Homicides of American Indians/Alaska Natives in urban versus rural areas: United States National Violent Death Reporting System, 2003-2020.

BACKGROUND: Missing and Murdered Indigenous People is a historic and contemporary issue that has gained national attention. In 2021, homicide was the eighth leading cause of death among American Indian/Alaska Native (AIAN) persons aged between 1 and 54 years old, and homicide is the sixth leading cause of death among all AIAN males aged 1-54 years old. AIM: These data will build knowledge around AIAN homicides and to identify circumstances that can aid in comprehensive Missing and Murdered Indigenous People prevention efforts. METHODS: AIAN homicide data came from Centers for Disease Control and Prevention's National Violent Death Reporting System, a state/jurisdiction-based surveillance system that collects detailed information about characteristics and circumstances of violent deaths. We examined data from 2003 to 2020 (all available years) from participating states/jurisdictions. We also assessed sociodemographic characteristics of victims and suspects, incident characteristics and differences across dichotomised urban/rural status. The study was conducted in 2022. RESULTS: The National Violent Death Reporting System provided data on 2959 AIAN homicides from 2003 to 2020 (54.2% urban and 45.8% rural). Significant differences based on the two locations included type of weapon used, the location of the injury, race of the primary suspect, the victim's relationship to the suspect and select circumstances precipitating the homicide including crimes precipitating the homicide and homicides stemming from intimate partner violence. OUTCOMES: These findings provide crucial information to strengthen public health efforts for prevention.

A critical assessment of the abuse, dependence and associated safety risks of naturally occurring and synthetic cannabinoids.

Various countries and US States have legalized cannabis, and the use of the psychoactive1 and non-psychoactive cannabinoids is steadily increasing. In this review, we have collated evidence from published non-clinical and clinical sources to evaluate the abuse, dependence and associated safety risks of the individual cannabinoids present in cannabis. As context, we also evaluated various synthetic cannabinoids. The evidence shows that delta-9 tetrahydrocannabinol (Δ9-THC) and other psychoactive cannabinoids in cannabis have moderate reinforcing effects. Although they rapidly induce pharmacological tolerance, the withdrawal syndrome produced by the psychoactive cannabinoids in cannabis is of moderate severity and lasts from 2 to 6 days. The evidence overwhelmingly shows that non-psychoactive cannabinoids do not produce intoxicating, cognitive or rewarding properties in humans. There has been much speculation whether cannabidiol (CBD) influences the psychoactive and potentially harmful effects of Δ9-THC. Although most non-clinical and clinical investigations have shown that CBD does not attenuate the CNS effects of Δ9-THC or synthetic psychoactive cannabinoids, there is sufficient uncertainty to warrant further research. Based on the analysis, our assessment is cannabis has moderate levels of abuse and dependence risk. While the risks and harms are substantially lower than those posed by many illegal and legal substances of abuse, including tobacco and alcohol, they are far from negligible. In contrast, potent synthetic cannabinoid (CB1/CB2) receptor agonists are more reinforcing and highly intoxicating and pose a substantial risk for abuse and harm. 1 "Psychoactive" is defined as a substance that when taken or administered affects mental processes, e.g., perception, consciousness, cognition or mood and emotions.

Navacaprant, a novel and selective kappa opioid receptor antagonist, has no agonist properties implicated in opioid-related abuse.

