Reduced drug use as an alternative valid outcome in individuals with stimulant use disorders: Findings from 13 multisite randomized clinical trials.

BACKGROUND AND AIMS: Total abstinence has historically been the goal of treatment for substance use disorders; however, there is a growing recognition of the health benefits associated with reduced use as a harm reduction measure in stimulant use disorders treatment. We aimed to assess the validity of reduced stimulant use as an outcome measure in randomized controlled trials (RCTs) of pharmacological interventions for stimulant use disorder. DESIGN: We conducted a secondary analysis of a pooled dataset of 13 RCTs. SETTING AND PARTICIPANTS: Participants were individuals seeking treatment for cocaine or methamphetamine use disorders (N = 2062) in a wide range of treatment facilities in the United States. MEASUREMENTS: We validated reduced stimulant use against a set of clinical indicators drawn from harmonized measurements, including severity of problems caused by drug use, comorbid depression, global severity of substance use and improvement, severity of drug-seeking behavior, craving and high-risk behaviors, all assessed at the end of the trial, as well as follow-up urine toxicology. A series of mixed effect regression models was conducted to validate reduction in frequency of use against no reduction in use and abstinence. FINDINGS: More participants reduced frequency of primary drug use than achieved abstinence (18.0% vs. 14.2%, respectively). Reduced use was significantly associated with decreases in craving for the primary drug [60.1%, 95% confidence interval (CI) = 54.3%-64.7%], drug seeking behaviors (41.0%, 95% CI = 36.6%-45.7%), depression severity (39.9%, 95% CI = 30.9%-48.3%), as well as multiple measures of global improvement in psychosocial functioning and severity of drug-related problems, albeit less strongly so than abstinence. Moreover, reduced use was associated with sustained clinical benefit at follow-up, as confirmed by negative urine tests (adjusted odds ratio compared with those with no reduction in use: 0.50, 95% CI = 0.35-0.71). CONCLUSION: Reduced frequency of stimulant use appears to be associated with meaningful improvement in various clinical indicators of recovery. Assessment of reduced use, in addition to abstinence, could broaden the scope of outcomes measured in randomized controlled trials of stimulant use disorders and facilitate the development of more diverse treatment approaches.

Lifetime use of alcohol and cannabis among U.S. adolescents across age: Exploring differential patterns by sex and race/ethnicity using the 2019 NSDUH data.

Background: Early use of alcohol and cannabis is associated with health and social problems. It is unclear how lifetime use changes for each additional year of age during adolescence, and whether this change varies by sex and race/ethnicity. This study characterized lifetime rates of alcohol and cannabis use by age among 12- to 17-year-old American youth and explored differential patterns by sex and race/ethnicity. Methods: Data were obtained from the 2019 National Survey on Drug Use and Health. Analyses were restricted to 12-17-year-olds who were non-Hispanic White, non-Hispanic Black, or Hispanic/Latino (n = 11,830). We estimated the increase in lifetime use of alcohol and cannabis by age for the full sample and stratified by sex and race/ethnicity. Slopes of the regression lines were compared to assess differential patterns across groups. Results: In these cross-sectional analyses, reported lifetime use increased substantially from age 12 to 17 for alcohol (6.4 % to 53.2 %) and cannabis (1.3 % to 35.9 %). The increase in lifetime alcohol use was slightly, but not significantly, steeper among girls than boys (F1,8 = 3.40, p = 0.09). White and Latino youth showed similar rates of increase in lifetime alcohol use, which was significantly flatter among Black youth (F2,12=21.26, p<0.0001). Latino youth had a slightly, but not significantly, steeper increase in lifetime cannabis use than White and Black youth (F2,12=3.17, p = 0.07). Conclusions: Reports of lifetime alcohol and cannabis use substantially increase from age 12 to 17 and the rates are different according to sex and race/ethnicity, highlighting the need for early and tailored substance use prevention in adolescents.

Lessons Learned From Implementation of Mpox Surveillance During an Outbreak Response in Tennessee, 2022.

