. Here we identify a cardiac lncRNA transcribed adjacent to myocardin, named CARDINAL, which antagonizes SRF-dependent mitogenic gene transcription in the heart. CARDINAL-deficient mice show ectopic TCF/SRF-dependent mitogenic gene expression and decreased cardiac contractility in response to age and ischemic stress. CARDINAL forms a nuclear complex with SRF and inhibits TCF-mediated transactivation of the promitogenic gene c-fos, suggesting CARDINAL functions as an RNA cofactor for SRF in the heart.

The notorious R.N.A.

The EMBO Journal discusses the current state of RNA research and presents a series of review articles throughout 2023 that will cover various aspects of RNA biology.

The EMBO Journal at 40-here's to the future!

Looking back at the journal's first issue in January 1982 provides an opportunity to reflect on its historical development and to introduce upcoming initiatives.

Lost in translation? Deciphering the role of language differences in the excess risk of psychosis among migrant groups.

BACKGROUND: Migration is a well-established risk factor for psychotic disorders, and migrant language has been proposed as a novel factor that may improve our understanding of this relationship. Our objective was to explore the association between indicators of linguistic distance and the risk of psychotic disorders among first-generation migrant groups. METHODS: Using linked health administrative data, we constructed a retrospective cohort of first-generation migrants to Ontario over a 20-year period (1992-2011). Linguistic distance of the first language was categorized using several approaches, including language family classifications, estimated acquisition time, syntax-based distance scores, and lexical-based distance scores. Incident cases of non-affective psychotic disorder were identified over a 5- to 25-year period. We used Poisson regression to estimate incidence rate ratios (IRR) for each language variable, after adjustment for knowledge of English at arrival and other factors. RESULTS: Our cohort included 1 863 803 first-generation migrants. Migrants whose first language was in a different language family than English had higher rates of psychotic disorders (IRR = 1.08, 95% CI 1.01-1.16), relative to those whose first language was English. Similarly, migrants in the highest quintile of linguistic distance based on lexical similarity had an elevated risk of psychotic disorder (IRR = 1.15, 95% CI 1.06-1.24). Adjustment for knowledge of English at arrival had minimal effect on observed estimates. CONCLUSION: We found some evidence that linguistic factors that impair comprehension may play a role in the excess risk of psychosis among migrant groups; however, the magnitude of effect is small and unlikely to fully explain the elevated rates of psychotic disorder across migrant groups.

Association between non-medical cannabis legalization and emergency department visits for cannabis-induced psychosis.

A major public health concern of cannabis legalization is that it may result in an increase in psychotic disorders. We examined changes in emergency department (ED) visits for cannabis-induced psychosis following the legalization and subsequent commercialization (removal of restrictions on retail stores and product types) of non-medical cannabis in Ontario, Canada (population of 14.3 million). We used health administrative data containing the cause of all ED visits to examine changes over three periods; 1) pre-legalization (January 2014-September 2018); 2) legalization with restrictions (October 2018 - February 2020); and 3) commercialization (March 2020 - September 2021). We considered subgroups stratified by age and sex and examined cocaine- and methamphetamine-induced psychosis ED visits as controls. During our study, there were 6300 ED visits for cannabis-induced psychosis. The restricted legalization period was not associated with changes in rates of ED visits for cannabis-induced psychosis relative to pre-legalization. The commercialization period was associated with an immediate increase in rates of ED visits for cannabis-induced psychosis (IRR 1.30, 95% CI 1.02-1.66) and no gradual monthly change; immediate increases were seen only for youth above (IRR 1.63, 1.27-2.08, ages 19-24) but not below (IRR 0.73 95%CI 0.42-1.28 ages, 15-18) the legal age of purchase, and similar for men and women. Commercialization was not associated with changes in rates of ED visits for cocaine- or methamphetamine-induced psychosis. This suggests that legalization with store and product restrictions does not increase ED visits for cannabis-induced psychosis. In contrast, cannabis commercialization may increase cannabis-induced psychosis presentations highlighting the importance of preventive measures in regions considering legalization.

