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Abstract Background Healthcare providers, including medical students, should maintain their basic life support (BLS) skills and be able to perform BLS in case of cardiac arrest. Research shows that the use of virtual reality (VR) has advantages such as improved accessibility, practice with lifelike situations, and real-time feedback during individual training sessions. A VR BLS module incorporating these advantages, called Virtual Life Support, has been developed especially for the medical domain. Virtual Life Support was collaboratively developed by software developers and stakeholders within the field of medical education. For this study, we explored whether the first version of this module capitalised on the advantages of VR and aimed to develop an understanding of barriers to feasibility of use. Methods This study was conducted to assess the feasibility of employing Virtual Life Support for medical training and pinpoint potential obstacles. Four groups of stakeholders were included through purposive sampling: physicians, BLS instructors, educational experts, and medical students. Participants performed BLS on a BLS mannequin while using Virtual Life Support and were interviewed directly afterwards using semi-structured questions. The data was coded and analysed using thematic analysis. Results Thematic saturation was reached after seventeen interviews were conducted. The codes were categorised into four themes: introduction, content, applicability, and acceptability/tolerability. Sixteen barriers for the use of Virtual Life Support were found and subsequently categorised into must-have (restraining function, i.e. necessary to address) and nice to have features (non-essential elements to consider addressing). Conclusion The study offers valuable insights into redesigning Virtual Life Support for Basic Life Support training, specifically tailored for medical students and healthcare providers, using a primarily qualitative approach. The findings suggest that the benefits of virtual reality, such as enhanced realism and immersive learning, can be effectively integrated into a single training module. Further development and validation of VR BLS modules, such as the one evaluated in this study, have the potential to revolutionise BLS training. This could significantly improve both the quality of skills and the accessibility of training, ultimately enhancing preparedness for real-life emergency scenarios.

Normothermic machine perfusion (NMP) is a clinical strategy to reduce renal ischemia-reperfusion injury (IRI). Optimal NMP should restore metabolism and minimize IRI induced inflammatory responses. Microdialysis was used to evaluate renal metabolism. This study aimed to assess the effect of complement inhibition on NMP induced inflammatory responses. Twenty-two pig kidneys underwent 18 h of static cold storage (SCS) followed by 4 h of NMP using a closed-circuit system. Kidneys were randomized to receive a C5-inhibitor or placebo during SCS and NMP. Perfusion resulted in rapidly stabilized renal flow, low renal resistance, and urine production. During SCS, tissue microdialysate levels of glucose and pyruvate decreased significantly, whereas glycerol increased (p < 0.001). In the first hour of NMP, glucose and pyruvate increased while glycerol decreased (p < 0.001). After 4 h, all metabolites had returned to baseline. Inflammatory markers C3a, soluble C5b-9, TNF, IL-6, IL-1β, IL-8, and IL-10 increased significantly during NMP in perfusate and kidney tissue. C5-inhibition significantly decreased perfusate and urine soluble C5b-9 (p < 0.001; p = 0.002, respectively), and tissue IL-1β (p = 0.049), but did not alter other inflammatory markers. Microdialysis can accurately monitor the effect of NMP on renal metabolism. Closed-circuit NMP induces inflammation, which appeared partly complement-mediated. Targeting additional immune inhibitors should be the next step.

Background: Chronic Kidney Disease (CKD), is often detected late due to its asymptomatic nature in the early stage of the disease. Overproduction of reactive oxygen species contributes to various pathological processes through oxidative stress (OS), impacting on cellular structures and functions with previous studies suggesting a link between OS and CKD progression. This study investigated the association between serum peroxiredoxin-4 (Prx4), a biomarker of oxidative stress, and the development of CKD in the general population. Methods: This study featured data from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, involving 5341 participants without CKD at baseline who underwent extensive prospective health evaluations. Serum Prx4 levels were quantified using an immunoluminometric assay. The primary outcome was new-onset CKD as defined by the composite of urinary albumin excretion (UAE) > 30 mg/24-h, an estimated glomerular filtration rate (eGFR)

Background: Post-COVID-19 syndrome (PCS) remains a major health issue worldwide, while its pathophysiology is still poorly understood. Systemic oxidative stress (OS) may be involved in PCS, which is reflected by lower circulating free thiols (R–SH, sulfhydryl groups), as they are receptive to rapid oxidation by reactive species. This study aimed to investigate the longitudinal dynamics of serum R–SH after SARS-CoV-2 infection and its association with the development of PCS in individuals with mild COVID-19. Methods: Baseline serum R–SH concentrations were measured and compared between 135 non-hospitalized COVID-19 subjects and 82 healthy controls (HC). In COVID-19 subjects, serum R–SH concentrations were longitudinally measured during the acute disease phase (up to 3 weeks) and at 3, 6, and 12 months of follow-up, and their associations with relevant clinical parameters were investigated, including the development of PCS. Results: Baseline albumin-adjusted serum R–SH were significantly reduced in non-hospitalized COVID-19 subjects as compared to HC (p = 0.041), reflecting systemic OS. In mild COVID-19 subjects, trajectories of albumin-adjusted serum R–SH levels over a course of 12 months were longitudinally associated with the future presence of PCS 18 months after initial infection (b = −9.48, p = 0.023). Conclusion: Non-hospitalized individuals with COVID-19 show evidence of systemic oxidative stress, which is longitudinally associated with the development of PCS. Our results provide a rationale for future studies to further investigate the value of R–SH as a monitoring biomarker and a potential therapeutic target in the development of PCS.

BackgroundPostoperative infections remain a crucial challenge in health care, resulting in high morbidity, mortality, and costs. Accurate identification and labeling of patients with postoperative bacterial infections is crucial for developing prediction models, validating biomarkers, and implementing surveillance systems in clinical practice. ObjectiveThis scoping review aimed to explore methods for identifying patients with postoperative infections using electronic health record (EHR) data to go beyond the reference standard of manual chart review. MethodsWe performed a systematic search strategy across PubMed, Embase, Web of Science (Core Collection), the Cochrane Library, and Emcare (Ovid), targeting studies addressing the prediction and fully automated surveillance (ie, without manual check) of diverse bacterial infections in the postoperative setting. For prediction modeling studies, we assessed the labeling methods used, categorizing them as either manual or automated. We evaluated the different types of EHR data needed for the surveillance and labeling of postoperative infections, as well as the performance of fully automated surveillance systems compared with manual chart review. ResultsWe identified 75 different methods and definitions used to identify patients with postoperative infections in studies published between 2003 and 2023. Manual labeling was the predominant method in prediction modeling research, 65% (49/75) of the identified methods use structured data, and 45% (34/75) use free text and clinical notes as one of their data sources. Fully automated surveillance systems should be used with caution because the reported positive predictive values are between 0.31 and 0.76. ConclusionsThere is currently no evidence to support fully automated labeling and identification of patients with infections based solely on structured EHR data. Future research should focus on defining uniform definitions, as well as prioritizing the development of more scalable, automated methods for infection detection using structured EHR data.

Placental macrophages, which include maternal decidual macrophages and fetal Hofbauer cells, display a high degree of phenotypical and functional plasticity. This provides these macrophages with a key role in immunologically driven events in pregnancy like host defense, establishing and maintaining maternal-fetal tolerance. Moreover, placental macrophages have an important role in placental development, including implantation of the conceptus and remodeling of the intrauterine vasculature. To facilitate these processes, it is crucial that placental macrophages adapt accordingly to the needs of each phase of pregnancy. Dysregulated functionalities of placental macrophages are related to placental malfunctioning and have been associated with several adverse pregnancy outcomes. Although fetal growth restriction is specifically associated with placental insufficiency, knowledge on the role of macrophages in fetal growth restriction remains limited. This review provides an overview of the distinct functionalities of decidual macrophages and Hofbauer cells in each trimester of a healthy pregnancy and aims to elucidate the mechanisms by which placental macrophages could be involved in the pathogenesis of fetal growth restriction. Additionally, potential immune targeted therapies for fetal growth restriction are discussed.

