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BACKGROUND: Oxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into additional proinflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a). METHODS: Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNA sequencing, ELISA, Western blot, and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions. RESULTS: Compared with healthy individuals with low/normal Lp(a) levels (median, 7 mg/dL [18 nmol/L]; n=13), individuals with elevated Lp(a) levels (median, 87 mg/dL [218 nmol/L]; n=12) demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in proinflammatory pathways related to leukocyte migration, chemotaxis, NF-κB (nuclear factor kappa B) signaling, and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL (interleukin)-6, IL-8, and IL-1β after DG(40:6) and DG(38:4) stimulation, which was, in part, mediated via the NLRP3 (NOD [nucleotide-binding oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated colocalization of Lp(a) with M1 macrophages, and an enrichment of CD68+IL-18+TLR4+ (toll-like receptor) TREM2+ (triggering receptor expressed on myeloid cells) resident macrophages and CD68+CASP1+ (caspase) IL-1B+SELL+ (selectin L) inflammatory macrophages compared with patients with low Lp(a). Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]). CONCLUSIONS: Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is, in part, NLRP3 inflammasome dependent.

AimsElevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a).Methods and resultsUsing transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (-17%, P

Since people's attitude toward lesbians, gay men and bisexual people (LGB) affects young LGB people's mental health and subsequently their quality of life, it is important to establish people's attitudes toward LGB people. The current study examined attitudes toward lesbian, gay and bisexual people among Dutch students and the psychometrical characteristics of adapted instruments measuring attitudes toward sexual diversity. The students in the sample (N = 1.633) were recruited from secondary schools. The participants completed questionnaires with scales measuring attitudes toward LGB people. The results indicate that participants hold positive attitudes overall, but there are differences with regard to gender and educational level. In addition, the used instruments prove to be psychometrically sound for measuring LGB attitudes and this work contributes to the empirical debate about whether adolescents' attitudes toward lesbians, gay men and bisexual people underly domains of a general attitude toward LGB people. Our results indicate that students do not seem to distinguish among sexually diverse subgroups much, possibly a sign of increased awareness and knowledge of LGB groups. The use of one general measure of attitudes of sexually diverse people may be considered in future research. [ABSTRACT FROM AUTHOR]

Purpose: Cognitive Adaptation Training (CAT) is a psychosocial intervention with demonstrated effectiveness. However, no validated fidelity instrument is available. In this study, a CAT Fidelity Scale was developed and its psychometric properties, including interrater reliability and internal consistency, were evaluated. Methods: The fidelity scale was developed in a multidisciplinary collaboration between international research groups using the Delphi method. Four Delphi rounds were organized to reach consensus for the items included in the scale. To examine the psychometric properties of the scale, data from a large cluster randomized controlled trial evaluating the implementation of CAT in clinical practice was used. Fidelity assessors conducted 73 fidelity reviews at four mental health institutions in the Netherlands. Results: After three Delphi rounds, consensus was reached on a 44-item CAT Fidelity Scale. After administration of the scale, 24 items were removed in round four resulting in a 20-item fidelity scale. Psychometric properties of the 20-item CAT Fidelity Scale shows a fair interrater reliability and an excellent internal consistency. Conclusions: The CAT fidelity scale in its current form is useful for both research purposes as well as for individual health professionals to monitor their own adherence to the protocol. Future research needs to focus on improvement of items and formulating qualitative anchor point to the items to increase generalizability and psychometric properties of the scale. The described suggestions for improvement provide a good starting point for further development.

Identification of molecular predictive markers of response to neoadjuvant chemoradiation could aid clinical decision‐making in patients with localized oesophageal cancer. Therefore, we subjected pretreatment biopsies of 75 adenocarcinoma (OAC) and 16 squamous cell carcinoma (OSCC) patients to targeted next‐generation DNA sequencing, as well as biopsies of 85 OAC and 20 OSCC patients to promoter methylation analysis of eight GI‐specific genes, and subsequently searched for associations with histopathological response and disease‐free (DFS) and overall survival (OS). Thereby, we found that in OAC, CSMD1 deletion (8%) and ETV4 amplification (5%) were associated with a favourable histopathological response, whereas SMURF1 amplification (5%) and SMARCA4 mutation (7%) were associated with an unfavourable histopathological response. KRAS (15%) and GATA4 (7%) amplification were associated with shorter OS. In OSCC, TP63 amplification (25%) and TFPI2 (10%) gene promoter methylation were associated with an unfavourable histopathological response and shorter DFS (TP63) and OS (TFPI2), whereas CDKN2A deletion (38%) was associated with prolonged OS. In conclusion, this study identified candidate genetic biomarkers associated with response to neoadjuvant chemoradiotherapy in patients with localized oesophageal cancer.