The experiences of familial mental illness stigma among individuals living with mental illnesses.

Persons with mental illnesses may experience stigma from their immediate family members in addition to other forms of stigma. Using semi-structured interviews, we investigated experiences of familial mental illness stigma among 15 people diagnosed with mental illnesses in a mid-sized city in Canada. We identified five themes that speak to participants' experiences of familial mental illness stigma and ways to reduce it. The themes include the following: diagnosis as a 'double-edged sword,' potential familial isolation, familial stigma as societal stigma localized, stories of acceptance, and confronting potential familial mental illness stigma. Participants' narratives indicate that familial mental illness stigma is rooted in the broader social or public stigma, which sees its way into familial relations as well. This stigma takes various forms, including relationship bias or unfair treatment, breakdown in romantic relationships, loss of status, verbal and emotional abuse, exclusion from decision-making, and alienation within their immediate and extended families. Familial mental illness stigma experiences negatively impact participant's psychological well-being and personal empowerment. However, participants also shared ways that family members create supportive environments or actively confront or prevent stigma. Overall, this study has contributed to knowledge on mental illness stigma, particularly familial mental illness stigma from the perspective of participants living with a mental illness in a high-income country. Suggestions for future research include a focus on strategies to prevent ongoing familial mental illness stigma and large-scale studies to explore familial mental illness stigma to understand why families might perpetrate stigma.

Disparities in Access to a Regular Primary Care Physician Among First-Generation Migrants with Early Psychosis in Ontario, Canada.

Disparities in primary care utilization among migrants with early psychosis may be related to lack of access to a regular primary care physician. This study aimed to investigate access to a regular primary care physician among first-generation migrants with early psychosis. People aged 14-35 years with first onset non-affective psychotic disorder in Ontario, Canada were identified in health administrative data (N = 39,440). Access to a regular primary care physician through enrollment in the year prior to diagnosis was compared between first-generation migrants (categorized by country of birth) and the general population using modified Poisson regression. Most migrant groups had a lower prevalence of regular primary care physician access relative to the general population, particularly migrants from Africa (African migrants: 81% vs. non-migrants: 89%). Adjustment for sociodemographic and clinical factors attenuated these differences, although the disparities for migrants from Africa remained (PR = 0.96, 95%CI = 0.94-0.99). Interventions aimed at improving primary care physician access in migrant groups may facilitate help-seeking and improve pathways to care in early psychosis.

Early Psychosis Intervention and Primary Care: A Mixed Methods Study of Family Physician Knowledge, Attitudes, Preferences, and Needs.

Family physicians (FPs) play an important but underappreciated role in the pathways to care for people with early psychosis. We conducted a mixed-methods study to describe the knowledge, attitudes, preferences, and needs of FPs towards the recognition and management of early psychosis. We sent a cross-sectional postal survey to a random sample of FPs in Ontario, Canada, and conducted in-depth qualitative interviews with twenty. FPs were generally aware of important early psychosis symptoms, however, there were some knowledge gaps. Among surveyed FPs, 25% were unsure of the availability of early psychosis intervention services in their region, and most (80%) would prefer to co-manage with specialists. In the qualitative interviews, FPs expressed varied comfort levels in recognizing psychosis, and that timely access to psychiatry was a main concern. Our findings suggest that FPs require better support in recognizing and managing early psychosis and facilitating connections with specialized care.

Dental hygiene clinical faculty attitudes and likelihood of working during the COVID-19 pandemic.

