Uppsala University Hospital

Objectives The aim was to assess the neuroglial compartment in the myenteric plexus of two subjects with genetically verified Waardenburg syndrome (WS) type 4 (WS4) and to compare the outcome with four “age‐matched” controls. Design Gut samples from four control cases and from two newborn subjects with WS4, one with peripheral demyelinating neuropathy, dysmyelinating leukodystrophy, WS and Hirschprung disease (PCWH) (SOX10, c.769A>T, p.Lys257*) and one with Waardenburg‐Shah syndrome (WSS) (EDN3, c.472C>T,p.Arg158Cys)—were assessed histologically and immunohistochemically. Antibodies directed to glial cells (SOX10), ganglion cells (HuC/D), and interstitial cells of Cajal (CD117) were applied. Results For the child with PCWH syndrome, both the small and large intestine showed a reduction in the number of glial cells (SOX10), in parallel with hypoganglionosis (HuC/D), when compared with “age‐matched” controls. In the child with WSS, a severe reduction in the number of glial cells (SOX10) was observed in both the small and large intestine accompanied by aganglionosis (HuC/D) with a skipped segment. The number of interstitial cells of Cajal (CD117) appeared unaffected in both PCWH and WSS cases. Conclusion A severe reduction of glial cells and a severe reduction or loss of ganglion cells (the number of cells assessed per unit length), were seen in our study subjects when compared with “age‐matched” controls. Contrary to the above the presence of Cajal cells was unaffected.

Background Global demographics show a steady increase in the number of octogenarians. Consequently, the number of degenerative spine procedures in the elderly has significantly increased. This study aims to describe patient satisfaction, the patient-reported health-related quality-of-life, and complications, following posterior cervical laminectomy for degenerative cervical myelopathy (DCM) in octogenarians based on the national Swedish experience. Methods The national Swedish spine registry, Swespine was reviewed between January 2006 and December 2020 for patients who underwent laminectomy for DCM. Complication rates, patient satisfaction, and Patient-Reported Outcome Measures (PROMs) one year after surgery, were analyzed and compared between propensity score matched octogenarian (≥ 80) and younger adult cohorts (< 80 years). Results A total of 1,382 patients, 162 octogenarians, and 1,220 younger patients were identified. At one-year after surgery there were no significant difference in patient satisfaction rate or in any of the other PROMS (Eq. 5D, NRS neck pain, NRS arm pain, EQ-VAS, Neck Disability Index (NDI), the European Myelopathy Score (EMS). Complication rates were also comparable, 8.0% in octogenarians (n = 13) and 11% in younger adults (n = 51), respectively. The length of hospital stay was significantly longer in the octogenarian group, with a mean hospitalization of 5.08 days (SD ± 4.86) compared to 3.76 days (SD ± 3.93) in the younger adult cohort (p < 0.001). Conclusions Octogenarians undergoing cervical spine surgery for DCM experience outcomes comparable to younger adults in terms of satisfaction, pain relief, and quality of life, indicating that age alone should not hinder surgical treatment. Level of evidence IV, Retrospective observational cohort study.

Objectives Patient perceived benefit of treatment for cleft lip and/or palate is of great importance since it is central to development of cleft care. CLEFT-Q is a cleft-specific questionnaire on health-related quality of life. Test-retest reliability, aspects of responsiveness and interpretability are yet to be established for CLEFT-Q. This study aims to investigate these psychometric characteristics of CLEFT-Q. Methods To establish the test-retest reliability of CLEFT-Q, data will be collected repeatedly and independently at approximately 1-week intervals. Inclusion of approximately 50 patients is considered adequate for a test-retest study. To improve the interpretability of CLEFT-Q norm data from a control population of volunteers without a cleft will be collected. A total of approximately 210 participants will be included from schools, high-schools and universities. To test the responsiveness of CLEFT-Q, patients will answer selected subscales of CLEFT-Q, longitudinal anchor questions and perform global ratings of change before and after surgery. To ensure robust results, approximately 50 patients for each type of treatment will be recruited. If CLEFT-Q is found to be responsive, the pre- and postoperative difference in scores of CLEFT-Q will be compared with the change in objective measurements based on assessments by professionals in cleft care obtained in this study. To evaluate interpretability, results will be analysed to investigate the minimal important change using anchor-based, distribution-based and qualitative approach. Registration details This study is registered at ClinicalTrials.gov under the ID 2021-06993-01.

