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Repetitive transcranial magnetic stimulation (rTMS) combined with exposure and response prevention is a promising treatment modality for treatment-refractory obsessive-compulsive disorder (OCD). However, not all patients respond sufficiently to this treatment. We investigated whether brain activation during a symptom provocation task could predict treatment response.

Pulmonary arteriovenous malformations (PAVMs) are direct connections between the pulmonary artery and vein, creating a right-to-left shunt (RLS). Embolization is indicated to prevent complications. Guidelines recommend follow-up chest CT scans to confirm persistent occlusion and embolization of all treatable PAVMs. Graded transthoracic contrast echocardiography (TTCE) after PAVM embolization may offer a reliable alternative in a subgroup of patients while preventing radiation exposure.

Cognitive deficits are a key source of disability in individuals with major depressive disorder (MDD) and worsen with disease progression. Despite their clinical relevance, the underlying mechanisms of cognitive deficits remain poorly elucidated, hampering effective treatment strategies. Emerging evidence suggests that alterations in white matter microstructure might contribute to cognitive dysfunction in MDD. We aimed to investigate the complex association between changes in white matter integrity, cognitive decline, and disease course in MDD in a comprehensive longitudinal dataset.

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Mesenteric artery stenting with a bare-metal stent is the current treatment for atherosclerotic chronic mesenteric ischaemia. Long-term patency of bare-metal stents is unsatisfactory due to in-stent intimal hyperplasia. Use of covered stents might improve long-term patency. We aimed to compare the patency of covered stents and bare-metal stents in patients with chronic mesenteric ischaemia.

Background: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON-related myopathy (SELENON-RM) are two rare neuromuscular diseases characterized by proximal and axial muscle weakness, scoliosis, spinal rigidity, low bone quality and respiratory impairment. Cardiac involvement has previously been described in retrospective studies and case reports, but large case series and prospective studies in unselected cohorts are lacking.Objective: The objective of this study is to conduct prevalence estimations, perform cardiac phenotyping, and provide recommendations for clinical care.Methods: In this case series including two time points, we conducted comprehensive assessments with electrocardiography (ECG) and transthoracic echocardiography (TTE). ECGs were systematically assessed for a large subset of variables. TTE included left and right ventricular ejection fraction (LVEF/RVEF) and left ventricular global longitudinal strain (GLS), the latter being a more early and sensitive marker of left ventricular dysfunction.Results: 21 LAMA2-MD (M = 5; 20±14 years) and 10 SELENON-RM patients (M = 7; 18±12 years) were included. In most patients, QRS fragmentation and Q waves, markers of heterogeneous ventricular activation, were present both at baseline and at follow-up. GLS was abnormal (age specific in children, > –18% in adults) in 33% of LAMA2-MD and 43% of SELENON-RM patients at baseline. Reduced LVEF (<52% in males, <54% in females and <55% in pediatric population) was observed in three LAMA2-MD patients at baseline and in none of the SELENON-RM patients. GLS and LVEF did not change between baseline and follow-up. RVEF was normal in all patients.Conclusion: ECG abnormalities and abnormal GLS are prevalent in LAMA2-MD and SELENON-RM, yet abnormal LVEF was only seen in LAMA2-MD patients. One LAMA2-MD patient had a clinically relevant deterioration in LVEF during 1.5-year follow-up. We advise routine screening of all patients with LAMA2-MD or SELENON-RM with ECG and echocardiography at diagnosis, minimally every two years from second decade of life and if new cardiac signs arise.

LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON-related myopathy (SELENON-RM) are two rare neuromuscular diseases characterized by proximal and axial muscle weakness, scoliosis, spinal rigidity, low bone quality and respiratory impairment. Cardiac involvement has previously been described in retrospective studies and case reports, but large case series and prospective studies in unselected cohorts are lacking. The objective of this study is to conduct prevalence estimations, perform cardiac phenotyping, and provide recommendations for clinical care. In this case series including two time points, we conducted comprehensive assessments with electrocardiography (ECG) and transthoracic echocardiography (TTE). ECGs were systematically assessed for a large subset of variables. TTE included left and right ventricular ejection fraction (LVEF/RVEF) and left ventricular global longitudinal strain (GLS), the latter being a more early and sensitive marker of left ventricular dysfunction. 21 LAMA2-MD (M = 5; 20±14 years) and 10 SELENON-RM patients (M = 7; 18±12 years) were included. In most patients, QRS fragmentation and Q waves, markers of heterogeneous ventricular activation, were present both at baseline and at follow-up. GLS was abnormal (age specific in children, > –18% in adults) in 33% of LAMA2-MD and 43% of SELENON-RM patients at baseline. Reduced LVEF (<52% in males, <54% in females and <55% in pediatric population) was observed in three LAMA2-MD patients at baseline and in none of the SELENON-RM patients. GLS and LVEF did not change between baseline and follow-up. RVEF was normal in all patients. ECG abnormalities and abnormal GLS are prevalent in LAMA2-MD and SELENON-RM, yet abnormal LVEF was only seen in LAMA2-MD patients. One LAMA2-MD patient had a clinically relevant deterioration in LVEF during 1.5-year follow-up. We advise routine screening of all patients with LAMA2-MD or SELENON-RM with ECG and echocardiography at diagnosis, minimally every two years from second decade of life and if new cardiac signs arise.

Non-pharmacological interventions, including cognitive-behavioral therapy (CBT), non-invasive brain stimulation (NIBS), electroconvulsive therapy (ECT), light therapy (LT), and physical rehabilitation/exercise, have shown promise as effective approaches to treat symptoms of depression and anxiety in individuals with Parkinson’s disease (PD). In this narrative literature overview, we discuss the state-of-the-art regarding these treatment options and address future perspectives for clinical practice and research. Non-pharmacological interventions hold promise to treat depression and anxiety in PD. There is meta-analytic evidence for the efficacy of CBT, NIBS, ECT, LT, and exercise on improving depressive symptoms. For the treatment of anxiety symptoms, CBT shows large effects but scientific evidence of other non-pharmacological interventions is limited. Importantly, these treatments are safe interventions with no or mild side-effects. More research is needed to tailor treatment to the individuals’ needs and combined interventions may provide synergistic effects.We conclude that non-pharmacological interventions should be considered as alternative or augmentative treatments to pharmacological and neurosurgical approaches for the treatment of depression and anxiety in individuals with PD.

Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation.

Causal inference from observational data requires untestable identification assumptions. If these assumptions apply, machine learning methods can be used to study complex forms of causal effect heterogeneity. Recently, several machine learning methods were developed to estimate the conditional average treatment effect (ATE). If the features at hand cannot explain all heterogeneity, the individual treatment effects can seriously deviate from the conditional ATE. In this work, we demonstrate how the distributions of the individual treatment effect and the conditional ATE can differ when a causal random forest is applied. We extend the causal random forest to estimate the difference in conditional variance between treated and controls. If the distribution of the individual treatment effect equals that of the conditional ATE, this estimated difference in variance should be small. If they differ, an additional causal assumption is necessary to quantify the heterogeneity not captured by the distribution of the conditional ATE. The conditional variance of the individual treatment effect can be identified when the individual effect is independent of the outcome under no treatment given the measured features. Then, in the cases where the individual treatment effect and conditional ATE distributions differ, the extended causal random forest can appropriately estimate the variance of the individual treatment effect distribution, whereas the causal random forest fails to do so.

Methadone is one of the most common medications currently prescribed for the treatment of opioid use disorders (OUDs). While methadone maintenance programs (MMPs) have been highly successful in the management and treatment of OUDs resulting in a reduced number of fatalities, the risk of overdose/toxicity remains. The current study was undertaken to analyze trends in overdoses attributed to prescribed and diverted methadone in South Australia (SA) between 2000 and 2019. Over the 20-year period, 344 methadone-related deaths occurred in SA with a significant increase in deaths over the study period (P= 0.03). The mean age of decedents was 42.5 years with a male to female ratio of 1.8:1, with approximately 20% of decedents enrolled in a MMP at the time of death. Overall, only 5.2% of cases demonstrated methadone diversion, which was associated with methadone prescribed for chronic pain and was most likely to be diverted from a friend/housemate or a partner. However, the source of methadone in more than half of cases was unknown, so this is likely a significant underestimate of actual MMP methadone diversion and total methadone diversion.