Introduction Patients undergoing invasive coronary angiography (ICA) experience anxiety due to various reasons. Procedural anxiety can lead to physiological and psychological complications, compromising patient comfort and overall procedural outcomes. Benzodiazepines are commonly used to reduce periprocedural anxiety, although the effect is modest. Virtual reality (VR) is a promising non-pharmacological intervention to reduce anxiety in patients undergoing ICA.Methods and analysis A single-centre open-label randomised controlled trial is conducted assessing the effectiveness of add-on VR therapy on anxiety in 100 patients undergoing ICA and experiencing anxiety in a periprocedural setting. The primary outcome is the Numeric Rating Scale (NRS) anxiety score measured just before obtaining arterial access. Secondary outcomes include postarterial puncture and postprocedural anxiety, patient-reported outcome measures (PROMs) of anxiety and physiological measurements associated with anxiety. The NRS anxiety level and physiological measurements are assessed five times during the procedure. The PROM State-Trait Anxiety Inventory and Perceived Stress Scale are completed preprocedure, and the PROM STAI and the Igroup Presence Questionnaire are performed postprocedure.Ethics and dissemination The protocol of this study has been approved by the Research Ethics Committee of the Radboud University Medical Centre, the Netherlands (CMO Arnhem-Nijmegen, 2023–16586). Informed consent is obtained from all patients. The trial is conducted according to the principles of the Helsinki Declaration and in accordance with Dutch guidelines, regulations, and acts (Medical Research involving Human Subjects Act, WMO).Registration details Trial registration number: NCT06215456.

Abstract Background Chronic pain is a disabling condition which is prevalent in about 20% of the adult population. Physiotherapy is the most common non-pharmacological treatment option for chronic pain, but often demonstrates unsatisfactory outcomes. Virtual Reality (VR) may offer the opportunity to complement physiotherapy treatment. As VR has only recently been introduced in physiotherapy care, it is unknown to what extent VR is used and how it is valued by physiotherapists. The aim of this study was to analyse physiotherapists’ current usage of, experiences with and physiotherapist characteristics associated with applying therapeutic VR for chronic pain rehabilitation in Dutch primary care physiotherapy. Methods This online survey applied two rounds of recruitment: a random sampling round (873 physiotherapists invited, of which 245 (28%) were included) and a purposive sampling round (20 physiotherapists using VR included). Survey results were reported descriptively and physiotherapist characteristics associated with VR use were examined using multivariable logistic regression analysis. Results In total, 265 physiotherapists participated in this survey study. Approximately 7% of physiotherapists reported using therapeutic VR for patients with chronic pain. On average, physiotherapists rated their overall experience with therapeutic VR at 7.0 and “whether they would recommend it” at 7.2, both on a 0–10 scale. Most physiotherapists (71%) who use therapeutic VR started using it less than two years ago and use it for a small proportion of their patients with chronic pain. Physiotherapists use therapeutic VR for a variety of conditions, including generalized (55%), neck (45%) and lumbar (37%) chronic pain. Physiotherapists use therapeutic VR mostly to reduce pain (68%), improve coordination (50%) and increase physical mobility (45%). Use of therapeutic VR was associated with a larger physiotherapy practice (OR = 2.38, 95% CI [1.14–4.98]). Unfamiliarity with VR seemed to be the primary reason for not using VR. Discussion Therapeutic VR for patients with chronic pain is in its infancy in Dutch primary care physiotherapy practice as only a small minority uses VR. Physiotherapists that use therapeutic VR are modestly positive about the technology, with large heterogeneity between treatment goals, methods of administering VR, proposed working mechanisms and chronic pain conditions to treat.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which kidney involvement, so-called lupus nephritis (LN), is common and one of the most severe manifestations. Oxidative stress (OS) may play a role in the pathogenesis of LN through the exacerbation of inflammation and immune cell dysfunction/dysregulation. Nuclear factor erythroid 2-related factor 2 (Nrf2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene and is regarded as a central regulator of the antioxidative response. Nrf2-activating compounds have been shown to alleviate oxidative stress in cells and tissues of lupus-prone mice. Although the precise mechanisms of Nrf2 activation on the immune system in SLE remain to be elucidated, Nrf2-activating compounds are considered novel therapeutical options to suppress OS and thereby might alleviate disease activity in SLE, especially in LN. This review therefore summarizes the role of the Nrf2 signaling pathway in the pathogenesis of SLE with LN and describes compounds modulating this pathway as potential additional clinical interventions.

Background: Obesity, Western diet (WD) consumption, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are co-occurring and modifiable factors associated with microbiome dysbiosis and anastomotic leakage. We studied the combined effect of a Western-type diet (WD) and diclofenac, a standard NSAID used in surgical patients, on anastomotic healing and gut microbiota composition following distal colon resection. Methods: Forty-two rats were fed a WD for 6 weeks, after which they were randomized to either parenteral diclofenac 3 mg/kg/day or saline started on the day of surgery and continued for three days. The surgical procedure involved distal colon resection with anastomosis. Animals were sacrificed on postoperative day (POD)-3 or POD-5. Anastomotic healing was assessed and correlated with diclofenac treatment and gut microbiota composition, analyzed by 16S rRNA marker gene amplicon sequencing. Mucosal integrity of the anastomosis was evaluated by histological analysis. Results: Anastomotic leakage rate was 100 percent (8/8) in diclofenac-treated rats and 10 percent (1/10) in saline-treated controls on POD-5. Diclofenac administration in WD-fed animals induced a shift in microbiota composition, characterized by an increase in microbiota diversity on POD-5 and a significant 15-fold, 4-fold, and 16-fold increase of Proteobacteria, Bacteroidetes, and Verrucomicrobia, respectively. Diclofenac use in WD-fed animals caused mucosal erosion on POD-5, a phenomenon not observed in control animals. Conclusions: Consumption of a Western diet combined with diclofenac administration shifts the microbiota composition, associated with clinically relevant AL in the distal colon of rats.

BackgroundDuring the first lockdown of the COVID-19 pandemic, an exponential increase in video consultations replacing in-person outpatient visits was observed in hospitals. Insight into patients’ experiences with this type of consultation is helpful for a broad, sustainable, and patient-centered implementation of video consultation. ObjectiveThis study aims to examine patients’ experiences with video consultation during the COVID-19 pandemic and identify discriminative patient and consultation characteristics to determine when video consultation is most feasible. MethodsA cross-sectional survey study was conducted. Patients aged ≥18 years and scheduled for a video consultation at the outpatient clinic of a Dutch university medical center from August 2020 to December 2020 for all medical specialties were eligible. Patients’ experiences were explored through a study-specific survey using descriptive quantitative statistics. Open-ended questions were qualitatively analyzed and thematically categorized into appreciated aspects and aspects for improvement. Discriminative patient and consultation characteristics were identified using 3 distinctive survey items. Characteristics of patients who scored and those who did not score all 3 items positively were analyzed using binary logistic regression. ResultsA total of 1054 patients were included in the analysis. Most patients (964/1054, 91.46%) were satisfied with their video consultation, with a mean overall grade of 8.6 (SD 1.3) of 10. In the qualitative analyses, 70.02% (738/1054) of the patients cited aspects they appreciated and 44.97% (474/1054) mentioned aspects for improvement during their consultation. Patients with better self-rated health reported a positive evaluation significantly more often (P=.001), which also held true for other medical specialties (vs surgical and nonsurgical specialties; P