Introduction Care transitions, particularly hospital discharge, present significant risks to patient safety. Deficient medication-related discharge communication is a major contributor, posing substantial risk of harm to older patients. This protocol outlines the Improved Medication communication and Patient involvement At Care Transitions (IMPACT-care) intervention study, designed to evaluate the effects of a multifaceted intervention for older hospitalised patients on medication-related discharge communication compared with usual hospital care. Methods and analysis A pre–post intervention study will be conducted in two surgical and one geriatric ward of a university hospital in Sweden. The study will begin with a control period delivering usual care, followed by a training period and then an intervention period. The intervention comprises four components performed by clinical pharmacists: (1) information package provided to patients and/or informal caregivers, (2) preparation of medication-related discharge documentation, (3) facilitation of discharge communication and (4) follow-up call to patients or their informal caregiver. Eligible participants are aged ≥65 years, manage their own medications independently or with informal caregiver support, and are admitted to the study wards. Each study period (control and intervention) will last until 115 patients have been included. The primary outcome is the quality of medication-related discharge documentation, assessed using the Complete Medication Documentation at Discharge Measure (CMDD-M). Secondary outcomes include patients’ perceptions of knowledge and involvement in discharge medication communication, and their sense of security in managing medication post-discharge; adherence to medication changes from hospitalisation that persist after discharge; and unplanned healthcare visits following discharge. A process evaluation is planned to explore how the intervention was implemented. Patient inclusion began in September 2024. Ethics and dissemination The study protocol has been approved by the Swedish Ethical Review Authority (registration no.: 2023-03518-01 and 2024-04079-02). Results will be published in open-access international peer-reviewed journals, and presented at national and international conferences. Trial registration number NCT06610214 .

Background Potassium binders mitigate hyperkalemia, allowing patients to maintain their renin-angiotensin-aldosterone-system inhibitor (RAASi) treatment. This study characterized patients treated with first- or second-generation potassium binders, usage patterns and their effectiveness in reducing potassium levels, and changes in RAASi treatment in a Swedish population-based study. Methods A National Cohort included patients who had record of a treatment episode with a first-generation or second-generation potassium binder between 2018 and 2022. A Mid-Sweden Cohort included patients from the National Cohort who also had a record of a potassium measurement within the 60 days prior to beginning potassium binder treatment. Comorbidities, prior medication use, persistence with potassium binder treatment, subsequent changes in potassium levels and RAASi treatment were evaluated. Persistence was analyzed using the Kaplan-Meier estimator and changes in potassium levels were assessed using linear mixed-effects models. Results 23,892 treatment episodes involving 14,235 patients (mean age 70 years, 33% women) were followed in the National Cohort, and 4860 episodes involving 3179 patients (mean age 72 years, 34% women) in the Mid-Sweden Cohort. Patients treated with second-generation potassium binders had more comorbidities and higher median persistence with treatment compared to those on first-generation potassium binders, 112.5 (95% CI:112.5-117.5) vs. 87.5 (95% CI: 87.5–87.5) days in the National Cohort; 165.5 (95% CI: 121.0-198.0) vs. 97.6 (95% CI: 87.5–110.0) days in the Mid-Sweden Cohort. Both first- and second-generation potassium binders reduced potassium levels from baseline by day 15, 5.7 [95% CI: 4.5–6.8] mmol/L to 4.7 [95% CI: 3.6–5.9] mmol/L and 5.5 (95% CI: 4.3–6.7) mmol/L to 4.9 (95% CI: 3.8–6.1) mmol/L, respectively. Dose reduction or discontinuation of renin-angiotensin system inhibitors (RASi) or mineralocorticoid receptor antagonists (MRAs) was found in 31.4% and 47.7%, respectively, within 120 days of initiating therapy. Conclusion Both potassium binders effectively reduced potassium levels, but frequent discontinuation or dose reduction of RAASi therapy were still observed during this period. The adjustments of RAASi therapy, despite the achievement of normokalemia within 15 days, may be premature and warrants careful reconsideration to ensure optimal patient outcomes.