Renal cell carcinoma (RCC) is the most common kidney tumor in adults. RCC is rare in children, although its incidence increases in the second decade of life. Renal medullary carcinoma (RMC) is a rare and often aggressive RCC subtype characterized by complete loss of SMARCB1/INI1, predominantly diagnosed in patients with sickle cell disease or -trait. Here, we describe a pediatric and a young adult patient with clinicopathological characteristics similar to RMC but without hemoglobinopathies. These tumors are currently classified as “RCC unclassified with medullary phenotype” (RCCU-MP). Both our patients had an infiltrating, rather small kidney tumor with SMARCB1/INI1 deficiency. Remarkably, the aggressiveness and clinical course and treatment differed greatly between these two cases. So far, only nine patients, predominantly adults, have been reported. In a literature overview, most cases were metastatic and progressed or relapsed after varying treatment approaches, with low survival. Whereas the classification of these tumors remains a topic of debate, case reports add to the current knowledge of RMCs without hemoglobinopathies, stressing the importance of sharing experience concerning rare renal neoplasms with often poor outcomes, also concerning younger age categories.

In Canada and the United States, ∼1 in 5 children live in poverty, contributing to poor health outcomes. Families with children with chronic illness may experience additional financial stress related to hospitalization. This study aimed to capture experiences of financial needs and supports among caregivers with a child admitted to a tertiary care pediatric hospital to inform hospital-based financial services to reduce financial stress in families.We recruited caregivers of children admitted to the general inpatient ward of an academic pediatric center using purposive sampling with no exclusion criteria. Individual, semistructured, in-depth interviews with participants were conducted. Data collected included socio-demographics, financial needs, and experiences with financial supports. Interviews were audio-recorded, transcribed verbatim, coded, and analyzed on NVivo software using a modified-grounded theory approach and summative content analysis.Fifteen caregivers of diverse backgrounds were interviewed, including non-English speakers (n = 4). Three themes and associated subthemes (in parentheses) were identified: (1) financial stress expressed by participants (acute admission-related and chronic financial stress), (2) challenges associated with accessing and utilizing financial supports (caregiver factors, systemic hospital factors, and systemic government factors), and (3) ideas for financial services at the pediatric hospital (services that will provide acute- and chronic financial assistance including education about financial supports and benefits).Our study highlighted acute and chronic financial needs as well as challenges in accessing financial support. Participants were interested in the healthcare system gaining a comprehensive understanding of their financial circumstances and accessing financial services in a hospital setting.

In the large body of literature that is available about the role of motivation in mathematics education, the focus is mostly on students’ attitudes and feelings toward mathematics in general. In the current small-scale explorative study, we zoomed in on what students think about the tasks they can come across in mathematics education. To investigate students’ appraisement of mathematics tasks, that is, their judgment of how much they like mathematics tasks, we used a mixed method approach with an online questionnaire including closed and open questions. We asked 67 Norwegian eight graders to give an appraisal score for 24 tasks and to express in their own words their reasons for liking/disliking them. In addition, the students also had to indicate for each task whether they think they can solve the tasks. The analysis of the data indicated that the students may prefer bare number problems over context problems. Similarly, students inclined to like puzzle-like tasks more than estimation or straightforward tasks. The reasons for liking/disliking a task most often refer to the difficulty or easiness of the task. The data about the perceived solvability revealed that the more the students believed that they can solve the task, the more they liked the task. Given the different appraisals that the students granted to the different task types and the comments they came with, there is much reason to afford students a stronger voice in mathematics education research, particularly when it is about the tasks used in mathematics education.

During transcription-coupled DNA repair (TCR), RNA polymerase II (Pol II) transitions from a transcriptionally active state to an arrested state that allows for removal of DNA lesions. This transition requires site-specific ubiquitylation of Pol II by the CRL4CSAubiquitin ligase, a process that is facilitated by ELOF1 in an unknown way. Using cryogenic electron microscopy, biochemical assays and cell biology approaches, we found that ELOF1 serves as an adaptor to stably position UVSSA and CRL4CSAon arrested Pol II, leading to ligase neddylation and activation of Pol II ubiquitylation. In the presence of ELOF1, a transcription factor IIS (TFIIS)-like element in UVSSA gets ordered and extends through the Pol II pore, thus preventing reactivation of Pol II by TFIIS. Our results provide the structural basis for Pol II ubiquitylation and inactivation in TCR.

