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Summary: Background: Although several types of psychotherapy effectively reduce psychological distress associated with personality disorders, randomised controlled trials (RCT) have systematically excluded older patients. We aimed to examine the effectiveness of group schema therapy combined with psychomotor therapy (GST + PMT) in later life compared with treatment as usual (TAU). Methods: We did an open-label, multicentre, RCT in eight outpatient clinics for geriatric psychiatry in the Netherlands. Adults aged 60 years or older with a full or subthreshold cluster B or C personality disorder according to DSM criteria were included and randomly assigned 1:1 to GST + PMT or TAU by an independent researcher applying a computer-generated sequence per study site when 8 to 16 patients had given informed consent; investigators and interviewers were kept blinded until end of follow-up. Included individuals received 20 weekly sessions of GST + PMT or TAU with 1 year of follow-up. The primary outcome was psychological distress, measured with the 53-item Brief Symptom Inventory. The trial was registered with International Clinical Trials Registry Platform, NTR6621. Findings: Of the 145 study participants recruited between Feb 21, 2018, and Jan 21, 2020, 102 patients (median age of 69 years [IQR 63–71], 62 [61%] female) who concluded therapy before the COVID-19 pandemic (cutoff March 20, 2020) were included in the intention-to-treat analysis (51 in each study group), because COVID-19 measures substantially disrupted delivery of group therapy. GST + PMT significantly improved psychological distress compared with TAU over the 6-month treatment period (Cohen's d 0·42, 95% CI 0·16 to 0·68; p=0·0016). The pre-post effect of GST + PMT remained stable during follow-up, whereas patients receiving TAU further improved, resulting in a non-significant difference between groups at 1 year (Cohen's d 0·21, 95% CI –0·07 to 0·48; p=0·14). No patients reported adverse events. Interpretation: Psychotherapy focused on personality disorders is effective in later life, resulting in a faster improvement in psychopathology than TAU. Future studies should focus on increasing effectiveness by intensifying or prolonging treatment. Funding: Netherlands Organization for Health Research and Development. Translation: For the Dutch translation of the abstract see Supplementary Materials section.

Introduction Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks.Methods and analysis The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients.Ethics and dissemination The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences.Trial registration number NCT06087952.

Physician-oriented online education could be a pathway to improve care for patients with heart failure, however, it is difficult to measure the impact of such education. Self-efficacy is a potential outcome measure. In this article, we develop a methodology for analyzing an educational intervention for general practitioners (GPs) using self-efficacy as a concept. This study was partly conducted within the setting of an observational study, IMPACT-B, where we developed online education for GPs. We designed and refined a 24-item questionnaire using item analysis, and exploratory and confirmatory factor analysis. Ninety-one GPs completed the questionnaire before and after the online education. Follow-up data after 6 months was available for 13 GPs. Item analysis revealed a high degree of internal consistency (coefficient alpha 0.95) and validity. Each additional year of experience was associated with an average baseline self-efficacy score of 0.50 points (95% CI [0.21-0.80]), and each additional patient in HF follow-up with an average score of 2.0 points (95% CI [0.48-3.5]). Items that differentiated most between GPs with high and low self-efficacy were the treatment of congestion as well as titrating medication and MRA in heart failure with reduced ejection fraction. Factor analysis reduced the number of questions to 14, mapping to three factors (diagnosis, treatment, and follow-up), and improved the model fit as measured by the goodness-of-fit indicator comparative-fit-index (from 0.83 to 0.91). We demonstrated a method to assess the impact of online education on general practitioners. This led to a questionnaire that was reliable, valid, and convenient to use in an implementation context.