Kappa opioid receptors (KORs) are implicated in the pathophysiology of various psychiatric and neurological disorders creating interest in targeting the KOR system for therapeutic purposes. Accordingly, navacaprant (NMRA-140) is a potent, selective KOR antagonist being evaluated as a treatment for major depressive disorder. In the present report, we have extended the pharmacological characterization of navacaprant by further demonstrating its selective KOR antagonist properties and confirming its lack of agonist activity at KORs and related targets involved in opioid-related abuse. Using CHO-K1 cells expressing human KOR, mu (MOR), or delta (DOR) opioid receptors, navacaprant demonstrated selective antagonist properties at KOR (IC50 = 0.029 µM) versus MOR (IC50 = 3.3 µM) and DOR (IC50 > 10 µM) in vitro. In vivo, navacaprant (10-30 mg/kg, i.p.) dose-dependently abolished KOR-agonist induced analgesia in the mouse tail-flick assay. Additionally, navacaprant (10, 30 mg/kg, p.o.) significantly reduced KOR agonist-stimulated prolactin release in mice and rats, confirming KOR antagonism in vivo. Navacaprant showed no agonist activity at any opioid receptor subtype (EC50 > 10 µM) in vitro and exhibited no analgesic effect in the tail-flick assays at doses ≤100 mg/kg, p.o. thereby confirming a lack of opioid receptor agonist activity in vivo. Importantly, navacaprant did not alter extracellular dopamine concentrations in the nucleus accumbens shell of freely-moving rats following doses ≤100 mg/kg, p.o., whereas morphine (10, 20 mg/kg, i.p.) significantly increased dopamine levels. These results demonstrate that navacaprant is a KOR-selective antagonist with no pharmacological properties implicated in opioid-related abuse.

Background Parenchymal Enhancement: A Comprehensive Update.

Breast MR imaging is a complementary screening tool for patients at high risk for breast cancer and has been used in the diagnostic setting. Normal enhancement of breast tissue on MR imaging is called breast parenchymal enhancement (BPE), which occurs after administration of an intravenous contrast agent. BPE varies widely due to menopausal status, use of exogenous hormones, and breast cancer treatment. Degree of BPE has also been shown to influence breast cancer risk and may predict treatment outcomes. The authors provide a comprehensive update on BPE with review of the recent literature.

Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder.

In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.

Association of Contact Sexual Violence Victimization and Health in the U.S.

INTRODUCTION: Sexual violence victimization is related to negative impacts, including chronic health conditions. Less is known about possible confounders of this relationship. This study examines the association between lifetime experience of contact sexual violence (CSV) and health conditions by sex, controlling for demographics and other victimization. METHODS: Data are from the 2016/2017 National Intimate Partner and Sexual Violence Survey, a nationally representative study of English- or Spanish-speaking adults. Ten health conditions (e.g., HIV/AIDS) and four activity limitations (e.g., difficulty dressing) were examined related to CSV victimization. Logistic regression models examined the association between CSV victimization and health controlling for demographics and other victimization experiences. Analyses were conducted in 2022 to 2023. RESULTS: For women and men, many health conditions and activity limitations were significantly associated with CSV after controlling for demographics. Accounting for other victimization, female CSV victims had higher odds of experiencing difficulty sleeping (Adjusted Odds Ratio [AOR]=1.3); difficulty concentrating, remembering, or making decisions (AOR=1.7); and difficulty doing errands alone (AOR=1.4) than nonvictims. Male victims had higher odds than nonvictims of having HIV/AIDS (AOR=5.2); frequent headaches (AOR=1.5); chronic pain (AOR=1.5); difficulty sleeping (AOR=1.4); serious difficulty hearing (AOR=1.3); and difficulty concentrating, remembering, or making decisions (AOR=1.5). CONCLUSIONS: CSV had a negative impact on health, although other types of victimization appear to also have an impact, especially for women. Demographic characteristics also aid the understanding of the relationship between CSV and health. Efforts to prevent CSV and other forms of violence can be coupled with healthcare- and population-level approaches to improve long-term health.

Rape and Sexual Coercion Related Pregnancy in the United States.