BackgroundMethodsResultsDiscussionCase management (CM) aims to facilitate access to and integration of health care and social services. We investigated the feasibility and effectiveness of CM.Randomized controlled trial with 219 patients and 114 caregivers randomly allocated to CM (109/59) or care as usual (110/55). CM was based on early and continuous online monitoring of problems and needs. Outcomes were assessed every 6 months with the Hospital Anxiety and Depression Scale (HADS). Secondary outcome domains were participant restrictions, life satisfaction, self-efficacy, caregiver burden, and needs. Multilevel modeling was used. Feasibility aspects were protocol delivery, participants’ and case managers’ satisfaction, and factors affecting implementation.There were no significant differences between groups. Participation restrictions and unmet needs decreased in both groups within 6 months. Monitoring was successful in 38, and 10 participants asked the CM for support. CM consisted mostly of providing information.CM based on early and continuous online monitoring does not have benefit in identifying and addressing problems early after relatively mild injury. Unsuccessful monitoring may have hindered access to the case manager and prevented us from evaluating CM as a complex intervention. It remains a challenge to early identify those who could benefit from care coordination. [ABSTRACT FROM AUTHOR]

Invaginations of the nuclear membrane occur in different shapes, sizes, and compositions. Part of these pleiomorphic invaginations make up the nucleoplasmic reticulum (NR), while others are merely nuclear folds. We define the NR as tubular invaginations consisting of either both the inner and outer nuclear membrane, or only the inner nuclear membrane. Specifically, invaginations of both the inner and outer nuclear membrane are also called type II NR, while those of only the inner nuclear membrane are defined as type I NR. The formation and structure of the NR is determined by proteins associated to the nuclear membrane, which induce a high membrane curvature leading to tubular invaginations. Here we review and discuss the current knowledge of nuclear invaginations and the NR in particular. An increase in tubular invaginations of the nuclear envelope is associated with several pathologies, such as laminopathies, cancer, (reversible) heart failure, and Alzheimer’s disease. Furthermore, viruses can induce both type I and II NR. In laminopathies, the amount of A-type lamins throughout the nucleus is generally decreased or the organization of lamins or lamin-associated proteins is disturbed. Also, lamin overexpression or modulation of lamin farnesylation status impacts NR formation, confirming the importance of lamin processing in NR formation. Virus infections reorganize the nuclear lamina via (de)phosphorylation of lamins, leading to an uneven thickness of the nuclear lamina and in turn lobulation of the nuclear membrane and the formation of invaginations of the inner nuclear membrane. Since most studies on the NR have been performed with cell cultures, we present additional proof for the existence of these structures in vivo, focusing on a variety of differentiated cardiovascular and hematopoietic cells. Furthermore, we substantiate the knowledge of the lamin composition of the NR by super-resolution images of the lamin A/C and B1 organization. Finally, we further highlight the essential role of lamins in NR formation by demonstrating that (over)expression of lamins can induce aberrant NR structures.