Abstract Background Deviated optical angles create visuospatial and psychomotor challenges during laparoscopic procedures, resulting in delayed operative time and possibly adverse events. If it is possible to train the skills needed to work under these deviated optical angles, this could benefit procedure time and patient safety. This study investigates the influence of the optical angle on development of basic laparoscopic surgical skills. Methods A total of 58 medical students performed a four-session laparoscopic training course on a Virtual Reality Simulator. During each session, they performed an identical task under optical angles of 0°, 45° and − 45°. Performance parameters of task duration and damage were compared between the optical angles to investigate the effect of optical angle on performance development. The 4th session performance was compared to the 2nd session performance for each angle to determine improvement. Results Participants performed the task significantly faster under the 0° optical angle compared to the plus and minus 45° optical angles during the last three sessions (z between − 2.95 and − 2.09, p

Abstract Background Triglyceride-rich lipoproteins (TRL) and low-density lipoproteins (LDL) are associated positively whereas high-density lipoproteins (HDL) are associated inversely with the development of new-onset type 2 diabetes (T2D). Here we studied potential associations between these lipoprotein particle concentrations and the risk of developing microvascular complications in patients with established T2D. Methods Lipoprotein particle concentrations (TRLP, LDLP, and HDLP) were determined in 278 patients with T2D participating in a primary care-based longitudinal cohort study (Zwolle Outpatient Diabetes project Integrating Available Care [ZODIAC] study) leveraging the Vantera nuclear magnetic resonance (NMR) platform using the LP4 algorithm. Associations between lipoprotein particles and incident microvascular complications (nephropathy, neuropathy, and retinopathy) were assessed using Cox proportional hazards regression models. Results In total, 136 patients had microvascular complications at baseline. During a median follow-up of 3.2 years, 49 (34.5%) of 142 patients without microvascular complications at baseline developed new-onset microvascular complications. In multivariable Cox proportional hazards regression analyses, both total LDLP and HDLP concentrations, but not total TRLP concentrations, were positively associated with an increased risk of developing any microvascular complications after adjustment for potential confounding factors, including age, sex, disease duration, HbA1c levels, history of macrovascular complications, and statin use (adjusted hazard ratio [HR] per 1 SD increment: 1.70 [95% CI 1.24–2.34], P

Introduction Shoulder pain is common and associated with substantial morbidity. Different treatment strategies are being prescribed with equivocal results. Virtual reality (VR) is a novel technology and emerging research suggests that VR may be a promising alternative to current treatments. Prior to effectiveness research or any large-scale introduction, VR-applications require appropriate scrutiny including feasibility- and acceptability of clinicians and patients. Therefore, the aim of this study was to collect experiences of physiotherapists after using immersive VR. Methods A qualitative interpretive design was used to explore physiotherapists’ experiences related to the use of VR for people with shoulder symptoms. 17 physiotherapists were asked to use VR at home for five days prior to a focus group interview. Data from the focus group interviews were analyzed using a six-phase process of thematic analysis. Results Three main themes were identified, each divided into subthemes. The main themes were: 1. VR as an extension of contemporary physiotherapy care: physiotherapists were positive about the potential of VR and its applicability in daily care. 2. Physiotherapist uncertainties of future care using VR: participants expressed concerns about their professional identity, particularly as patients engage in independent home exercises. 3. Physiotherapist's requirements for implementation of VR: participants shared their needs for evidence regarding the effectiveness and parameters such as frequency, dosage and intensity of the VR intervention. Conclusion Physiotherapists were positive about VR as an intervention tool. However, they felt more knowledge is needed about parameters of VR. The findings of this study inform researchers and technology developers about optimal design of interventions and applications using VR.

Background Low‐grade systemic inflammation is a relevant pathogenic mechanism underlying the development of hypertension. In this study, we hypothesized that plasma calprotectin levels, as a biomarker of neutrophil‐mediated inflammation, is associated with developing new‐onset hypertension in the general population. Methods and Results Plasma calprotectin levels were determined in 3524 participants who participated in the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) study, a prospective population‐based cohort study. Plasma calprotectin levels were studied for associations with the risk of new‐onset hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or the first recorded use of antihypertensives. Participants with hypertension at baseline were excluded. Median plasma calprotectin levels were 0.48 (0.34–0.66) mg/L, and median systolic blood pressure was 117 (109–126) mm Hg. Plasma calprotectin levels were significantly associated with the risk of new‐onset hypertension (hazard ratio [HR], per doubling 1.30 [95% CI, 1.21–1.41]; P9.3 mg per 24 hours) compared with lower urinary albumin excretion (≤9.3 mg per 24 hours). Conclusions Higher plasma calprotectin levels are associated with an increased risk of new‐onset hypertension in the general population. This association is dependent on baseline systolic blood pressure and is particularly prominent in men compared with women.

Thiosulfate sulfurtransferase (TST, EC 2.8.1.1) was discovered as an enzyme that detoxifies cyanide by conversion to thiocyanate (rhodanide) using thiosulfate as substrate; this rhodanese activity was subsequently identified to be almost exclusively located in mitochondria. More recently, the emphasis regarding its function has shifted to hydrogen sulfide metabolism, antioxidant defense, and mitochondrial function in the context of protective biological processes against oxidative distress. While TST has been described to play an important role in liver and colon, its function in the brain remains obscure. In the present study, we therefore sought to address its potential involvement in maintaining cerebral redox balance in a murine model of global TST deficiency (Tst−/− mice), primarily focusing on characterizing the biochemical phenotype of TST loss in relation to neuronal activity and sensitivity to oxidative stress under basal conditions. Here, we show that TST deficiency is associated with a perturbation of the reactive species interactome in the brain cortex secondary to altered ROS and RSS (specifically, polysulfide) generation as well as mitochondrial OXPHOS remodeling. These changes were accompanied by aberrant Nrf2-Keap1 expression and thiol-dependent antioxidant function. Upon challenging mice with the redox-active herbicide paraquat (25 mg/kg i.p. for 24 h), Tst−/− mice displayed a lower antioxidant capacity compared to wildtype controls (C57BL/6J mice). These results provide a first glimpse into the molecular and metabolic changes of TST deficiency in the brain and suggest that pathophysiological conditions associated with aberrant TST expression and/or activity renders neurons more susceptible to oxidative stress-related malfunction.

Summary: Background: Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in patients with SSc. There is an unmet need for predictive biomarkers to identify patients with SSc at risk of ILD. Previous studies have shown that interferon (IFN) pathways may play a role in SSc. We assessed the use of C-X-C motif chemokine ligand 10 (CXCL10) as a predictive biomarker for new onset of ILD in patients with SSc. Methods: One-hundred-sixty-five (Female, N = 130) patients with SSc (SSc-ILD, N = 41) and 13 (Female, N = 8) healthy controls were investigated retrospectively. CXCL10 protein levels were measured by ELISA. We performed log rank analysis with baseline CXCL10 serum levels. CXCL10 nanoString data from lung tissues obtained from transplanted patients with SSc-ILD were extracted. Fifteen (Female, N = 10) patients with SSc (SSc-ILD, N = 7) were recruited for bronchoalveolar lavage (BAL) procedure. Lung fibroblasts were treated with BAL-fluid or serum from patients with SSc with or without ILD. Inflammatory/fibrotic genes were assessed. Findings: Serum CXCL10 levels were higher in patients with SSc-ILD compared to SSc patients without ILD [Median (IQR):126 pg/ml (66–282.5) vs. 78.5 pg/ml (50–122), P = 0.029, 95% CI: 1.5 × 10−6 to 0.4284]. Survival analysis showed that baseline CXCL10 levels >78.5 pg/ml have a 2.74-fold increased risk of developing new onset of ILD (Log-rank: P = 0.119) on follow-up. CXCL10 levels in BAL supernatant were not different in patients with SSc-ILD compared to SSc without ILD [76.1 pg/ml (7.2–120.8) vs. 22.3 pg/ml (12.1–43.7), P = 0.24, 95% CI: −19.5 to 100]. NanoString showed that CXCL10 mRNA expression was higher in inflammatory compared to fibrotic lung tissues [4.7 (4.2–5.6) vs. 4.3 (3.6–4.7), P = 0.029]. Fibroblasts treated with SSc-ILD serum or BAL fluids overexpressed CXCL10. Interpretations: Clinical, transcriptomic, and in vitro data showed that CXCL10 is potentially involved in early SSc-ILD. More research is needed to confirm whether CXCL10 can be classified as a prospective biomarker to detect patients with SSc at higher risk of developing new onset ILD. Funding: This collaborative project is co-financed by the Ministry of Economic Affairs and Climate Policy of the Netherlands utilizing the PPP-allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships (PPP-2019_007). Part of this study is financially supported by Sanofi Genzyme (NL8921).