The authors report the natural history of three patients with late-diagnosed Classic Galactosemia (CG) (at 16, 19 and 28 years). This was due to a combination of factors: absence of neonatal screening, absence of some typical acute neonatal symptoms, and negative galactosemia screening. This report underlines the value of neonatal screening and the importance of further diagnostic testing in case of late-onset manifestations.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can hijack the normal bone marrow microenvironment to create a leukemic niche which facilitates blast cell survival and promotes drug resistance. Bone marrow-derived mesenchymal stromal cells (MSCs) mimic this protective environment in ex vivo co-cultures with leukemic cells obtained from children with newly diagnosed BCP-ALL. We examined the potential mechanisms of this protection by RNA sequencing of flowsorted MSCs after co-culture with BCP-ALL cells. Leukemic cells induced an interferon (IFN)-related gene signature in MSCs, which was partially dependent on direct cell-cell signaling. The signature was selectively induced by BCP-ALL cells, most profoundly by ETV6-RUNX1 positive ALL cells, as coculture of MSCs with healthy immune cells did not provoke a similar IFN signature. Leukemic cells and MSCs both secreted IFNα and IFNβ, but no IFNγ. In line, the IFN-gene signature was sensitive to blockade of IFNα/β signaling, but less to that of IFNγ. The viability of leukemic cells and level of resistance to three chemotherapeutic agents was not affected by interference with IFN signaling using selective IFNα/β inhibitors or silencing of IFN-related genes. Taken together, our data suggest that the leukemia-induced expression of IFNα/β-related genes by MSCs does not support survival of BCPALL cells but may serve a different role in the pathobiology of BCP-ALL.

BackgroundIndividuals with intellectual disabilities (ID) are more likely to have problems with executive functioning (EF) and challenging behavior (CB), which are negatively linked to well-being. Among clinical populations, music interventions have been shown to improve various outcome measures, such as CB and EF. Until now, no randomized controlled trials (RCTs) have been conducted to examine the effectiveness of an individual music intervention for adults with ID and CB. ObjectiveThe study aims to identify the effect and feasibility of an individual music intervention compared with care-as-usual for people with ID and CB. MethodsIn this study, a 2-group RCT with a pretest, posttest, and follow-up assessment after 8 weeks is presented. Participants of the music intervention condition will receive 16 individual music sessions within 8 to 10 weeks. The music intervention will be guided by a manual for music workers, in which every session will have a different focus (introduction, emotions, different EF, and end performance). Participants receiving care as usual will function as a control group. After the research is finished, they will be offered a budget, which they can spend on musical activities or musical instruments as they wish. Assessments will include caregiver rating scales and self-report questionnaires and tests, which will assess outcome measures of CB, well-being, depression, anxiety, self-esteem, and 4 domains of EF. A process evaluation will be conducted after the completion of the study, which entails the analysis of data on multiple aspects of the intervention and the study overall. ResultsEnrollment commenced in July 2021, and data collection ended in May 2023. A total of 97 participants were recruited, with 44 participants allocated to the intervention group and 53 allocated to the control group. Data will be analyzed after this protocol has been accepted for publication. ConclusionsBecause there are currently no published RCTs of an individual music intervention for adults with ID and CB, this study will provide insight into the effectiveness and experiences of an individual music intervention for this target group. Trial RegistrationInternational Clinical Trials Registry Platform NL8482; http://tinyurl.com/4565s5pd International Registered Report Identifier (IRRID)DERR1-10.2196/52497

The authors of “Integration or Fragmentation of Health Care? Examining Policies and Politics in a Belgian Case Study” present a fresh perspective on the inertia of integrated care (IC) implementation. They conclude that the decisive power in Belgium is fragmented and undermines efforts towards IC. As researchers in integrated heart failure (HF) care and active primary healthcare professionals, we comment on the three policy initiatives evaluated by Martens et al from a bottom-up perspective. A Learning Healthcare Network (LHCN) was established September 2019 to overcome fragmentation, the lack of evaluation and capacity loss each time a pilot project ends. This commentary wishes to illustrate that a LHCN can be a powerful meso-level mechanism to engage in alignment work and to overcome macro-level barriers that are often difficult to change and not supportive of IC

