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Background: Sleep problems are common in adults with ADHD and may be bidirectionally associated with ADHD severity and other psychiatric symptoms. We investigated the prevalence of positive screenings for various sleep disorders, and their association with psychiatric comorbidities in a large sample of adults with ADHD from a specialized outpatient clinic. Methods: We included data of 3,691 adult patients diagnosed with ADHD, who had filled out a screener for sleep disorders (Holland Sleep Disorders Questionnaire (HSDQ)) as part of routine diagnostic assessment. The HSDQ screens for the sleep disorders insomnia, parasomnia, hypersomnia, circadian rhythm sleep disorders (CRSD), restless legs syndrome (RLS)/periodic limb movement disorder (PLMD), and sleep-related breathing disorders (SBD). As delayed sleep phase syndrome (DSPS) is very frequent in ADHD, we additionally screened for DSPS. Psychiatric comorbidities were diagnosed through clinical assessment and the Mini International Neuropsychiatric Interview (M.I.N.I.) Plus, which assesses 26 psychiatric disorders following the classification of the DSM-5. All data were retrieved from the electronic patient files. Results: Mean age was 35.4 and 49.4% of the patients were female. About 60% of the adults with ADHD screened positive for any sleep disorder. Highest prevalences were found for symptoms of DSPS (36%), insomnia (30%), and RLS/ PLMD (29%). Sleep problems in adults with ADHD were associated with comorbid depression, anxiety, substance use disorder, personality disorder, and post-traumatic stress disorder. Conclusion: Adults with ADHD often report sleep problems, which are associated with specific psychiatric comorbidities. Systematic screening for sleep disorders in adult patients with ADHD can contribute to a better understanding of their complaints and may aid improved and integrated treatment for the sleep and psychiatric problems.

Background: ADHD is highly comorbid with Delayed Sleep Phase Syndrome (DSPS). Both are associated with obesity and diabetes, which can be caused by long-term dysregulations of appetite and glucose metabolism. This study explores hormones involved in these processes and the effects of chronotherapeutic interventions in a small sample of adults with ADHD and DSPS. Methods: Exploratory, secondary analysis of data from the PhASE study, a three-armed randomized clinical trial, are presented, including 37 adults (18-53 years) with ADHD and DSPS receiving three weeks of 0.5 mg/day (1) placebo, (2) melatonin, or (3) melatonin plus 30 minutes of bright light therapy (BLT). Leptin (appetite-suppressing), ghrelin (appetite-stimulating), insulin, insulin-like growth factor-1 (IGF-1), and glucose were measured from blood collected at 08:00 hours. Salivary cortisol was collected during the first 30 minutes after awakening and self-reported appetite was assessed. Results: Baseline leptin and IGF-1 levels were higher than reference ranges, and ghrelin and cortisol levels were lower, while insulin and glucose were normal. Melatonin treatment decreased leptin and insulin. Other outcomes remained unchanged and melatonin + BLT had no effects. Conclusion: Due to the small sample size and exploratory nature of the study, results should be interpreted with caution. Overall, these results show no strong indications for dysregulation of appetite and glucose metabolism to suggest high risk of obesity and diabetes in this small sample of adults with ADHD and DSPS. However, baseline appetite was suppressed, likely because measurements took place in the early morning which could be considered the biological night for this study population. Melatonin treatment seemed to cause subtle changes in appetite-regulating hormones suggesting increased appetite. Chronotherapeutic treatment may affect appetite-regulating hormones by advancing the biological rhythm and/or altering eating behaviors, but this remains to be investigated in larger samples using detailed food diaries.