OBJECTIVES: Mpox surveillance was integral during the 2022 outbreak response. We evaluated implementation of mpox surveillance in Tennessee during an outbreak response and made recommendations for surveillance during emerging infectious disease outbreaks. METHODS: To understand surveillance implementation, system processes, and areas for improvement, we conducted 8 semistructured focus groups and 7 interviews with 36 health care, laboratory, and health department representatives during September 9-20, 2022. We categorized and analyzed session transcription and notes. We analyzed completeness and timeliness of surveillance data, including 349 orthopoxvirus-positive laboratory reports from commercial, public health, and health system laboratories during July 1-August 31, 2022. RESULTS: Participants described an evolving system and noted that existing informatics platforms inefficiently supported iterations of reporting requirements. Clear communication, standardization of terminology, and shared, adaptable, and user-friendly informatics platforms were prioritized for future emerging infectious disease surveillance systems. Laboratory-reported epidemiologic information was often incomplete; only 55% (191 of 349) of reports included patient address and telephone number. The median time from symptom onset to specimen collection was 5 days (IQR, 3-6 d), from specimen collection to laboratory reporting was 3 days (IQR, 1-4 d), from laboratory reporting to patient interview was 1 day (IQR, 1-3 d), and from symptom onset to patient interview was 9 days (IQR, 7-12 d). CONCLUSIONS: Future emerging infectious disease responses would benefit from standardized surveillance approaches that facilitate rapid implementation. Closer collaboration among informatics, laboratory, and clinical partners across jurisdictions and agencies in determining system priorities and designing workflow processes could improve flexibility of the surveillance platform and completeness and timeliness of laboratory reporting. Improved timeliness will facilitate public health response and intervention, thereby mitigating morbidity.

Reduced Ejection Fraction in Elite Endurance Athletes: Clinical and Genetic Overlap With Dilated Cardiomyopathy.

BACKGROUND: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes. METHODS: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years. RESULTS: Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; P=0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; P<0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; P=0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile (P=0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%. CONCLUSIONS: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268.

Implementation of Overdose Prevention in Maryland: Implications for Resource Allocation, Program Scale-Up, and Evaluation.

Overdose mortality in the United States continues to climb, with Maryland being one of the hardest hit states. We summarized implementation of overdose prevention and response programs in Maryland and identified associations between opioid overdose deaths by jurisdiction in 2019 and implementation of overdose programs by 2021. Data on program implementation are from Maryland's Opioid Operational Command Center (OOCC) Program Inventory. OOCC coordinates the state's response to overdose, and their Program Inventory tracks implementation of 145 programs across 12 domains (e.g., public health, education, and judiciary), including 10 programs designed to broaden naloxone access. The level of program implementation was dichotomized as substantial implementation versus other levels (i.e., partial, planned, and none). We estimated associations between per capita opioid overdose deaths and substantial implementation of: all 145 programs in the Inventory, programs within each of 12 domains, and 10 naloxone programs. Data on program implementation and overdose mortality are summarized at the jurisdiction level. Across jurisdictions, the median proportion of programs with substantial implementation was 51% across all programs and 70% among naloxone programs. Overdose mortality was associated with subsequent substantial implementation of programs within the public health domain (p = .04), but not in the other 11 domains. We did not find evidence that per capita overdose deaths in 2019 spurred overdose program implementation by 2021, with the exception of public health programs. The OOCC Program Inventory is a novel way to track implementation across jurisdictions. Findings can inform the implementation and evaluation of overdose programs in other jurisdictions across the United States.

"I've smoked weed with my daughter": Cannabis Use within Families Affected by Parental Opioid Misuse.