The daily association between 24-hour physical behavior compositions (moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), standing, sedentary, and sleep) and psychological outcomes—such as momentary affective state assessments and working memory—remains understudied. We investigated whether the daily 24-hour compositions, particularly MVPA and SB considering the remaining behaviors, are associated with affective states and working memory. We conducted an ambulatory assessment study with 199 university employees. Physical behaviors were measured continuously via thigh-worn accelerometers throughout the day. Affective states (i.e., valence, energetic arousal, and calmness) and working memory performance (i.e., numeric updating task) were captured up to six times a day via electronic diaries and tasks on a smartphone. We conducted Bayesian multilevel compositional data analysis to analyze within-person, and between-person associations of 24-hour physical behavior composition with affective states, and working memory. Aggregated same-day outcomes were used for main analyses to capture concurrent associations, and next-day outcomes were used for exploratory analyses to capture prospective associations. Concurrent analyses showed that higher moderate-to-vigorous physical activity relative to the remaining physical behaviors was associated with 2.49 [95%CI 1.00, 4.06] higher valence and 3.65 [95%CI 2.11, 5.28] higher energetic arousal (but not calmness) ratings at the within-person, but not at the between-person level. Sedentary behavior relative to the remaining physical behaviors was not associated with any affective states. Spending more time in moderate-to-vigorous physical activity, followed by light physical activity, and standing, each at the expense of the other behaviors was associated with higher affective state ratings on the same day (between-person: ≥1.29 [0.19, 2.51] higher valence, 1.23 [0.04, 2.40] higher calmness; within-person: ≥0.62 [0.04, 1.22] higher valence, ≥ 1.10 [0.63, 1.58] higher energetic arousal, ≥ 0.95 [0.18, 1.74] higher calmness). The 24-hour physical behavior composition was not associated with working memory. Findings underline the importance of the 24-hour composition of physical behavior for mental health, by demonstrating significant concurrent associations with affective states. Even small reallocations of behaviors may positively influence affective states, providing valuable insights for the development of future interventions. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-025-99266-4.

Glioblastoma (GBM) is a highly malignant brain tumor with extensive cellular heterogeneity and plasticity. Bone morphogenetic protein 4 (BMP4) has shown potential as a therapeutic agent by promoting differentiation, but its effects are complex and context dependent. While BMP4’s role in differentiation is well established, its impact on senescence remains unclear. This study investigates BMP4’s ability to induce senescence in GBM cells. Primary GBM cultures were treated with BMP4 and analyzed for senescence markers, including cell enlargement, p21 expression, senescence-related gene enrichment, and senescence-associated-β-galactosidase activity. A p21 knockout model was used to determine its role in BMP4-induced senescence, and sensitivity to the senolytic agent navitoclax was evaluated. BMP4 induced senescence in the GBM cultures, particularly in mesenchymal (MES)-like GBM cells with high baseline p21 levels. The knockout of p21 nearly abolished BMP4-induced senescence, maintaining cell size and proliferation. Furthermore, navitoclax effectively eliminated BMP4-induced senescent cells through apoptosis, while sparing cells with normal p21 expression. Our findings highlight BMP4 as an inducer of p21-dependent senescence in GBM, particularly in MES-like cells. This study clarifies BMP4’s dual roles in differentiation and senescence, emphasizing their context dependence. Given the strong link between MES-like cells and therapy resistance, their heightened susceptibility to senescence may aid in developing targeted therapies for GBM and potentially other cancers with similar cellular dynamics.