This study systematically develops an online training program improving line managers’ career-oriented people management behavior, including a pilot test. This program was developed based on the six steps of the Intervention Mapping protocol. Interviews were held with line managers and physicians to understand their needs and challenges with regard to people management. The program aimed to create (self-)awareness, enhance knowledge, support the exchange of experiences, and stimulate reflection on career-oriented people management behavior and leadership style and skills. Eight senior line managers of medical professionals employed in a large Dutch academic public hospital followed the training as part of the pilot test. The program was evaluated through observations, follow-up interviews, and a survey. This study makes a methodological and theoretical contribution to the human resource management literature. It shows how career-oriented people management behavior of line managers can be enhanced, which is important as earlier studies have demonstrated the benefits of this behavior. Systematically developing this program is relevant as studies have shown that the effectiveness of leadership programs is limited because of research design issues. Moreover, this study contributes to leadership development programs as this training could be offered as part of leadership programs.

The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3–90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain.

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.

Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.

BackgroundWe assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors.MethodsIn this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability.Results16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well.ConclusionA clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell’s criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.

ObjectiveThis randomised study in preterm infants on non-invasive respiratory support investigated the effectiveness of automated oxygen control (A-FiO2) in keeping the oxygen saturation (SpO2) within a target range (TR) during a 28-day period compared with manual titration (M-FiO2).DesignA single-centre randomised control trial.SettingA level III neonatal intensive care unit.PatientsPreterm infants (<28 weeks’ gestation) on non-invasive respiratory support.InterventionsA-FiO2versus M-FiO2control.MethodsMain outcomes were the proportion of time spent and median area of episodes in the TR, hyperoxaemia, hypoxaemia and the trend over 28 days using a linear random intercept model.Results23 preterm infants (median gestation 25.7 weeks; birth weight 820 g) were randomised. Compared with M-FiO2, the time spent within TR was higher in the A-FiO2group (68.7% vs 48.0%, p<0.001). Infants in the A-FiO2group spent less time in hyperoxaemia (13.8% vs 37.7%, p<0.001), but no difference was found in hypoxaemia. The time-based analyses showed that the A-FiO2efficacy may differ over time, especially for hypoxaemia. Compared with the M-FiO2group, the A-FiO2group had a larger intercept but with an inversed slope for the daily median area below the TR (intercept 70.1 vs 36.3; estimate/day −0.70 vs 0.69, p<0.001).ConclusionA-FiO2control was superior to manual control in keeping preterm infants on non-invasive respiratory support in a prespecified TR over a period of 28 days. This improvement may come at the expense of increased time below the TR in the first days after initiating A-FiO2control.Trial registration numberNTR6731.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5and DCC), synaptic structure and function genes (for example, PCLO, NCAM1and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Covalent DNA–protein cross-links (DPCs) are toxic DNA lesions that block replication and require repair by multiple pathways. Whether transcription blockage contributes to the toxicity of DPCs and how cells respond when RNA polymerases stall at DPCs is unknown. Here we find that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and a method for the genome-wide mapping of DNA–protein adducts, DPC sequencing, we discover that Cockayne syndrome (CS) proteins CSB and CSA provide resistance to DPC-inducing agents by promoting DPC repair in actively transcribed genes. Consequently, CSB- or CSA-deficient cells fail to efficiently restart transcription after induction of DPCs. In contrast, nucleotide excision repair factors that act downstream of CSB and CSA at ultraviolet light-induced DNA lesions are dispensable. Our study describes a transcription-coupled DPC repair pathway and suggests that defects in this pathway may contribute to the unique neurological features of CS.

Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges by harmonizing data collection to identify consistent brain signatures of OCD that are reproducible and generalizable. Single-shell diffusion measures (e.g., fractional anisotropy), multi-shell Neurite Orientation Dispersion and Density Imaging (NODDI) and fixel-based measures, were extracted from skeletonized white matter tracts in 260 medication-free adults with OCD and 252 healthy controls. We additionally performed structural connectome analysis. We compared cases with controls and cases with early (<18) versus late (18+) OCD onset using mixed-model and Bayesian multilevel analysis. Compared with healthy controls, adult OCD individuals showed higher fiber density in the sagittal stratum (B[SE]= 0.10[0.05], P= 0.04) and credible evidence for higher fiber density in several other tracts. When comparing early (n= 145) and late-onset (n= 114) cases, converging evidence showed lower integrity of the posterior thalamic radiation —particularly radial diffusivity (B[SE]= 0.28[0.12], P= 0.03)—and lower global efficiency of the structural connectome (B[SE]= 15.3[6.6], P= 0.03) in late-onset cases. Post-hoc analyses indicated divergent direction of effects of the two OCD groups compared to healthy controls. Age of OCD onset differentially affects the integrity of thalamo-parietal/occipital tracts and the efficiency of the structural brain network. These results lend further support for the role of the thalamus and its afferent fibers and visual attentional processes in the pathophysiology of OCD.

Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n= 284 acutely depressed, n= 177 partially and n= 198 fully remitted patients, and n= 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n= 1642; Control n= 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR< 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

This study explored the experiences and needs of adolescents, ranging from 12 to 18 years old, who have recently been diagnosed with cancer and participated in a nationwide germline genetic sequencing study within the context of pediatric oncology. The 21 adolescents in this qualitative interview study viewed genetic sequencing as an integral part of their cancer journey. They often characterized germline sequencing as “good-to-know” without specifying immediate utility. While the adolescents comprehended the significance of germline genetic sequencing, they were less focused on its potential long-term implications. Adolescents expressed a strong desire to be actively engaged in decisions related to genetics. They advocated for a participatory role in genetic decision-making from a young age onwards. They recommended that re-consent should be sought before re-analysis of their genetic data is performed and believe that patients should have the opportunity to provide (re-)consent once they reach adulthood. Moreover, the adolescents emphasized the importance of developing counseling materials that are not only concise but also visually attractive. In conclusion, this study underscores the positive perception that adolescents diagnosed with cancer hold regarding germline genetic sequencing. They articulate a strong interest in being actively involved in genetic decision-making. To address these articulated needs and preferences, we recommend the development of visually engaging counseling materials. These materials should effectively convey both the immediate and long-term implications of genetic sequencing, enabling adolescents with cancer to make informed decisions about genetic sequencing.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) “OCD vs. healthy controls” (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) “unmedicated OCD vs. healthy controls” (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) “medicated OCD vs. unmedicated OCD” (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6–79.1 in adults; 35.9–63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

Microplastics require a risk assessment framework that takes their multidimensionality into account while exclusively considering robust data. Therefore, effect tests should use a diverse, environmentally relevant microplastic (ERMP) standard material that adheres to high-quality requirements. In this study, we provide chronic dose–effect relationships and effect thresholds for 16 benthic species exposed to ERMP. The ERMP was created from plastic items collected from natural sources and cryogenically milled to represent the diversity of microplastics. The test design met 20 previously published quality assurance and quality control criteria. Adverse effect thresholds (EC10) were determined at ERMP concentrations of 0.11 ± 0.17% sediment dry weight (Gammarus pulex, growth), 0.49 ± 0.68% sediment dry weight (Lumbriculus variegatus, growth), and 1.90 ± 1.08% sediment dry weight (L. variegatus, reproduction). A positive effect of microplastics, such as decreased mortality, was observed for Cerastoderma edule(EC10= 0.021 ± 0.027% sediment dry weight) and Sphaerium corneum(EC10= 7.67 ± 3.41% sediment dry weight), respectively. Several of these laboratory-based single-species effect thresholds for ERMP occurred at concentrations lower than those found in the environment. For other species, no significant effects were detected up to an ERMP dose of 10% dry weight.

In dit artikel delen we de meerwaarde van een participatief ontwerpgerichte aanpak van een e-healthapplicatie ter preventie van diabetische voetwonden. We hopen hiermee lezers te stimuleren om samen te werken aan praktijkgericht onderzoek voor een hogere kwaliteit van leven voor mensen met diabetes.

