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Indigenous Australian students generally attain poorer educational outcomes compared to non-Indigenous students. However, some remote schools are challenging the status quo by providing schooling experiences where Indigenous students thrive. Using an Indigenous research paradigm and a comparative case study methodology, we conducted interviews with stakeholders from two different remote community schools where students were predominantly Indigenous. Recognising the limitations of assessing student success solely on westernised concepts of success, we adopted a strengths-based approach. Using thematic analysis, qualitative data were analysed to yield themes that were sorted using a model of Indigenous wellbeing comprising five dimensions (academic, cultural, physical, psychological and social wellbeing). Responses from stakeholders (teachers, community leaders and students) show that success can be achieved when local culture is respected and incorporated into the curriculum by dedicated staff who maintain open communication with community. While both schools shared a largely common approach to Indigenous education, a hallmark was their responsiveness to local needs.

Abstract Seasonal rhythms are gaining attention given their impact on metabolic disorders development such as obesity gut microbiota is emerging as a key factor in mediating this link. However, the underlying mechanisms are still poorly understood. In this regard, corticosterone may play a role as it has been shown to be affected by gut bacteria and seasonal rhythms, and has been linked to obesity. Thus, this study aimed to investigate if seasonal rhythms effects on corticosterone are influenced by gut microbiota in obese rats and whether this may be related to seasonal and clock genes expression in the pituitary gland and colon. Fischer 344 male rats fed with cafeteria diet (CAF) were housed under different photoperiods for 9 weeks and treated with an antibiotic cocktail (ABX) in drinking water during the last 4 weeks. Rats fed with standard chow and CAF-fed rats without ABX were included as controls. ABX altered gut microbiota, corticosterone levels and seasonal clock expression in the pituitary depending on photoperiod conditions. These results suggest a link between gut bacteria, seasonal rhythms and corticosterone and a novel nutrigenomic target for obesity.

Resilience is defined as the maintenance or relatively quick recovery of mental health during and after adversity. Rather than focusing on psychopathology and its causes, resilience research aims to understand what protective mechanisms shield individuals against developing such disorders and translate these insights to improve psychosocial care. This resilience approach seems especially promising for the field of oncology because patients face stressor after stressor from diagnosis to survivorship. Helping patients to learn how they can best use the resources and abilities available to them can empower patients to handle subsequent stressors. In the past few decades, resilience has increasingly been considered as a dynamic process of adaptation. While researchers use this definition, resilience has not yet been studied as a dynamic process in the field of oncology. As a result, the potential of resilience research to gain insight into what helps protect cancer patients from developing psychopathology is limited. We discuss conceptual and methodological proposals to advance resilience research in oncology. Most importantly, we propose applying prospective longitudinal designs to capture the dynamic resilience process. By gaining insight in how cancer patients engage in protective factors, resilience research can come to its full potential and help prevent psychopathology.

ObjectivesWe determined whether adding cannabis to oxycodone for chronic non-cancer pain management could reduce treatment-related adverse effects (AEs) while maintaining effective analgesia.MethodsIn this open-label study, fibromyalgia patients aged ≥18 years were randomized to receive 5 mg oxycodone tablets (max. four times/day), 150 mg of inhaled cannabis containing 6.3% Δ9-tetrahydrocannabinol and 8% cannabidiol (max. times inhalation sessions/day), or a combination of both for 6 weeks. The primary endpoint was treatment-related adverse events, assessed using a 10-point composite adverse event (cAE) score; additionally, we recorded daily reported pain relief and daily tablet and cannabis consumption.ResultsIn total, 23 patients were treated with oxycodone, 29 with cannabis, and 29 with the oxycodone/cannabis combination. Three patients from the oxycodone group (13%) and 18 patients from the cannabis groups (31%, 9 in each group) withdrew from the trial within 2–3 weeks because of the severity of AEs. There were no differences in treatment-related cAE scores among the three groups that completed the study (p = 0.70). The analgesic responder rate showed a ≥1- point reduction in pain in 50% and a ≥2-point reduction in 20% of patients, while 50% of patients experienced no treatment benefit. The combination treatment reduced oxycodone tablet consumption by 35% (p = 0.02), but it did not affect the number of cannabis inhalation sessions.ConclusionsCannabis combined with oxycodone offered no advantage over either treatment alone, except for a reduction in opioid tablet intake; however, the overall drug load was the highest in the combination group. Moreover, cannabis was poorly tolerated and led to treatment discontinuation in one-third of participants treated with cannabis.Clinical Trial RegistrationThe trial was registered at the WHO International Clinical Trials Registry Platform (trialsearch.who.int) on July 26, 2019, identifier NL7902.