Abstract Background Healthcare workers’ (HCWs) compliance with infection prevention and control (IPC) is crucial to reduce the infection transmission risk. However, HCWs’ compliance with IPC in residential care facilities (RCFs) for people with intellectual and developmental disabilities (IDDs) is known to be suboptimal. Therefore, this study examined sociodemographic and psychosocial determinants associated with IPC non-compliance in this setting, to inform IPC policy and promotion programmes for adequate IPC behaviour. Methods An online questionnaire was administered to 285 HCWs from 16 RCFs between March 2021 and March 2022. Determinants associated with IPC non-compliance were assessed using logistic regression analyses. Results Being a woman (OR: 3.57; 1.73–7.37), and being a non-medical professional were associated with increased odds of non-compliance (social workers, OR: 2.83; 1.65–4.85; behavioural specialists, OR: 6.09; 1.98–18.72). Perceived inadequate education/training (aOR: 1.62; 1.15–2.27) and perceived time constraints/competing priorities (aOR: 1.43; 1.03–1.98) were also associated with increased odds of non-compliance, independent of sociodemographic variables. In contrast, the belief that the supervisor complies with IPC (descriptive norm supervisor) was associated with decreased odds of non-compliance (aOR: 0.60; 0.41–0.88). Conclusions To improve IPC in disability care settings, the implementation of tailored and structural IPC education and training programmes (e.g., on-the-job training) is recommended to increase HCWs’ capabilities and bridge the IPC compliance gap between medical and non-medical professionals. In addition, role models, particularly supervisors, are crucial for promoting IPC behaviour. Facilities should create a culture of IPC compliance by norm setting, acting on, and modelling IPC behaviours at all levels of the organisation (management, medical, and non-medical staff).

AbstractObjective The TARGET program for integrated, person-centered care for people with chronic conditions offers primary care (PC) professionals a set of tools and trainings to actively engage in population segmentation and person-centered needs assessments (PCNAs). A pilot study was conducted to gain insight into the program’s feasibility and acceptability, and identify preconditions for successful implementation.Design and setting Seven Dutch PC practices participated in a half-year pilot study starting in August 2020. We performed a review of the population segmentation tool, observed four training sessions and 15 PCNAs, and interviewed 15 professionals and 12 patients.Results Regarding feasibility and acceptability, we found that the tools and trainings provided professionals with skills to use the segmentation tool and take a more coaching role in the well-appreciated PCNAs. Concerning implementation preconditions, we found that team commitment and network connections need improvement, although work pleasure increased and professionals generally wanted the program to continue.Conclusions While the content of the TARGET program is supported by its users, the implementation process, for instance team commitment to the program, needs more attention in future upscaling efforts.

Abstract Dental caries is the most common human disease caused by oral biofilms despite the widespread use of fluoride as the primary anticaries agent. Recently, an FDA-approved iron oxide nanoparticle (ferumoxytol, Fer) has shown to kill and degrade caries-causing biofilms through catalytic activation of hydrogen peroxide. However, Fer cannot interfere with enamel acid demineralization. Here, we show notable synergy when Fer is combined with stannous fluoride (SnF2), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, we discover that the stability of SnF2 is enhanced when mixed with Fer in aqueous solutions while increasing catalytic activity of Fer without any additives. Notably, Fer in combination with SnF2 is exceptionally effective in controlling dental caries in vivo, even at four times lower concentrations, without adverse effects on host tissues or oral microbiome. Our results reveal a potent therapeutic synergism using approved agents while providing facile SnF2 stabilization, to prevent a widespread oral disease with reduced fluoride exposure.

