Comparative analysis of gonadal hormone receptor expression in the postnatal house mouse, meadow vole, and prairie vole brain.

The socially monogamous prairie vole (Microtus ochrogaster) and promiscuous meadow vole (Microtus pennsylvanicus) are closely related, but only prairie voles display long-lasting pair bonds, biparental care, and selective aggression towards unfamiliar individuals after pair bonding. These social behaviors in mammals are largely mediated by steroid hormone signaling in the social behavior network (SBN) of the brain. Hormone receptors are reproducible markers of sex differences that can provide more information than anatomy alone and can even be at odds with anatomical dimorphisms. We reasoned that behaviors associated with social monogamy in prairie voles may emerge in part from unique expression patterns of steroid hormone receptors in this species, and that these expression patterns would be more similar across males and females in prairie than in meadow voles or the laboratory mouse. To obtain insight into steroid hormone signaling in the developing prairie vole brain, we assessed expression of estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), and androgen receptor (Ar) within the SBN, using in situ hybridization at postnatal day 14 in mice, meadow, and prairie voles. We found species-specific patterns of hormone receptor expression in the hippocampus and ventromedial hypothalamus, as well as species differences in the sex bias of these markers in the principal nucleus of the bed nucleus of the stria terminalis. These findings suggest the observed differences in gonadal hormone receptor expression may underlie species differences in the display of social behaviors.

Estrogen masculinizes neural pathways and sex-specific behaviors.

Sex hormones are essential for neural circuit development and sex-specific behaviors. Male behaviors require both testosterone and estrogen, but it is unclear how the two hormonal pathways intersect. Circulating testosterone activates the androgen receptor (AR) and is also converted into estrogen in the brain via aromatase. We demonstrate extensive sexual dimorphism in the number and projections of aromatase-expressing neurons. The masculinization of these cells is independent of AR but can be induced in females by either testosterone or estrogen, indicating a role for aromatase in sexual differentiation of these neurons. We provide evidence suggesting that aromatase is also important in activating male-specific aggression and urine marking because these behaviors can be elicited by testosterone in males mutant for AR and in females subjected to neonatal estrogen exposure. Our results suggest that aromatization of testosterone into estrogen is important for the development and activation of neural circuits that control male territorial behaviors.

Disclosure to South African children about their own HIV status over time.

Disclosure to children living with HIV (CLHIV) about their own status is associated with positive outcomes such as treatment adherence, but prior cross-sectional studies in sub-Saharan Africa report disclosure rates of <50%. This study aims to assess pediatric disclosure over time. 548 CLHIV were followed from 2/2013-4/2018 in Johannesburg, South Africa. Cumulative incidence of disclosure was calculated with Kaplan-Meier analysis, and disclosure characteristics assessed with a Cox model. By end of follow-up, cumulative disclosure was 70.3% (95% confidence interval: 60.0-79.9). Median age at disclosure was 9 years (range: 3-13). Baseline predictors of disclosure included older child age and the child having a history of going hungry. Prior to disclosure, 98.0% of caregivers who disclosed had conversed with their child about their illness or an HIV-related topic, or their child had asked about HIV, versus 88.6% of caregivers who never disclosed. While many children did not receive disclosure during this relatively large, longitudinal study of South African CLHIV, caregivers who had not yet disclosed may have been preparing to do so by discussing their child's health or HIV generally with their child. This highlights the need for clinicians to consistently support caregivers throughout the incremental disclosure process.

Daily Cannabis Use Is a Barrier to Tobacco Cessation Among Tobacco Quitline Callers at 7-Month Follow-up.