Background: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness.Objective: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care.Methods: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry.Results: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3–42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures.Conclusions: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

Childhood maltreatment (CM) has been associated with changes in structural brain connectivity even in the absence of mental illness. Social support, an important protective factor in the presence of childhood maltreatment, has been positively linked to white matter integrity. However, the shared effects of current social support and CM and their association with structural connectivity remain to be investigated. They might shed new light on the neurobiological basis of the protective mechanism of social support. Using connectome-based predictive modeling (CPM), we analyzed structural connectomes of N= 904 healthy adults derived from diffusion-weighted imaging. CPM predicts phenotypes from structural connectivity through a cross-validation scheme. Distinct and shared networks of white matter tracts predicting childhood trauma questionnaire scores and the social support questionnaire were identified. Additional analyses were applied to assess the stability of the results. CM and social support were predicted significantly from structural connectome data (all rs ≥ 0.119, all ps≤ 0.016). Edges predicting CM and social support were inversely correlated, i.e., positively correlated with CM and negatively with social support, and vice versa, with a focus on frontal and temporal regions including the insula and superior temporal lobe. CPM reveals the predictive value of the structural connectome for CM and current social support. Both constructs are inversely associated with connectivity strength in several brain tracts. While this underlines the interconnectedness of these experiences, it suggests social support acts as a protective factor following adverse childhood experiences, compensating for brain network alterations. Future longitudinal studies should focus on putative moderating mechanisms buffering these adverse experiences.

Patients with COPD are at high risk of lung cancer developing, but no validated predictive biomarkers have been reported to identify these patients. Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for early detection of lung cancer in patients with COPD.

Background: Peritubular capillary rarefaction plays an important role in the progression of chronic kidney disease. Little is known about the relation between peritubular capillary density, glomerular volume and filtration rate in the healthy kidney. Methods: In this single-center study, we included 69 living kidney donors who donated between 2005 and 2008 and had representative renal biopsies available. In all donors, glomerular filtration rate was measured using 125I-Iothalamate before donation and at five years after donation. Before donation, the increase in glomerular filtration rate after dopamine stimulation was measured. Glomerular volume and peritubular capillary density were determined in biopsies taken at the time of transplantation. Pearson’s correlation coefficient and linear regression were used to assess relations between parameters. Results: Mean donor age was 52 ± 11 years and mean measured glomerular filtration rate was 119 ± 22 mL/min before donation and 82 ± 15 mL/min at five years after donation. While peritubular capillary density (measured by either number of peritubular capillaries/50,000 μm2or number of peritubular capillaries/tubule) was not associated with measured glomerular filtration rate before or after donation, number of peritubular capillaries/tubule was associated with the increase in measured glomerular filtration rate after dopamine stimulation (St.β= 0.33, p= 0.004), and correlated positively with glomerular volume (R= 0.24, p= 0.047). Glomerular volume was associated with unstimulated measured glomerular filtration rate before donation (St.β= 0.31, p= 0.01) and at five years (St.β= 0.30, p= 0.01) after donation, independent of age. Conclusions: In summary, peritubular capillary density was not related to unstimulated kidney function before or after kidney donation, in contrast to glomerular volume. However, number of peritubular capillaries/tubule correlated with the increase in glomerular filtration rate after dopamine stimulation in healthy kidneys, and with glomerular volume. These findings suggest that peritubular capillary density and glomerular volume differentially affect kidney function in healthy living kidney donors. Graphical abstract:

•MAC has probable drug efflux pumps.•EPIs are antibiotic specific.•M. avium can’t modify amikacin.

Interventions to address poverty and food insecurity in pediatric hospital care have been scarce. Access to government support is based on the completion of taxes. Medical-financial partnerships are defined as novel cross-sector collaborations in which health care systems and financial service organizations work collaboratively to improve health by reducing financial stress. The objective of our pilot study was to assess the feasibility of implementing a “free tax service” within a pediatric academic hospital setting.A pilot randomized controlled trial “TAX4U” was conducted from November 2020 until April 2021 in the general inpatient setting of an academic pediatric hospital. Eligible families were randomly assigned to receive either “free tax services” according to the Canada Revenue Agency-funded Community Volunteer Income Tax Program (CVITP) or “care as usual.”A total of 140 caregivers filled in the 8-question recruitment survey. We found that 101 (72%) families were not eligible to participate in the study. Reasons for ineligibility were not meeting CVITP criteria (n = 59, 58%), already filed tax (n = 25, 25%), and families did not sign the consent form (n = 17, 17%). Thirty-nine families were randomly assigned, with 20 (51.3%) families assigned to the intervention and 19 (48.7%) families receiving care as usual. Ultimately, 7 (35%) families received the tax intervention.Offering free tax services may be feasible and reached vulnerable families in a pediatric hospital setting; however, the inclusion criteria of the CVITP program did not meet the needs of caregivers. Further research should explore offering a full-scope medical-financial partnership that meets the needs of low-income families in a hospital setting.