INTRODUCTION: Sexual violence is a major public health problem in the U.S. that is associated with numerous health impacts, including pregnancy. U.S. population-based estimates (2010-2012) found that three million women experienced a rape-related pregnancy during their lifetimes. The current study presents more recent estimates of rape and sexual coercion-related pregnancy and examines prevalence by demographic characteristics. METHODS: Data years 2016/2017 were pooled from the National Intimate Partner and Sexual Violence Survey, a random-digit-dial telephone survey of U.S. non-institutionalized adults 18 years and older. The analysis, conducted in 2023, examined lifetime experience of rape-related pregnancy, sexual coercion-related pregnancy, or both among U.S. women. Authors calculated prevalence estimates with 95% CIs and conducted pairwise chi-square tests (p-value<0.05) to describe experiences by current age, race/ethnicity, and region of residence among U.S. women overall and among victims. RESULTS: One in 20 women in the U.S., or over 5.9 million women, experienced a pregnancy from either rape, sexual coercion, or both during their lifetimes. Non-Hispanic Multiracial women experienced a higher prevalence of all three outcomes compared with non-Hispanic White, non-Hispanic Black, and Hispanic women. Among victims who experienced pregnancy from rape, 28% experienced a sexually transmitted disease, 66% were injured, and over 80% were fearful or concerned for their safety. CONCLUSIONS: Pregnancy as a consequence of rape or sexual coercion is experienced by an estimated six million U.S. women. Prevention efforts may include healthcare screenings to identify violence exposure and use of evidence-based prevention approaches to reduce sexual violence.

Sex work-related homicides: Insights from the National Violent Death Reporting System, 2012-2020.

Homicide is a prevalent cause of death among sex workers, given their increased risk of violence due to proximity to criminal activities such as drug trade and human trafficking. This study analyzes homicide data from the National Violent Death Reporting System (NVDRS) covering 49 US states, the District of Columbia, and Puerto Rico from 2012 to 2020. Case inclusion criteria included: (1) manner of death of homicide, and (2) sex work-related circumstance. Descriptive analyses examined victim and injury characteristics, suspect information, and circumstances. The study identified 321 sex work-related homicides (54% female, 41% male, 6% transgender). Among female victims, 94% were sex workers, and 54% of their suspects were clients. Money conflicts (23%) and other crimes (30%), most often in progress, commonly precipitated homicides of female victims. Substance use problems were reported in 49% of female victims, with 25% of their suspected perpetrators reportedly using substances in the preceding hours. For male victims, 54% were clients and 9% were sex workers. Suspects in male homicides were primarily sex workers (34%) or individuals engaged in sex work-adjacent criminal activities (36%). Money conflicts (49%), other crimes (47%) most often in progress, and sex trafficking involvement (25%) commonly precipitated homicides with male victims. Transgender sex worker victims were mostly transfeminine (94%) and non-Hispanic black (89%). Money conflicts (78%) most commonly precipitated homicides among transgender sex worker victims. These findings can inform prevention strategies addressing underlying risk factors for persons involved in sex work.

Prevalence estimates and factors associated with violence among older adults: National Intimate Partner and Sexual Violence (NISVS) Survey, 2016/2017.

Abuse of older adults is a public health problem. The National Intimate Partner and Sexual Violence Survey (NISVS) is a nationally-representative, telephone survey for non-institutionalized adults in the United States. To determine the prevalence and factors of intimate partner psychological aggression and physical violence and sexual violence by any perpetrator against older adults, we analyzed NISVS 2016/2017 data (n = 10,171, aged ≥ 60 years). Past 12-month prevalence of psychological aggression, physical violence, and sexual violence was 2.1%, 0.8%, and 1.7%, respectively. Odds of psychological aggression were significantly higher among those with hearing or vision impairment, and lower among those aged ≥70 years. Odds of physical violence were significantly higher for males and for those with hearing or vision impairment. Odds of sexual violence were significantly higher for unpartnered individuals and those with cognitive impairment; and lower for those aged ≥ 70 years. Epidemiologic studies of violence against older adults can inform population-specific prevention strategies.

Equity with equality? Contextualising everyone can widen participation in medical school admissions.