OBJECTIVE: To identify circumstances that influenced dental hygiene clinical faculty's likelihood of working during the COVID-19 pandemic, and to explore attitudes (responsibilities, personal issues, ethics, and policy statements) about working. METHODS: This cross-sectional study used a purposive sample of dental hygienists (n = 1710) employed in academic clinical settings that held full-time, part-time, or adjunct appointments. The Health Care Workers' Attitudes to Working During a Pandemic survey was utilized. Likelihood scores were calculated based on respondents more or less likely to work under differing circumstances. Frequencies of agreement for attitudes were developed. Correlations were explored between likelihood scores and demographic data. Answers to the open-ended questions were categorized and described. RESULTS: The response rate was 13.5% (225/1710). Only one-third of respondents had a likelihood score of 100%. Factors with the greatest impact on likelihood to work were personal protective equipment. Almost all respondents' attitudes of working indicated that their employer is responsible for providing PPE. Over 90% felt their main responsibility was to themselves/family. Correlation analyses resulted in no significant associations between likelihood scores and age, etc. Faculty are considering leaving their jobs because of pay cuts and/or not feeling safe. CONCLUSION: Likelihood of working for dental hygiene faculty represents several personal and ethical decisions. Most respondents want employers to be responsible for their on-the-job safety. In addition, personal and work-related issues were causes of unease. The pandemic has had far-reaching implications on day-to-day work of dental hygiene clinical faculty as well as on the long-term trajectories and views on employment in higher education.

Neighbourhood-level social capital, marginalisation, and the incidence of schizophrenia and schizoaffective disorder in Toronto, Canada: a retrospective population-based cohort study.

BACKGROUND: Studies have shown mixed results regarding social capital and the risk of developing a psychotic disorder, and this has yet to be studied in North America. We sought to examine the relationship between neighbourhood-level marginalisation, social capital, and the incidence of schizophrenia and schizoaffective disorder in Toronto, Canada. METHODS: We used a retrospective population-based cohort to identify incident cases of schizophrenia and schizoaffective disorder over a 10 year period and accounted for neighbourhood-level marginalisation and a proxy indicator of neighbourhood social capital. Mixed Poisson regression models were used to estimate adjusted incidence rate ratios (aIRRs). RESULTS: In the cohort (n = 649 020) we identified 4841 incident cases of schizophrenia and schizoaffective disorder. A 27% variation in incidence was observed between neighbourhoods. All marginalisation dimensions, other than ethnic concentration, were associated with incidence. Compared to areas with low social capital, areas with intermediate social capital in the second [aIRR = 1.17, 95% confidence interval (CI) 1.03-1.33] and third (aIRR = 1.23, 95% CI 1.08-1.40) quintiles had elevated incidence rates after accounting for marginalisation. There was a higher risk associated with the intermediate levels of social capital (aIRR = 1.18, 95% CI 1.00-1.39) when analysed in only the females in the cohort, but the CI includes the possibility of a null effect. CONCLUSIONS: The risk of developing schizophrenia and schizoaffective disorder in Toronto varies by neighbourhood and is associated with socioenvironmental exposures. Social capital was not linearly associated with risk, and risk differs by sex and social capital quintile. Future research should examine these relationships with different forms of social capital and examine how known individual-level risk factors impact these findings.

Incorporating Added Therapeutic Benefit and Domestic Reference Pricing Into Medicare Payment for Expensive Part B Drugs.

OBJECTIVES: Identify expensive Part B drugs and evidence for each drug's added benefit and model a reimbursement policy for Medicare that integrates added benefit assessment and domestic reference pricing. METHODS: A retrospective analysis using a 20% nationally representative sample of 2015 to 2019 traditional Medicare Part B claims. Expensive drugs were defined as having average annual spending per beneficiary exceeding the average annual social security benefit ($17 532 in 2019). For expensive drugs identified in 2019, added benefit assessments conducted by the French Haute Autorité de Santé were collected. For expensive drugs with a low added benefit rating, comparator drugs were identified in French Haute Autorité de Santé reports. For each comparator, average annual spending per beneficiary in Part B was computed. Potential savings from 2 reference pricing scenarios were calculated: reimbursing expensive Part B drugs with low added benefit at the level of each drug's (1) lowest cost comparator and (2) beneficiary-weighted-average cost of all comparators. RESULTS: The number of expensive Part B drugs grew from 56 in 2015 to 92 in 2019. Of the 92 expensive drugs in 2019, 34 offer low added benefit. Implementing reference pricing for these expensive drugs with low added benefit could have saved an estimated $2.1 billion if prices were set based on spending for their lowest cost comparator, or $1 billion if prices were set based on the weighted average of spending for comparators. CONCLUSION: Reference pricing based on added benefit assessment could be used to address the launch prices for expensive Part B drugs with low added benefit.