In symptomatic patients undergoing coronary CTA for suspected coronary artery disease (CAD), we assessed if quantification of plaque burden, in addition to luminal narrowing and clinical risk factors, offers incremental value for the identification of ischemic CAD on a per patient level. We evaluated 2145 patients who underwent coronary CTA for suspected CAD with sequential selective downstream ¹⁵O-water positron emission tomography (PET) myocardial perfusion imaging. Coronary CTA scans were analyzed using Artificial Intelligence-guided Quantitative Computed Tomography (AI-QCT), with measurement of maximum diameter stenosis, percent atheroma volume (PAV), percent calcified plaque volume (CPV) and percent noncalcified plaque volume (NCPV). Ischemic CAD was defined as the presence of abnormal stress perfusion on ¹⁵O-water PET. PAV on top of the clinical variables and ≥ 50% stenosis improved the prediction of ischemic CAD on a per patient level as compared to clinical variables and ≥ 50% stenosis (AUC = 0.91 vs. AUC = 0.87, p < 0.001). The best diagnostic performance was achieved when PAV with a cut-off value of 12.2% was applied in patients with intermediate (30–70%) stenosis; using this approach, the sensitivity, specificity, positive and negative predictive values and diagnostic accuracy for ischemic CAD were 76%, 91%, 64%, 95% and 88%. The addition of quantitative plaque volume on top of clinical variables and ≥ 50% diameter stenosis improves the detection of ischemic CAD as defined by PET perfusion imaging. Applying a PAV threshold of 12.2% in patients with intermediate stenosis provided the best diagnostic performance. Graphical abstract Symptomatic patients with suspected CAD underwent coronary CTA and selective ¹⁵O-water PET myocardial perfusion imaging. Adding AI-QCT plaque burden improved the detection of ischemic CAD in comparison with diameter stenosis only. CAD = coronary artery disease, CTA = computed tomography angiography, PET = positron emission computed tomography, AI-QCT = artificial intelligence-guided quantitative computed tomography, PAV = percent atheroma volume

This study provides a comprehensive guide to robotic-assisted microsurgery. Following more than 900 clinical cases in 13 centers, this joint project was initiated to summarize and consent to the user experience. Two robotic systems specifically designed for the needs of open microsurgery received the first certification for clinical application (CE mark) in 2019 and 2020. Since their introduction into clinical application, several European microsurgical centers have implemented these systems, generating user experiences in multiple microsurgical subspecialties. All institutions using the MUSA-2 microsurgical robot (Microsure B.V., Eindhoven, Netherlands) or Symani Surgical System (Medical Microinstruments, Inc., Wilmington, Delaware, US) were invited to join the multicenter project. A modified nominal group technique was applied to answer five major questions regarding current and future indications and developments in open robotic-assisted microsurgery. Steep preclinical and clinical learning curves were characterized. General considerations concerning the two different systems are presented. Specifics for each microsurgical subspecialty are reported. Following two voting rounds, a consensus was reached in three of the five major questions with “lymphatics” being the top indication, “higher precision” being the top benefit, and “automation” being the top long-term goal of robotic-assisted microsurgery. This joint project of all Symani and MUSA-2 users presents clinical cases and the subsequent initial knowledge and experience. Lymphatics as a top indicator and a higher precision as the top benefit point toward the capabilities of robotic-assisted microsurgery in manipulation of smallest structures. Automation may further enhance and simplify robotic procedures in future. This project also provides a comprehensive guide to any institution aiming to introduce such a system for open robotic-assisted microsurgery in future.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), in late 2019 initiated a global health crisis marked by widespread infection, significant mortality, and long-term health implications. While SARS-CoV-2 primarily targets the respiratory system, recent findings indicate that it also significantly disrupts the human microbiome, particularly the gut microbiota, contributing to disease severity, systemic inflammation, immune dysregulation, and increased susceptibility to secondary infections and chronic conditions. Dysbiosis, or microbial imbalance, exacerbates the clinical outcomes of COVID-19 and has been linked to long-COVID, a condition affecting a significant proportion of survivors and manifesting with over 200 symptoms across multiple organ systems. Despite the growing recognition of microbiome alterations in COVID-19, the precise mechanisms by which SARS-CoV-2 interacts with the microbiome and influences disease progression remain poorly understood. This narrative review investigates the impact of SARS-CoV-2 on host-microbiota dynamics and evaluates its implications in disease severity and for developing personalized therapeutic strategies for COVID-19. Furthermore, it highlights the dual role of the microbiome in modulating disease progression, and as a promising target for advancing diagnostic, prognostic, and therapeutic approaches in managing COVID-19.

