Leiden University Medical Center

Sleep and headache are strongly interconnected, this narrative review gives an overview of the current pathophysiological and clinical correlates of sleep in primary headache disorders. Circuits across the brainstem and hypothalamus that are involved in the regulation of sleep and wake overlap with known headache and pain pathways, offering a possible pathophysiological basis for this relationship. Furthermore, growing evidence supports a key role for orexin (hypocretin), with dysregulated signalling and widespread orexin receptor expression in the trigeminocervical complex and trigeminal ganglion, key structures in headache pathophysiology. Clinically, people with migraine frequently report poor subjective sleep quality, high rates of insomnia, and an increased prevalence of sleep disorders such as restless legs syndrome. Additionally, reduced sleep is often reported as a trigger for migraine attacks. Cluster headache (CH) shows a particularly close relationship with sleep with attacks that occur at night during sleep. Polysomnography studies did not provide evidence for an association between specific sleep stages and attacks. Nonetheless, attacks often lead to impaired sleep quality and excessive daytime sleepiness in people with CH. Hypnic headache (HH) is characterized by headache attacks that occur exclusively during sleep. Lastly, sleep disturbances are also common in people with tension-type headache (TTH), particularly insomnia and daytime sleepiness. However, objective sleep studies generally show normal sleep architecture. Overall, substantial (patho)physiological and clinical overlap between headache and sleep disorders highlights the importance of systematically assessing and addressing of sleep disturbances in people with headache.

The nocebo effect, negative treatment outcomes arising from patient expectations, therapeutic context, or clinician communication, plays a possibly significant yet often under-estimated role in psychotherapy. Drawing on recent empirical and theoretical contributions, possible mechanisms how nocebo effects occur and can be attenuated in psychotherapeutic practice are discussed. Nocebo effects may arise from therapist communication, previous treatment failures, adverse therapeutic dynamics, poorly managed expectations, social influences outside the therapy, or context-factor elements such as waiting lists. Strategies for mitigating such effects include, for example, empathic engagement, expectation management, and reconditioning of previous negative treatment experiences in clinical settings.

Digitalization in geriatric rehabilitation presents unique challenges, making it essential to align eHealth solutions with patients' digital skills. The Quickscan Digital Skills (QDS) is a tool designed to help health care professionals match eHealth interventions to individual skill levels. This study aimed to explore the applicability of QDS by comparing it to self-reported digital skills and to gain insight into the digital skills of patients in geriatric rehabilitation. In this multicenter cross-sectional study, participants from 13 geriatric rehabilitation centers in the Netherlands completed a survey, including demographic questions, QDS, and a numeric rating scale (NRS) for self-reported digital skills. Participants were categorized into 3 skill levels (beginner, intermediate, and experienced) based on the cutoff points in QDS scores. Cutoff points were predetermined, guided by the information provided on QDS. Descriptive statistics for median age and frequencies for skill levels were calculated. Comparative analysis using a Kruskal-Wallis test assessed differences between QDS and NRS within these groups, and Spearman rank-order correlation examined the relationship between the two measures. To gain more insight into the different skill levels between groups, data were visualized and associations among age, gender, and digital skill levels were examined using ordinal logistic regression analysis. A total of 463 patients (median age 78, IQR 12 years; 282/463, 60.9% female) participated in this study. Based on QDS scores, 42.1% (195/463) were classified as beginners, 19.4% (90/463) as intermediates, and 38.4% (178/463) as experienced users. A moderate positive correlation was found between QDS and NRS scores. Digital skills generally declined with age: 69.8% (37/53) of participants younger than 65 years were experienced users compared to only 13.2% (5/38) of those older than 91 years. A logistic regression analysis showed that increasing age was significantly associated with lower digital skill levels (odds ratio 0.93, 95% CI 0.92-0.95; P<.001). The association between age and digital skills does not differ between males and females. This study suggests that QDS is a promising and practical screening tool for assessing digital skills in patients in geriatric rehabilitation. Self-reported digital skills with an NRS do not capture the differentiation in the assessed abilities by QDS. QDS could be a practical tool for identifying digital skill levels in patients in geriatric rehabilitation and can support more personalized eHealth implementation. Further research should explore the parametric properties of QDS and how the scores relate to actual eHealth use.

Patient-reported pain during intravitreal injection (IVI) may vary by injection quadrant and influence adherence to repeated treatments. Hence, this study aimed to quantify whether patient-reported pain differs by IVI quadrant and identify the least-painful approach. We searched 13 literature databases on 15 October 2025 for clinical studies reporting patient-reported IVI pain stratified by injection quadrant (superotemporal [ST], superonasal [SN], inferotemporal [IT], inferonasal [IN]). Random-effects meta-analyses synthesized mean differences (MD) in 0-10 visual analogue scale (VAS) pain across all six pairwise quadrant contrasts. All eligible studies were included for a qualitative review and a meta-analysis. The review was prospectively registered (PROSPERO CRD420251164189). Seven studies comprising 2048 IVI were included (ST 611, SN 469, IT 556, IN 412). Most injections involved anti-VEGF agents. All injections were performed under topical anesthesia (100%; drops or gel), with no subconjunctival anesthesia reported (0%), and pain was recorded immediately post-procedure using VAS-derived scales. Across all six pairwise contrasts, pooled mean differences between quadrants were small (typically < 1 VAS unit on a 0-10 scale), and all 95% confidence intervals crossed zero. Across quadrant comparisons, pooled pain differences were small and inconsistent; none of the pairwise pooled estimates demonstrated a statistically consistent difference, and between-study heterogeneity was substantial to considerable (I2 generally > 80%). Current evidence does not demonstrate a clearly less painful quadrant for intravitreal injections. Estimates varied across studies and heterogeneity was substantial, limiting confidence in any single average quadrant effect. Efforts to minimize IVI-related pain should prioritize optimized anesthesia protocols, communication, and injection technique, while future studies should standardize pain measurement and quadrant allocation to clarify whether subtle quadrant effects exist. PROSPERO registration:CRD420251164189.