Abstract Sigmoid volvulus is a common surgical emergency, especially in elderly patients. Patients can present with a wide range of clinical states: from asymptomatic, to frank peritonitis secondary to colonic perforation. These patients generally need urgent treatment, be it endoscopic decompression of the colon or an upfront colectomy. The World Society of Emergency Surgery united a worldwide group of international experts to review the current evidence and propose a consensus guidelines on the management of sigmoid volvulus.

Abstract Background A new hemostatic sealant based on a N-hydroxy-succinimide polyoxazoline (NHS-POx) polymer was evaluated to determine hemostatic efficacy and long-term wound healing and adverse effects in a large animal model of parenchymal organ surgical bleeds. Methods Experiment 1 included 20 pigs that were treated with two NHS-POx patch prototypes [a gelatin fibrous carrier (GFC) with NHS-POx and an oxidized regenerated cellulose (ORC) with poly(lactic-co-glycolic acid)-NHS-POx:NU-POx (nucleophilically activated polyoxazoline)], a blank gelatin patch (GFC Blank), TachoSil® and Veriset™ to stop moderate liver and spleen punch bleedings. After various survival periods (1–6 weeks), pigs were re-operated to evaluate patch degradation and parenchymal healing. During the re-operation, experiment 2 was performed: partial liver and spleen resections with severe bleeding, and hemostatic efficacy was evaluated under normal and heparinized conditions of the two previous prototypes and one additional NHS-POx patch. In the third experiment an improved NHS-POx patch (GATT-Patch; GFC-NHS-POx and added 20% as nucleophilically activated polyoxazoline; NU-POx) was compared with TachoSil®, Veriset™ and GFC Blank on punch bleedings and partial liver and spleen resections for rapid (10s) hemostatic efficacy. Results NHS-POx-based patches showed better (GFC-NHS-POx 83.1%, ORC-PLGA-NHS-POx: NU-POx 98.3%) hemostatic efficacy compared to TachoSil® (25.0%) and GFC Blank (43.3%), and comparable efficacy with Veriset™ (96.7%) on moderate standardized punch bleedings on liver and spleen. All patches demonstrated gradual degradation over 6 weeks with a reduced local inflammation rate and an improved wound healing. For severe bleedings under non-heparinized conditions, hemostasis was achieved in 100% for Veriset™, 40% for TachoSil and 80–100% for the three NHS-POx prototypes; similar differences between patches remained for heparinized conditions. In experiment 3, GATT-Patch, Veriset™, TachoSil and GFC Blank reached hemostasis after 10s in 100%, 42.8%, 7.1% and 14.3%, respectively, and at 3 min in 100%, 100%, 14.3% and 35.7%, respectively, on all liver and spleen punctures and resections. Conclusions NHS-POx-based patches, and particularly the GATT-Patch, are fast in achieving effective hemostatic sealing on standardized moderate and severe bleedings without apparent long-term adverse events.

Abstract Background Chronic low back pain (CLBP) is the most common chronic pain condition worldwide. Currently, primary care physiotherapy is one of the main treatment options, but effects of this treatment are small. Virtual Reality (VR) could be an adjunct to physiotherapy care, due to its multimodal features. The primary aim of this study is to assess the (cost-)effectiveness of physiotherapy with integrated multimodal VR for patients with complex CLBP, compared to usual primary physiotherapy care. Methods A multicenter, two-arm, cluster randomized controlled trial (RCT) including 120 patients with CLBP from 20 physiotherapists will be conducted. Patients in the control group will receive 12 weeks of usual primary physiotherapy care for CLBP. Patients in the experimental group will receive treatment consisting of 12 weeks of physiotherapy with integrated, immersive, multimodal, therapeutic VR. The therapeutic VR consists of the following modules: pain education, activation, relaxation and distraction. The primary outcome measure is physical functioning. Secondary outcome measures include pain intensity, pain-related fears, pain self-efficacy and economic measures. Effectiveness of the experimental intervention compared to the control intervention on primary and secondary outcome measures will be analyzed on an intention-to-treat principle, using linear mixed-model analyses. Discussion This pragmatic, multicenter cluster randomized controlled trial, will determine the clinical and cost-effectiveness of physiotherapy with integrated, personalized, multimodal, immersive VR in favor of usual physiotherapy care for patients with CLBP. Trial registration This study is prospectively registered at ClinicalTrials.gov (identifier: NCT05701891).

Abstract Background A translational ex vivo perfusion-based mandibular pig model was developed as an alternative to animal experiments, for initial assessment of biomaterials in dental and maxillofacial surgery and training. This study aimed to assess the face and content validity of the novel perfusion-based model. Methods Cadaveric porcine heads were connected to an organ assist perfusion device for blood circulation and tissue oxygenation. Dental professionals and dental trainees performed a surgical procedure on the mandibula resembling a submandibular extraoral incision to create bone defects. The bone defects were filled and covered with a commercial barrier membrane. All participants completed a questionnaire using a 5-point Likert scale to assess the face and content validity of the model. Validation data between the two groups of participants were compared with Mann–Whitney U test. Results Ten dental professionals and seven trainees evaluated the model for face and content validity. Participants reported model realism, with a mean face validity score of 3.9 ± 1.0 and a content validity of 4.1 ± 0.8. No significant differences were found for overall face and content validity between experts and trainees. Conclusion We established face and content validity in a novel perfusion-based mandibular surgery model. This model can be used as an alternative for animal studies evaluating new biomaterials and related dental and maxillofacial surgical procedural training.

Abstract Background Selected patients with adhesion-related chronic abdominal pain can be treated effectively by adhesiolysis with the application of adhesion barriers. These patients might also have an increased risk to develop adhesive small bowel obstruction (ASBO). It is unknown how frequently these patients develop ASBO, and how elective adhesiolysis for pain impacts the risk of ASBO. Methods Patients with adhesion-related chronic pain were included in this cohort study with long-term follow-up. The diagnosis of adhesions was confirmed using CineMRI. The decision for operative treatment of adhesions was made by shared agreement based on the correlation of complaints with CineMRI findings. The primary outcome was the 5-years incidence of readmission for ASBO. Incidence was compared between patients with elective adhesiolysis and those treated non-operatively and between patients with and without previous ASBO. Univariable and multivariable Cox regression analysis was performed to identify predictive factors for ASBO. Secondary outcomes included reoperation for ASBO and self-reported pain and other abdominal symptoms. Results A total of 122 patients were included, 69 patients underwent elective adhesiolysis. Thirty patients in both groups had previous episodes of ASBO in history. During 5-year follow-up, the readmission rate for ASBO was 6.5% after elective adhesiolysis compared to 26.9% after non-operative treatment (p = 0.012). These percentages were 13.3% compared to 40% in the subgroup of patients with previous episodes of ASBO (p = 0.039). In multivariable analysis, elective adhesiolysis was associated with a decreased risk of readmission for ASBO with an odds ratio of 0.21 (95% CI 0.07–0.65), the risk was increased in patients with previous episodes with a odds ratio of 19.2 (95% CI 2.5–144.4). There was no difference between the groups in the prevalence of self-reported abdominal pain. However, in surgically treated patients the impact of pain on daily activities was lower, and the incidence of other symptoms was lower. Conclusion More than one in four patients with chronic adhesion-related pain develop episodes of ASBO when treated non-operatively. Elective adhesiolysis reduces the incidence of ASBO in patients with chronic adhesion-related symptoms, both in patients with and without previous episodes of ASBO in history. Trial registration The study was registered at Clinicaltrials.gov under NCT01236625.