Maartje Goorden,1 Christina M van der Feltz-Cornelis,2,3 Kirsten M van Steenbergen-Weijenburg,4 Eva K Horn,5 Aartjan TF Beekman,6,7 Leona Hakkaart-van Roijen1 1Institute of Health Policy and Management (iBMG)/Institute for Medical Technology Assessment (iMTA), Erasmus University Rotterdam, Rotterdam, 2Tranzo Department, Tilburg University, 3Clinical Centre of Excellence for Body, Mind and Health, GGzBreburg, Tilburg, 4Trimbos Instituut, Utrecht, 5Viersprong Institute for Studies on Personality Disorders, Halsteren, 6Department of Psychiatry, 7EMGO+ Research Institute VUmc, VU University Medical Centre, Amsterdam, the Netherlands Purpose: Major depressive disorder (MDD) is highly prevalent in patients with a chronic physical condition, and this comorbidity has a negative influence on quality of life, health care costs, self-care, morbidity, and mortality. Research has shown that collaborative care (CC) may be a cost-effective treatment. However, its cost-effectiveness in this patient group has not yet been established. Therefore, the aim of this study was to evaluate the cost-utility of CC for the treatment of comorbid MDD in chronically ill patients in the outpatient general hospital setting. The study was conducted from a health care and societal perspective.Patients and methods: In this randomized controlled trial, 81 patients with moderate-to-severe MDD were included; 42 were randomly assigned to the CC group and 39 to the care as usual (CAU) group. We applied the TiC-P, short-form Health-Related Quality of Life questionnaire, and EuroQol EQ-5D 3 level version, measuring the use of health care, informal care, and household work, respectively, at baseline and at 3, 6, 9, and 12 months follow-up.Results: The mean annual direct medical costs in the CC group were €6,718 (95% confidence interval [CI]: 3,541 to 10,680) compared to €4,582 (95% CI: 2,782 to 6,740) in the CAU group. The average quality-adjusted life years (QALYs) gained were 0.07 higher in the CC group, indicating that CC is more costly but also more effective than CAU. From a societal perspective, the incremental cost-effectiveness ratio was €24,690/QALY.Conclusion: This first cost-utility analysis in chronically ill patients with comorbid MDD shows that CC may be a cost-effective treatment depending on willingness-to-pay levels. Nevertheless, the low utility scores emphasize the need for further research to improve the cost-effectiveness of CC in this highly prevalent and costly group of patients. Keywords: collaborative care, randomized controlled trial, chronic physical condition, major depressive disorder, cost-utility, general hospital, CC–DIM

BackgroundOver the past 30 years, there have been significant advances in the understanding of the mechanisms associated with loss and recovery of consciousness following severe brain injury. This work has provided a strong grounding for the development of novel restorative therapeutic interventions. Although all interventions are aimed at modulating and thereby restoring brain function, the landscape of existing interventions encompasses a very wide scope of techniques and protocols. Despite vigorous research efforts, few approaches have been assessed with rigorous, high-quality randomized controlled trials. As a growing number of exploratory interventions emerge, it is paramount to develop standardized approaches to reporting results. The successful evaluation of novel interventions depends on implementation of shared nomenclature and infrastructure. To address this gap, the Neurocritical Care Society's Curing Coma Campaign convened nine working groups and charged them with developing common data elements (CDEs). Here, we report the work of the Therapeutic Interventions Working Group.MethodsThe working group reviewed existing CDEs relevant to therapeutic interventions within the National Institutes of Health National Institute of Neurological Disorders and Stroke database and reviewed the literature for assessing key areas of research in the intervention space. CDEs were then proposed, iteratively discussed and reviewed, classified, and organized in a case report form (CRF).ResultsWe developed a unified CRF, including CDEs and key design elements (i.e., methodological or protocol parameters), divided into five sections: (1) patient information, (2) general study information, (3) behavioral interventions, (4) pharmacological interventions, and (5) device interventions.ConclusionsThe newly created CRF enhances systematization of future work by proposing a portfolio of measures that should be collected in the development and implementation of studies assessing novel interventions intended to increase the level of consciousness or rate of recovery of consciousness in patients with disorders of consciousness.

Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are present but fluctuate. Disorders of consciousness are commonly encountered as a consequence of both acute and chronic brain injuries, yet reliable epidemiological estimates would require inclusive, operational definitions of the concept, as well as wider knowledge dissemination among involved professionals. Whereas several manifestations have been described, including coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state, a comprehensive neurobiological definition for disorders of consciousness is still lacking. The scientific literature is primarily observational, and studies-specific aetiologies lead to disorders of consciousness. Despite advances in these disease-related forms, there remains uncertainty about whether disorders of consciousness are a disease-agnostic unitary entity with a common mechanism, prognosis or treatment response paradigm. Our knowledge of disorders of consciousness has also been hampered by heterogeneity of study designs, variables, and outcomes, leading to results that are not comparable for evidence synthesis. The different backgrounds of professionals caring for patients with disorders of consciousness and the different goals at different stages of care could partly explain this variability. The Prospective Studies working group of the Neurocritical Care Society Curing Coma Campaign was established to create a platform for observational studies and future clinical trials on disorders of consciousness and coma across the continuum of care. In this narrative review, the author panel presents limitations of prior observational clinical research and outlines practical considerations for future investigations. A narrative review format was selected to ensure that the full breadth of study design considerations could be addressed and to facilitate a future consensus-based statement (e.g. via a modified Delphi) and series of recommendations. The panel convened weekly online meetings from October 2021 to December 2022. Research considerations addressed the nosographic status of disorders of consciousness, case ascertainment and verification, selection of dependent variables, choice of covariates and measurement and analysis of outcomes and covariates, aiming to promote more homogeneous designs and practices in future observational studies. The goal of this review is to inform a broad community of professionals with different backgrounds and clinical interests to address the methodological challenges imposed by the transition of care from acute to chronic stages and to streamline data gathering for patients with disorders of consciousness. A coordinated effort will be a key to allow reliable observational data synthesis and epidemiological estimates and ultimately inform condition-modifying clinical trials.