Youth with parents who use opioids are more likely to engage in early substance use, especially cannabis use. The purpose of this study was to describe the context of cannabis use among families affected by parental opioid misuse. We conducted 25 in-depth interviews with families affected by parental opioid misuse. Participants were parents with a history of opioid misuse and young adults (ages 18-24) who had parents with a history of opioid misuse. Interviews were digitally recorded and professionally transcribed. Data were analyzed inductively using a qualitative content analytic approach. Familial cannabis use was common among young people and their parents. Participants described familial cannabis use as a bonding activity that felt safe and lightened the mood. Additional research is needed to understand the complex role that cannabis use may play in families affected by opioid misuse. Strategies for intergenerational substance use prevention are discussed.

Promoting anti-racism in the legal system: an application of the STYLE framework.

Racism is a critical social problem, and we present a framework to guide professionals in engaging in anti-racist practices. Professionals on the frontlines in psychology and related fields such as social work and public health have a responsibility to engage in anti-racist practices. Part of the professional role must be to advocate for justice through increased proximity to the issues and engagement in anti-oppressive practices. The current discourse introduces a framework through which people working in psychology and other related professions can promote anti-racism work, highlighting the legal system for illustrative purposes. While some professionals in psychology may not have direct experience with the legal system, many of the individuals served by psychologists do (e.g., clients/patients, students, community members). Our framework is represented by the acronym STYLE (Self-examination, Talk about racism, Yield time to anti-racism work, Learn about structural racism, Evaluate policies and practices). The goal of STYLE is to expand anti-racism science and practice within psychology and related fields. We describe new roles for professionals in dismantling health inequities and offer specific pathways to develop critical partnerships toward this aim. STYLE explicitly encourages active, intentional involvement of affected community members in the development and evaluation of approaches to health services. To achieve equity and to promote individual and organizational growth in anti-racism and ultimately anti-oppression work, professionals must focus on changing their STYLE.

DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies.

BACKGROUND: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. METHODS: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. RESULTS: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. CONCLUSIONS: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management.

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants.

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

Non-medical prescription opioid use among high school students in 38 U.S. States.

Background: Lifetime prevalence of non-medical prescription opioid use (NMPOU) among adolescents exceeds 10%. Building on that work, we estimate lifetime and recent (i.e., past 30-day) NMPOU and examine associations with alcohol and cannabis use. Methods: We used 2019 YRBS data from 38 states with a question on lifetime NMPOU (n = 151,910), a subsample of 8 states also inquired about recent NMPOU (n = 28,439). We estimated the prevalence and frequency of NMPOU for boys and girls in each state. Multivariable logistic regression was used to derive odds ratios (OR) and 95% confidence intervals (CIs) representing recent NMPOU in association with alcohol and cannabis use adjusting for state, race/ethnicity, and grade. Results: The prevalence of lifetime NMPOU ranged from 9.4% to 22.7% for girls and 8.6% to 23.2% for boys; significant sex difference in Florida. Recent NMPOU among lifetime users ranged from 33.0% to 50.7% for girls and 40.7% to 52.3% for boys, no significant sex differences. Students reporting recent NMPOU had significantly higher odds of recent alcohol (OR: 5.1, 95% CI: 4.3-6.1) and cannabis use (OR: 3.7, 95% CI: 2.8-4.8). Higher frequency (1-2 and ≥ 3 times vs. 0 times) of NMPOU had significantly greater odds of alcohol (3-9-fold) and cannabis use (3-5-fold). The magnitude of association was higher for boys compared to girls. Conclusion: The prevalence of recent NMPOU among lifetime users is high and is associated with alcohol and cannabis use. NMPOU can be a steppingstone towards other forms of opioid use therefore, opioid prevention programs should emphasize prescription drug misuse and consider socio-contextual and geographical variations.

Disruptions to naloxone training among lay and occupational responders in Maryland during the emergence of COVID-19: early impacts, recovery, and lessons learned.