Abstract Laser speckle contrast imaging (LSCI) is so sensitive to motion that it can measure the movement of red blood cells. However, this extreme sensitivity to motion is also its pitfall as the clinical translation of LSCI is slowed down due to the inability to deal with motion artefacts. In this paper we study the effectiveness of a real-time, multi-spectral motion artefact correction and compensation by subduing an in vitro flow phantom and ex vivo porcine kidney to computer-controlled motion artefacts. On the in vitro flow phantom, the optical flow showed a good correlation with the total movement. This model results in a better signal-to-noise ratios for multiple imaging distances and the overestimation of perfusion was reduced. In the ex vivo kidney model, the perfusion overestimation was also reduced and we were still able to distinguish between ischemia and non-ischemia in the stabilized data whereas this was not possible in the non-stabilized data. This leads to a notably better perfusion estimation that could open the door to a multitude of new clinical applications for LSCI.

Abstract Acute mesenteric ischemia (AMI) is a group of diseases characterized by an interruption of the blood supply to varying portions of the intestine, leading to ischemia and secondary inflammatory changes. If untreated, this process may progress to life-threatening intestinal necrosis. The incidence is low, estimated at 0.09–0.2% of all acute surgical admissions, but increases with age. Although the entity is an uncommon cause of abdominal pain, diligence is required because if untreated, mortality remains in the range of 50%. Early diagnosis and timely surgical intervention are the cornerstones of modern treatment to reduce the high mortality associated with this entity. The advent of endovascular approaches in parallel with modern imaging techniques is evolving and provides new treatment options. Lastly, a focused multidisciplinary approach based on early diagnosis and individualized treatment is essential. Thus, we believe that updated guidelines from World Society of Emergency Surgery are warranted, in order to provide the most recent and practical recommendations for diagnosis and treatment of AMI.

ABSTRACTIn many digital health technologies, the design does not align with the needs and values of users within a specific healthcare context. This results in low uptake of these technologies. Health technology assessments should encourage successful technology adoption. Yet, its traditional focus on the cost-effectiveness of technology results in missing important qualitative insights. More recent initiatives to include qualitative outcomes in assessments generally remain too speculative to identify the actual effect of technology on individual needs and values. In this article, we adjust the ‘guidance ethics’ framework to study the lived value experiences of users while interacting with technology in context. We apply this novel framework in a case study of developing and evaluating a virtual reality rehabilitation service for long COVID patients. We end the article by evaluating the strengths and limitations of this novel framework as an addition to traditional health technology assessments.

Summary: Background: COVID-19 has raised special concern for patients with β-thalassemia major (β-TM) due to frequent comorbidities, regular blood transfusions, and iron overload. However, the exact implications of COVID-19 for patients with β-TM remain uncertain. We aimed to explore the COVID-19 incidence and severity, and the serological response to SARS-CoV-2 infection and vaccination in patients with β-TM. Methods: Patients with β-TM (n = 105) and age-matched healthy controls, all individuals of all control groups were health care workers of the hospital, were prospectively enrolled at the haematology department of Al-Shifa hospital in the Gaza Strip from January 1st, 2021 to December 31st, 2021. Data on COVID-19 incidence and severity were analysed, with Alpha, Beta, and Delta SARS-CoV-2 variants dominating at that time. Anti-SARS-CoV-2 IgG antibody levels were measured and compared between study groups. Findings: Patients with β-TM showed a higher incidence of SARS-CoV-2 infection than the general population (61.9% vs. 7.1%, p

IntroductionAccelerated by the coronavirus pandemic, the healthcare landscape is rapidly evolving, with a shift towards hybrid care models combining in-person and online care. To support this shift, the Radboudumc, an academic hospital in the Netherlands, decided to redesign an existing space facilitating the conduction of video consultations.MethodThe design process involved participation of end-users to ensure that the physical space met their needs. The look and feel of the area was based on evidence-based design guidelines. Two prototype setups were built and tested, and the feedback informed the final design of the Garden Room.ResultsIdentified end-user needs were divided into 3 major categories entailing consultation room setup, optimal use of technology and practical issues involving room availability. Combined with the look and feel of the hospital, final design requirements were developed. The Garden Room consists of 18 video consultation rooms, 4 shared workspaces, relaxation area with kitchen, and meeting rooms. Specific attention is given to the ergonomics, technology and privacy in the rooms to facilitate optimal video conversations between patients and healthcare providers. In the Garden Room, natural elements and an open design supports working in a healing environment.DiscussionNext challenge will be optimizing the use of the Garden Room, which may be hindered by various barriers like resistance to change, existing work processes, and lack of skills training. To address these barriers and support use of the Garden Room, the hospital should focus on the implementation of education, changes in work processes, and the presence of advocates for telehealth.

IntroductionPulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Until now, no prospective biomarker to predict new onset of SSc-ILD or SSc-PAH in patients with SSc has reached clinical application. In homeostasis, the receptor for advanced glycation end products (RAGE) is expressed in lung tissue and involved in cell-matrix adhesion, proliferation and migration of alveolar epithelial cells, and remodeling of the pulmonary vasculature. Several studies have shown that sRAGE levels in serum and pulmonary tissue vary according to the type of lung-related complication. Therefore, we investigated levels of soluble RAGE (sRAGE) and its ligand high mobility group box 1 (HMGB1) in SSc and their abilities to predict SSc-related pulmonary complications.MethodsOne hundred eighty-eight SSc patients were followed retrospectively for the development of ILD, PAH, and mortality for 8 years. Levels of sRAGE and HMGB1 were measured in serum by ELISA. Kaplan-Meier survival curves were performed to predict lung events and mortality and event rates were compared with a log-rank test. Multiple linear regression analysis was performed to examine the association between sRAGE and important clinical determinants.ResultsAt baseline, levels of sRAGE were significantly higher in SSc-PAH-patients (median 4099.0 pg/ml [936.3-6365.3], p = 0.011) and lower in SSc-ILD-patients (735.0 pg/ml [IQR 525.5-1988.5], p = 0.001) compared to SSc patients without pulmonary involvement (1444.5 pg/ml [966.8-2276.0]). Levels of HMGB1 were not different between groups. After adjusting for age, gender, ILD, chronic obstructive pulmonary disease, anti-centromere antibodies, the presence of puffy fingers or sclerodactyly, use of immunosuppression, antifibrotic therapy, or glucocorticoids, and use of vasodilators, higher sRAGE levels remained independently associated with PAH. After a median follow-up of 50 months (25-81) of patients without pulmonary involvement, baseline sRAGE levels in the highest quartile were predictive of development of PAH (log-rank p = 0.01) and of PAH-related mortality (p = 0.001).ConclusionsHigh systemic sRAGE at baseline might be used as a prospective biomarker for patients with SSc at high risk to develop new onset of PAH. Moreover, high sRAGE levels could predict lower survival rates due to PAH in patients with SSc.