Widening participation outcomes in admissions to UK medical schools have not changed 2007-2018, partly due to inequity in selection. This study models the effects of changing selection, using a novel method of contextualising applicants, on widening participation. We studied 1084 English school leaver applicants to a single medical school over two years, using data from their public exams taken 2 years pre-application (GCSE) and recent admissions test (UCAT). Widening participation was defined by postcode.We modelled two shortlists for a pre-determined number of 500; one ranked on UCAT total score, and the other on a metric that contextualised applicants' GCSE grades against their schools' average GCSE performance. There was a significant difference in the postcode-defined widening participation characteristics of the two shortlists; 46% by contextualisation and 32.2% by UCAT (Chisquare p < 0.00001). As widening participation covers 42% of postcodes, the "contextualise everyone" method achieves equity.Conventionally, contextual admissions identify individuals belonging to under-represented groups and gives them preferential treatment. Changing the rules for everyone, by using a relative attainment instead of simple absolute attainment metric, benefits from treating applicants equally; and could promote equity through widening participation.

Impacts of a University Research Assistant Program: The First Decade.

Purpose: There is a declining number of physician-scientists. Little is published about the potential for university student experiences to contribute to the pipeline of future researchers. The purpose of this study was to describe a unique university research program and report the outcomes of the first 10 years. Method: The University Research Assistant Program (URAP) was described including course content, research experiences, and student composition. Outcomes of URAP student contributions to the literature and research presentations was reported. URAP students were also surveyed to assess their perspectives on the impact of the URAP program on career choices after graduation. Results: URAP began as an independent study course and grew into for-credit university courses. A total of 212 students have taken at least one semester and 88 responded to the survey. All students who participated in URAP have graduated, and 77% (n = 68) reported the URAP program prepared them to reach their career goals. Most graduates pursued health care careers including medical school (55%), Master's programs in health care (29%), or PhD in health care (5%). URAP students participated in research involving 11 different pediatric subspecialties. Many attained co-authorship of abstracts and publications, 53 first-authored an abstract presentation and 7 manuscripts. Conclusions: URAP significantly influenced university students who overwhelmingly entered health care fields. While difficult to assess if these early experiences will influence participation as future physician -scientists, these students made meaningful research contributions while enrolled in these courses. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01852-6.

AAV Gene Augmentation of Truncated Complement Factor H Differentially Rescues Ocular Complement Dysregulation in a Mouse Model.

Purpose: Complement dysregulation in the eye has been implicated in the pathogenesis of age-related macular degeneration (AMD), and genetic variants of complement factor H (CFH) are strongly associated with AMD risk. We therefore aimed to untangle the role of CFH and its splice variant, factor H-like 1 (FHL-1), in ocular complement regulation derived from local versus circulating sources. We assessed the therapeutic efficacy of adeno-associated viruses (AAVs) expressing human FHL-1 and a truncated version of CFH (tCFH), which retains the functional N- and C-terminal ends of the CFH protein, in restoring the alternative complement pathway in Cfh-/- mouse eyes and plasma. Methods: Using Cfh-/- mice as a model of complement dysregulation, AAV vectors expressing tCFH or FHL-1 were injected subretinally or via tail vein, and the efficacy of the constructs was evaluated. Results: Following subretinal injections, tCFH expression rescued factor B (FB) retention in the eye, but FHL-1 expression did not. By contrast, both constructs restored FB detection in plasma following tail vein injections. Both tCFH and FHL-1 proteins accumulated in the posterior eyecup from the circulation following liver transduction; however, neither was able to significantly regulate local ocular complement. Conclusions: Our findings demonstrate that the C-terminus of human CFH is necessary for complement regulation in the murine eye. Furthermore, exogenous CFH must be synthesized locally to maximize complement regulation in the retina. These findings establish a critical foundation for development of CFH augmentation-based gene therapies for the eye.

Permafrost thaw induces short-term increase in vegetation productivity in northwestern Canada.

