Studies show stimulant medications are effective for different ADHD presentations (predominantly inattentive [IA], predominantly hyperactive-impulsive [HI] or combined [C]); however, few studies have evaluated nonstimulant efficacy in different ADHD presentations. Viloxazine ER [VLX ER] is a nonstimulant, FDA-approved medication for pediatric (≥6 yrs) and adult ADHD. This post-hoc analysis of 4 double-blind (DB), Phase 3, clinical trials (2 in adolescents [NCT03247517 and NCT03247556], 2 in children [NCT03247530 and NCT03247543]), evaluates VLX ER efficacy by ADHD presentation as derived from ADHD Rating Scale, 5th Edition (ADHD-RS-5) assessments at Baseline.

Children and adolescents with ADHD and an ADHD-RS-5 Total score ≥ 28 were eligible for enrollment. ADHD presentation was defined as a rating of ≥2 on at least 6 of 9 ADHD-RS-5 inattention items, or hyperactive-impulsive items or both. For each ADHD presentation, the change from Baseline (CFB) in ADHD-RS-5 Total score (primary outcome in each study) was assessed using mixed models for repeated measures (MMRM). Responder rate (secondary outcome), ≥50% reduction from baseline in ADHD-RS-5 Total score, was analyzed using generalized estimating equations (GEE).

Of 1354 subjects [placebo N = 452, VLX ER N = 902], ADHD presentation was assigned as 288 (21.3%) [IA], 1010 (74.5%) [C], 40 (3.0%) [HI], 16 (1.2%) [none of these]. Due to the small sample size of [HI], only the [IA] and [C] results are presented. At Week 6 (pooled data endpoint), ADHD-RS-5 Total scores were significantly improved for VLX ER relative to placebo for both the [IA] and [C] ADHD presentations. LS mean (SE) treatment differences, p-values were: [IA] -3.1 (1.35), p = 0.0219, and [C] 5.8 (0.97), p < 0.0001. Responder rates were also significantly higher for VLX ER: 43.0% [IA] and 42.7% [C] relative to placebo 29.5% [IA] and 25.5 % [C] (p=.0311 and p<.0001).

Viloxazine ER significantly reduced ADHD symptoms in individuals meeting criteria for ADHD [IA] or [C] presentations at Baseline. Limitations include post-hoc methodology, smaller sample sizes of [IA] and [HI] groups, and the ADHD-RS-5 ≥ 28 eligibility requirement, that may favor enrollment of individuals with ADHD [C] over ADHD [IA] or [HI] presentations. Consistency of response during long-term use should be evaluated.

Supernus Pharmaceuticals, Inc.

Viloxazine ER (extended-release capsules; Qelbree®) is a nonstimulant medication, FDA-approved for ADHD in children (≥6 years) and adults. Efficacy and safety for children and adolescents were evaluated in one phase 2 [NCT02633527]and four phase 3 [NCT03247517, NCT03247556, NCT03247530, and NCT03247543], double-blind (DB), placebo-controlled trials that fed into a long-term, open-label extension (OLE) trial [NCT02736656]. Here we report the findings from this OLE trial.

Participants completing the DB trials were eligible for the OLE. Viloxazine ER was initiated at 100 mg/day (children) or 200 mg/day (adolescents) and adjusted (if needed) over a 12-week Dose-Optimization Period (up to 400 mg/day [children] or 600 mg/day [adolescents]). Maintenance treatment then continued up to 72 months. Safety assessments included adverse events (AEs), clinical laboratory tests, vital signs, ECG (12-lead), and the Columbia Suicide Severity Rating Scale (C-SSRS). Efficacy assessments included the ADHD Rating Scale, 4th (Phase 2) or 5th (Phase 3) Edition (ADHD-RS-IV/5), and the Clinical Global Impression-Improvement (CGI-I) scale. Efficacy was assessed relative to DB baseline at study visits ˜ 3 months apart. Two response measures, 50% improvement in ADHD-RS-IV/5 Total score and CGI-I score of 1-2, were also evaluated.

1100 individuals (646 children; 454 adolescents; 66.5% male/33.5% female) received treatment. Median (range) exposure to viloxazine ER was 260 (1 to 1896) days. AEs were reported by 57.3% participants, most commonly (≥5%) nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%) decreased appetite (6.0%), and fatigue (5.7%). AEs were mostly mild or moderate in severity (3.9% reported any severe AE); AEs led to viloxazine ER discontinuation for 8.2%. The mean (SD) changes from DB baseline in ADHD-RS IV/5 Total score were -17.0 (14.18) (viloxazine ER) and -11.2 (13.19) (placebo) at the last DB study visit, 24.3 (11.96) at OLE Month 3, and 22.4 (13.62) at participants’ last OLE study visit. ADHD-RS-IV/5 and CGI-I responder rates each exceeded 65% at all OLE visits following Dose-Optimization.