INTRODUCTION: Cannabis use is increasing among cigarette smokers in the United States. Prior studies suggest that cannabis use may be a barrier to smoking cessation. Yet, the extent to which this is the case among adults seeking to quit tobacco use remains unclear. Tobacco quitlines are the most common provider of no-cost treatment for adults who use smoke in the United States. This study investigated the association between cannabis use and smoking cessation outcomes among quitline callers. AIMS AND METHODS: Participants included callers to the New York State Smokers' Quitline, who were seeking to quit smoking cigarettes and were contacted for outcome assessment 7 months after intake. Thirty-day point prevalence abstinence rates were calculated and compared among cannabis use groups, based on frequency of past-30-day cannabis use at baseline (none: 0 days, occasional: 1-9 days, regular: 10-19 days, and daily: 20-30 days). RESULTS: Approximately 8.3% (n = 283) of participants (n = 3396) reported past-30-day cannabis use at baseline. Callers with daily cannabis use (20-30 days per month) had significantly lower odds of 30-day abstinence, relative to those who did not use cannabis (odds ratio = 0.5; 95% confidence interval [0.3, 0.9]). CONCLUSIONS: Daily cannabis use appears to be associated with poorer smoking cessation treatment outcomes among adults seeking to quit smoking cigarettes via a quitline. Because quitlines are among the most accessible, affordable, and frequently utilized community-based treatments available in the United States, and the prevalence of cannabis use is increasing among cigarette smokers, detailed inquiry into cannabis use might enhance cigarette smoking cessation outcomes. IMPLICATIONS: Quitlines are free of cost and accessible to millions of smokers in the United States. The current study found an inverse relationship between daily cannabis use at baseline and 30-day abstinence from cigarette smoking at 7-month follow-up among New York State Smokers' Quitline callers. Findings suggest that daily cannabis use may be a barrier to smoking cessation and sustained abstinence among those seeking help to stop smoking cigarettes.

A Central Extended Amygdala Circuit That Modulates Anxiety.

Both the amygdala and the bed nucleus of the stria terminalis (BNST) have been implicated in maladaptive anxiety characteristics of anxiety disorders. However, the underlying circuit and cellular mechanisms have remained elusive. Here we show that mice with Erbb4 gene deficiency in somatostatin-expressing (SOM+) neurons exhibit heightened anxiety as measured in the elevated plus maze test and the open field test, two assays commonly used to assess anxiety-related behaviors in rodents. Using a combination of electrophysiological, molecular, genetic, and pharmacological techniques, we demonstrate that the abnormal anxiety in the mutant mice is caused by enhanced excitatory synaptic inputs onto SOM+ neurons in the central amygdala (CeA), and the resulting reduction in inhibition onto downstream SOM+ neurons in the BNST. Notably, our results indicate that an increase in dynorphin signaling in SOM+ CeA neurons mediates the paradoxical reduction in inhibition onto SOM+ BNST neurons, and that the consequent enhanced activity of SOM+ BNST neurons is both necessary for and sufficient to drive the elevated anxiety. Finally, we show that the elevated anxiety and the associated synaptic dysfunctions and increased dynorphin signaling in the CeA-BNST circuit of the Erbb4 mutant mice can be recapitulated by stress in wild-type mice. Together, our results unravel previously unknown circuit and cellular processes in the central extended amygdala that can cause maladaptive anxiety.SIGNIFICANCE STATEMENT The central extended amygdala has been implicated in anxiety-related behaviors, but the underlying mechanisms are unclear. Here we found that somatostatin-expressing neurons in the central amygdala (CeA) controls anxiety through modulation of the stria terminalis, a process that is mediated by an increase in dynorphin signaling in the CeA. Our results reveal circuit and cellular dysfunctions that may account for maladaptive anxiety.

Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize behavior.

Masculinization of the altricial rodent brain is driven by estrogen signaling during a perinatal critical period. Genetic deletion of estrogen receptor alpha (Esr1/ERα) results in altered hypothalamic-pituitary-gonadal (HPG) axis signaling and a dramatic reduction of male sexual and territorial behaviors. However, the role of ERα in masculinizing distinct classes of neurons remains unexplored. We deleted ERα in excitatory or inhibitory neurons using either a Vglut2 or Vgat driver and assessed male behaviors. We find that Vglut2-Cre;Esr1lox/lox mutant males lack ERα in the ventrolateral region of the ventromedial hypothalamus (VMHvl) and posterior ventral portion of the medial amygdala (MePV). These mutants recapitulate the increased serum testosterone levels seen with constitutive ERα deletion, but have none of the behavioral deficits. In contrast, Vgat-Cre;Esr1lox/lox males with substantial ERα deletion in inhibitory neurons, including those of the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr), posterior dorsal MeA (MePD), and medial preoptic area (MPOA) have normal testosterone levels, but display alterations in mating and territorial behaviors. These mutants also show dysmasculinized expression of androgen receptor (AR) and estrogen receptor beta (Esr2). Our results demonstrate that ERα masculinizes GABAergic neurons that gate the display of male-typical behaviors.

Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons.

Robust incorporation of new principal cells into pre-existing circuitry in the adult mammalian brain is unique to the hippocampal dentate gyrus (DG). We asked if adult-born granule cells (GCs) might act to regulate processing within the DG by modulating the substantially more abundant mature GCs. Optogenetic stimulation of a cohort of young adult-born GCs (0 to 7 weeks post-mitosis) revealed that these cells activate local GABAergic interneurons to evoke strong inhibitory input to mature GCs. Natural manipulation of neurogenesis by aging-to decrease it-and housing in an enriched environment-to increase it-strongly affected the levels of inhibition. We also demonstrated that elevating activity in adult-born GCs in awake behaving animals reduced the overall number of mature GCs activated by exploration. These data suggest that inhibitory modulation of mature GCs may be an important function of adult-born hippocampal neurons. © 2015 Wiley Periodicals, Inc.

Functional dissociation of adult-born neurons along the dorsoventral axis of the dentate gyrus.

Adult-born granule cells in the mammalian dentate gyrus have long been implicated in hippocampal dependent spatial learning and behavioral effects of chronic antidepressant treatment. Although recent anatomical and functional evidence indicates a dissociation of the dorsal and ventral regions of the hippocampus, it is not known if adult neurogenesis within each region specifically contributes to distinct functions or whether adult-born cells along the entire dorsoventral axis are required for these behaviors. We examined the role of distinct subpopulations of adult-born hippocampal granule cells in learning- and anxiety-related behaviors using low-dose focal x-irradiation directed specifically to the dorsal or ventral dentate gyrus. Our findings indicate a functional dissociation between adult-born neurons along the longitudinal axis of the dentate gyrus wherein new neurons in the dorsal dentate gyrus are required for timely acquisition of contextual discrimination while immature neurons in the ventral dentate gyrus are necessary for anxiolytic/antidepressant-related effects of fluoxetine. Interestingly, when contexts are presented with altered temporal cues, or fluoxetine is administered alongside chronic glucocorticoid treatment, this dissociation is abrogated such that adult-born neurons across the entire dorsoventral extent of the dentate gyrus appear to contribute to these behaviors. Our results suggest that individual subpopulations of adult-born hippocampal neurons may be sufficient to mediate distinct behaviors in certain conditions, but are required to act in concert in more challenging situations.

Development of a Digital Patient Assistant for the Management of Cyclic Vomiting Syndrome: Patient-Centric Design Study.

