Pain and fatigue in adult patients with multiple osteochondromas: The Netherlands.

BACKGROUND: Multiple Osteochondromas (MO) is a rare genetic disorder characterised by the presence of numerous benign bone tumours, known as osteochondromas. Within the spectrum of debilitating symptoms associated with MO, pain is recognized as a major problem. Interestingly, our clinical observations suggest that fatigue is also a significant concern but has merely been touched upon in MO literature. This study aims to (1) assess the level of pain and fatigue in adult patients with MO; (2) compare fatigue in MO to healthy subjects and patients with Rheumatoid Arthritis (RA); (3) identify associated variables for pain and fatigue in patients with MO. METHODS: In this cross-sectional study, 353 adult MO patients completed a survey with validated questionnaires on pain, fatigue and psychosocial factors. Pain and fatigue were assessed with the Numeric Rating Scale (NRS), and fatigue was also measured with the Checklist Individual Strength (CIS). Fatigue (CIS) was compared with reference scores of healthy subjects and patients with RA, using a one-sample t-test. Multiple linear regression models for pain and fatigue were developed using a-priori selected independent variables based on a theoretical framework (ICF-model). RESULTS: Pain was reported by 87.8% (NRS = 3.19±2.6) and fatigue by 90.4% (NRS = 4.1±2.6) of patients with MO. Fatigue scores for MO (CIS = 84.1±15.3) were significantly higher (p<0.001) compared to reference scores of healthy subjects and patients with RA. The multivariable analysis for pain provided a final regression model with six variables (R2 = 0.445, p<0.001) of which fear avoidance beliefs and fatigue had the strongest association. For the fatigue models NRS (R2 = 0.455, p<0.001) and CIS (R2 = 0.233, p<0.001), the strongest associations were found with anxiety and depression respectively. CONCLUSIONS: Pain and fatigue are highly prevalent in patients with MO. Fatigue is significantly higher compared to healthy subjects and patients with RA. Several variables associated with pain and fatigue have been identified that could help improve multidisciplinary treatment plans.

Trends in incidence of pneumothorax in England before, during and after the COVID-19 pandemic (2017-2023): a population-based observational study.

Background: COVID-19 is a risk factor for pneumothorax. The pandemic may have influenced healthcare-seeking behaviour for pneumothorax. This study aimed to investigate recent trends in the incidence of pneumothorax in England. Methods: A population-based epidemiological study was conducted using an English national dataset of hospital admissions (Hospital Episode Statistics) from 2017 to 2023. Record-linkage was used to identify multiple admissions per person and co-morbidity. Pneumothoraces co-occurring with COVID-19 were identified by concurrent COVID-19 diagnostic coding. The pre-pandemic (January 2017-February 2020), pandemic (March-2020-February-2021) and post-pandemic periods (March 2021-March 2023) were compared. Findings: From 2017 to 2023, there were 72,275 hospital admissions for spontaneous pneumothorax among 59,130 patients. Admissions showed marked variability, peaking in January 2021 when the rate of admissions was about two-thirds higher than that of the pre-pandemic level (Incidence rate ratio [IRR] 1.65, 95% CI: 1.48-1.84). However, when excluding patients with a concurrent COVID-19 diagnosis, the overall trend shifted to a reduction during the pandemic period. Post-pandemic rates were not significantly different from pre-pandemic levels (IRR = 0.96, 95% CI: 0.89-1.04). The incidence of spontaneous pneumothorax was significantly higher in males (rate ratio compared to females: 2.29, 95% CI: 2.19-2.39). However, the trends were consistent in both males and females. Interpretation: This study highlights a significant peak in COVID-19 related cases but a corresponding trough in non-COVID-related cases (end 2020, early 2021). Despite a previous report of increasing incidence of (non-COVID-related) hospitalised spontaneous pneumothorax over the long-term between 1968 and 2016, we did not observe any continued increase throughout this study period, prompting further investigation into the impact of recent guidelines. Funding: Authors are supported by the NIHR Oxford BRC, Li Ka Shing and Robertson Foundations, MRC, and HDR UK.

Development and validation of AI-derived segmentation of four-chamber cine cardiac magnetic resonance.