Abstract Objectives Psychiatric symptoms occur frequently in people living with human immunodeficiency virus (PLWH), which may affect quality of life, sexual risk behavior, and adherence to antiretroviral therapy (ART). Data from large cohorts are limited, and symptoms are often analyzed in isolation. Therefore, we applied a network analysis to assess the interrelatedness of mental health indicators in a large cohort of PLWH. Methods We included 1615 PLWH on ART. Participants reported on the severity of depression, anxiety, impulsivity, substance use, quality of life, sexual risk behavior, and ART adherence. An Ising network model was constructed to analyze interrelations between mental health indicators and connections with clinical consequences. Results Our network analysis revealed that symptoms of depression, anxiety, and indicators of impulsivity were interrelated. Substance use was prevalent and strongly connected with sexual risk behavior. Quality of life was most strongly connected with symptoms of depression. Unexpectedly, ART adherence did not display connections with any of the mental health indicators. Conclusion In PLWH, the interrelatedness between symptoms of depression and anxiety and indicators of impulsivity is high. Mainly, depressive symptoms seem to impact quality of life, which warrants attention for depression in PLWH. We did not observe evidence for the common assumption that patients suffering from psychiatric symptoms are less adherent to HIV treatment.

Molecules that stabilize protein-protein interactions (PPIs) are invaluable as tool compounds for biophysics and (structural) biology, and as starting points for molecular glue drug discovery. However, identifying initial starting points for PPI stabilizing matter is highly challenging, and chemical optimization is labor-intensive. Inspired by chemical crosslinking and reversible covalent fragment-based drug discovery, we developed an approach that we term "molecular locks" to rapidly access molecular glue-like tool compounds. These dual-covalent small molecules reversibly react with a nucleophilic amino acid on each of the partner proteins to dynamically crosslink the protein complex. The PPI between the hub protein 14-3-3 and estrogen-related receptor γ (ERRγ) was used as a pharmacologically relevant case study. Based on a focused library of dual-reactive small molecules, a molecular glue tool compound was rapidly developed. Biochemical assays and X-ray crystallographic studies validated the ternary covalent complex formation and overall PPI stabilization via dynamic covalent crosslinking. The molecular lock approach is highly selective for the specific 14-3-3/ERRγ complex, over other 14-3-3 complexes. This selectivity is driven by the interplay of molecular reactivity and molecular recognition of the composite PPI binding interface. The long lifetime of the dual-covalent locks enabled the selective stabilization of the 14-3-3/ERRγ complex even in the presence of several other competing 14-3-3 clients with higher intrinsic binding affinities. The molecular lock approach enables systematic, selective, and potent stabilization of protein complexes to support molecular glue drug discovery.

Abstract Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = −0.32, p = 0.0023, n = 88) and remission (r = −0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.

Objectives The COVID-19 pandemic and related lockdown measures disrupted global healthcare provision, including opioid prescribing. In North America, opioid sales declined while opioid-related deaths increased. In Europe, the effect of the pandemic on prescribing is not yet known. Given the ongoing increase in opioid-related harm and mortality, it is crucial to analyse the impact of the COVID-19 crisis and lockdown measures on opioid prescribing. Therefore, the objective of this study was to characterise opioid prescribing in the Netherlands during the COVID-19 pandemic.Design A nationwide register-based study characterising opioid prescribing using aggregated insurance reimbursement data.Setting Dutch healthcare during the first 2 years of the COVID lockdown.Participants The whole Dutch population.Primary and secondary outcome measures Comparing the number of opioid prescriptions during the pandemic with a prepandemic period using a risk ratio (RR), with separate analysis on the prescription type (first-time or repeat prescription), patients’ sex, age and socioeconomic status. We also explored lockdown effects.Results During the first lockdown, the total number of new opioid prescriptions and prescriptions to young patients (briefly) decreased (RR 0.88, 95% CI 0.88 to 0.89 and RR 0.73, 95% CI 0.70 to 0.75, respectively), but the overall number of opioid prescriptions remained stable throughout the pandemic compared with prepandemic. Women, older patients and patients living in lower socioeconomic areas received more opioids per capita, but the pandemic did not amplify these differences.Conclusions The pandemic appears to have had a limited impact on opioid prescribing in the Netherlands. Yet, chronic use of opioids remains an important public health issue.