BACKGROUND: Cyclic vomiting syndrome (CVS) is an enigmatic and debilitating disorder of gut-brain interaction that is characterized by recurrent episodes of severe vomiting and nausea. It significantly impairs patients' quality of life and can lead to frequent medical visits and substantial health care costs. The diagnosis for CVS is often protracted and complex, primarily due to its exclusionary diagnosis nature and the lack of specific biomarkers. This typically leads to a considerable delay in accurate diagnosis, contributing to increased patient morbidity. Additionally, the absence of approved therapies for CVS worsens patient hardship and reflects the urgent need for innovative, patient-centric solutions to improve CVS management. OBJECTIVE: We aim to develop a digital patient assistant (DPA) for patients with CVS to address their unique needs, and iteratively enhance the technical features and user experience on the initial DPA versions. METHODS: The development of the DPA for CVS used a design thinking approach, prioritizing user needs. A literature review and Patient Advisory Board shaped the initial prototype, focusing on diagnostic support and symptom tracking. Iterative development, informed by the design thinking approach and feedback from patients with CVS and caregivers through interviews and smartphone testing, led to significant enhancements in user interaction and artificial intelligence integration. The final DPA's effectiveness was validated using the System Usability Scale and feedback questions, ensuring it met the specific needs of the CVS community. RESULTS: The DPA developed for CVS integrates an introductory bot, daily and weekly check-in bots, and a knowledge hub, all accessible via a patient dashboard. This multicomponent solution effectively addresses key unmet needs in CVS management: efficient symptom and impacts tracking, access to comprehensive disease information, and a digital health platform for disease management. Significant improvements, based on user feedback, include the implementation of artificial intelligence features like intent recognition and data syncing, enhancing the bot interaction and reducing the burden on patients. The inclusion of the knowledge hub provides educational resources, contributing to better disease understanding and management. The DPA achieved a System Usability Scale score of 80 out of 100, indicating high ease of use and relevance. Patient feedback highlighted the DPA's potential in disease management and suggested further applications, such as integration into health care provider recommendations for patients with suspected or confirmed CVS. This positive response underscores the DPA's role in enhancing patient engagement and disease management through a patient-centered digital solution. CONCLUSIONS: The development of this DPA for patients with CVS, via an iterative design thinking approach, offers a patient-centric solution for disease management. The DPA development framework may also serve to guide future patient digital support and research scenarios.

Area postrema neurons mediate interleukin-6 function in cancer cachexia.

Interleukin-6 (IL-6) has been long considered a key player in cancer cachexia. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia. However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, is a critical mediator of IL-6 function in cancer cachexia in male mice. We find that circulating IL-6 can rapidly enter the AP and activate neurons in the AP and its associated network. Peripheral tumor, known to increase circulating IL-6, leads to elevated IL-6 in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons and AP network hyperactivity. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an anti-IL-6 antibody attenuates cachexia and the hyperactivity in the AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra, the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing Gfral-expressing AP neurons also attenuates cancer cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer cachexia.

Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia.

Interleukin-6 (IL-6) has been long considered a key player in cancer-associated cachexia 1-15 . It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia 16-20 . However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, mediate the function of IL-6 in cancer-associated cachexia in mice. We found that circulating IL-6 can rapidly enter the AP and activate AP neurons. Peripheral tumor, known to increase circulating IL-6 1-5,15,18,21-23 , leads to elevated IL-6 and neuronal hyperactivity in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an IL-6 antibody prevents cachexia, reduces the hyperactivity in an AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra , the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing of Gfral-expressing AP neurons also ameliorates the cancer-associated cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer-associated cachexia.

Clinical and Cost Benefits of Anti-Obesity Medication for US Veterans Participating in the MOVE! Weight Management Program.

Abstract This study investigated the clinical and economic impact of anti-obesity medications (AOMs; orlistat, liraglutide, phentermine/topiramate extended-release [ER], naltrexone ER/bupropion ER) among United States Veterans with obesity participating in Motivating Overweight/Obese Veterans Everywhere! (MOVE!), a government-initiated weight management program. The study population was identified from electronic medical records of the Veterans Health Administration (2010-2020). Clinical indices of obesity and health care resource utilization and costs were evaluated at 6, 12, and 24 months after the initial dispensing of an AOM in the AOM+MOVE! cohort (N = 3732, mean age 57 years, 79% male) or on the corresponding date of an inpatient or outpatient encounter in the MOVE! cohort (N = 7883, mean age 58 years, 81% male). At 6 months postindex, the AOM+MOVE! cohort had better cardiometabolic indices (eg, systolic blood pressure, diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, hemoglobin A1c) than the MOVE! cohort, with the trends persisting at 12 and 24 months. The AOM+MOVE! cohort was significantly more likely than the MOVE! cohort to have weight decreases of 5%-10%, 10%-15%, and >15% and lower body mass index at 6, 12, and 24 months. The AOM+MOVE! cohort also had fewer inpatient and emergency department visits than the MOVE! cohort, which was associated with lower mean total medical costs including inpatient costs. These results suggest that combining AOM treatment with the MOVE! program could yield long-term cost savings for the Veterans Affairs network and meaningful clinical improvements for Veterans with obesity.

Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R〿2-targeting CAR T cells: an interim analysis.

Outcomes for pediatric brain tumor patients remain poor, and there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T cells delivered weekly into the lateral cerebral ventricles, identifying clonal expansion of endogenous CAR-negative CD8+ T cells in the cerebrospinal fluid (CSF) over time. Additionally, of the five patients evaluable for disease response, three experienced transient radiographic and/or clinical benefit not meeting protocol criteria for response. The first three patients received CAR T cells alone; later patients received lymphodepletion before the first infusion. There were no dose limiting toxicities (DLTs). Aside from expected cytopenias in patients receiving lymphodepletion, serious adverse events possibly attributed to CAR T cell infusion were limited to one episode of headache and one of liver enzyme elevation. One patient withdrew from treatment during the DLT period due to a Grade 3 catheter-related infection and was not evaluable for disease response, although this was not attributed to CAR T cell infusion. Importantly, scRNA- and scTCR-sequence analyses provided insights into CAR T cell interaction with the endogenous immune system. In particular, clonally expanded endogenous CAR- T cells were recovered from the CSF, but not the peripheral blood, of patients who received intraventricular IL13BBζ-CAR T cell therapy. Additionally, although immune infiltrates in CSF and post-therapy tumor did not generally correlate, a fraction of expanded T cell receptors (TCRs) was seen to overlap between CSF and tumor. This has important implications for what samples are collected on these trials and how they are analyzed. These initial findings provide support for continued investigation into locoregionally-delivered IL13BBζ-CAR T cells for children with brain tumors.

Trends in U.S. Depression Prevalence From 2015 to 2020: The Widening Treatment Gap.

INTRODUCTION: Major depression is a common and potentially lethal condition. Early data suggest that the population-level burden of depression has been exacerbated by the COVID-19 pandemic. Prepandemic estimates of depression prevalence are required to quantify and comprehensively address the pandemic's impact on mental health in the U.S. METHODS: Data were drawn from the 2015-2020 National Survey on Drug Use and Health, a nationally representative study of U.S. individuals aged ≥12 years. The prevalence of past-year depression and help seeking for depression were estimated from 2015 to 2019, and time trends were tested with Poisson regression with robust SEs. Point estimates were calculated for 2020 and not included in statistical trend analyses because of differences in data collection procedures. RESULTS: In 2020, 9.2% (SE=0.31) of Americans aged ≥12 years experienced a past-year major depressive episode. Depression was more common among young adults aged 18-25 years (17.2%, SE=0.78), followed closely by adolescents aged 12-17 years (16.9%, SE=0.84). Depression increased most rapidly among adolescents and young adults and increased among nearly all sex, racial/ethnic, income, and education groups. Depression prevalence did not change among adults aged ≥35 years, and the prevalence of help seeking remained consistently low across the study period. CONCLUSIONS: From 2015 to 2019, there were widespread increases in depression without commensurate increases in treatment, and in 2020, past 12‒month depression was prevalent among nearly 1 in 10 Americans and almost 1 in 5 adolescents and young adults. Decisive action involving a multipronged public health campaign that includes evidence-based prevention and intervention to address this ongoing mental health crisis is urgently needed.

Impact of switching to infliximab biosimilars on treatment patterns among US veterans receiving innovator infliximab.