Household food insecurity and health service use for mental and substance use disorders among children and adolescents in Ontario, Canada.

BACKGROUND: Food insecurity is a serious public health problem and is linked to the mental health of children and adolescents; however, its relationship with mental health service use is unknown. We sought to estimate the association between household food insecurity and contact with health services for mental or substance use disorders among children and adolescents in Ontario, Canada. METHODS: We used health administrative data, linked to 5 waves of the Canadian Community Health Survey, to identify children and adolescents (aged 1-17 yr) who had a household response to the Household Food Security Survey Module. We identified contacts with outpatient and acute care services for mental or substance use disorders in the year before survey completion using administrative data. We estimated prevalence ratios for the association between household food insecurity and use of mental health services, adjusting for several confounding factors. RESULTS: The sample included 32 321 children and adolescents, of whom 5216 (16.1%) were living in food-insecure households. Of the total sample, 9.0% had an outpatient contact and 0.6% had an acute care contact for a mental or substance use disorder. Children and adolescents in food-insecure households had a 55% higher prevalence of outpatient contacts (95% confidence interval [CI] 41%-70%), and a 74% higher prevalence of acute care contacts (95% CI 24%-145%) for a mental or substance use disorder, although contacts for substance use disorders were uncommon. INTERPRETATION: Children and adolescents living in a food-insecure household have greater use of health services for mental or substance use disorders than those living in households without food insecurity. Focused efforts to support food-insecure families could improve child and adolescent mental health and reduce strain on the mental health system.

Sex differences in the clinical presentation of early psychosis in a primary care setting.

Primary care is an important part of the help-seeking pathway for young people experiencing early psychosis, but sex differences in clinical presentation in these settings are unexplored. We aimed to identify sex differences in clinical presentation to primary care services in the 1-year period prior to a first diagnosis of psychotic disorder. We identified first-onset cases of non-affective psychotic disorder over a 10-year period (2005-2015) using health administrative data linked with electronic medical records (EMRs) from primary care (n = 465). Detailed information on encounters in the year prior to first diagnosis was abstracted, including psychiatric symptoms, other relevant behaviours, and diagnoses recorded by the family physician (FP). We used modified Poisson regression models to examine sex differences in the signs, symptoms, and diagnoses recorded by the FP, adjusting for various clinical and sociodemographic factors. Positive symptoms (PR = 0.76, 95%CI: 0.58, 0.98) and substance use (PR = 0.54, 95%CI: 0.40, 0.72) were less prevalent in the medical records of women. Visits by women were more likely to be assigned a diagnosis of depression or anxiety (PR = 1.18, 95%CI: 1.00, 1.38), personality disorder (PR = 5.49, 95%CI: 1.22, 24.62), psychological distress (PR = 11.29, 95%CI: 1.23, 103.91), and other mental or behavioral disorders (PR = 3.49, 95%CI: 1.14, 10.66) and less likely to be assigned a diagnosis of addiction (PR = 0.33, 95%CI: 0.13, 0.87). We identified evidence of sex differences in the clinical presentation of early psychosis and recorded diagnoses in the primary care EMR. Further research is needed to better understand sex differences in clinical presentation in the primary care context, which can facilitate better understanding, detection, and intervention for first-episode psychotic disorders.

Differences in clinical presentation at first hospitalization and the impact on involuntary admissions among first-generation migrant groups with non-affective psychotic disorders.