Background: Placental insufficiency is an important mechanism underlying early-onset fetal growth restriction (eoFGR). Reduced placental function causes impaired metabolic and gaseous exchange. This unfavorable placental environment is among other processes characterized by increased oxidative stress. Systemic free thiols (FT) are known for their reactive oxygen species scavenging capacity, and higher plasma levels of FT are associated with a better outcome in a multitude of ischemic and inflammatory diseases. We aimed to investigate the relationships between systemic FT levels and maternal and perinatal clinical characteristics and outcomes. Study design: In a post hoc analysis of the Dutch Strider study, a cohort of women with eoFGR, we investigated the association between the maternal redox status (FT) levels at study inclusion, placental biomarkers, and maternal and neonatal outcomes in 108 patients. Results: FT were significantly lower in pregnancies complicated with eoFGR with concurrent maternal hypertensive disorders (pregnancy-induced hypertension; ρ = −0.281 p = 0.004, pre-eclampsia; ρ = −0.505 p = 0.000). In addition, lower FT levels were significantly associated with higher systolic (ρ = −0.348 p = 0.001) and diastolic blood pressure (ρ = −0.266 p = 0.014), but not with the severity of eoFGR. FT levels were inversely associated with sFlt (ρ = −0.366, p < 0.001). A strong relation between systemic FT levels and PlGF levels was observed in women with pre-eclampsia at delivery (ρ = 0.452, p = 0.002), which was not found in women without hypertensive disorders (ρ = 0.008, p = 0.958). Conclusions: In women with pregnancies complicated with eoFGR, FT levels reflect the severity of maternal disease related to the underlying placental insufficiency rather than the severity of the placental dysfunction as reflected in eoFGR or perinatal outcomes.

Abstract Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), also known as Rhodanese, was initially discovered as a cyanide detoxification enzyme. However, it was recently also found to be a genetic predictor of resistance to obesity-related type 2 diabetes. Diabetes type 2 is characterized by progressive loss of adequate β-cell insulin secretion and onset of insulin resistance with increased insulin demand, which contributes to the development of hyperglycemia. Diabetic complications have been replicated in adult hyperglycemic zebrafish, including retinopathy, nephropathy, impaired wound healing, metabolic memory, and sensory axonal degeneration. Pancreatic and duodenal homeobox 1 (Pdx1) is a key component in pancreas development and mature beta cell function and survival. Pdx1 knockdown or knockout in zebrafish induces hyperglycemia and is accompanied by organ alterations similar to clinical diabetic retinopathy and diabetic nephropathy. Here we show that pdx1-knockdown zebrafish embryos and larvae survived after incubation with thiosulfate and no obvious morphological alterations were observed. Importantly, incubation with hTST and thiosulfate rescued the hyperglycemic phenotype in pdx1-knockdown zebrafish pronephros. Activation of the mitochondrial TST pathway might be a promising option for therapeutic intervention in diabetes and its organ complications.

Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are intimately associated with inflammation and overproduction of reactive oxygen species (ROS). Temporal and inter-individual variabilities in disease activity and response to therapy pose significant challenges to diagnosis and patient care. Discovery and validation of truly integrative biomarkers would benefit from embracing redox metabolomics approaches with prioritization of central regulatory hubs. We here make a case for applying a personalized redox medicine approach that aims to selectively inhibit pathological overproduction and/or altered expression of specific enzymatic sources of ROS without compromising physiological function. To this end, improved ‘clinical-omics integration’ may help to better understand which particular redox signaling pathways are disrupted in what patient. Pharmacological interventions capable of activating endogenous antioxidant defense systems may represent viable therapeutic options to restore local/systemic redox status, with HIF-1α and NRF2 holding particular promise in this context. Achieving the implementation of clinically meaningful mechanism-based biomarkers requires development of easy-to-use, robust and cost-effective tools for secure diagnosis and monitoring of treatment efficacy. Ultimately, matching redox-directed pharmacological interventions to individual patient phenotypes using predictive biomarkers may offer new opportunities to break the therapeutic ceiling in IBD.

Abstract Background The objectives of the study were to investigate the organizational characteristics of acute care facilities worldwide in preventing and managing infections in surgery; assess participants’ perception regarding infection prevention and control (IPC) measures, antibiotic prescribing practices, and source control; describe awareness about the global burden of antimicrobial resistance (AMR) and IPC measures; and determine the role of the Coronavirus Disease 2019 pandemic on said awareness. Methods A cross-sectional web-based survey was conducted contacting 1432 health care workers (HCWs) belonging to a mailing list provided by the Global Alliance for Infections in Surgery. The self-administered questionnaire was developed by a multidisciplinary team. The survey was open from May 22, 2021, and June 22, 2021. Three reminders were sent, after 7, 14, and 21 days. Results Three hundred four respondents from 72 countries returned a questionnaire, with an overall response rate of 21.2%. Respectively, 90.4% and 68.8% of participants stated their hospital had a multidisciplinary IPC team or a multidisciplinary antimicrobial stewardship team. Local protocols for antimicrobial therapy of surgical infections and protocols for surgical antibiotic prophylaxis were present in 76.6% and 90.8% of hospitals, respectively. In 23.4% and 24.0% of hospitals no surveillance systems for surgical site infections and no monitoring systems of used antimicrobials were implemented. Patient and family involvement in IPC management was considered to be slightly or not important in their hospital by the majority of respondents (65.1%). Awareness of the global burden of AMR among HCWs was considered very important or important by 54.6% of participants. The COVID-19 pandemic was considered by 80.3% of respondents as a very important or important factor in raising HCWs awareness of the IPC programs in their hospital. Based on the survey results, the authors developed 15 statements for several questions regarding the prevention and management of infections in surgery. The statements may be the starting point for designing future evidence-based recommendations. Conclusion Adequacy of prevention and management of infections in acute care facilities depends on HCWs behaviours and on the organizational characteristics of acute health care facilities to support best practices and promote behavioural change. Patient involvement in the implementation of IPC is still little considered. A debate on how operationalising a fundamental change to IPC, from being solely the HCWs responsibility to one that involves a collaborative relationship between HCWs and patients, should be opened.

Oxidative stress is a key pathophysiological process associated with the development and progression of inflammatory bowel disease (IBD). Biomarkers for oxidative stress, however, are scarce, as are diagnostic tools that can interrogate an individual’s gut redox status. This proof-of-concept study aimed to evaluate the potential utility of an oxidation-reduction potential (ORP) measurement probe, to quantify redox status in the feces of both patients with IBD and healthy controls. Previous studies using this ORP measurement probe demonstrated promising data when comparing ORP from severely malnourished individuals with that of healthy controls. To date, ORP analyses have not been performed in the context of IBD. We hypothesized that measuring the ORP of fecal water in patients with IBD might have diagnostic value. The current study, however, did not show significant differences in ORP measurement values between patients with IBD (median [IQR] 46.5 [33.0–61.2] mV) and healthy controls (25 [8.0–52.0] mV; p = 0.221). Additionally, ORP measurements were highly unstable and rapidly fluctuated throughout time, with ORP values varying from +24 to +303 mV. Due to potential biological processes and limitations of the measuring equipment, this study was unable to reliably measure ORP. As a result, our findings indicate that ORP quantification may not be a suitable method for assessing fecal redox status and, therefore, does not currently support further exploration as a diagnostic or monitoring tool.

Abstract On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.

Abstract In kidney transplantation, microthrombi and fibrin deposition may lead to local perfusion disorders and subsequently poor initial graft function. Microthrombi are often regarded as donor-derived. However, the incidence, time of development, and potential difference between living donor kidneys (LDK) and deceased donor kidneys(DDK), remains unclear. Two open-needle biopsies, taken at preimplantation and after reperfusion, were obtained from 17 LDK and 28 DDK transplanted between 2005 and 2008. Paraffin-embedded sections were immunohistochemically stained with anti-fibrinogen antibody. Fibrin deposition intensity in peritubular capillaries(PTC) and glomeruli was categorized as negative, weak, moderate or strong and the number of microthrombi/mm2 was quantified. Reperfusion biopsies showed more fibrin deposition (20% to 100% moderate/strong, p

A scientific paradigm consists of a set of shared rules, beliefs, values, methods, and instruments for addressing scientific problems. Currently, health care embraces the paradigm of evidence-based health care (EBH). This paradigm prompts health care institutions to base decisions on the best available evidence, which is commonly generated in large-scale randomized controlled trials. We illustrate the application of EBH via the evaluation of drugs. We show how EBH is challenged when it is applied to the evaluation of digital therapeutics, which refers to technology and data to prevent, manage, or treat a medical disorder or disease. We conclude that amid the growing application of digital therapeutics, the paradigm of EBH is challenged in four domains: population, intervention, comparison, outcome. In the second part of this viewpoint, we argue for a paradigm shift in health care so we can optimally evaluate and implement digital therapeutics, and we sketch out the contours of this novel paradigm. We address the need for considering design in health care and evaluation processes, studying user values so that health care can move from a focus on health to well-being, focusing on individual experiences rather than the average, addressing the need for evaluation in authentic use contexts, and stressing the need for continuous evaluation of the dynamic relations between users, context, and digital therapeutics. We conclude that the transition from EBH toward evidence-based well-being would improve the successful implementation of digital technologies in health care.