BACKGROUND: Cardiac magnetic resonance (CMR) in the four-chamber plane offers comprehensive insight into the volumetrics of the heart. We aimed to develop an artificial intelligence (AI) model of time-resolved segmentation using the four-chamber cine. METHODS: A fully automated deep learning algorithm was trained using retrospective multicentre and multivendor data of 814 subjects. Validation, reproducibility, and mortality prediction were evaluated on an independent cohort of 101 subjects. RESULTS: The mean age of the validation cohort was 54 years, and 66 (65%) were males. Left and right heart parameters demonstrated strong correlations between automated and manual analysis, with a ρ of 0.91-0.98 and 0.89-0.98, respectively, with minimal bias. All AI four-chamber volumetrics in repeatability analysis demonstrated high correlation (ρ = 0.99-1.00) and no bias. Automated four-chamber analysis underestimated both left ventricular (LV) and right ventricular (RV) volumes compared to ground-truth short-axis cine analysis. Two correction factors for LV and RV four-chamber analysis were proposed based on systematic bias. After applying the correction factors, a strong correlation and minimal bias for LV volumetrics were observed. During a mean follow-up period of 6.75 years, 16 patients died. On stepwise multivariable analysis, left atrial ejection fraction demonstrated an independent association with death in both manual (hazard ratio (HR) = 0.96, p = 0.003) and AI analyses (HR = 0.96, p < 0.001). CONCLUSION: Fully automated four-chamber CMR is feasible, reproducible, and has the same real-world prognostic value as manual analysis. LV volumes by four-chamber segmentation were comparable to short-axis volumetric assessment. TRIALS REGISTRATION: ClinicalTrials.gov: NCT05114785. RELEVANCE STATEMENT: Integrating fully automated AI in CMR promises to revolutionise clinical cardiac assessment, offering efficient, accurate, and prognostically valuable insights for improved patient care and outcomes. KEY POINTS: • Four-chamber cine sequences remain one of the most informative acquisitions in CMR examination. • This deep learning-based, time-resolved, fully automated four-chamber volumetric, functional, and deformation analysis solution. • LV and RV were underestimated by four-chamber analysis compared to ground truth short-axis segmentation. • Correction bias for both LV and RV volumes by four-chamber segmentation, minimises the systematic bias.

Evaluating the conduct and reporting of the T-cell dependent antibody response in the Extended One-Generation Reproductive Toxicity study provided under the EU REACH regulation.

The European Union (EU) Chemicals Strategy for Sustainability regards chemicals that affect the immune system among the most harmful ones. The Extended One-Generation Reproductive Toxicity study (EOGRTS; Organisation for Economic Co-Operation and Development (OECD) Test Guideline (TG) 443), addresses, among others, potential effects of chemicals on development. In specific cases, the EOGRTS is performed with addition of a so-called cohort 3, that addresses potential effects on the developing immune system, by means of a central assay measuring the T-cell dependent antibody response (TDAR). This assay is based on an interplay of antigen presentation, T-cell help and antibody production by B-cells, and together comprises a functional immune response. In the context of the EOGRTS review project of the European Chemicals Agency (ECHA), we evaluated 15 available TDARs for compliance with conduct and reporting requirements. Collectively, the majority of the TDAR studies were considered to be adequately conducted. We however observed: (i) the protocols differed by the antigen used (sheep red blood cells (SRBC) or KLH), the route of administration (intravenous, intraperitoneal, or subcutaneous), prime or prime/boost immunizations, and whether IgG was measured. (ii) There was major variation in the effects of the positive control for immunosuppression, cyclophosphamide. (iii) Proficiency was not always shown. (iv) Statistical analysis was not always done or reported. (v) Results of effects on lymphocyte populations or other immunotoxicity observations obtained in cohort 1 (or 2) of the EOGRTS were not always discussed together with results of the TDAR. Taken together, next to an improved quality of reporting, this may suggest a need to better define the conduct of the TDAR in OECD TG 443 and OECD Guidance Document (GD) 151, at least for certain aspects.

Application of the IASP Grading System to Identify Underlying Pain Mechanisms in Patients with Knee Osteoarthritis: A Prospective Cohort Study.

OBJECTIVES: This study aimed to apply the International Association for the Study of Pain (IASP) grading system for identifying nociplastic pain in knee osteoarthritis (KOA) awaiting total knee arthroplasty (TKA) and propose criteria to finetune decision-making. Additionally, the study aimed to characterize a 'probable' versus 'no or possible' nociplastic pain mechanism using biopsychosocial variables and compare both groups in their one-year post-TKA response. METHODS: A secondary analysis of baseline data of a longitudinal prospective study involving 197 KOA patients awaiting total knee arthroplasty in Belgium and the Netherlands was performed. Two approaches, one considering four and the other three pain locations (step 2 of the grading system), were presented. Linear mixed model analyses were performed to compare the 'probable' and 'no or possible' nociplastic pain mechanism groups for several preoperative biopsychosocial-related variables and one-year postoperative pain. Also, a sensitivity analysis, comparing exclusively 'probable' versus 'no' nociplastic pain mechanism groups, was performed. RESULTS: Thirty (15.22% - approach four pain locations) and 46 (23.35% - approach three pain locations) participants were categorized under 'probable' nociplastic pain. Irrespective of the pain location approach or sensitivity analysis, the 'probable' nociplastic pain group included more woman, were younger, exhibited worse results on various preoperative pain-related and psychological variables, and had more pain one-year post-TKA compared to the other group. DISCUSSION: This study proposed additional criteria to finetune the grading system for nociplastic pain (except for discrete/regional/multifocal/widespread pain) and characterized a subgroup of KOA patients with 'probable' nociplastic pain. Future research is warranted for further validation.