OBJECTIVE: To compare treatment patterns of United States (US) veterans stable on innovator infliximab (IFX) who switched to an IFX biosimilar (switchers) or remained on innovator IFX (continuers). METHODS: US Veterans Healthcare Administration data (01/2012-12/2019) were used to identify adults with rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis (PsO), ankylosing spondylitis (AS), or Crohn's disease and ulcerative colitis (i.e. inflammatory bowel disease [IBD]), treated with innovator or biosimilar IFX. Index date was the first IFX biosimilar administration for switchers or a random innovator IFX administration for continuers. Patients were required to have ≥5 innovator IFX administrations during the 12 months pre-index (prevalent population). Patients with ≥12 months of observation prior to the first innovator IFX administration were analyzed as the primary population (incident population), and data were assessed from start of innovator IFX. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Treatment patterns were evaluated post-index; continuers were censored before switching to IFX biosimilar. Discontinuation was defined as switching to another biologic (including innovator IFX) or having ≥120 days between 2 consecutive index treatment records. RESULTS: In the incident population, mean [median] duration of follow-up was 737 [796] days among switchers (N = 838) and 479 [337] days among continuers (N = 849). Compared to continuers, switchers were 2.88-times more likely to discontinue index therapy (hazard ratio [HR] = 2.88, p < .001) and 4.99-times more likely to switch to another innovator biologic (HR = 4.99, p < .001). Of 653 switchers switching to another innovator biologic, 594 (91.0%) switched back to innovator IFX. Results were similar among the prevalent population and RA and IBD subgroups. CONCLUSION: Patients switching from innovator to biosimilar IFX were more likely to discontinue treatment and switch to another innovator biologic (notably back to innovator IFX) than those remaining on innovator IFX; however, reasons for discontinuation and switching are unknown.

A difference-in-difference approach to examining the impact of cannabis legalization on disparities in the use of cigarettes and cannabis in the United States, 2004-17.

AIMS: To estimate the impact of recreational and medical cannabis laws (RCL, MCL) on the use of cannabis and cigarettes in the United States. DESIGN: A difference-in-difference approach was applied to data from the 2004-17 National Survey on Drug Use and Health (NSDUH). SETTING: United States. PARTICIPANTS: Nationally representative cross-sectional survey of Americans aged 12 years and older (combined analytical sample for 2004-17, n = 783 663). MEASUREMENTS: Data on past-month use of (1) cigarettes and (2) cannabis were used to classify respondents into four groups: cigarette and cannabis co-use, cigarette-only use, cannabis-only use or no cigarette or cannabis use. State of residence was measured by self-report. MCL/RCL status came from state government websites. FINDINGS: Difference-in-difference analyses suggest that MCL was associated with an increase in cigarette-cannabis co-use overall [adjusted odds ratio (aOR) = 1.09; 95% confidence interval (CI) = 1.02-1.16], with the greatest increases among those aged 50 years and above (aOR = 1.60; CI = 1.39-1.84), married (aOR = 1.19; CI = 1.07-1.31), non-Hispanic (NH) black (aOR = 1.14; CI = 1.02-1.07) and with a college degree or above (aOR = 1.15; CI = 1.06-1.24). MCL was associated with increases in cigarette-only use among those aged 50 years and above (aOR = 1.07; CI = 1.01-1.14) and NH black (aOR = 1.16; CI = 1.06-1.27) and increases in cannabis-only use among those aged 50 years and above (aOR = 1.24; CI = 1.07-1.44) and widowed/divorced/separated (aOR = 1.18; CI = 1.01-1.37). RCL was associated with an increase in cannabis-only use overall (aOR = 1.21; 95% CI = 1.09-1.34), a decline in cigarette-only use overall (aOR = 0.89; 95% CI = 0.81-0.97) and increases in co-use among those who were married (aOR = 1.24; CI = 1.02-1.50) and aged 50 years and above (aOR = 1.37; CI = 1.03-1.84). CONCLUSIONS: Recreational and medical cannabis legalization have had a varying impact on the use, and co-use, of cannabis and cigarettes in the United States.

Literature Review of Fatigue Scales and Association with Clinically Meaningful Improvements in Outcomes Among Patients With and Without Paroxysmal Nocturnal Hemoglobinuria.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by anemia and debilitating fatigue. Limited evidence characterizes the association between hemoglobin, an indicator of anemia and disease activity, and patient-reported fatigue scales. This review identifies benchmarks for clinically meaningful improvements in patients with and without PNH. METHODS: MEDLINE, Embase, Cochrane, and PsycINFO databases were searched along with Google Scholar to identify publications for patients with and without PNH. Full-text articles and conference abstracts of clinical trials or observational studies that examined patient-reported fatigue or associations between fatigue and hemoglobin were included. RESULTS: Fourteen publications were included in this study. Four clinical trials conducted in patients with PNH reported that patients achieved and sustained clinically meaningful improvements in fatigue. However, these studies did not examine the association between fatigue and hemoglobin. Ten studies conducted in patients with cancer and anemia (with or without chemotherapy) demonstrated an association between increased hemoglobin and improvements in fatigue (P < 0.05). The greatest incremental gain in fatigue improvement was observed when hemoglobin increased from 11 to 12 g/dL. CONCLUSION: Evidence among patients with cancer without PNH demonstrates that increased hemoglobin levels are associated with clinically significant improvements in fatigue. Future studies should validate this relationship among patients with PNH.