Oxidative stress plays an important role in systemic lupus erythematosus (SLE) and especially in lupus nephritis (LN). The aim of this study was to compare redox-related biomarkers between patients with active LN, quiescent SLE (Q-SLE) and healthy controls (HC) and to explore their association with clinical characteristics such as disease activity in patients. We investigated levels of plasma free thiols (R-SH, sulfhydryl groups), levels of soluble receptor for advanced glycation end products (sRAGE) and levels of malondialdehyde (MDA) in SLE patients with active LN (n = 23), patients with quiescent SLE (n = 47) and HC (n = 23). Data of LN patients who previously participated in Dutch lupus nephritis studies and longitudinal samples up to 36 months were analyzed. Thiol levels were lower in active LN at baseline and Q-SLE patients compared to HC. In generalized estimating equation (GEE) modelling, free thiol levels were negatively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) over time (p < 0.001). sRAGE and MDA were positively correlated with the SLEDAI over time (p = 0.035 and p = 0.016, respectively). These results indicate that oxidative stress levels in LN patients are increased compared to HC and associated with SLE disease activity. Therefore, interventional therapy to restore redox homeostasis may be useful as an adjunctive therapy in the treatment of oxidative damage in SLE.

Puffy fingers and Raynaud’s phenomenon (RP) are important clinical predictors of the development of systemic sclerosis (SSc). We aim to assess the prevalence of SSc-related symptoms, explore pulmonary symptoms, and test the usefulness of skin autofluorescence (SAF) as a non-invasive marker for Advanced Glycation Endproducts (AGEs). Subjects from the Lifelines Cohort Study with known connective tissue disease (CTD) were excluded. Patient characteristics, SAF, self-reported pulmonary symptoms, and spirometry were obtained. Subjects (n = 73,948) were categorized into definite RP (5.3%) with and without SSc-related symptoms and non-RP. Prevalence of at least one potential SSc-related symptom (other than RP) was 8.7%; 23.5% in subjects with RP and 7.1% without RP (p < 0.001). Subjects with RP and additional SSc-related symptoms more frequently reported dyspnea at rest, dyspnea after exertion, and self-reported pulmonary fibrosis, and had the lowest mean forced vital capacity compared to the other groups (RP without SSc-related symptoms and no RP, both p < 0.001). In multivariate regression, dyspnea at rest/on exertion remained associated with an increased risk of SSc-related symptoms in subjects with RP (both p < 0.001). SAF was higher in subjects with RP and SSc-related symptoms compared to the other groups (p < 0.001), but this difference was not significant after correction for potential confounders. The prevalence of SSc-related symptoms was approximately three-fold higher in subjects with RP. Pulmonary symptoms are more prevalent in subjects with RP who also reported additional potential SSc-related symptoms. This might suggest that (suspected) early SSc develops more insidiously than acknowledged. According to this study, SAF is no marker for early detection of SSc.

Abstract Background Small bowel obstruction (SBO) is a common surgical emergency, causing high morbidity and healthcare costs. The majority of SBOs are caused by adhesions that result from previous surgeries. Bowel obstruction, however, also occurs in patients without previous operation or known pathology, a so called virgin abdomen. It is unknown if small bowel obstruction in the virgin abdomen (SBO-VA) can be managed according to the same principles as other cases of small bowel obstruction. The aim of this position paper is to evaluate the available evidence on etiology and management of small bowel obstruction in the virgin abdomen. Methods This is a narrative review with scoping aspects. Clinical topics covered in this review include epidemiology and etiology of SBO-VA, diagnosis and imaging, initial assessment, the role of surgical management in SBO-VA, and the role of non-operative management in SBO-VA. Results Our scoping search revealed seven original studies reporting original patient data related to SBO-VA. All the included studies are retrospective cohorts, with populations ranging between 44 and 103 patients with SBO-VA. Adhesions were found to be the cause of the obstruction in approximately half of the reported cases of SBO-VA. A relatively high number of cases of SBO-VA were managed surgically with studies reporting 39–83%. However, in cases where a trial of non-operative management was started, this was generally successful. Conclusion The data available suggest that etiology and treatment results for patients with SBO-VA are largely comparable to the results in patients with SBO after previous abdominal surgery. We therefore propose that patients with a virgin abdomen could be treated according to existing guidelines for SBO and adhesive small bowel obstruction.

Abstract Background Adaptive training is an approach in which training variables change with the needs and traits of individual trainees. It has potential to mitigate the effect of personality traits such as impulsiveness on surgical performance. Selective performance feedback is one way to implement adaptive training. This paper investigates whether selective feedback can direct performance of trainees of either high- or low impulsiveness. Methods A total of 83 inexperienced medical students of known impulsiveness performed a four-session laparoscopic training course on a Virtual Reality Simulator. They performed two identical series of tasks every session. During one series of tasks they received performance feedback on duration and during the other series they received feedback on damage. Performance parameters (duration and damage) were compared between the two series of tasks to assess whether selective performance feedback can be used to steer emphasis in performance. To assess the effectiveness of selective feedback for people of high- or low impulsiveness, the difference in performance between the two series for both duration and damage was also assessed. Results Participants were faster when given performance feedback for speed for all exercises in all sessions (average z-value = − 4.14, all p values < .05). Also, they performed better on damage control when given performance feedback for damage in all tasks and during all sessions except for one (average z-value = − 4.19, all but one p value < .05). Impulsiveness did not impact the effectiveness of selective feedback. Conclusion Selective feedback on either duration or damage can be used to improve performance for the variable that the trainee receives feedback on. Trainee impulsiveness did not modulate this effect. Selective feedback can be used to steer training focus in adaptive training systems and can mitigate the negative effects of impulsiveness on damage control.

BackgroundBetween 30% to 76% of COVID-19 patients have persistent physical and mental symptoms, sometimes up to 9 months after acute COVID-19. Current rehabilitation is mostly focused on the physical symptoms, whereas experts have agreed on the need for a biopsychosocial approach. A novel approach such as virtual reality (VR) rehabilitation at home might benefit patients and therapists, especially considering the expected rush of patients with post–COVID-19 condition needing rehabilitation. ObjectiveThe aim of this study was to investigate the feasibility of self-administered VR exercises at home for post–COVID-19 condition. MethodsThis was a single-arm feasibility study in an outpatient care setting. Patients who needed physiotherapy because of post–COVID-19 condition were included as determined by the treating physiotherapist. Participants performed VR physical exercises at home for a period of 6 weeks and were allowed to perform VR mental exercise through applications available on the VR platform to reduce stress and anxiety and promote cognitive functioning. The main outcomes were related to feasibility (ie, duration and frequency of VR use), safety (ie, adverse events), patient satisfaction, and reasons to withdraw. Physical performance, daily activities, cognitive functioning, anxiety and depression, and the quality of life were measured before and after. ResultsIn total, 48 patients were included; 1 (2%) patient did not start VR, and 7 (15%) patients withdrew, mostly due to dizziness. Almost 70% (33/47) of participants reported experiencing any adverse event during VR exercising. However, only 25% (9/36) recalled these events at the end of the intervention period. The majority (27/36, 75%) of the patients described VR as having a positive influence on their recovery, and the global satisfaction score was 67%. The average VR use was 30 minutes per session, 3-4 times a week for 3-6 weeks. The overall use of VR applications was almost equally distributed over the 3 sets of VR exercises (physical, relaxing, and cognitive). However, the use frequency of physical exercises seemed to decrease over time, whereas the use of cognitive and relaxation exercises remained stable. Physical performance and quality of life outcomes were significantly improved after 6 weeks. ConclusionsVR physical exercises at home is feasible and safe with good acceptance in a significant percentage of patient with post–COVID-19 condition. Trial RegistrationClinicalTrials.gov NCT04505761; https://clinicaltrials.gov/ct2/show/NCT04505761