BACKGROUND: Some migrant and ethnic minority groups have a higher risk of coercive pathways to care; however, it is unclear whether differences in clinical presentation contribute to this risk. We sought to assess: (i) whether there were differences in clinician-rated symptoms and behaviours across first-generation immigrant and refugee groups at the first psychiatric hospitalization after psychosis diagnosis, and (ii) whether these differences accounted for disparities in involuntary admission. METHODS: Using population-based health administrative data from Ontario, Canada, we constructed a sample (2009-2013) of incident cases of non-affective psychotic disorder followed for two years to identify first psychiatric hospitalization. We compared clinician-rated symptoms and behaviours at admission between first-generation immigrants and refugees and the general population, and adjusted for these variables to ascertain whether the elevated prevalence of involuntary admission persisted. RESULTS: Immigrants and refugee groups tended to have lower ratings for affective symptoms, self-harm behaviours, and substance use, as well as higher levels of medication nonadherence and poor insight. Immigrant groups were more likely to be perceived as aggressive and a risk of harm to others, and both groups were perceived as having self-care issues. Adjustment for perceived differences in clinical presentation at admission did not attenuate the higher prevalence of involuntary admission for immigrant and refugee groups. CONCLUSIONS: First-generation migrant groups may differ in clinical presentation during the early course of psychotic illness, although these perceived differences did not explain the elevated rates of involuntary admission. Further research using outpatient samples and tools with established cross-cultural validity are warranted.

Comparing youth with vs without outpatient mental health services on subsequent acute mental health care visits.

BACKGROUND: Use of acute care for mental health concerns has been increasing among youth in recent years. Improving access to outpatient mental health services may prevent downstream acute care visits. PURPOSE: To examine differences in rates of acute mental health care visits among youth with- versus without prior outpatient mental health services. METHODOLOGY: A total of 2,442 youth ages 14-17 years participated in a provincially representative cross-sectional epidemiological survey, the 2014 Ontario Child Health Study. This sample was individually linked to health administrative databases, with nearly universal coverage of all medically necessary physician and acute care visits. Our exposure was parent and youth reported outpatient mental health service use in the six-month period prior to completing the survey. Exposed youth (n=691) were matched with unexposed youth using a propensity score informed by a range of clinical and socio-demographic factors. Our outcome was acute mental health care visits in the 18-month period following completion of the survey, ascertained though the linked health administrative data. RESULTS: In our propensity score matched sample, we found no difference in rates of subsequent acute mental health care visits (HR= 1.14, 95%CI 0.44, 2.98) between youth with- versus without prior outpatient mental health services. CONCLUSIONS: There is a need to further understand the types of services youth are receiving in outpatient settings to determine if, and for whom, outpatient mental health services reduces the likelihood of future acute mental health care visits.

Models of shared care for the management of psychotic disorder after first diagnosis in Ontario.

OBJECTIVE: To describe the provision of care for young people following first diagnosis of psychotic disorder. DESIGN: Retrospective cohort study using health administrative data. SETTING: Ontario. PARTICIPANTS: People aged 14 to 35 years with a first diagnosis of nonaffective psychotic disorder in Ontario between 2005 and 2015 (N=39,449). MAIN OUTCOME MEASURES: Models of care, defined by psychosis-related service contacts with primary care physicians and psychiatrists during the 2 years after first diagnosis of psychotic disorder. RESULTS: During the 2-year follow-up period, 29% of the cohort received only primary care, 30% received only psychiatric care, and 32% received both primary and psychiatric care (shared care). Among the shared care group, 72% received care predominantly from psychiatrists, 20% received care predominantly from primary care physicians, and 9% received approximately equal care from psychiatry and primary care. Variation in patient and physician characteristics was observed across the different models of care. CONCLUSION: One in 3 young people with psychotic disorder received shared care during the 2-year period after first diagnosis. The findings highlight opportunities for increasing collaboration between primary care physicians and psychiatrists to enhance the quality of care for those with early psychosis.