Objective To explore secondary outcomes at endpoint comparing treatments with adequate self-mediated physical activity combined with either night-time brace (NB), scoliosis-specific exercise (SSE), or adequate self-mediated physical activity alone (PA) in Adolescent Idiopathic Scoliosis (AIS). Methods A longitudinal, prospective, multicenter RCT was conducted including 135 girls/boys, Cobb angle 25–40°, 9–17 years, and ≥1-year remaining growth were randomly allocated into NB, SSE, or PA group. Endpoint was curve progression of ≤6° (success) at skeletal maturity or >6° (failure). Outcomes included angle of trunk rotation (ATR), major curve Cobb angle, Spinal Appearance Questionnaire (pSAQ), Scoliosis Research Society-22r (SRS-22r), EQ-5Dimensions Youth 3Levels (EQ-5D-Y-3L), and EQ-Visual-Analogue-Scale (EQ-VAS), adherence to treatment and International Physical Activity Questionnaire (IPAQ-SF). Results At endpoint, 122 patients were analyzed per protocol, mean age 12.7 (±1.4) years, and mean Cobb angle 31° (±4.3). A significant difference in change for ATR favored NB group compared to SSE group -2.0º (95% CI -3.7 to -0.3). EQ-5D-Y-3L dimensions showed a significant difference in change with decrease in mobility (p=0.031), and usual activities (p=0.003) for SSE compared to NB and PA groups. Treatment adherence was adequate but slightly better in NB and PA groups compared to SSE on self-report (p=0.012), and health care provider (HCP) report was better in PA compared to SSE group (p=0.013). Higher motivation and capability explained 53% of the variability and gave better odds for higher adherence (OR = 11.12, 95% CI = 1.5 to 34.4; OR = 7.23, 95% CI = 2.9 to 43.3), respectively. Conclusions Night-time brace, scoliosis-specific exercise or physical activity interventions for adolescents with idiopathic scoliosis showed small differences between groups in trunk rotation, spinal deformity and appearance, health-related quality of life, and treatment adherence but not likely reaching clinical relevance.