Background: : Opioid overdose death rates increased during the COVID-19 pandemic. Disruptions in community-based naloxone trainings could have reduced the likelihood of overdose reversal and increased the chances of a fatal overdose. We investigated changes in the number of people trained in naloxone administration and distribution in Maryland before, during, and after COVID-related stay-at-home orders. Methods: : Data on naloxone training are from the Maryland Department of Health. We used interrupted time series models to estimate changes in average monthly number of people trained: [1] pre-interruption (4/2019-3/2020), [2] 1-month post-interruption (4/2020-5/2020), and [3] 12-months post-interruption (4/2020-3/2021). Trainees were classified as lay (e.g., people who use drugs) or occupational (e.g., law enforcement officers and harm reduction workers) responders. Results: : There were 101,332 trainees; 54.1% lay, 21.5% occupational, and 23.4% unknown responder status. We observed a decrease in the average monthly number of trainees in the pre-interruption period (-235, p<0.001), a larger decrease of 93.2% during the 1-month post-interruption (-846, p=0.013), and an increase 12-months post-interruption (+217, p<0.001). There was a significant decrease among occupational responders 1-month post-interruption, and a significant increase among lay responders in the 12-month post-interruption period. Conclusions: : Findings suggest a marked decrease in naloxone trainees immediately after stay-at-home order, followed by a moderate rebound in the 12-months after stay-at-home order. The decrease in occupational responders trained may have limited access to naloxone, but would likely have been offset by increases in number of lay responders trained. Strengthening lay and occupational responder connections could maintain naloxone distribution during public health crises.

Classification of Students by Race and Hispanic/Latino/a/x Ethnicity Impacts Estimates of the Prevalence of Substance Use.

Multiracial and Hispanic/Latino/a/x youth are rapidly growing populations in the United States. When considered in substance use studies, they are often treated as homogeneous groups despite important demographic and cultural differences. The current study explores how substance use prevalence may differ depending on how precisely race and ethnicity groups are categorized. Data are from the 2018 High School Maryland Youth Risk Behavior Survey (n = 41,091, 48.4% female). We estimate prevalence of past 30-day substance use (i.e., alcohol, combustible tobacco, e-cigarettes, and marijuana) for all combinations of race and Hispanic/Latino/a/x ethnicity. Substance use prevalence across the specific Multiracial and Hispanic/Latino/a/x categories showed a wider range of estimates than within the traditional CDC racial and ethnic categories. Findings from this study suggest that state- and national-level surveillance of adolescent risk behavior should add further measures of race and ethnic identity to improve researchers' ability to increase precision of substance use prevalence estimates.

Psychosocial and pharmacologic interventions to reduce harmful alcohol use in low- and middle-income countries.