Over the past several decades, various trends in vegetation productivity, from increases to decreases, have been observed throughout Arctic-Boreal ecosystems. While some of this variation can be explained by recent climate warming and increased disturbance, very little is known about the impacts of permafrost thaw on productivity across diverse vegetation communities. Active layer thickness data from 135 permafrost monitoring sites along a 10° latitudinal transect of the Northwest Territories, Canada, paired with a Landsat time series of normalized difference vegetation index from 1984 to 2019, were used to quantify the impacts of changing permafrost conditions on vegetation productivity. We found that active layer thickness contributed to the observed variation in vegetation productivity in recent decades in the northwestern Arctic-Boreal, with the highest rates of greening occurring at sites where the near-surface permafrost recently had thawed. However, the greening associated with permafrost thaw was not sustained after prolonged periods of thaw and appeared to diminish after the thaw front extended outside the plants' rooting zone. Highest rates of greening were found at the mid-transect sites, between 62.4° N and 65.2° N, suggesting that more southernly sites may have already surpassed the period of beneficial permafrost thaw, while more northern sites may have yet to reach a level of thaw that supports enhanced vegetation productivity. These results indicate that the response of vegetation productivity to permafrost thaw is highly dependent on the extent of active layer thickening and that increases in productivity may not continue in the coming decades.

Violent Victimization During Childhood in the United States: Associations With Revictimization and Health.

Childhood violence victimization is a serious adverse childhood experience with lasting health impacts. This study examined the prevalence and characteristics of five forms of childhood violence victimization and their association with revictimization and negative health conditions among adults. Data are from the 2010-2012 National Intimate Partner and Sexual Violence Survey. Age at first victimization and perpetrator sex were assessed; adjusted odds ratios assessed associations with revictimization and health. Ages 14-17 were the most common age at first victimization for most violence types; almost half of male (46.7%) and a quarter of female (27.0%) rape victims reported first victimization before age 10. Most victimization was associated with revictimization and negative health, controlling for adult victimization. Primary prevention of childhood violence may reduce later health risks.

Psychedelic drug abuse potential assessment for new drug applications and controlled substance scheduling: A United States perspective.

BACKGROUND: Psychedelics are an increasingly active area of research and pharmaceutical development. This includes abuse potential assessment to better understand their pharmacological mechanisms and effects and guide controlled substance regulation. Psychedelics pose challenges to abuse assessments to ensure valid, reliable, and generalizable outcomes and safe study conduct. FINDINGS: Key nonclinical techniques, for example, receptor binding and functional assays in vitro, and nonclinical physical dependence determinations, are easily adaptable to psychedelics. However, the entactogens (weak reinforcers) and hallucinogens (non-reinforcers) require more flexible approaches than typically recommended by regulatory agencies. Phase 1 pharmacokinetic/pharmacodynamic safety studies and Phases 2/3 efficacy/safety trials with systematic monitoring of abuse-related adverse events are readily applicable to psychedelics. Human abuse trials require modification because supratherapeutic doses may not be safe and procedures, for example, personal monitors to manage serious adverse events, might bias outcomes. RECOMMENDATIONS: Abuse-related studies for psychedelics requiring approval by Food and Drug Administration and other agencies should take into consideration existing knowledge that will vary from extensive, for example, psilocybin, to zero for novel hallucinogens and entactogens. Many abuse assessments can be reasonably applied to animals and humans without compromising scientific integrity. Modification of existing techniques and incorporating a broader range of nonclinical tests should ensure generalizable outcomes. Human abuse studies merit reconsideration and possible modification to ensure safety and validity for psychedelic drug evaluation. Other nonclinical and clinical methods can provide evaluations of the pharmacological equivalence of test drugs to known drugs of abuse to provide context to the abuse assessment and guide drug scheduling.

What does it mean to be affiliated with care?: Delphi consensus on the definition of "unaffiliation" and "specialist" in sickle cell disease.