Amination of C(sp3)–H bonds is a powerful tool to introduce nitrogen into complex organic frameworks in a direct manner. Despite significant advances in catalyst design, full site- and enantiocontrol in complex molecular regimes remain elusive using established catalyst systems. To address these challenges, we herein describe a new class of peptide-based dirhodium(II) complexes derived from aspartic acid-containing β-turn-forming tetramers. This highly modular system can serve as a platform for the rapid generation of new chiral dirhodium(II) catalyst libraries, as illustrated by the facile synthesis of a series of 38 catalysts. Critically, we present the first crystal structure of a dirhodium(II) tetra-aspartate complex, which unveils retention of the β-turn conformation of the peptidyl ligand; a well-defined hydrogen-bonding network is evident, along with a near-C4symmetry that renders the rhodium centers inequivalent. The utility of this catalyst platform is illustrated by the enantioselective amination of benzylic C(sp3)–H bonds, in which state-of-the-art levels of enantioselectivity up to 95.5:4.5 er are obtained, even for substrates that present challenges with previously reported catalyst systems. Additionally, we found these complexes to be competent catalysts for the intermolecular amination of N-alkylamides via insertion into the C(sp3)–H bond α to the amide nitrogen, yielding differentially protected 1,1-diamines. Of note, this type of insertion was also observed to occur on the amide functionalities of the catalyst itself in the absence of the substrate but did not appear to be detrimental to reaction outcomes when the substrate was present.

IMPORTANCE: Colorectal surgery is associated with substantial morbidity rates and a lowered functional capacity. Optimization of the patient’s condition in the weeks prior to surgery may attenuate these unfavorable sequelae. OBJECTIVE: To determine whether multimodal prehabilitation before colorectal cancer surgery can reduce postoperative complications and enhance functional recovery. DESIGN, SETTING, AND PARTICIPANTS: The PREHAB randomized clinical trial was an international, multicenter trial conducted in teaching hospitals with implemented enhanced recovery after surgery programs. Adult patients with nonmetastasized colorectal cancer were assessed for eligibility and randomized to either prehabilitation or standard care. Both arms received standard perioperative care. Patients were enrolled from June 2017 to December 2020, and follow-up was completed in December 2021. However, this trial was prematurely stopped due to the COVID-19 pandemic. INTERVENTIONS: The 4-week in-hospital supervised multimodal prehabilitation program consisted of a high-intensity exercise program 3 times per week, a nutritional intervention, psychological support, and a smoking cessation program when needed. MAIN OUTCOMES AND MEASURES: Comprehensive Complication Index (CCI) score, number of patients with CCI score more than 20, and improved walking capacity expressed as the 6-minute walking distance 4 weeks postoperatively. RESULTS: In the intention-to-treat population of 251 participants (median [IQR] age, 69 [60-76] years; 138 [55%] male), 206 (82%) had tumors located in the colon and 234 (93%) underwent laparoscopic- or robotic-assisted surgery. The number of severe complications (CCI score >20) was significantly lower favoring prehabilitation compared with standard care (21 of 123 [17.1%] vs 38 of 128 [29.7%]; odds ratio, 0.47 [95% CI, 0.26-0.87]; P = .02). Participants in prehabilitation encountered fewer medical complications (eg, respiratory) compared with participants receiving standard care (19 of 123 [15.4%] vs 35 of 128 [27.3%]; odds ratio, 0.48 [95% CI, 0.26-0.89]; P = .02). Four weeks after surgery, 6-minute walking distance did not differ significantly between groups when compared with baseline (mean difference prehabilitation vs standard care 15.6 m [95% CI, −1.4 to 32.6]; P = .07). Secondary parameters of functional capacity in the postoperative period generally favored prehabilitation compared with standard care. CONCLUSIONS AND RELEVANCE: This PREHAB trial demonstrates the benefit of a multimodal prehabilitation program before colorectal cancer surgery as reflected by fewer severe and medical complications postoperatively and an optimized postoperative recovery compared with standard care. TRIAL REGISTRATION: trialregister.nl Identifier: NTR5947