BACKGROUND: Harmful alcohol use is defined as unhealthy alcohol use that results in adverse physical, psychological, social, or societal consequences and is among the leading risk factors for disease, disability and premature mortality globally. The burden of harmful alcohol use is increasing in low- and middle-income countries (LMICs) and there remains a large unmet need for indicated prevention and treatment interventions to reduce harmful alcohol use in these settings. Evidence regarding which interventions are effective and feasible for addressing harmful and other patterns of unhealthy alcohol use in LMICs is limited, which contributes to this gap in services. OBJECTIVES: To assess the efficacy and safety of psychosocial and pharmacologic treatment and indicated prevention interventions compared with control conditions (wait list, placebo, no treatment, standard care, or active control condition) aimed at reducing harmful alcohol use in LMICs. SEARCH METHODS: We searched for randomized controlled trials (RCTs) indexed in the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, the Cochrane Clinical Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, Embase, PsycINFO, CINAHL, and the Latin American and Caribbean Health Sciences Literature (LILACS) through 12 December 2021. We searched clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, Web of Science, and Opengrey database to identify unpublished or ongoing studies. We searched the reference lists of included studies and relevant review articles for eligible studies. SELECTION CRITERIA: All RCTs comparing an indicated prevention or treatment intervention (pharmacologic or psychosocial) versus a control condition for people with harmful alcohol use in LMICs were included. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 66 RCTs with 17,626 participants. Sixty-two of these trials contributed to the meta-analysis. Sixty-three studies were conducted in middle-income countries (MICs), and the remaining three studies were conducted in low-income countries (LICs). Twenty-five trials exclusively enrolled participants with alcohol use disorder. The remaining 51 trials enrolled participants with harmful alcohol use, some of which included both cases of alcohol use disorder and people reporting hazardous alcohol use patterns that did not meet criteria for disorder. Fifty-two RCTs assessed the efficacy of psychosocial interventions; 27 were brief interventions primarily based on motivational interviewing and were compared to brief advice, information, or assessment only. We are uncertain whether a reduction in harmful alcohol use is attributable to brief interventions given the high levels of heterogeneity among included studies (Studies reporting continuous outcomes: Tau² = 0.15, Q =139.64, df =16, P<.001, I² = 89%, 3913 participants, 17 trials, very low certainty; Studies reporting dichotomous outcomes: Tau²=0.18, Q=58.26, df=3, P<.001, I² =95%, 1349 participants, 4 trials, very low certainty). The other types of psychosocial interventions included a range of therapeutic approaches such as behavioral risk reduction, cognitive-behavioral therapy, contingency management, rational emotive therapy, and relapse prevention. These interventions were most commonly compared to usual care involving varying combinations of psychoeducation, counseling, and pharmacotherapy. We are uncertain whether a reduction in harmful alcohol use is attributable to psychosocial treatments due to high levels of heterogeneity among included studies (Heterogeneity: Tau² = 1.15; Q = 444.32, df = 11, P<.001; I²=98%, 2106 participants, 12 trials, very low certainty). Eight trials compared combined pharmacologic and psychosocial interventions with placebo, psychosocial intervention alone, or another pharmacologic treatment. The active pharmacologic study conditions included disulfiram, naltrexone, ondansetron, or topiramate. The psychosocial components of these interventions included counseling, encouragement to attend Alcoholics Anonymous, motivational interviewing, brief cognitive-behavioral therapy, or other psychotherapy (not specified). Analysis of studies comparing a combined pharmacologic and psychosocial intervention to psychosocial intervention alone found that the combined approach may be associated with a greater reduction in harmful alcohol use (standardized mean difference (standardized mean difference (SMD))=-0.43, 95% confidence interval (CI): -0.61 to -0.24; 475 participants; 4 trials; low certainty). Four trials compared pharmacologic intervention alone with placebo and three with another pharmacotherapy. Drugs assessed were: acamprosate, amitriptyline, baclofen disulfiram, gabapentin, mirtazapine, and naltrexone. None of these trials evaluated the primary clinical outcome of interest, harmful alcohol use.   Thirty-one trials reported rates of retention in the intervention. Meta-analyses revealed that rates of retention between study conditions did not differ in any of the comparisons (pharmacologic risk ratio (RR) = 1.13, 95% CI: 0.89 to 1.44, 247 participants, 3 trials, low certainty; pharmacologic in addition to psychosocial intervention: RR = 1.15, 95% CI: 0.95 to 1.40, 363 participants, 3 trials, moderate certainty). Due to high levels of heterogeneity, we did not calculate pooled estimates comparing retention in brief (Heterogeneity: Tau² = 0.00; Q = 172.59, df = 11, P<.001; I2 = 94%; 5380 participants; 12 trials, very low certainty) or other psychosocial interventions (Heterogeneity: Tau² = 0.01; Q = 34.07, df = 8, P<.001; I2 = 77%; 1664 participants; 9 trials, very low certainty). Two pharmacologic trials and three combined pharmacologic and psychosocial trials reported on side effects. These studies found more side effects attributable to amitriptyline relative to mirtazapine, naltrexone and topiramate relative to placebo, yet no differences in side effects between placebo and either acamprosate or ondansetron. Across all intervention types there was substantial risk of bias. Primary threats to validity included lack of blinding and differential/high rates of attrition. AUTHORS' CONCLUSIONS: In LMICs there is low-certainty evidence supporting the efficacy of combined psychosocial and pharmacologic interventions on reducing harmful alcohol use relative to psychosocial interventions alone. There is insufficient evidence to determine the efficacy of pharmacologic or psychosocial interventions on reducing harmful alcohol use largely due to the substantial heterogeneity in outcomes, comparisons, and interventions that precluded pooling of these data in meta-analyses. The majority of studies are brief interventions, primarily among men, and using measures that have not been validated in the target population. Confidence in these results is reduced by the risk of bias and significant heterogeneity among studies as well as the heterogeneity of results on different outcome measures within studies. More evidence on the efficacy of pharmacologic interventions, specific types of psychosocial interventions are needed to increase the certainty of these results.

