Explore the vast range of titles available.

Background Bipolar disorder (BD) is a severe mental illness associated with marked functional impairment and reduced life expectancy. Early indicators such as mood instability, circadian rhythm disturbance, and anxiety symptoms often precede the first manic or depressive episode, providing a potential window for preventive intervention. Currently, no structured early intervention program exists for individuals at risk for BD who do not yet meet diagnostic criteria. This study aims to evaluate the feasibility and acceptability of a novel, personalized early intervention program combining light therapy, lifestyle psychoeducation, and imagery-focused cognitive therapy (ImCT) for individuals at risk for BD. Methods The study employs a single-case experimental A-B-A design with staggered baseline and multiple daily assessments. Fifty participants aged 16–35 years identified as being at risk for BD by a specialized early detection team will be included. The intervention consists of three core components: (1) a chronotherapeutic intervention (bright light therapy or blue-light blocking glasses) tailored to individual symptom profiles; (2) one session of lifestyle-focused psychoeducation targeting sleep, nutrition, and physical activity; and (3) six sessions of ImCT to address mood instability and maladaptive mental imagery. Feasibility and acceptability will be assessed through drop-out rates, adherence, and participant feedback. Secondary outcomes include changes in depressive, hyperactive, anxiety, and imagery-related symptoms, as well as sleep quality and activity levels, measured through validated questionnaires and actigraphy. Discussion By combining chronotherapeutic, psychological, and lifestyle components, this intervention targets multiple mechanisms implicated in BD risk. Findings will inform the development of preventive strategies for individuals in an at-risk mental state for BD. The study will also provide data on the feasibility of integrating early interventions within routine mental health services and guide the design of future randomized controlled trials. Trial registration Medical Ethical Committee Brabant (METC Brabant; identifier P2314); ClinicalTrials.gov Identifier: NCT06282250. Registered 20 February 2024.

Abstract Background In psychosis spectrum disorders, maladaptive mental imagery is associated with auditory verbal hallucinations (AVHs). This study evaluates the feasibility, acceptability, and effectiveness of the following 4 imagery techniques in targeting mental imagery and AVHs severity: Imagery Rescripting (ImRs), Promoting positive Imagery de novo (Pos-Im), Metacognitive Imagery techniques (Meta-Im), and playing Tetris. Study Design Four replicated single-case series experimental designs were used. Participants were randomized to 1 of the 4 treatment conditions. Primary, we measured the severity of mental imagery and AVHs thrice daily on an 11-point VAS scale during a 2-week baseline, throughout 3 weeks of therapy, and during a 2-week follow-up phase. Randomization tests were used to examine whether daily severity levels of momentary mental imagery and AVHs decreased post-therapy. Secondary, questionnaires assessing the severity of AVHs, mental imagery characteristics, and levels of mood, anxiety, and functioning were administered at baseline, before, and posttreatment. Results Twenty-eight participants completed all treatment sessions. Mental imagery significantly decreased after ImRs (P < .001, d = 1.13) and Pos-Im (P = .039, d = 0.22), with no significant effects observed following Meta-Im or Tetris. AVHs significantly decreased with all treatment conditions, with largest effects for ImRs (P = .001, d = 1.39) and Pos-Im (P < .001, d = 1.99). Secondary results demonstrated reductions in the severity of AVHs, mood, anxiety, imagery frequency, and appraisals. Conclusions Imagery techniques appear feasible and acceptable for addressing mental imagery and AVHs in the psychosis continuum and may be valuable additions to current treatment for AVHs.

Introduction: Sufficient high quality dietary protein intake is required to prevent or treat sarcopenia in elderly people. Therefore, the intake of specific protein sources as well as their timing of intake are important to improve dietary protein intake in elderly people. Objectives: to assess the consumption of protein sources as well as the distribution of protein sources over the day in community-dwelling, frail and institutionalized elderly people. Methods: Habitual dietary intake was evaluated using 2- and 3-day food records collected from various studies involving 739 community-dwelling, 321 frail and 219 institutionalized elderly people. Results: Daily protein intake averaged 71 ± 18 g/day in community-dwelling, 71 ± 20 g/day in frail and 58 ± 16 g/day in institutionalized elderly people and accounted for 16% ± 3%, 16% ± 3% and 17% ± 3% of their energy intake, respectively. Dietary protein intake ranged from 10 to 12 g at breakfast, 15 to 23 g at lunch and 24 to 31 g at dinner contributing together over 80% of daily protein intake. The majority of dietary protein consumed originated from animal sources (≥60%) with meat and dairy as dominant sources. Thus, 40% of the protein intake in community-dwelling, 37% in frail and 29% in institutionalized elderly originated from plant based protein sources with bread as the principle source. Plant based proteins contributed for >50% of protein intake at breakfast and between 34% and 37% at lunch, with bread as the main source. During dinner, >70% of the protein intake originated from animal protein, with meat as the dominant source. Conclusion: Daily protein intake in these older populations is mainly (>80%) provided by the three main meals, with most protein consumed during dinner. More than 60% of daily protein intake consumed is of animal origin, with plant based protein sources representing nearly 40% of total protein consumed. During dinner, >70% of the protein intake originated from animal protein, while during breakfast and lunch a large proportion of protein is derived from plant based protein sources.