Aims The aim of this study is to investigate incident and total benzodiazepine prescribing in the Netherlands during the COVID-19 pandemic, including the impact of lockdown periods. Methods A national Dutch pharmacological registry was used, investigating extramural psychiatric drug prescriptions, between March 2020 and March 2022. Data included incident and total prescriptions as well as daily defined doses (DDDs) of benzodiazepines. The data covered 96% out of a total Dutch population of 17.5 million people. This was compared with the previous calendar year as a reference expressed as a monthly risk ratio (RR) and was corrected for population growth. Changes over time will be discussed if the RR was above 1.1 or below 0.9. Results A total of 13.4 million prescriptions over a period of three years were included of which 5.8% were incident prescriptions. Three lockdown periods were identified during pandemic. When analysing the total benzodiazepine prescription group, prescriptions and DDDs remained mostly stable throughout the pandemic. A brief relative increase in prescription DDD amounts was found during the second lockdown (RR: 1.11). When viewing the incident benzodiazepine prescriptions, there was a short period between the first and second lockdown when both prescription numbers and DDDs decreased (RR: 0.86 and RR: 0.83 respectively). The DDDs of incident prescriptions increased sharply during the second and third lockdown period and remained elevated between both, with an average RR of 1.13. Conclusion Total monthly benzodiazepine prescriptions and DDDs remained mostly stable during the COVID-19 pandemic in the Netherlands. COVID-19 related lockdowns seem to have mainly influenced incident benzodiazepine DDDs dispensed during the second and third lockdown. Increased incident DDDs, but not prescription numbers, imply that new patients on average received larger benzodiazepine prescriptions. The increase in incident prescription DDDs could be indicative of decreased accessibility to (psychiatric) healthcare. It could also have been driven by an increase of the incidence and/or severity of sleep and anxiety symptoms during the second and third lockdown. A better understanding of exact causes and mechanisms behind these changes is relevant in order to limit the psychiatric repercussions of future (inter)national emergencies.

In this paper an advanced modulation strategy is proposed that generates the switch control signals of a power converter while inherently guaranteeing zero-voltage switching (ZVS) operation. The proposed modulator is based on a first-order $\Delta \Sigma$-modulator combined with a hold-off circuit. This hold-off circuit consists of a D-latch and maintains the converter's switching state until ZVS commutation can be achieved while an integrator ensures the correct average output. Furthermore, features are implemented to improve start-up and transient behavior. The operating principle and stability of the proposed modulator is discussed and simulation results are presented. Finally, the proposed modulator is validated on a $2 \,\mathrm{k}\mathrm{W}$ GaN-based synchronous buck converter. Results show that the converter naturally operates under ZVS conditions by continuously varying its switching frequency without having to compute switching times or frequencies. The proposed method is an interesting alternative to pulse-width modulation especially when operating at high switching frequencies or when the switching loss in the power converter is significant.

Internationally, there is a gap in high-school completion rates for Indigenous and non-Indigenous students. In Australia, gap estimates are commonly based on lag indicators, precluding examination of underlying mechanisms. Using two longitudinal representative samples of Australian youth, we explored differences in high-school completion between Australian Indigenous and non-Indigenous rates, and whether the gap varies for students of similar academic ability. Using an intersectional approach, we show the Indigenous gap is significant, is mostly a function of differences in academic achievement, but varies by socioeconomic status (SES) and location. Specifically, high SES and living in urban settings are protective factors for non-Indigenous students, but not for Indigenous students. Conversely, rural and poor non-Indigenous students appeared to have dropout rates as large or even larger than similarly poor and rural Indigenous youth. Overall, the results suggest the need for a more nuanced perspective on 'Indigenous gaps' in educational attainment.

BackgroundMisconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.MethodsWe reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.ResultsWe generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents.ConclusionsMany findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