Medication Appropriateness for Older Nursing Home Patients With a Limited Life Expectancy: From STOPP/START Version 2 to the ReNeWAL Criteria.

OBJECTIVES: To adapt the 2015 Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) criteria to older nursing home patients with a limited life expectancy of 1.5 to 2 years. DESIGN: A modified Delphi consensus study. SETTING AND PARTICIPANTS: The study was established in The Netherlands and conducted online. The international panel consisted of 23 experts with experience in medicine for older people. METHODS: The expert panel was presented with the 2015 STOPP/START criteria using an online survey program (Survey Monkey). The panelists were asked for their opinion on the appropriateness of the STOPP and START criteria, and adaptations to these criteria for older nursing home patients with a limited life expectancy on 4-point Likert scales. Consensus was defined as ≥70% of the panelists answering (very) inappropriate or (very) appropriate, and (completely) disagree or (completely) agree. RESULTS: Twenty-one panelists completed all 3 Delphi rounds. The final list of "Represcribing for Nursing home residents With A Limited life expectancy (ReNeWAL)" criteria comprises 132 criteria: 98 criteria to stop (70 original STOPP criteria and 28 adapted) and 34 criteria to start (16 original START criteria and 18 adapted) for older nursing home patients with a limited life expectancy. Considerations that panelists mentioned for adapting criteria were mainly prevention and treatment of discomfort. CONCLUSION AND IMPLICATIONS: It is clear that represcribing for older nursing home patients is highly complex and requires the consideration of various elements. The ReNeWAL criteria may be useful in enhancing represcribing for older nursing home patients with a limited life expectancy.

Optimal Threshold and Interpatient Variability in Left Atrial Ablation Scar Assessment by Dark-Blood LGE CMR.

BACKGROUND: Dark-blood late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) has better correlation with bipolar voltage (BiV) to define ablation scar in the left atrium (LA) compared to conventional bright-blood LGE CMR. OBJECTIVES: This study sought to determine the optimal signal intensity threshold of dark-blood LGE CMR to identify LA ablation scar. METHODS: In 54 patients scheduled for atrial fibrillation ablation, image intensity ratios (IIRs) were derived from preprocedural dark-blood LGE CMR. In 26 patients without previous ablation, the upper limit of normal was derived from the 95th and 98th percentiles of pooled IIR values. In 28 patients with previous atrial fibrillation ablation, BiV was compared with the corresponding IIR. Receiver-operating characteristics analyses were employed to determine the optimal IIR threshold (ie, the point with the smallest distance to the upper left corner of the receiver-operating characteristics) for LA ablation scar (BiV ≤0.15 mV). RESULTS: Upper limit of normal corresponded to IIR values 1.16 and 1.21, yielding low sensitivities of 0.32 and 0.09 to detect LA ablation scar. Receiver-operating characteristics analysis of IIR and BiV comparison achieved a median area under the curve of 0.77. Median optimal IIR threshold for LA ablation scar was 1.09, with an average sensitivity of 0.73, specificity of 0.75, and accuracy of 0.71. Median IIR thresholds of 1.00 and 1.10 corresponded to 80% sensitivity and 80% specificity, respectively. There was considerable interpatient variability: optimal IIR thresholds per patient ranged from 1.01 to 1.22. CONCLUSIONS: The optimal IIR threshold to identify LA ablation scar by dark-blood LGE CMR is 1.09. Because of interpatient variability, the investigators recommend using a lower (1.00) and upper (1.10) threshold to prevent over- or underestimation of ablation scar.

The TCR assigns naive T cells to a preferred lymph node.