Remote monitoring of disease activity in patients with rheumatoid arthritis (RA) offers a promising solution to increasing healthcare demands. This study aimed to develop and validate a model using selected clinical and patient-reported outcome measure (PROM) items that efficiently and accurately reflect the original disease activity score (DAS). Data from 5802 visits of 612 patients with RA from the treatment in the Rotterdam Early Arthritis Cohort and TApering strategies in RA trials were randomly split (1:1) into derivation and internal validation sets. An external validation was performed using 4404 visits from 1554 patients with RA from the Early Arthritis Cohort. A model was developed using Least Absolute Shrinkage and Selection Operator (LASSO) regression that incorporated age, sex, disease duration, autoantibody status, and individual PROM items, including visual analogue scale (VAS) general health, all Health Assessment Questionnaire-Disability Index (HAQ-DI) items, VAS pain, and VAS fatigue, to predict the DAS. The model's ability to detect active disease (DAS >2.4) and remission (DAS <1.6) was evaluated using the area under the receiver operating characteristic curve (AUC-ROC), along with sensitivity and specificity across predefined thresholds. The final model included 12 out of 28 predictors: age, sex, disease duration, VAS general health, 7 HAQ-DI items, and VAS pain. It showed excellent discriminative ability for detecting active disease with AUC-ROC values of 0.89 in both the development and internal validation sets, and 0.82 in the external validation set. For detecting remission, the AUC-ROC values were 0.86, 0.85, and 0.82, respectively. Test characteristics were provided for different thresholds. The proposed DAS intended for digital remote assessment combines clinical and PROM items and can accurately and efficiently distinguish between disease activity states in RA, supporting its potential use in remote monitoring in the future.

Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.

Evidence on risk factors for a complicated course of lower respiratory tract infections (LRTIs) in primary care remains limited and often consensus based. While socioeconomic status (SES) and migration background have been linked to complicated LRTIs in population-based studies, their predictive value in primary care remains unclear. Consequently, these factors are not incorporated within current guidelines, which may contribute to health inequalities. Therefore, we aimed to evaluate the added value of SES and migration background as predictive factors of a complicated course of LRTIs in primary care. Routine care data from Dutch general practices participating in the Extramural LUMC Academic Network database (Leiden-The Hague-Zoetermeer region) from 2014 to 2023, excluding COVID-19 years, was linked to sociodemographic and hospital claims data from Statistic Netherlands. Adults presenting with LRTI complaints were included (n = 145,445). Multivariable logistic regression models were constructed to predict 30-day hospitalisation or death following LRTI. Models included conventional risk factors with SES and migration background subsequently added. In this study we show that after adjusting for conventional clinical factors, SES is a strong predictor of a complicated course of LRTI, whereas migration background is not. Patients in the lowest SES category have an adjusted odds ratio of 1.46 (95%CI: 1.31 - 1.62) for a complicated course compared to the highest. SES is a strong predictor of a complicated course of LRTI in primary care, even after adjusting for conventional risk factors. The incorporation of SES into clinical decision tools and guidelines has the potential to enhance risk-stratification of patients with LRTI in daily practice of primary care, thereby supporting more equitable care.

Transoral laser microsurgery (TOLMS) is an established organ-preserving treatment for early-stage and selected intermediate-stage laryngeal squamous cell carcinoma (SCC). Initially indicated for Tis-T1 lesions, its use has progressively expanded to carefully selected T2 and T3 tumors, providing oncologic outcomes comparable to open surgery and (chemo)radiotherapy [(C)RT] while offering favorable functional results. The CO₂ (carbon dioxide) laser is the preferred device for TOLMS due to its precision and minimal thermal injury, allowing accurate tumor resection with optimal margin control. Successful application of TOLMS relies on strict patient selection and comprehensive pre- and intraoperative assessment. High-definition videolaryngoscopy, angled telescopes, bioendoscopic techniques, advanced imaging modalities, and emerging artificial intelligence tools have significantly improved the evaluation of tumor extent, biological behavior, and laryngeal function. Adequate laryngeal exposure is a critical prerequisite, as difficult exposure is associated with higher rates of positive margins and inferior oncological outcomes. Preoperative imaging, particularly magnetic resonance imaging (MRI) and dual-energy computed tomography (CT), is essential for assessing deep tumor extension, cartilage invasion, and involvement of key anatomical subsites, including the anterior commissure (AC), paraglottic space (PGS), and pre-epiglottic space (PES). AC involvement alone is not an absolute contraindication to TOLMS; however, vertical trans-AC extension and posterior PGS invasion, especially when associated with arytenoid fixation, represent major limitations due to the difficulty in achieving adequate oncologic margins. Surgical margin assessment remains challenging because of specimen shrinkage and variability in pathological evaluation, yet positive margins-particularly deep or multiple-are associated with worse disease-specific survival and laryngeal preservation. In supraglottic SCC, TOLMS is feasible for T1-T2 and selected T3 tumors, although functional outcomes decline with increasing extent of resection and patient age. The role of TOLMS in the salvage setting is limited and requires highly selective indications. In conclusion, TOLMS is an effective treatment for appropriately selected laryngeal cancers, provided that meticulous diagnostic work-up, surgical expertise, and multidisciplinary decision-making are ensured.