The safety and efficacy of viloxazine ER were maintained with long-term use in children and adolescents with ADHD. No new safety concerns emerged, and efficacy results suggested potential for continued improvement over that seen during DB treatment.

Supernus Pharmaceuticals, Inc.

Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical end-points in early Alzheimer's disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments, considering the resources required for their administration and monitoring.

To estimate the scale of real-world demand for monoclonal antibodies for Alzheimer's disease in the UK.

We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab, with consideration given to diagnosis, cognitive performance, cerebrovascular disease and willingness to receive treatment.

We examined the records of 82 386 people referred to services covering around 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30 200 people if extrapolated nationally.

Monoclonal antibody treatments for Alzheimer's disease are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly.

The focus on social determinants of health (SDOH) and their impact on health outcomes is evident in U.S. federal actions by Centers for Medicare & Medicaid Services and Office of National Coordinator for Health Information Technology. The disproportionate impact of COVID-19 on minorities and communities of color heightened awareness of health inequities and the need for more robust SDOH data collection. Four Clinical and Translational Science Award (CTSA) hubs comprising the Texas Regional CTSA Consortium (TRCC) undertook an inventory to understand what contextual-level SDOH datasets are offered centrally and which individual-level SDOH are collected in structured fields in each electronic health record (EHR) system potentially for all patients.

Hub teams identified American Community Survey (ACS) datasets available via their enterprise data warehouses for research. Each hub’s EHR analyst team identified structured fields available in their EHR for SDOH using a collection instrument based on a 2021 PCORnet survey and conducted an SDOH field completion rate analysis.

One hub offered ACS datasets centrally. All hubs collected eleven SDOH elements in structured EHR fields. Two collected Homeless and Veteran statuses. Completeness at four hubs was 80%–98%: Ethnicity, Race; < 10%: Education, Financial Strain, Food Insecurity, Housing Security/Stability, Interpersonal Violence, Social Isolation, Stress, Transportation.

Completeness levels for SDOH data in EHR at TRCC hubs varied and were low for most measures. Multiple system-level discussions may be necessary to increase standardized SDOH EHR-based data collection and harmonization to drive effective value-based care, health disparities research, translational interventions, and evidence-based policy.

Normal pressure hydrocephalus (NPH) is characterized by pathologically enlarged ventricles without elevated cerebrospinal fluid (CSF) pressure along with a triad of clinical symptoms including gait disturbances, urinary incontinence, and cognitive impairment. NPH is evaluated with lumbar drain trials (LDTs) where CSF is removed over several days to determine if patients would benefit from ventricular shunting. Candidate selection and success for these surgeries remains challenging because other diseases such as Alzheimer’s disease (AD) share common features with NPH in cognitive impairment and enlarged ventricles. Prior research has found that 20%-40% of presumed NPH cases have AD pathology as determined by brain biopsy or autopsy. CSF biomarkers of AD can be altered in NPH and are not always conclusive, complicating the interpretation of results when formulating diagnoses and prognoses. Studies to refine the analyses of AD CSF biomarkers in NPH are needed. We aimed to examine the frequency of CSF biomarker results among patients presenting for NPH evaluations with LDTs.

62 patients presented for LDTs upon physician recommendations. CSF specimens were sent to Mayo Clinic Laboratories for Alzheimer Disease Evaluation (ADEVL) that utilizes Elecsys (Lenexa, KS) CSF electrochemiluminescence immunoassays (Roche Diagnostics, Basel, Switzerland) to measure levels of amyloid-beta 42 (Aβ42), total tau (t-tau), and phosphorylatedtau (p-tau), and p-tau:Aβ42 ratio. Results were classified based on interpretation through the Amyloid/Tau/Neurodegeneration (ATN) framework1: 1) AD - biomarker profile consistent with AD pathologic change, 2) non-AD profile - biomarker levels normal or inconsistent with AD pathologic change, or 3) indeterminate - biomarkers were incongruous with only one or two abnormal levels of Aβ42, t-tau, p-tau, or ptau: Aβ42. Indeterminate cases may represent altered protein levels due to CSF dynamics or AD-related pathologic change. In reviewing recent research on CSF dynamics and AD biomarkers in NPH2 a p-tau threshold of 15 pg/mL was derived and implemented such that cases with Aß42 <=1026 pg/mL and p-tau <15 pg/mL were designated as suspected non-AD, and those with Aß42 <=1026 pg/mL and p-tau >15 pg/mL were designated suspected AD.