Purpose Adequate dietary protein intake is required to postpone and treat sarcopenia in elderly people. Insight into dietary protein intake in this heterogeneous population segment is needed to locate dietary inadequacies and to identify target populations and feeding strategies for dietary interventions. Therefore, we assessed dietary protein intake, distribution of protein intake throughout the day, and the use of protein-containing food sources in community-dwelling, frail, and institutionalized elderly people in the Netherlands. Methods Secondary analyses were carried out using dietary data collected from studies among community-dwelling, frail, and institutionalized elderly people to evaluate protein intake characteristics. Results Dietary protein intake averaged 1.1 ± 0.3 g/kg-bw/day in community-dwelling, 1.0 ± 0.3 g/kg-bw/day in frail, and 0.8 ± 0.3 g/kg-bw/day in institutionalized elderly men. Similar protein intakes were found in women. Ten percent of the community-dwelling and frail elderly and 35% of the institutionalized elderly people showed a protein intake below the estimated average requirement (0.7 g/kg-bw/day). Protein intake was particularly low at breakfast in community-dwelling (10 ± 10 g), frail (8 ± 5 g), and institutionalized elderly people (12 ± 6 g) with bread and dairy products as predominant protein sources. Conclusions Whereas daily protein intake is generally well above the recommended dietary allowance in community-dwelling and frail elderly people, a significant proportion of institutionalized elderly showed an intake below the current protein requirement, making them an important target population for dietary interventions. Particularly at breakfast, there is scope for improving protein intake.

The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×108 cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×108 cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis—all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1–2 events seen in all patients), fatigue (grade 1–2 in 20 patients, grade 3 in two), and pyrexia (grade 1–2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.

A population-based cohort of children aged 1–18 years with acute lymphoblastic leukaemia (ALL) was treated with a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). We aimed to confirm the results of the most effective DCOG ALL protocol for non-high-risk (NHR) patients to date (ALL-6), compare results with ALL-7 and ALL-8, and study prognostic factors in a non-randomised setting. From Jan 1, 1997, until Nov 1, 2004, patients with ALL were treated according to the ALL-9 protocol in eight Dutch academic centres with their affiliated peripheral hospitals. Patients were stratified into NHR and high risk (HR) groups. HR criteria were white-blood-cell count of 50 000 cells per μL or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement; patients who did not fulfil these criteria were deemed to be NHR. The NHR group was treated with a three-drug induction (dexamethasone, vincristine, and asparaginase) for 6 weeks, medium-dose methotrexate for 3 weeks, then maintenance therapy. HR patients received a four-drug induction (as for the NHR patients plus daunorubicin) for 6 weeks, high-dose methotrexate for 8 weeks, and two intensification courses before receiving maintenance therapy. Triple intrathecal medication was given 13 times in NHR patients, 15 times in HR patients (17 times for patients with initial CNS involvement). No patient received cranial irradiation. Maintenance therapy was given until 109 weeks for all patients and consisted of mercaptopurine and methotrexate for 5 weeks, alternated with dexamethasone and vincristine for 2 weeks. Kaplan–Meier analysis was done on an intention-to-treat basis with event-free survival as the primary endpoint. This trial is registered at trialregister.nl, number NTR460/SNWLK-ALL-9. 859 patients were recruited to the study. Complete remission was achieved in 592 (98·5%) of the 601 patients in the NHR group and 250 (96·9%) of the 258 in the HR group. Five patients in the NHR group and four in the HR group died during induction. Median follow-up for patients alive was 72·2 (range 4·8–132·7) months as of August, 2008. 5-year event-free survival was 81% (SE 1%) in all patients: 84% (2%) in NHR patients, and 72% (3%) in HR patients. Isolated CNS relapses occurred in 22 (2·6%) of 842 patients. In a multivariate analysis, DNA index was the strongest predictor of outcome (<1·16 vs ≥1·16; relative risk 0·42, 95% CI 0·22–0·78), followed by age (1–9 vs ≥10 years; 2·23, 1·60–3·11) and white-blood-cell count (<50 000 vs ≥50 000 cells per μL; 1·60, 1·13–2·26). The overall results of the dexamethasone-based DCOG ALL-9 protocol are better than those of our previous Berlin–Frankfurt–Münster-based protocols ALL-7 and ALL-8. The results for NHR patients were achieved with high cumulative doses of dexamethasone and vincristine, but without the use of anthracyclines, etoposide, cyclophosphamide, or cranial irradiation, therefore minimising the risk of side-effects. Dutch Health Insurers.