Abstract This post-hoc analysis of the SABINA III study evaluated the association of short-acting β2-agonist (SABA) prescriptions and self-reported over-the-counter (OTC) SABA purchase in the previous 12 months with asthma-related outcomes using multivariable regression models in 4556 patients (mean age, 48.9 years). Of the 2810 patients prescribed ≥3 SABA canisters, 776 (27.6%) also purchased ≥1 SABA OTC. This subset of 776 patients reported the highest disease burden; 73.2% had ≥1 severe exacerbation and 55.7% had uncontrolled asthma. Asthma-related outcomes worsened with any SABA OTC purchase, regardless of SABA prescriptions; disease burden was the highest in patients with ≥3 SABA prescriptions and ≥1 SABA OTC purchase vs 1–2 SABA prescriptions only (86% lower odds of having at least partly controlled asthma and 124% increased incidence of severe asthma (both P

Summary: Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Abstract Background Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined. Methods We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B‐cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high‐dose methotrexate (HD‐MTX) containing chemotherapy regimens: MPV/Ara‐C (HD‐MTX, procarbazine, and vincristine, followed by cytarabine [Ara‐C]) (n = 94, 50%), MATRix (HD‐MTX, Ara‐C, thiotepa, and rituximab) (n = 19, 10%), HD‐MTX/Ara‐C (n = 31, 16%), HD‐MTX monotherapy (n = 35, 18%) and MBVP (HD‐MTX, carmustine, teniposide, prednisolone) (n = 11, 6%). Results Cumulative median HD‐MTX and Ara‐C doses were 17 g/m2 (range: 1–64 g/m2) and 12 g/m2 (0–32 g/m2) respectively. Using 14 g/m2 as the reference dose, the median HD‐MTX relative dose intensity (HD‐MTX‐RDI) was 1.25 (0.27‐4.57) with 84% receiving > 0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD‐MTX. At a median follow‐up of 3.41 years (0.06–9.42), progression‐free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara‐C cohort (2‐year PFS 74%, 2‐year OS 82%; p = 0.0001 and p = 0.0024 respectively). On multivariate analysis, MPV/Ara‐C administration and HD‐MTX‐RDI > 0.75 were associated with longer PFS and OS. Conclusion Sequential, response‐adapted approaches can improve outcomes, even in older patients who are ineligible for a high‐intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies.

Abstract Molecular effects of lifestyle interventions are typically studied in a single tissue. Here, we perform a secondary analysis on the sex-specific effects of the Growing Old TOgether trial (GOTO, trial registration number GOT NL3301 ( https://onderzoekmetmensen.nl/nl/trial/27183 ), NL-OMON27183 , primary outcomes have been previously reported in ref. 1), a moderate 13-week combined lifestyle intervention on the transcriptomes of postprandial blood, subcutaneous adipose tissue (SAT) and muscle tissue in healthy older adults, the overlap in effect between tissues and their relation to whole-body parameters of metabolic health. The GOTO intervention has virtually no effect on the postprandial blood transcriptome, while the SAT and muscle transcriptomes respond significantly. In SAT, pathways involved in HDL remodeling, O2/CO2 exchange and signaling are overrepresented, while in muscle, collagen and extracellular matrix pathways are significantly overexpressed. Additionally, we find that the effects of the SAT transcriptome closest associates with gains in metabolic health. Lastly, in males, we identify a shared variation between the transcriptomes of the three tissues. We conclude that the GOTO intervention has a significant effect on metabolic and muscle fibre pathways in the SAT and muscle transcriptome, respectively. Aligning the response in the three tissues revealed a blood transcriptome component which may act as an integrated health marker for metabolic intervention effects across tissues.