Of the 62 LDT cases, 12 (19.35%) were classified as AD, 31 (50%) were indeterminate and 22 (35.48%) were non-AD. Of the 31 indeterminate cases, 21 (33.87% of the overall sample) were suspected non-AD and 7 (11.29% of the full sample) were categorized as suspected AD.

Our findings show that 20%-30% of patients presenting for LDT showed evidence for AD-type pathologic change, consistent with prior reports of AD pathology in cases of possible NPH. Half of all LDT cases had indeterminate AD CSF biomarker results, the interpretations of which were confounded by the potential alterations of CSF biomarkers levels due to NPH independent of AD. Our findings emphasize the need to establish better approaches to interpreting CSF AD biomarkers in evaluating NPH. Future research should examine the discriminative utility of CSF AD biomarkers and the selected p-tau threshold in indeterminate cases for predicting response to LDT and shunting.

To investigate the effect of body mass index on hearing outcomes, operative time and complication rates following stapes surgery.

This is a five-year retrospective review of 402 charts from a single tertiary otology referral centre from 2015 to 2020.

When the patient's shoulder was adjacent to the surgeon's dominant hand, the average operative time of 40 minutes increased to 70 minutes because of a significant positive association between higher body mass index and longer operative times (normal body mass index group (<25 kg/m2) r = 0.273, p = 0.032; overweight body mass index group (25–30 kg/m2) r = 0.265, p = 0.019). Operative times were not significantly longer upon comparison of low and high body mass index groups without stratification by laterality (54.9 ± 19.6 minutes vs 57.8 ± 19.2 minutes, p = 0.127).

There is a clinically significant relationship between body mass index and operating times. This may be due to access limitations imposed by shoulder size.

Clinical trials are a vital component of translational science, providing crucial information on the efficacy and safety of new interventions and forming the basis for regulatory approval and/or clinical adoption. At the same time, they are complex to design, conduct, monitor, and report successfully. Concerns over the last two decades about the quality of the design and the lack of completion and reporting of clinical trials, characterized as a lack of “informativeness,” highlighted by the experience during the COVID-19 pandemic, have led to several initiatives to address the serious shortcomings of the United States clinical research enterprise.

Against this background, we detail the policies, procedures, and programs that we have developed in The Rockefeller University Center for Clinical and Translational Science (CCTS), supported by a Clinical and Translational Science Award (CTSA) program grant since 2006, to support the development, conduct, and reporting of informative clinical studies.

We have focused on building a data-driven infrastructure to both assist individual investigators and bring translational science to each element of the clinical investigation process, with the goal of both generating new knowledge and accelerating the uptake of that knowledge into practice.

Cannabis use has been linked to psychotic disorders but this association has been primarily observed in the Global North. This study investigates patterns of cannabis use and associations with psychoses in three Global South (regions within Latin America, Asia, Africa and Oceania) settings.

Case–control study within the International Programme of Research on Psychotic Disorders (INTREPID) II conducted between May 2018 and September 2020. In each setting, we recruited over 200 individuals with an untreated psychosis and individually-matched controls (Kancheepuram India; Ibadan, Nigeria; northern Trinidad). Controls, with no past or current psychotic disorder, were individually-matched to cases by 5-year age group, sex and neighbourhood. Presence of psychotic disorder assessed using the Schedules for Clinical Assessment in Neuropsychiatry and cannabis exposure measured by the World Health Organisation Alcohol, Smoking and Substance Involvement Screening Test (ASSIST).

Cases reported higher lifetime and frequent cannabis use than controls in each setting. In Trinidad, cannabis use was associated with increased odds of psychotic disorder: lifetime cannabis use (adj. OR 1.58, 95% CI 0.99–2.53); frequent cannabis use (adj. OR 1.99, 95% CI 1.10–3.60); cannabis dependency (as measured by high ASSIST score) (adj. OR 4.70, 95% CI 1.77–12.47), early age of first use (adj. OR 1.83, 95% CI 1.03–3.27). Cannabis use in the other two settings was too rare to examine associations.

In line with previous studies, we found associations between cannabis use and the occurrence and age of onset of psychoses in Trinidad. These findings have implications for strategies for prevention of psychosis.

Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact.

We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations.

BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI.

We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.