Purpose A comparison of acute toxicity between photon and proton radiotherapy (RT) for children undergoing treatment for medulloblastoma. Methods This retrospective multi-institutional cohort study included 96 children < 18 years treated for medulloblastoma in Sweden during 2008–2020. Patients treated with protons (n = 37) and photons (n = 59) were compared regarding acute side effects and radiation dose to intracerebral organs at risk (OARs). Data was collected from a prospectively maintained national database and was supplemented from a retrospective review of medical records. Acute symptoms were graded according to CTCAE (Common Terminology Criteria for Adverse Events), maximum grade occurring during RT and within 2 months after RT. Hematological toxicity was evaluated according to maximum grade and percentual reduction during RT. Results No significant differences in incidence or severity of acute symptoms were observed between proton-RT and photon-RT; grade ≥ 2 fatigue (5.4 vs. 10.2%), headache (2.7 vs. 3.4%), nausea (43.2 vs. 42.4%), dermatitis (5.4 vs. 15.3%), gastrointestinal toxicity (0 vs. 0%), weight loss (10.8 vs. 8.5%). Median percentual reduction (0% vs. -11,25%) in hemoglobin was significantly smaller during proton-RT (p < 0.001). No difference was observed for leucocytes, neutrophiles, or platelets. Absorbed mean dose to intracranial OARs was significantly lower with proton-RT. Conclusion This is one of the largest studies comparing acute side effects of proton-RT and photon-RT including only paediatric medulloblastoma patients. Proton-RT was safe and well tolerated regarding acute side effects. Absorbed dose to intracranial OARs was significantly lower with proton-RT. Further investigations of long-term side effects and cognitive evaluation is needed to show that this will translate into true clinical value for patients.

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of training to increase parental participation in the care of infants in neonatal units, compared to no training or a different type of training.

Context The literature on preventative measures against anxiety and antithrombotic management in children undergoing urological procedures is still limited, resulting in a generally low level of evidence. These guidelines aim to provide a practical approach based on a consensus from the European Association of Urology (EAU)/European Society for Paediatric Urology (ESPU) Paediatric Urology Guidelines Panel. Objective The authors aim to provide the 2024 EAU/ESPU Paediatric Urology Guidelines Panel update of the chapter on perioperative management of urological procedures in children. Evidence acquisition A structured literature review was performed for all relevant publications published from the last update until April 03, 2023. Evidence synthesis The most important updates include the following: anxiety and distress should be prevented or relieved by combining measures such as premedication, distraction techniques, and presence of parents or caregivers. Clinicians should select the appropriate premedication depending on the patient’s age, underlying conditions, and psychological status. A particular focus must be placed on paediatric patients with “special needs”, including children with psychophysical disorders that impact their relational and cognitive abilities. This unique population requires carefully tailored perioperative management. The incidence of perioperative thromboembolic events in the paediatric population is generally low. Controversies still exist on whether to perform a preoperative coagulation panel test on a routine basis. Neonates and adolescents are at a higher risk of perioperative thromboembolic events than the other children. Standard perioperative antithrombotic prophylaxis is not recommended due to a lack of high-quality evidence-based data. Conclusions This paper is a summary of evidence on preventative measures against anxiety and antithrombotic management in children undergoing urological procedures. Patient summary In this summary and update of the European Association of Urology/European Society for Paediatric Urology guidelines on paediatric urology, we provide practical considerations for preventative measures against anxiety and antithrombotic management in children undergoing urological procedures.

Objective Primary aldosteronism (PA) is a common cause of hypertension. It entails elevated morbidity and mortality that do not sufficiently improve with conventional antihypertensive therapy. Screening for PA by plasma aldosterone–renin ratio (ARR) enables discovery and specific treatment of affected patients. By screening primary care patients with hypertension and evaluating them further according to the Endocrine Society guidelines, we aimed to assess the prevalence of PA, the factors affecting biochemical diagnostics, and the outcome of lateralization studies and of specific treatment of the discovered PA cases. Design, patients, and methods Prospective evaluation of screening for PA was conducted in 1,181 patients. Screening by ARR was performed under current therapy, but without mineralocorticoid receptor antagonists (MRA), under normokalemia, and confirmed by the intravenous saline suppression test, SST#1. Those with results in a defined gray zone underwent therapy adjustment and then completed SST#2. Plasma aldosterone and ARR were compared under different stages of the diagnostic process. All patients with PA were offered adrenal venous sampling, or, in certain cases, adrenocortical-specific positron emission tomography. Lateralizing cases were offered laparoscopic adrenalectomy. Patients with bilateral disease were treated with MRA. Treatment results were assessed after a minimum of 6 months. Results A total of 53 discovered cases of (mostly mild) PA corresponded to its prevalence of 4.5%. Initial seated ARR was higher than recumbent ARR before SST#1. At SST#2, initial ARR and final aldosterone were higher than at SST#1. Localizing studies (accepted by 45 patients) found 14 lateralized cases. Of the 11 operated cases, 4 had aldosterone-producing adenoma, and the remainder had micro- and macronodular histopathology. A total of 31 patients had bilateral PA. Both surgical and conservative treatments were well tolerated and led to improved blood pressure and higher renin, indicating risk amelioration. Conclusions PA is prevalent among primary care patients with hypertension and can be screened for under current antihypertensive therapy. Aldosterone-producing adenoma was rare in this cohort. The study results support active screening of primary care patients with hypertension for PA in order to offer appropriate treatment options.