Naive T cells recirculate between the spleen and lymph nodes where they mount immune responses when meeting dendritic cells presenting foreign antigen. As this may happen anywhere, naive T cells ought to visit all lymph nodes. Here, deep sequencing almost-complete TCR repertoires led to a comparison of different lymph nodes within and between individual mice. We find strong evidence for a deterministic CD4/CD8 lineage choice and a consistent spatial structure. Specifically, some T cells show a preference for one or multiple lymph nodes, suggesting that their TCR interacts with locally presented (self-)peptides. These findings are mirrored in TCR-transgenic mice showing localized CD69 expression, retention, and cell division. Thus, naive T cells intermittently sense antigenically dissimilar niches, which is expected to affect their homeostatic competition.

Posterior Cervical Foraminotomy Compared with Anterior Cervical Discectomy with Fusion for Cervical Radiculopathy: Two-Year Results of the FACET Randomized Noninferiority Study.

BACKGROUND: Posterior cervical foraminotomy (posterior surgery) is a valid alternative to anterior discectomy with fusion (anterior surgery) as a surgical treatment of cervical radiculopathy, but the quality of evidence has been limited. The purpose of this study was to compare the clinical outcome of these treatments after 2 years of follow-up. We hypothesized that posterior surgery would be noninferior to anterior surgery. METHODS: This multicenter, randomized, noninferiority trial assessed patients with single-level cervical radiculopathy in 9 Dutch hospitals with a follow-up duration of 2 years. The primary outcomes measured reduction of cervical radicular pain and were the success ratio based on the Odom criteria, and arm pain and decrease in arm pain, evaluated with the visual analog scale, with a 10% noninferiority margin, which represents the maximum acceptable difference between the new treatment (posterior surgery) and the standard treatment (anterior surgery), beyond which the new treatment would be considered clinically unacceptable. The secondary outcomes were neck pain, Neck Disability Index, Work Ability Index, quality of life, complications (including reoperations), and treatment satisfaction. Generalized linear mixed effects modeling was used for analyses. The study was registered at the Overview of Medical Research in the Netherlands (OMON), formerly the Netherlands Trial Register (NTR5536). RESULTS: From January 2016 to May 2020, 265 patients were randomized (132 to the posterior surgery group and 133 to the anterior surgery group). Among these, 25 did not have the allocated intervention; 11 of these 25 patients had symptom improvement, and the rest of the patients did not have the intervention due to various reasons. At the 2-year follow-up, of 243 patients, primary outcome data were available for 236 patients (97%). Predicted proportions of a successful outcome were 0.81 after posterior surgery and 0.74 after anterior surgery (difference in rate, -0.06 [1-sided 95% confidence interval (CI), -0.02]), indicating the noninferiority of posterior surgery. The between-group difference in arm pain was -2.7 (1-sided 95% CI, 7.4) and the between-group difference in the decrease in arm pain was 1.5 (1-sided 95% CI, 8.2), both confirming the noninferiority of posterior surgery. The secondary outcomes demonstrated small between-group differences. Serious surgery-related adverse events occurred in 9 patients (8%) who underwent posterior surgery, including 9 reoperations, and 11 patients (9%) who underwent anterior surgery, including 7 reoperations (difference in reoperation rate, -0.02 [2-sided 95% CI, -0.09 to 0.05]). CONCLUSIONS: This trial demonstrated that, after a 2-year follow-up, posterior surgery was noninferior to anterior surgery with regard to the success rate and arm pain reduction in patients with cervical radiculopathy. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

A deprescribing programme aimed to optimise blood glucose-lowering medication in older people with type 2 diabetes mellitus, the OMED2-study: the study protocol for a randomised controlled trial.

BACKGROUND: Older patients with type 2 diabetes mellitus (T2D) have an increased risk of hypoglycaemic episodes when using sulphonylureas or insulin. In the Netherlands, guidelines exist for reducing glucose-lowering medication in older patients. However, evidence is lacking that a medication reduction in older patients can be safely pursued. Here, we will examine if promoting the deprescribing of insulin/sulphonylureas with a deprescribing programme (DPP) in general practice affects T2D-complications in older overtreated patients. METHODS: We will perform a 1:1 cluster randomised controlled trial in 86 general practices in the Netherlands. The DPP will consist of education sessions with general practitioners and practice nurses about reducing glucose-lowering medication in older patients (≥ 70 years). Topics of the sessions include the necessity of deprescribing, tools to initiate deprescribing and strategies to discuss deprescribing with patients (shared decision making). The DPP further includes a support programme with practice visits. The study will employ a selection tool to identify possibly overtreated older patients from the electronic medical records of the general practitioner. Eligibility for enrolment in the study will be based on HbA1c targets indicated by the Dutch guidelines, which depend on age, diabetes duration, presence of frailty, and life expectancy. The control group will provide usual care. We aim to include 406 patients. The follow-up period will be 2 years. For the primary outcome, the effect of the DPP on T2D-complications will be assessed by counting the cumulative incidence of events related to under- and overtreatment in T2D as registered in the electronic medical records. We shall perform an intention-to-treat analysis and an analysis including only patients for whom deprescribing was initiated. The implementation of the DPP in general practice will be evaluated quantitatively and qualitatively using the Extended Normalisation Process Theory (ENPT) and the Reach, Efficacy - Adoption, Implementation and Maintenance (RE-AIM) model. Other secondary outcomes include quality of life, cognitive functioning, events related to overtreatment or undertreatment, biomarkers of health, amount of blood glucose-lowering medication prescriptions, and cost-effectiveness. DISCUSSION: This study will provide insight into the safety and feasibility of a programme aimed at deprescribing sulphonylureas/insulin in older people with T2D who are treated in general practice. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN50008265 , registered 09 March, 2023.