Accruing evidence reveals best practices for how to help individuals living with Sickle Cell Disease (SCD); yet, the implementation of these evidence-based practices in healthcare settings is lacking. The Sickle Cell Disease Implementation Consortium (SCDIC) is a national consortium that uses implementation science to identify and address barriers to care in SCD. The SCDIC seeks to understand how and why patients become unaffiliated from care and determine strategies to identify and connect patients to care. A challenge, however, is the lack of agreed-upon definition for what it means to be unaffiliated and what it means to be a "SCD expert provider". In this study, we conducted a Delphi process to obtain expert consensus on what it means to be an "unaffiliated patient" with SCD and to define an "SCD specialist," as no standard definition is available. Twenty-eight SCD experts participated in three rounds of questions. Consensus was defined as 80% or more of respondents agreeing. Experts reached consensus that an individual with SCD who is unaffiliated from care is "someone who has not been seen by a sickle cell specialist in at least a year." A sickle cell specialist was defined as someone with knowledge and experience in SCD. Having "knowledge" means: being knowledgeable of the 2014 NIH Guidelines, "Evidence-Based Management of SCD", trained in hydroxyurea management and transfusions, trained on screening for organ damage in SCD, trained in pain management and on SCD emergencies, and is aware of psychosocial and cognitive issues in SCD. Experiences that are expected of a SCD specialist include experience working with SCD patients, mentored by a SCD specialist, regular attendance at SCD conferences, and obtains continuing medical education on SCD every 2 years." The results have strong implications for future research, practice, and policy related to SCD by helping to lay a foundation for an new area of research (e.g., to identify subpopulations of unaffiliation and targeted interventions) and policies that support reaffiliation and increase accessibility to quality care.

Acute tryptophan depletion alters affective touch perception.

RATIONALE: Affiliative tactile interactions help regulate physiological arousal and confer resilience to acute and chronic stress. C-tactile afferents (CTs) are a population of unmyelinated, low threshold mechanosensitive cutaneous nerve fibres which respond optimally to a low force stimulus, moving at between 1 and 10 cm/s. As CT firing frequencies correlate positively with subjective ratings of touch pleasantness, they are hypothesised to form the first stage of encoding affiliative tactile interactions. Serotonin is a key modulator of social responses with known effects on bonding. OBJECTIVES: The aim of the present study was to determine the effect of acutely lowering central serotonin levels on perceptions of CT-targeted affective touch. METHODS: In a double blind, placebo-controlled design, the effect of acute tryptophan depletion (ATD) on 25 female participants' ratings of directly and vicariously experienced touch was investigated. Psychophysical techniques were used to deliver dynamic tactile stimuli; some velocities were targeted to optimally activate CTs (1-10 cm/s), whereas other, faster and slower strokes fell outside the CT optimal range. Discriminative tactile function, cold pain threshold and tolerance were also measured. RESULTS: ATD significantly increased pleasantness ratings of both directly and vicariously experienced affective touch, increasing discrimination of the specific hedonic value of CT targeted velocities. While ATD had no effect on either tactile or cold pain thresholds, there was a trend for reduced tolerance to cold pain. CONCLUSIONS: These findings are consistent with previous reports that depletion of central serotonin levels modulates neural and behavioural responsiveness to appetitive sensory signals.

New Drugs to Treat ADHD: Opportunities and Challenges in Research and Development.

Since the landmark MTA (Multimodal Treatment of ADHD) trial unequivocally demonstrated the efficacy of methylphenidate, catecholaminergic drugs, especially stimulants, have been the therapeutic mainstay in treatment of Attention-Deficit Hyperactivity Disorder (ADHD). We review the new drugs which have entered the ADHD formulary. The lessons learned from drug-candidates that have succeeded in clinical trials together with those that have not have also been considered. What emerges confirms and consolidates the hypothesis that clinically effective ADHD drugs indirectly or directly increase catecholaminergic neurotransmission in the prefrontal cortex (PFC). Attempts to enhance catecholaminergic signalling through modulatory neurotransmitter systems or cognitive-enhancing drugs have all failed. New drugs approved for ADHD are catecholaminergic reuptake inhibitors and releasing agents, or selective noradrenaline reuptake inhibitors. Triple reuptake inhibitors with preferential effects on dopamine have not been successful. The substantial number of failures probably accounts for a continued focus on developing novel catecholaminergic and noradrenergic drugs, and a dearth of drug-candidates with novel mechanisms entering clinical development. However, substantial improvements in ADHD pharmacotherapy have been achieved by the almost exclusive use of once-daily medications and prodrugs, e.g. lisdexamfetamine and Azstarys®, which improve compliance, deliver greater efficacy and reduce risks for diversion and abuse.