Background The effect of positive end-expiratory pressure (PEEP) on intracranial pressure (ICP) dynamics in patients with acute brain injury (ABI) remains controversial. PEEP can benefit oxygenation by promoting alveolar recruitment, but its influence on ICP is complex. The primary aims of this study were to investigate 1) how lung recruitability influences oxygenation and 2) how lung recruitability and regional gas distribution, measured via recruitment-to-inflation (RI) ratio and electrical impedance tomography (EIT), affect ICP in response to PEEP changes in critically ill patients in their early phase of ABI. Methods Ten mechanically ventilated ABI patients were included. Pressure reactivity index (PRx) was estimated. Using RI manoeuvre and EIT, lung recruitability and gas distribution were assessed in response to a standardised PEEP change (from high to low levels, with a delta of 10 cmH 2 O). Changes in ICP (ΔICP) were calculated between high and low PEEP. Lung inhomogeneity indices (global inhomogeneity index [GI] and local inhomogeneity index [LI]) were derived from EIT. Correlations between ventilatory variables and ICP were analysed. Results Blood oxygenation significantly decreased, going from high (14 [IQR: 12–15] cmH₂O) to low (4 [IQR: 2–5] cmH₂O) PEEP. Reducing PEEP significantly increased ICP (from 9 [IQR: 5–13] to 12 [IQR: 8–16] mmHg, p < 0.01), while cerebral perfusion pressure (CPP) improved (from 71 [IQR:67–83] to 75 [IQR: 70–84] mmHg, p = 0.03) and mean arterial pressure (MAP) increased (from 79 [IQR: 69–95] to 84 [IQR: 76–99] mmHg, p < 0.01). The RI ratio correlated significantly with ΔICP (rho = 0.87, p < 0.01), as did Vrec% (proportion of recruited volume, rho = 0.65) and GI (rho = 0.5). LI did not correlate with ΔICP. PRx was 0.30 [IQR: 0.12–0.42], indicating a deranged cerebral autoregulation. Conclusions Patients with a higher potential for lung recruitability had a more beneficial effect of PEEP on oxygenation. These effects should be interpreted cautiously, given that lung recruitability and global inhomogeneity of gas distribution significantly influenced the intracranial response to PEEP in ABI patients. As indicated by MAP and CPP, PEEP may impact systemic haemodynamics and cerebral perfusion when cerebral autoregulation is deranged. These findings underscore the importance of multimodal (i.e. respiratory, cerebral and haemodynamics) monitoring for optimising ventilation strategies in ABI patients and provide a framework for future research. Trial registration Registration number: NCT05363085, Date of registration: May 2022

The production of Cultured Epithelial Autografts (CEAs), autologous keratinocyte-sprays, and tissue-engineered skin substitutes in hospital-based laboratories is considered an Advanced Therapy Medicinal Product (ATMP). The production of ATMPs in Europe has to follow GMP (Good Manufacturing Practice) conditions and is regulated by Regulation 1394/2007 and Commission Directive 2009/120/EC. European regulation establishes the need of carrying out a complex process of characterization and quality controls during production, in order to release these products for clinical use. They are carried out at each critical stage of production: reception of the skin biopsy, extraction of keratinocytes and/or fibroblasts, media change, cell growth, cell passaging, and on the finished products. Here, we describe the production for autologous skin products at each critical stage: harvesting and biopsy reception, isolation of keratinocytes and fibroblasts, cell culture, and preparation of the final product.