Abstract Background People with acquired brain injury may suffer from cognitive, emotional and behavioural changes in the long term. Continuity of care is often lacking, leading to a variety of unmet needs and hindering psychosocial functioning from the occurrence of brain injury up to years thereafter. Case management aims to prevent (escalation of) problems and to facilitate timely access to appropriate services. In other populations, case management has shown to improve psychosocial well-being. In this study, we aim to evaluate the feasibility of case management after acquired brain injury and its effectiveness and cost-effectiveness, compared to care as usual. Methods This is a pragmatic randomized controlled superiority trial with two parallel groups and repeated measures in adults with ABI and their family, taking place between November 2019 and December 2021 in three provinces in the Netherlands. Participants will be randomly allocated to either the case management group, receiving case management from hospital discharge up to 2 years thereafter, or the control group, receiving care as usual. Effectiveness will be evaluated every 6 months for 18–24 months by patient-reported psychosocial well-being (Hospital Anxiety and Depression Scale (HADS), Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) restriction subscale and the Life Satisfaction Questionnaire (LiSat)), self-management (Patient Activation Measure (PAM)) and care needs (Longer-term Unmet Needs after Stroke (LUNS)). Family outcomes include self-efficacy (Carer Self-Efficacy Scale (CSES)), caregiver burden (Caregiver Strain Index (CSI)), psychosocial well-being (LiSat, HADS), family needs (Family Needs Questionnaire (FNQ)). Feasibility will be evaluated using qualitative methods, assessing fidelity, dose delivered, dose received, reach, recruitment and context. Cost-effectiveness will be determined by the EQ-5D-3L and service use. Discussion At the moment, there is no integrated health care service for people with acquired brain injury and their family members in the long term. If case management is shown to be feasible and (cost)-effective, it could bridge the gap between patients’ and families’ needs and the available services. Trial registration Netherlands Trial Register NL8104 . Registered on 22 October 2019.

Abstract Background Epidemiological studies substantiated that subjects with elevated lipoprotein(a) [Lp(a)] have a markedly increased cardiovascular risk. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers both LDL cholesterol (LDL-C) as well as Lp(a), albeit modestly. Effects of PCSK9 inhibition on circulating metabolites such as lipoprotein subclasses, amino acids and fatty acids remain to be characterized. Methods We performed nuclear magnetic resonance (NMR) metabolomics on plasma samples derived from 30 individuals with elevated Lp(a) (> 150 mg/dL). The 30 participants were randomly assigned into two groups, placebo (N = 14) and evolocumab (N = 16). We assessed the effect of 16 weeks of evolocumab 420 mg Q4W treatment on circulating metabolites by running lognormal regression analyses, and compared this to placebo. Subsequently, we assessed the interrelationship between Lp(a) and 14 lipoprotein subclasses in response to treatment with evolocumab, by running multilevel multivariate regression analyses. Results On average, evolocumab treatment for 16 weeks resulted in a 17% (95% credible interval: 8 to 26%, P

ObjectiveStudies have shown preliminary support for mindfulness-based interventions benefitting people with dementia and their caregivers. However, most studies focus on these two groups separately. This study examined whether it would be possible and beneficial for people with dementia and their caregiver to jointly undergo an adjusted Mindfulness-Based Stress Reduction (MBSR) training, named TANDEM.MethodsThe 8-week MBSR training was adjusted based on a literature review and interviews with experts (clinicians and mindfulness trainers). Seven couples (a person with early-stage dementia and their caregiver) participated together in the 8-week TANDEM program. Semi-structured qualitative interviews were conducted after completion. Questionnaires (administered before and after the intervention) assessed the primary outcomes of quality of life and psychological distress (stress, anxiety and depressive symptoms). Secondary outcomes were mindfulness, self-compassion, positive mental health, worrying, and perceived burden (for caregivers).ResultsAll participants completed the program and reported beneficial effects (relaxation, awareness, acceptance, and resilience). Most managed to integrate exercises into their daily lives and planned to continue their practice. Participating in a group was considered valuable and supportive. Furthermore, it was appreciated that participants could follow the training together (as a couple). The quantitative results showed a small effect on increased quality of life for caregivers. No substantial decrease in psychological distress was apparent. Caregivers displayed a large increase in mindfulness.ConclusionThe results of this mixed-methods study suggest that an adjusted mindfulness program is feasible and well-received among couples of persons with early-stage dementia and their caregiver, warranting further research in this area.

The nuclear lamins are the major components of the nuclear lamina in the nuclear envelope. Lamins are involved in numerous functions, including a role in providing structural support to the cell and the mechanosensing of the cell. Mutations in the genes encoding for lamins lead to the rare diseases termed laminopathies. However, not only laminopathies show alterations in the nuclear lamina. Deregulation of lamin expression is reported in multiple cancers and several viral infections lead to a disrupted nuclear lamina. The structural and mechanical effects of alterations in the nuclear lamina can partly explain the phenotypes seen in disease, such as muscular weakness in certain laminopathies and transmigration of cancer cells. However, a lot of answers to questions about the relation between changes in the nuclear lamina and disease development remain elusive. Here, we review the current understandings of the contribution of the nuclear lamina in the structural support and mechanosensing of healthy and diseased cells.