Abstract Background What we teach our (bio)medical students today may differ from the future context under which they will operate as health professionals. This shifting and highly demanding profession requires that we equip these students with adaptive competencies for their future careers. We aimed to develop a framework to promote and facilitate professional development from day one, guided by self-awareness and self-directed learning. Approach Based on self-directed, transformative and experiential learning, patient involvement and teamwork, we developed a 3-year longitudinal personal-professional development (LPPD) program in the (bio)medical sciences undergraduate curriculum to stimulate self-driven professional development in a variable context. Through group meetings and individual coach consultations, students address topics such as self-awareness, self-directed and lifelong learning, collaboration, well-being and resilience. To drive learning students receive extensive narrative feedback on an essay assignment. Evaluation Experiences and outcomes were evaluated with questionnaires and in-depth interviews. Students and coaches value personal and professional development in a safe learning environment that encourages self-exploration, diversity and connection. Over time, students show more self-awareness and self-directedness and increasingly apply trained skills, resulting in professional identity formation. Students need more clarification to understand the concept of assessment as learning. Implications With the generic content of a longitudinal program embedded in a meaningful environment, the personal and professional development of students can be facilitated and stimulated to face future challenges. When translating to other curricula, we suggest considering the complexity of professional development and the time expenditure needed for students to explore, experiment and practice. An early start and thorough integration are recommended.

Abstract Background Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. Methods We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA- (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. Results Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4, PDE4D, MMP8, CRISP3, and BCL2L15. Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay (pre-DEXA: 42 [29–49] vs. 18 [13–27] days, p

Abstract Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood–brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell—endothelial cell signalling leading to blood–brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood–brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood–brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood–brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1α and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood–brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1α/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood–brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease.

Abstract Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value

Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the “Nicotinic acetylcholine receptor signaling pathway”. Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics.

In this study, the potential of silk fibroin biomaterials for enhancing wound healing is explored, focusing on their integration into a human 3D ex vivo wound model derived from abdominoplasties. For this purpose, cast silk fibroin membranes and electrospun nonwoven matrices from Bombyx mori silk cocoons were compared to untreated controls over 20 days. Keratinocyte behavior and wound healing were analyzed qualitatively and quantitatively by histomorphometric and immune histochemical methods (HE, Ki67, TUNEL). Findings reveal rapid keratinocyte proliferation on both silk fibroin membrane and nonwoven matrices, along with enhanced infiltration in the matrix, suggesting improved early wound closure. Silk fibroin membranes exhibited a significantly improved early regeneration, followed by nonwoven matrices (p < 0.05) compared to untreated wounds, resulting in the formation of multi-layered epidermal structures with complete regeneration. Overall, the materials demonstrated excellent biocompatibility, supporting cell activity with no signs of increased apoptosis or early degradation. These results underscore silk fibroin’s potential in clinical wound care, particularly in tissue integration and re-epithelialization, offering valuable insights for advanced and—as a result of the electrospinning technique—individual wound care development. Furthermore, the use of an ex vivo wound model appears to be a viable option for pre-clinical testing.

(1) Background: This study aimed to describe upper-limb (UL) movement quality parameters in women after breast cancer surgery and to explore their clinical relevance in relation to post-surgical pain and disability. (2) Methods: UL movement quality was assessed in 30 women before and 3 weeks after surgery for breast cancer. Via accelerometer data captured from a sensor located at the distal end of the forearm on the operated side, various movement quality parameters (local dynamic stability, movement predictability, movement smoothness, movement symmetry, and movement variability) were investigated while women performed a cyclic, weighted reaching task. At both test moments, the Quick Disabilities of the Arm, Shoulder, and Hand (Quick DASH) questionnaire was filled out to assess UL disability and pain severity. (3) Results: No significant differences in movement quality parameters were found between the pre-surgical and post-surgical time points. No significant correlations between post-operative UL disability or pain severity and movement quality were found. (4) Conclusions: From this study sample, no apparent clinically relevant movement quality parameters could be derived for a cyclic, weighted reaching task. This suggests that the search for an easy-to-use, quantitative analysis tool for UL qualitative functioning to be used in research and clinical practice should continue.