Bevacizumab-IRDye800CW for tumor detection in fluorescence-guided meningioma surgery (LUMINA trial): a single-center phase I study.

OBJECTIVE: Meningiomas are one of the most frequently occurring brain tumors and can be curatively treated with gross-total resection. A subtotal resection increases the chances of recurrence. The intraoperative identification of invisible tumor remnants by using a fluorescent tracer targeting an upregulated biomarker could help to optimize meningioma resection. This is called molecular fluorescence-guided surgery (MFGS). Vascular endothelial growth factor α (VEGFα) has been identified as a suitable meningioma biomarker and can be targeted with bevacizumab-IRDye800CW. METHODS: The aim of this prospective phase I trial was to determine the safety and feasibility of bevacizumab-IRDye800CW for MFGS for intracranial meningiomas by administering 4.5, 10, or 25 mg of the tracer 2-4 days prior to surgery. Fluorescence was verified during the operation with the standard neurosurgical microscope, and tissue specimens were postoperatively analyzed with fluorescence imaging systems (Pearl and Odyssey CLx) and spectroscopy to determine the optimal dose. Uptake was compared in several tissue types and correlated with VEGFα expression. RESULTS: No adverse events related to the use of bevacizumab-IRDye800CW occurred. After two interim analyses, 10 mg was the optimal dose based on ex vivo tumor-to-background ratio. Although the standard intraoperative imaging revealed no fluorescence, postoperative analyses with tailored imaging systems showed high fluorescence uptake in tumor compared with unaffected dura mater and brain. Additionally, tumor invasion of the dura mater (dural tail) and invasion of bone could be distinguished using fluorescence imaging. Fluorescence intensity showed a good correlation with VEGFα expression. CONCLUSIONS: Bevacizumab-IRDye800CW can be safely used in patients with meningioma; 10 mg bevacizumab-IRDye800CW provided an adequate tumor-to-background ratio. Adjustments of the currently available neurosurgical microscopes are needed to achieve visualization of targeted IRDye800CW intraoperatively. A phase II/III trial is needed to methodically investigate the benefit of MFGS with bevacizumab-IRDye800CW for meningioma surgery in a larger cohort of patients.

Detectability of intracranial vessel wall atherosclerosis using black-blood spectral CT: a phantom and clinical study.

BACKGROUND: Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations. METHODS: A phantom with tubes of known diameters and wall thickness was scanned for wall detectability, wall thickness, and contrast-to-noise ratio (CNR) on conventional and spectral black-blood (SBB) images. The clinical study included 34 stroke patients. Diagnostic certainty and conspicuity of normal/abnormal intracranial vessels using SBB were compared to conventional. Sensitivity/specificity/accuracy of SBB and conventional were compared for plaque detectability. CNR of the wall/lumen and quantitative comparison of remodeling index, plaque burden, and eccentricity were obtained for SBB imaging and high-resolution magnetic resonance imaging (hrMRI). RESULTS: The phantom study showed improved detectability of tube walls using SBB (108/108, 100% versus conventional 81/108, 75%, p < 0.001). CNRs were 75.9 ± 62.6 (mean ± standard deviation) for wall/lumen and 22.0 ± 17.1 for wall/water using SBB and 26.4 ± 15.3 and 101.6 ± 62.5 using conventional. Clinical study demonstrated (i) improved certainty and conspicuity of the vessels using SBB versus conventional (certainty, median score 3 versus 0; conspicuity, median score 3 versus 1 (p < 0.001)), (ii) improved sensitivity/specificity/accuracy of plaque (≥ 1.0 mm) detectability (0.944/0.981/0.962 versus 0.239/0.743/0.495) (p < 0.001), (iii) higher wall/lumen CNR of SBB of (78.3 ± 50.4/79.3 ± 96.7) versus hrMRI (18.9 ± 8.4/24.1 ± 14.1) (p < 0.001), and (iv) excellent reproducibility of remodeling index, plaque burden, and eccentricity using SBB versus hrMRI (intraclass correlation coefficient 0.85-0.94). CONCLUSIONS: SBB can enhance the detectability of intracranial plaques with an accuracy similar to that of hrMRI. RELEVANCE STATEMENT: This new spectral black-blood technique for the detection and characterization of intracranial vessel atherosclerotic disease could be a time-saving and cost-effective diagnostic step for clinical stroke patients. It may also facilitate prevention strategies for atherosclerosis. KEY POINTS: • Blooming artifacts can blur vessel wall morphology on conventional CT angiography. • Spectral black-blood (SBB) images are generated from material decomposition from spectral CT. • SBB images reduce blooming artifacts and noise and accurately detect small plaques.