The phagocyte NAPDH-oxidase complex consists of several phagocyte oxidase (phox) proteins, generating reactive oxygen species (ROS) upon activation. ROS are involved in the defense against microorganisms and also in immune regulation. Defective ROS formation leads to chronic granulomatous disease (CGD) with increased incidence of autoimmunity and disturbed resolution of inflammation. Because regulatory T cells (Tregs) suppress autoimmune T-cell responses and are crucial in down-regulating immune responses, we hypothesized that ROS deficiency may lead to decreased Treg induction. Previously, we showed that in p47 phox -mutated mice, reconstitution of macrophages (Mph) with ROS-producing capacity was sufficient to protect the mice from arthritis. Now, we present evidence that Mph-derived ROS induce Tregs. In vitro, we showed that Mph ROS-dependently induce Treg, using an NADPH-oxidase inhibitor. This finding was confirmed genetically: rat or human CGD Mph with mutated p47 phox or gp91 phox displayed hampered Treg induction and T-cell suppression. However, basal Treg numbers in these subjects were comparable to those in controls, indicating a role for ROS in induction of peripheral Tregs. Induction of allogeneic delayed-type hypersensitivity with p47 phox -mutated Mph confirmed the importance of Mph-derived ROS in Treg induction in vivo. We conclude that NAPDH oxidase activity in Mph is important for the induction of Tregs to regulate T cell-mediated inflammation.

COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential benefit of a pre-emptive screening strategy for CAPA in ICUs in the Netherlands/Belgium during immunosuppressive COVID-19 treatment. A retrospective, observational, multicentre study was performed from September 2020–April 2021 including patients admitted to the ICU who had undergone diagnostics for CAPA. Patients were classified based on 2020 ECMM/ISHAM consensus criteria. CAPA was diagnosed in 295/1977 (14.9%) patients. Corticosteroids were administered to 97.1% of patients and interleukin-6 inhibitors (anti-IL-6) to 23.5%. EORTC/MSGERC host factors or treatment with anti-IL-6 with or without corticosteroids were not risk factors for CAPA. Ninety-day mortality was 65.3% (145/222) in patients with CAPA compared to 53.7% (176/328) without CAPA (p = 0.008). Median time from ICU admission to CAPA diagnosis was 12 days. Pre-emptive screening for CAPA was not associated with earlier diagnosis or reduced mortality compared to a reactive diagnostic strategy. CAPA is an indicator of a protracted course of a COVID-19 infection. No benefit of pre-emptive screening was observed, but prospective studies comparing pre-defined strategies would be required to confirm this observation. •Incidence of COVID-19 associated pulmonary aspergillosis (CAPA) was 14.9%.•Treatment with interleukin-6 inhibitors was not a risk factor for CAPA.•Ninety-day mortality was higher in patients with CAPA than in patients without CAPA.•Median time from ICU admission to CAPA diagnosis was 12 days.•No benefit of a pre-emptive screening strategy for CAPA was observed.

Persons with diabetes mellitus may have an increased risk of severe illness or death from COVID-19 compared to persons without diabetes. Prior studies indicate that immune response and thus vaccine effectiveness might be lower in persons with diabetes. We aimed to systematically review the effectiveness of COVID-19 vaccines in adults with diabetes. Pubmed, Embase, Web of Science and Cochrane Library were searched for studies that evaluated the effectiveness of COVID-19 vaccines in adults with diabetes, published before 4 March 2022. Risk of bias in the included studies was evaluated using the ROBINS-I tool. At least two reviewers conducted the study selection, data extraction, and risk of bias assessment independently. After screening of 2196 studies, a total of 17 articles were included. Six different COVID-19 vaccines (Ad5-nCoV-S, AZD1222, BNT162b2, CoronaVac, JNJ-78436735, and mRNA-1273) were included in the synthesis. Vaccine effectiveness was reported for SARS-CoV-2 infection, symptomatic COVID-19, hospitalization, and death, and ranged from 24 to 96% in persons with diabetes, and from 33 to 97% in total study populations; effectiveness was generally lower for persons with diabetes. Odds ratios for breakthrough infection or severe COVID-19 ranged from 1.03 to 2.41 in vaccinated persons with diabetes compared to persons without diabetes. Even though the included studies were very heterogeneous, results from the synthesis indicate that effectiveness of COVID-19 vaccines might be lower in persons with diabetes. More research is needed on the comparison of vaccine effectiveness between persons with and without diabetes, and the effectiveness of repeat COVID-19 vaccinations.

Plants constantly adjust their repertoire of plasma membrane proteins that mediates transduction of environmental and developmental signals as well as transport of ions, nutrients, and hormones. The importance of regulated secretory and endocytic trafficking is becoming increasingly clear; however, our knowledge of the compartments and molecular machinery involved is still fragmentary. We used immunogold electron microscopy and confocal laser scanning microscopy to trace the route of cargo molecules, including the BRASSINOSTEROID INSENSITIVE1 receptor and the REQUIRES HIGH BORON1 boron exporter, throughout the plant endomembrane system. Our results provide evidence that both endocytic and secretory cargo pass through the trans-Golgi network/early endosome (TGN/EE) and demonstrate that cargo in late endosomes/multivesicular bodies is destined for vacuolar degradation. Moreover, using spinning disc microscopy, we show that TGN/EEs move independently and are only transiently associated with an individual Golgi stack.