Abstract Background The coronavirus disease 2019 (COVID‐19) pandemic and related restrictions globally impacted mental health, particularly for those with pre‐existing severe mental illness (SMI). This qualitative study examined how adults with SMI perceived the effects of the COVID‐19 pandemic and related restrictions in the Netherlands, focusing on their personal recovery, well‐being and daily life, including an exploration of factors influencing these effects. Methods Semi‐structured interviews were conducted, audio‐recorded and transcribed verbatim. Reflexive thematic analysis was applied. Purposive sampling was used to ensure diversity of individuals with SMI (i.e., age, gender, diagnosis, cultural background and mental healthcare institution). Results Twenty participants (median age: 45 years [SD: 12, 8]; 11 females) were interviewed between May and July 2023. Findings revealed a wide range of experiences: while some individuals reported a negative impact on their existing psychiatric symptoms, others described adaptability, resilience and even positive effects of COVID‐19 restrictions on their mental health and well‐being. Factors influencing the heterogeneic perceptions of the COVID‐19 pandemic and related restrictions include the availability of trusted social relationships and enduring interactions with health professionals. Conclusion Personalised support, both socially and professionally, is crucial for addressing fears, building resilience, reducing isolation and encouraging positive coping strategies for individuals with SMI during external crises. In this project, a participatory research approach that integrated the lived experience perspective helped uncover the unique perceptions of people with SMI with regard to the pandemic and related restrictions. Patient or Public Contribution The study used a participatory action research approach, with experts‐by‐experience involved in every stage of the project as part of the research team. This included engagement with the funding application process, recruitment strategies for interviews, developing the interview guide, piloting the interview, interpreting findings, and knowledge dissemination activities.

Objectives Approximately 10% of chronic pain patients who receive opioids develop an opioid use disorder (OUD). Tapering programmes for these patients show high drop-out rates. Insight into chronic pain patients’ experiences with tapering programmes for prescription OUD could help improve such programmes. Therefore, we investigated the perspectives of chronic pain patients with prescription OUD to identify facilitators and barriers to initiate and complete a specialised OUD tapering programme.Design A qualitative study using semi-structured interviews on experiences with initiation and completion of opioid tapering was audio recorded, transcribed and subject to directed content analysis.Setting This study was conducted in two facilities with specialised opioid tapering programmes in the Netherlands.Participants Twenty-five adults with chronic pain undergoing treatment for prescription OUD participated.Results Participants indicated that tapering is a personal process, where willingness and motivation to taper, perceived (medical) support and pain coping strategies have an impact on the tapering outcome. The opportunity to join a medical-assisted tapering programme, shared decision-making regarding tapering pace, tapering location, and receiving medical and psychological support facilitated completion of an opioid tapering programme.Conclusions According to patients, a successful treatment of prescription OUD requires a patient-centred approach that combines personal treatment goals with shared decision-making on opioid tapering. Referral to a specialised tapering programme that incorporates opioid rotation, non-judgmental attitudes, and psychological support can create a safe and supportive environment, fostering successful tapering and recovery.

Abstract The primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator’s Brochures (IBs) of studies performed at the Centre for Human Drug Research (CHDR) reporting statistically significant results of CNS activity related to the drug’s mechanism of action were included. The quality of IBs was assessed based on the presence of a rationale for the chosen animal model, completeness of pharmacokinetic (PK) results in reporting and internal validity information of the preclinical evidence. The IB-derisk tool was used to generate preclinical and early clinical data overviews data. For each compound, the overlap between pharmacologically active dose ranges and well-tolerated levels was calculated for three pharmacokinetic (PK) parameters: human equivalent dose (HED), maximum plasma concentration (C max) and area under the curve (AUC). Twenty-five IBs were included. In general, the quality of reporting in IBs was assessed as poor. About a third of studies did not explore the entire concentration-effect curve (pre)clinically. Single dose tolerability ranges were most accurately predicted by C max. Human equivalent dose and AUC were the best predictors of pharmacologically active ranges. Tolerable and pharmacologically active dose ranges in healthy volunteers can be reasonably well predicted from preclinical data with the IB-derisk tool. The translatability of preclinical studies can be improved by applying a higher reporting standard in IBs including comparable PK measurements across all preclinical and clinical studies.

Background: The prevalence of Substance Use Disorder (SUD) in people with Mild Intellectual Disability and Borderline Intellectual Functioning (MID-BIF) is high and evidence-based treatment programs are scarce. The present study describes the development of a personalised SUD treatment for people with MID-BIF. Method: The personalised SUD treatment is developed according to the steps of the Intervention Mapping approach, based on literature review, theoretical intervention methods, clinical experience and consultation with experts in the field of addiction and intellectual disability care. Results: We developed a treatment manual called Take it Personal!+. Take it Personal!+ aims to reduce substance use, is based on motivational interviewing and cognitive behavior therapy and personalised based on the client's personality profile. Furthermore, an mHealth application supports the treatment sessions. Conclusion: Take it Personal!+ is the first personalised SUD treatment for individuals with MID-BIF. Future research should test the effectiveness of Take it Personal!+ in reducing SU.