Clusters of resilience and vulnerability: executive functioning, coping and mental distress in patients with diffuse low-grade glioma.

PURPOSE: Diffuse low-grade gliomas (dLGG) often have a frontal location, which may negatively affect patients' executive functions (EF). Being diagnosed with dLGG and having to undergo intensive treatment can be emotionally stressful. The ability to cope with this stress in an adaptive, active and flexible way may be hampered by impaired EF. Consequently, patients may suffer from increased mental distress. The aim of the present study was to explore profiles of EF, coping and mental distress and identify characteristics of each profile. METHODS: 151 patients with dLGG were included. Latent profile analysis (LPA) was used to explore profiles. Additional demographical, tumor and radiological characteristics were included. RESULTS: Four clusters were found: 1) overall good functioning (25% of patients); 2) poor executive functioning, good psychosocial functioning (32%); 3) good executive functioning, poor psychosocial functioning (18%) and; 4) overall poor functioning (25%). Characteristics of the different clusters were lower educational level and more (micro)vascular brain damage (cluster 2), a younger age (cluster 3), and a larger tumor volume (cluster 4). EF was not a distinctive factor for coping, nor was it for mental distress. Maladaptive coping, however, did distinguish clusters with higher mental distress (cluster 3 and 4) from clusters with lower levels of mental distress (cluster 1 and 2). CONCLUSION: Four distinctive clusters with different levels of functioning and characteristics were identified. EF impairments did not hinder the use of active coping strategies. Moreover, maladaptive coping, but not EF impairment, was related to increased mental distress in patients with dLGG.

Unravelling relationships between obesity, diabetes, and factors related to somatosensory functioning in knee osteoarthritis patients.

OBJECTIVE: This study explores the association between obesity, diabetes, and somatosensory functioning in patients with knee osteoarthritis (OA), aiming to understand how metabolic conditions are related to pain mechanisms in this patient population. We hypothesized that higher body mass index (BMI), fat mass, and glycated hemoglobin levels (HbA1c) are associated with signs of altered somatosensory functioning. METHODS: A cross-sectional analysis was conducted as part of a larger multicentre prospective cohort study. Data were collected from patients awaiting total knee arthroplasty in Belgium and the Netherlands. Associations between BMI, fat mass, HbA1c, and various pain-related variables were examined employing Pearson and Spearman correlation analyses which were further analyzed with linear regression techniques. RESULTS: The study included 223 participants. Analysis revealed a significant although weak negative correlation between fat mass and pressure pain thresholds (PPT) at multiple locations, suggesting a link between higher fat mass and increased mechanical hyperalgesia. There were no significant correlations between BMI and pain-related outcomes. HbA1c levels showed very weak positive correlations with pain measures but did not withstand correction for multiple testing. CONCLUSION: The findings indicate that fat mass may be closely associated with altered somatosensory functioning in patients with knee OA. However, no significant correlations were found between BMI or HbA1c levels and pain-related outcomes. Future research should focus on longitudinal studies to elucidate the causal relationships and further explore the impact of metabolic factors on pain mechanisms in this patient population. Key Points • The findings indicate that fat mass may be closely associated with altered somatosensory functioning in patients with knee OA.

Overdose responses among rural people who use drugs: A multi-regional qualitative study.