Impact of unsolicited reporting notifications on providers' prescribing behavior: An experimental study on Maryland PDMP data.

BACKGROUND: Unsolicited Reporting Notifications(URNs) have been a component of Maryland's Prescription Drug Monitoring Program (PDMP) since 2016. We evaluated the effect of URNs on providers' prescription behaviors. METHODS: This is a quasi-experimental study of providers who were issued at least one URN from January 2018 to April 2021. Providers for whom URNs were not successfully delivered were designated as a comparison group. The outcome variables were average daily opioid and benzodiazepine prescriptions, average morphine milligram equivalents per patient, and proportion of overlapping opioid and benzodiazepine, either with or without muscle relaxant prescriptions. Changes were compared before versus after the issuance of a URN among the intervention and comparison groups using "Generalized Estimation Equation" and "Generalized Linear" Models. We also conducted stratified analyses by types of URN, including notifications for multiple provider episodes (MPE), overdose fatality (ODF), and dangerous drug combinations (DDC). RESULTS: The average daily number of opioids prescriptions (3.3% decrease in the intervention group vs 22.7% increase in the comparison group, P<0.001), co-prescription of opioids and benzodiazepines either with muscle relaxants (68.0% decrease vs. 36.1% decrease, P<0.001), or without muscle relaxants (6.0% decrease vs. 16.3% increase, P<0.001), significantly reduced after the first URN regardless of the type of URN. Stratified analysis by types of URNs showed that ODF and DDC URNs had a significant effect on most of the outcomes of interest. CONCLUSION: The findings suggest that unsolicited reporting, especially particular types of URNs including ODF and DDC, is associated with subsequent changes in unsafe prescribing behaviors.

Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant.

BACKGROUND: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype. OBJECTIVE: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G. METHODS: Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers. We used in silico predictors and functional studies with peripheral blood and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Isolated RNA was studied by reverse transcription polymerase chain reaction. iPSC-CMs were further characterized at baseline and after nonsense-mediated decay (NMD) inhibition, using quantitative polymerase chain reaction (qPCR), RNA-sequencing, and cellular electrophysiology. American College of Medical Genetics and Genomics (ACMG) criteria were used to adjudicate variant pathogenicity. RESULTS: Variant heterozygotes displayed a spectrum of disease phenotypes, spanning from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation. Consistent with in silico predictors, the c.970-4A>G FLNC variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon. NMD inhibition upregulated aberrantly spliced transcripts by qPCR and RNA-sequencing. Patch clamp studies revealed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current in proband-derived iPSC-CMs. These findings fulfilled multiple ACMG criteria for pathogenicity. CONCLUSION: Clinical, in silico, and functional evidence support the prediction that the intronic c.970-4A>G VUS disrupts splicing and drives ACM, enabling reclassification from VUS to pathogenic.

Intrathecal Dexamethasone in Febrile Infection-Related Epilepsy Syndrome: A Case Report.