Patient and Physician Factors Associated with First Diagnosis of Non-affective Psychotic Disorder in Primary Care.

Primary care physicians play a central role in pathways to care for first-episode psychosis, and their increased involvement in early detection could improve service-related outcomes. The aim of this study was to estimate the proportion of psychosis first diagnosed in primary care, and identify associated patient and physician factors. We used linked health administrative data to construct a retrospective cohort of people aged 14-35 years with a first diagnosis of non-affective psychosis in Ontario, Canada between 2005-2015. We restricted the sample to patients with help-seeking contacts for mental health reasons in primary care in the six months prior to first diagnosis of psychotic disorder. We used modified Poisson regression models to examine patient and physician factors associated with a first diagnosis of psychosis in primary care. Among people with early psychosis (n = 39,449), 63% had help-seeking contacts in primary care within six months prior to first diagnosis. Of those patients, 47% were diagnosed in primary care and 53% in secondary/tertiary care. Patients factors associated with lower likelihood of diagnosis in primary care included male sex, younger age, immigrant status, and comorbid psychosocial conditions. Physician factors associated with lower likelihood of diagnosis in primary care included solo practice model, urban practice setting, international medical education, and longer time since graduation. Our findings indicate that primary care is an important contact for help-seeking and diagnosis for a large proportion of people with early psychosis. For physicians less likely to diagnose psychosis in primary care, targeted resources and interventions could be provided to support them in caring for patients with early psychosis.

LncRNAs at the heart of development and disease.

Long noncoding RNAs (LncRNAs) have emerged as a diverse class of functional molecules that contribute to nearly every facet of mammalian cardiac development and disease. Recent examples show that lncRNAs can be important co-regulators of cardiac patterning and morphogenesis and modulators of the pathogenic signaling that drives heart disease. The flexibility and chemical nature of RNA allows lncRNAs to utilize diverse mechanisms, mediating their effects through their sequence, structure, and molecular interactions with DNA, protein, and other RNAs. In vivo, i.e., animal, studies of individual lncRNAs highlight their ability to balance conserved cardiac gene expression networks, serve as specific and early biomarkers, and indicate their promise as useful therapeutic targets to treat human heart disease. Here, we review recent functionally characterized lncRNAs in cardiac biology and pathology and provide a perspective on emerging approaches to decipher the role of lncRNAs in the heart.

Cancer incidence and stage at diagnosis among people with recent-onset psychotic disorders: A retrospective cohort study using health administrative data from Ontario, Canada.

OBJECTIVE: Prior evidence on the relative risk of cancer among people with psychotic disorders is equivocal. The objective of this study was to compare incidence and stage at diagnosis of cancer for people with psychotic disorders relative to the general population. METHOD: We constructed a retrospective cohort of people with a first diagnosis of non-affective psychotic disorder and a comparison group from the general population using linked health administrative databases in Ontario, Canada. The cohort was followed for incident diagnoses of cancer over a 25-year period. We used Poisson and logistic regression models to compare cancer incidence and stage at diagnosis between people with psychotic disorders and the comparison group, adjusting for confounding factors. RESULTS: People with psychotic disorders had an 8.6% higher incidence (IRR = 1.09, 95%CI = 1.05,1.12) of cancer overall relative to the comparison group, with effect modification by sex and substantial variation across cancer sites. People with psychotic disorders also had 23% greater odds (OR = 1.23, 95%CI = 1.13,1.34) of being diagnosed with more advanced stage cancer relative to the comparison group. CONCLUSIONS: We found evidence of elevated cancer incidence in people with non-affective psychotic disorders relative to the general population. The higher odds of more advanced stage cancer diagnoses in people with psychotic disorders represents an opportunity to improve patient participation in recommended cancer screening, as well as timely access to services for cancer diagnosis and treatment. Future research should examine confounding effects of lifestyle factors and antipsychotic medications on the risk of developing cancer among people with psychotic disorders.