BACKGROUND: Efforts to distribute naloxone have equipped more people with the ability to reverse opioid overdoses but people who use drugs are often reluctant to call 911 due to concerns for legal repercussions. Rural communities face unique challenges in reducing overdose deaths compared to urban communities, including limited access to harm reduction services as well as greater concerns about stigma and privacy. METHODS: The Rural Opioid Initiative was funded in 2017 to better understand the health-related harms associated with the opioid crisis in rural US communities and consists of eight studies spanning ten states and 65 counties. Each study conducted semi-structured qualitative interviews with people who use drugs to understand contextual factors influencing drug use and health behaviors. We analyzed qualitative data from seven studies with data available at the time of analysis to understand peer response to overdose. RESULTS: Of the 304 participants interviewed, 55% were men, 70% were white, 80% reported current injection drug use, and 60% reported methamphetamine use. Similar to what has been found in studies focused on urban settings, people who use drugs in rural communities use a range of strategies to reverse overdoses, including non-evidence-based approaches. Several reported that multiple doses of naloxone are needed to reverse overdose. Three themes emerged around the willingness to call 911, including (1) hesitancy to call 911 for fear of legal consequences, (2) negative perceptions or experiences with law enforcement officers, and (3) efforts to obtain medical intervention while avoiding identification/law enforcement involvement. CONCLUSION: People who use drugs employ multiple strategies to attempt overdose reversal, including non-evidence-based approaches. Greater education about the most effective and least harmful strategies is needed. Reluctance to call 911 is rooted in concerns about potential legal consequences as well as perceptions about law enforcement officers, which may be heightened in rural communities where people who use drugs are more easily identified by law enforcement. People who use drugs will go to great strides to connect their peers to needed medical services, suggesting that comprehensive interventions to reduce interactions with law enforcement officers and eliminate legal consequences for reporting overdoses are critical.

YajC, a predicted membrane protein, promotes Enterococcus faecium biofilm formation in vitro and in a rat endocarditis model.

Biofilm formation is a critical step in the pathogenesis of difficult-to-treat Gram-positive bacterial infections. We identified that YajC, a conserved membrane protein in bacteria, plays a role in biofilm formation of the clinically relevant Enterococcus faecium strain E1162. Deletion of yajC conferred significantly impaired biofilm formation in vitro and was attenuated in a rat endocarditis model. Mass spectrometry analysis of supernatants of washed ΔyajC cells revealed increased amounts in cytoplasmic and cell-surface-located proteins, including biofilm-associated proteins, suggesting that proteins on the surface of the yajC mutant are only loosely attached. In Streptococcus mutans YajC has been identified in complex with proteins of two cotranslational membrane protein-insertion pathways; the signal recognition particle (SRP)-SecYEG-YajC-YidC1 and the SRP-YajC-YidC2 pathway, but its function is unknown. In S. mutans mutation of yidC1 and yidC2 resulted in impaired protein insertion in the cell membrane and secretion in the supernatant. The E. faecium genome contains all homologous genes encoding for the cotranslational membrane protein-insertion pathways. By combining the studies in S. mutans and E. faecium, we propose that YajC is involved in the stabilization of the SRP-SecYEG-YajC-YidC1 and SRP-YajC-Yid2 pathway or plays a role in retaining proteins for proper docking to the YidC insertases for translocation in and over the membrane.

Association between stringency of lockdown measures and emergency department visits during the COVID-19 pandemic: A Dutch multicentre study.

INTRODUCTION: The COVID-19 outbreak disrupted regular health care, including the Emergency Department (ED), and resulted in insufficient ICU capacity. Lockdown measures were taken to prevent disease spread and hospital overcrowding. Little is known about the relationship of stringency of lockdown measures on ED utilization. OBJECTIVE: This study aimed to compare the frequency and characteristics of ED visits during the COVID-19 outbreak in 2020 to 2019, and their relation to stringency of lockdown measures. MATERIAL AND METHODS: A retrospective multicentre study among five Dutch hospitals was performed. The primary outcome was the absolute number of ED visits (year 2018 and 2019 compared to 2020). Secondary outcomes were age, sex, triage category, way of transportation, referral, disposition, and treating medical specialty. The relation between stringency of lockdown measures, measured with the Oxford Stringency Index (OSI) and number and characteristics of ED visits was analysed. RESULTS: The total number of ED visits in the five hospitals in 2019 was 165,894, whereas the total number of visits in 2020 was 135,762, which was a decrease of 18.2% (range per hospital: 10.5%-30.7%). The reduction in ED visits was greater during periods of high stringency lockdown measures, as indicated by OSI. CONCLUSION: The number of ED visits in the Netherlands has significantly dropped during the first year of the COVID-19 pandemic, with a clear association between decreasing ED visits and increasing lockdown measures. The OSI could be used as an indicator in the management of ED visits during a future pandemic.