Real-World Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 2015-2020.

Real-world evidence (RWE) has garnered great interest to support registration of new therapies and label expansions by the United States Food and Drug Administration (FDA). Currently, practical insights on the design and analysis of regulatory-grade RWE are lacking. This study aimed to analyze attributes of real-world studies in FDA's decision-making and characteristics of full versus accelerated approvals through a systematic review of oncology product approvals. Oncology approvals from 2015 to 2020 were reviewed from FDA.gov. Applications were screened for inclusion of RWE, and variables related to regulatory designations of the application, pivotal clinical trial, and real-world studies were extracted. FDA feedback was reviewed to identify takeaways and best practices for adequate RWE. Among 133 original and 573 supplemental approvals for oncology, 11 and 2, respectively, included RWE; none predated 2017. All real-world studies were retrospective in nature; the most common data source was chart review, and the most common primary endpoint was overall response rate, as in the pivotal trial. The FDA critiqued the lack of the following: a prespecified study protocol, inclusion/exclusion criteria matching to the trial, comparability of endpoint definitions, methods to minimize confounding and address unmeasured confounding, and plans to handle missing data. All full (versus accelerated) approvals shared the following characteristics: high magnitude of efficacy in the pivotal trial; designations of orphan disease, breakthrough therapy, and priority review; and no advisory committee meeting held. This study found that findings from external control real-world studies complemented efficacy data from single-arm trials in successful oncology product approvals.

Trends in cannabis use among adults with children in the home in the United States, 2004-2017: impact of state-level legalization for recreational and medical use.

BACKGROUND AND AIMS: Cannabis use among parents may be increasing with legalization, but perception of associated risk has declined. The study investigated the association between cannabis legalization and cannabis use among adults with children in the home over time in the United States (US). DESIGN: A difference-in-difference approach was applied to public and restricted-use data from the 2004-2017 National Survey on Drug Use and Health (NSDUH), an annual cross-sectional survey. SETTING: A representative sample of the United States. PARTICIPANTS/CASES: Respondents ages 18+ with children living in the home drawn from the NSDUH (n = 287,624), which is administered to non-institutionalized civilians in the 50 states and District of Columbia. MEASUREMENTS: Exposures were year and state-level cannabis policy in state of residence annually. Outcomes were past-30-day cannabis use and daily cannabis use. Sociodemographic variables included age, gender, marital status, annual family income, race/ethnicity, educational attainment, and strength of state-level tobacco control. FINDINGS: In 2017, past-month cannabis use (11.9%, 9.3%, and 6.1%) and daily cannabis use (4.2%, 3.2%, and 2.3%) were more common in states with recreational marijuana laws (RML), followed by states with medical marijuana laws (MML) and without legal cannabis use, respectively. RML and MML were associated with significantly higher prevalence of past-month cannabis use (adjusted odds ratio [AOR] = 1.28, 95% confidence interval [CI] = 1.12-1.46; AOR = 1.12, 95% CI = 1.03-1.22) and daily cannabis use (AOR = 1.25, 95% CI = 1.03-1.51; AOR = 1.16, 95% CI = 1.02-1.32), respectively. The impact of MML was particularly salient among adults ages 50+ and the highest income and education subgroups. CONCLUSIONS: Among adults with children living in the home, cannabis use appears to be more common in US states with legalized cannabis use compared with states with no legal cannabis use. Recreational legalization appears to increase use among adults with children in the home broadly across nearly all sociodemographic groups, whereas the effect of legalization for medical use is heterogeneous by age and socioeconomic status.