Objectives: Febrile infection-related epilepsy syndrome (FIRES) is characterized by explosive onset refractory status epilepticus (RSE) in healthy individuals that is refractory to antiseizure medication (ASM), continuous anesthetic infusions (CIs), and immunomodulators. Recently, a case series of patients receiving intrathecal dexamethasone (IT-DEX) was reported with improved RSE control. Methods: We present a child with FIRES with favorable outcome after receiving concomitant anakinra and IT-DaEX. A 9-year-old male patient presented with encephalopathy following a febrile illness. He developed seizures evolving to RSE refractory to multiple ASM, 3 CIs, steroids, IVIG, plasmapheresis, ketogenic diet (KD), and anakinra. After continued seizures and inability to wean off CI, IT-DEX was initiated. Results: He received 6 doses of IT-DEX with resolution of RSE, rapid wean off CI, and improved inflammatory markers. At discharge, he was ambulating with assistance, speaking 2 languages, and ingesting food orally. Discussion: FIRES is a neurologically devastating syndrome with high mortality and morbidity. Proposed guidelines and various treatment strategies are becoming available in the literature. Although treatment with KD, anakinra, and tocilizumab has been successful in previous FIRES cases, our results suggest that the addition of IT-DEX may allow for faster weaning off CI and better cognitive outcomes when initiated early in the course.

Drug-resistant seizures associated with hyperinflammatory monocytes in FIRES.

OBJECTIVE: Therapeutic strategies for patients with febrile infection-related epilepsy syndrome (FIRES) are limited, ad hoc, and frequently ineffective. Based on evidence that inflammation drives pathogenesis in FIRES, we used ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) to characterize the monocytic response profile before and after therapy in a child successfully treated with dexamethasone delivered intrathecally six times between hospital Day 23 and 40 at 0.25 mg/kg/dose. METHODS: PBMCs were isolated from serial blood draws acquired during refractory status epilepticus (RSE) and following resolution associated with intrathecal dexamethasone therapy in a previously healthy 9-year-old male that presented with seizures following Streptococcal pharyngitis. Cells were stimulated with bacterial or viral ligands and cytokine release was measured and compared to responses in age-matched healthy control PBMCs. Levels of inflammatory factors in the blood and CSF were also measured and compared to pediatric healthy control ranges. RESULTS: During RSE, serum levels of IL6, CXCL8, HMGB1, S100A8/A9, and CRP were significantly elevated. IL6 was elevated in CSF. Ex vivo stimulation of PBMCs collected during RSE revealed hyperinflammatory release of IL6 and CXCL8 in response to bacterial stimulation. Following intrathecal dexamethasone, RSE resolved, inflammatory levels normalized in serum and CSF, and the PBMC hyperinflammatory response renormalized. SIGNIFICANCE: FIRES may be associated with a hyperinflammatory monocytic response to normally banal bacterial pathogens. This hyperinflammatory response may induce a profound neutrophil burden and the consequent release of factors that further exacerbate inflammation and drive neuroinflammation. Intrathecal dexamethasone may resolve RSE by resetting this inflammatory feedback loop.

"What Do You Consider Use?" Perspectives of Black Youth on Cannabis Use.

PURPOSE: Adolescent health surveillance systems are critical for understanding patterns of cannabis use; however, their limitations underscore the need for studies that generate new insights, particularly from individuals who are most impacted by negative outcomes. Our objectives were to learn about youths' cannabis use and their perceptions of their peers' cannabis use; their perspectives about trajectories of cannabis use over time and factors that influence trajectories; and perceived risks and benefits associated with cannabis use. METHODS: A group model building approach was used to gather data about cannabis use from a sample of urban, Black youth. Information about participants' cannabis use was assessed on eligibility screener, enrollment survey, and through structured activities over the course of four group model building workshops. RESULTS: Participants [(n = 20) mean age 18; 35% male and 95% Black] exclusively used the terms weed and blunts for cannabis. Youth who consume peers' blunts would not characterize themselves as cannabis users. Collectively, youth estimated the majority of Baltimore youth used cannabis by age 16 and that most used daily. Youth described cannabis as more beneficial than harmful. There were no gender differences in prevalence of use, but there were gender dynamics to shared use. DISCUSSION: Participatory research with urban, Black youth suggests youths' perceptions are misaligned with the ways that researchers conceptualize cannabis use. To better understand the scope of youth cannabis use and its harms, it is critical to leverage input from youth with lived experience to ensure survey tools adequately capture the way youth see themselves using cannabis.