Preoperative glycaemic control, number of pain locations, structural knee damage, self-reported central sensitisation, satisfaction and personal control are predictive of 1-year postoperative pain, and change in pain from pre- to 1-year posttotal knee arthroplasty.

PURPOSE: The aim of this study was to identify preoperative predictors for 1-year posttotal knee arthroplasty (TKA) pain and pre- to post-TKA pain difference in knee osteoarthritis (KOA) patients. METHODS: From March 2018 to July 2023, this prospective longitudinal cohort study enrolled KOA patients awaiting TKA from four hospitals in Belgium and the Netherlands. Different biopsychosocial predictors were assessed preoperatively by questionnaires and physical examinations (input variables). The Knee injury and Osteoarthritis Outcome Score (KOOS) subscale pain was used to measure pain intensity. The absolute KOOS subscale pain score 1-year post-TKA and the difference score (ΔKOOS = 1-year postoperative - preoperative) were used as primary outcome measures (output variables). Two multivariable linear regression analyses were performed. RESULTS: Two hundred and twenty-three participants were included after multiple imputation. Worse absolute KOOS subscale pain scores 1-year post-TKA and negative or closer to zero ΔKOOS subscale pain scores were predicted by self-reported central sensitisation, lower KOA grade and preoperative satisfaction, and higher glycated haemoglobin, number of pain locations and personal control (adjusted R2 = 0.25). Additional predictors of negative or closer to zero ΔKOOS subscale pain scores were being self-employed, higher preoperative pain and function (adjusted R2 = 0.37). CONCLUSION: This study reports different biopsychosocial predictors for both outcomes that have filtered out other potential predictors and provide value for future studies on developing risk assessment tools for the prediction of chronic TKA pain. PROTOCOL REGISTRATION: The protocol is registered at clinicaltrials.gov (NCT05380648) on 13 May 2022. LEVEL OF EVIDENCE: Level II.

Colonization of vancomycin-resistant Enterococcus faecium in human-derived colonic epithelium: unraveling the transcriptional dynamics of host-enterococcal interactions.

Enterococcus faecium is an opportunistic pathogen able to colonize the intestines of hospitalized patients. This initial colonization is an important step in the downstream pathogenesis, which includes outgrowth of the intestinal microbiota and potential infection of the host. The impact of intestinal overgrowth on host-enterococcal interactions is not well understood. We therefore applied a RNAseq approach in order to unravel the transcriptional dynamics of E. faecium upon co-culturing with human derived colonic epithelium. Co-cultures of colonic epithelium with a hospital-associated vancomycin resistant (vanA-type) E. faecium (VRE) showed that VRE resided on top of the colonic epithelium when analyzed by microscopy. RNAseq revealed that exposure to the colonic epithelium resulted in upregulation of 238 VRE genes compared to the control condition, including genes implicated in pili expression, conjugation (plasmid_2), genes related to sugar uptake, and biofilm formation (chromosome). In total, 260 were downregulated, including the vanA operon located on plasmid_3. Pathway analysis revealed an overall switch in metabolism to amino acid scavenging and reduction. In summary, our study demonstrates that co-culturing of VRE with human colonic epithelium promotes an elaborate gene response in VRE, enhancing our insight in host-E. faecium interactions, which might facilitate the design of novel anti-infectivity strategies.

Nano(bio)Materials Do Not Affect Macrophage Phenotype-A Study Conducted by the REFINE Project.

Macrophages are well known for their involvement in the biocompatibility, as well as biodistribution, of nano(bio)materials. Although there are a number of rodent cell lines, they may not fully recapitulate primary cell responses, particularly those of human cells. Isolation of tissue-resident macrophages from humans is difficult and may result in insufficient cells with which to determine the possible interaction with nano(bio)materials. Isolation of primary human monocytes and differentiation to monocyte-derived macrophages may provide a useful tool with which to further study these interactions. To that end, we developed a standard operating procedure for this differentiation, as part of the Regulatory Science Framework for Nano(bio)material-based Medical Products and Devices (REFINE) project, and used it to measure the secretion of bioactive molecules from M1 and M2 differentiated monocytes in response to model nano(bio)materials, following an initial assessment of pyrogenic contamination, which may confound potential observations. The SOP was deployed in two partner institutions with broadly similar results. The work presented here shows the utility of this assay but highlights the relevance of donor variability in responses to nano(bio)materials. Whilst donor variability can provide some logistical challenges to the application of such assays, this variability is much closer to the heterogeneous cells that are present in vivo, compared to homogeneous non-human cell lines.