Background Knee pain is often an early sign of knee osteoarthritis (KOA). Physical activities (PA) constitute the recommended regime to those affected. However, knee-loading PA at work is linked to an increased risk for KOA. The primary aim of this study was to investigate associations between knee pain and accelerometer-measured knee-loading PA, at work and leisure respectively. The secondary aim was to investigate knee-related problems in relation to self-reported physical effort at work. Methods This cross-sectional study included 107 working participants (aged 30–67) with knee pain. Knee pain was evaluated using the Knee Injury and Osteoarthritis Outcome Scale (KOOS), subscale Pain. Knee-loading PA (including daily steps, time in upright position, stair walking), and sitting/lying were measured by accelerometer for one week. Each knee-loading PA was analysed separately for the measurement periods: (1) total period, (2) time at work, and (3) leisure on workdays. Knee-related problems were evaluated by the KOOS subscales Symptoms, Activities of Daily Living, Function in Sport and Recreation, and Quality of Life. Analyses were made with linear regression, and stratified by high or low self-reported physical effort at work. Results Participants with more knee pain walked on average fewer steps per day, and spent less time in an upright position during leisure on workdays, unstandardized coefficient (β) = 0.001, p = 0.044, β = 0.075, p = 0.001 respectively, i.e. spent less time in knee-loading PA. The associations were stronger for those reporting high physical effort at work, β = 0.116, p = 0.016. Participants with high physical effort at work rated their (knee-related) quality of life worse. There were no associations between knee pain and knee-loading PA during work hours. Conclusions Participants with more knee pain were less physically active during leisure, with stronger associations among those with higher physical effort at work. Those reporting high physical effort at work had worse (knee-related) quality of life compared to participants reporting low effort at work. This highlights the importance of taking knee-loading PA at work and leisure into account when recommending exercise regimes to individuals with knee pain. Trial registration ClinicalTrials.Gov (NCT04928170), Date of registration: 2017-12-20.

Gamma-aminobutyric acid (GABA) and glutamate are implicated in the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS), though findings from magnetic resonance spectroscopy (MRS) are inconsistent. Furthermore, the relationship between GABAA-receptor availability and rTMS outcomes remains largely unexplored. In this study, GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) were measured using a ¹H-MRS MEGA-PRESS sequence in 42 patients with bipolar or unipolar depression, both before and after a sham-controlled, double-blind clinical trial involving intermittent theta-burst stimulation (iTBS) over the dorsomedial prefrontal cortex. A subset of 28 patients also underwent [¹¹C]flumazenil positron emission tomography (PET) to measure whole-brain GABAA-receptor availability and mean receptor availability in the nucleus accumbens and dACC. Depressive symptoms were assessed using the self-rated Montgomery Åsberg Depression Rating Scale (MADRS-S). The results indicated no significant changes in neurotransmitter levels or GABAA-receptor availability post-iTBS in either the active or sham conditions. However, changes in MADRS-S scores after active iTBS were positively correlated with changes in GABA levels in the dACC (r(13) = 0.54, p = 0.04) and baseline GABAA-receptor availability in the nucleus accumbens (r(11) = 0.66, p = 0.02). These correlations were absent in the sham group. The findings suggest that a reduction in GABA within targeted frontostriatal circuits can be part of the antidepressant mechanism of iTBS, challenging previous research. Additionally, they indicate a potential predictive role for frontostriatal GABAA-receptor availability in the treatment of depression using dorsomedial prefrontal iTBS.