Introduction: Genetic studies have identified associations of carnosinase 1 (CN1) polymorphisms with diabetic kidney disease (DKD). However, CN1 levels and activities have not been assessed as diagnostic or prognostic markers of DKD in cohorts of patients with type 2 diabetes (T2D).Methods: We established high-throughput, automated CN1 activity and concentration assays using robotic systems. Using these methods, we determined baseline serum CN1 levels and activity in a T2D cohort with 970 patients with no or only mild renal impairment. The patients were followed for a mean of 1.2 years. Baseline serum CN1 concentration and activity were assessed as predictors of renal function impairment and incident albuminuria during follow up.Results: CN1 concentration was significantly associated with age, gender and estimated glomerular filtration rate (eGFR) at baseline. CN1 activity was significantly associated with glycated hemoglobin A1c (HbA1c) and eGFR. Serum CN1 at baseline was associated with eGFR decline and predicted renal function impairment and incident albuminuria during the follow-up.Discussion: Baseline serum CN1 levels were associated with presence and progression of renal function decline in a cohort of T2D patients. Confirmation in larger cohorts with longer follow-up observation periods will be required to fully establish CN1 as a biomarker of DKD.

Abdominal adhesions present a diagnostic challenge, and classic imaging modalities can miss their presence. Cine-MRI, which records visceral sliding during patient-controlled breathing, has proven useful in detecting and mapping adhesions. However, patient movements can affect the accuracy of these images, despite there being no standardized algorithm for defining sufficiently high-quality images. This study aims to develop a biomarker for patient movements and determine which patient-related factors influence movement during cine-MRI. Included patients underwent cine-MRI to detect adhesions for chronic abdominal complaints, data were collected from electronic patient files and radiologic reports. Ninety slices of cine-MRI were assessed for quality, using a five-point scale to quantify amplitude, frequency, and slope, from which an image-processing algorithm was developed. The biomarkers closely correlated with qualitative assessments, with an amplitude of 6.5 mm used to distinguish between sufficient and insufficient-quality slices. In multivariable analysis, the amplitude of movement was influenced by age, sex, length, and the presence of a stoma. Unfortunately, no factor was changeable. Strategies for mitigating their impact may be challenging. This study highlights the utility of the developed biomarker in evaluating image quality and providing useful feedback for clinicians. Future studies could improve diagnostic quality by implementing automated quality criteria during cine-MRI.

Raynaud’s Phenomenon (RP) leading to repetitive ischemia and reperfusion (IR) stress, is the first recognizable sign of systemic sclerosis (SSc) leading to increased oxidative stress. High-mobility group box-1 (HMGB1) is a nuclear factor released by apoptotic and necrotic cells after oxidative stress. Since HMGB1 can signal through the receptor for advanced glycation end products (RAGE), we investigated whether an RP attack promotes the release of HMGB1, leading to fibroblast activation and the upregulation of interferon (IFN)-inducible genes. A cold challenge was performed to simulate an RP attack in patients with SSc, primary RP (PRP), and healthy controls. We measured levels of HMGB1 and IFN gamma-induced Protein 10 (IP-10) at different time points in the serum. Digital perfusion was assessed by photoplethysmography. In vitro, HMGB1 or transforming growth factor (TGF-β1) (as control) was used to stimulate healthy human dermal fibroblasts. Inflammatory, profibrotic, and IFN-inducible genes, were measured by RT-qPCR. In an independent cohort, sera were obtained from 20 patients with SSc and 20 age- and sex-matched healthy controls to determine HMGB1 and IP-10 levels. We found that HMGB1 levels increased significantly 30 min after the cold challenge in SSc compared to healthy controls. In vitro stimulation with HMGB1 resulted in increased mRNA expression of IP-10, and interleukin-6 (IL-6) while TGF-β1 stimulation promoted IL-6 and Connective Tissue Growth Factor (CTGF). In serum, both HMGB1 and IP-10 levels were significantly higher in patients with SSc compared to healthy controls. We show that cold challenge leads to the release of HMGB1 in SSc patients. HMGB1 induces IP-10 expression in dermal fibroblasts partly through the soluble RAGE (sRAGE) axis suggesting a link between RP attacks, the release of HMGB1 and IFN-induced proteins as a putative early pathogenetic mechanism in SSc.

Oxidative stress plays a pivotal role in cardiovascular (CV) disease, but current biomarkers used to predict CV events are still insufficient. In this study, we comparatively assessed the utility of redox-related biomarkers in predicting the risk of CV events and all-cause mortality in male and female subjects from the general population. Subjects (n = 5955) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) population-based cohort study were included. Blood homocysteine, gamma-GT, HDL cholesterol, bilirubin and protein-adjusted free thiol (R-SH, sulfhydryl groups) levels were quantified at baseline and were prospectively analyzed in association with the risk of CV events and all-cause mortality. After adjustment for potentially confounding factors, protein-adjusted R-SH and homocysteine levels were significantly associated with the risk of CV events in men (HR 0.63 [0.40–0.99], p = 0.045 and HR 1.58 [1.20–2.08], p = 0.001, respectively). Protein-adjusted R-SH and HDL cholesterol levels were significantly associated with the risk of all-cause mortality in men (HR 0.52 [0.32–0.85], p = 0.009 and HR 0.90 [0.85–0.94], p < 0.001, respectively), while the same was observed for bilirubin and homocysteine levels in women (HR 0.68 [0.48–0.98], p = 0.040 and HR 2.30 [1.14–3.76], p < 0.001, respectively). Lower levels of protein-adjusted R-SH were robustly associated with an increased risk of CV events and all-cause mortality in men. Our results highlight the value of R-SH levels in cardiovascular risk assessment and their potential significance as being amenable to therapeutic intervention, while reaffirming the importance of other oxidative stress-related biomarkers, such as homocysteine, HDL cholesterol and bilirubin.

Kidney extraction time has a detrimental effect on post-transplantation outcome. This study aims to improve the flush-out and potentially decrease ischemic injury by the addition of hydrogen sulphide (H2S) to the flush medium. Porcine kidneys (n = 22) were extracted during organ recovery surgery. Pigs underwent brain death induction or a Sham operation, resulting in four groups: donation after brain death (DBD) control, DBD H2S, non-DBD control, and non-DBD H2S. Directly after the abdominal flush, kidneys were extracted and flushed with or without H2S and stored for 13 h via static cold storage (SCS) +/− H2S before reperfusion on normothermic machine perfusion. Pro-inflammatory cytokines IL-1b and IL-8 were significantly lower in H2S treated DBD kidneys during NMP (p = 0.03). The non-DBD kidneys show superiority in renal function (creatinine clearance and FENa) compared to the DBD control group (p = 0.03 and p = 0.004). No differences were seen in perfusion parameters, injury markers and histological appearance. We found an overall trend of better renal function in the non-DBD kidneys compared to the DBD kidneys. The addition of H2S during the flush out and SCS resulted in a reduction in pro-inflammatory cytokines without affecting renal function or injury markers.

BackgroundDigital health refers to the proper use of technology for improving the health and well-being of people and enhancing the care of patients through the intelligent processing of clinical and genetic data. Despite increasing interest in well-being in both health care and technology, there is no clear understanding of what constitutes well-being, which leads to uncertainty in how to create well-being through digital health. In an effort to clarify this uncertainty, Brey developed a framework to define problems in technology for well-being using the following four categories: epistemological problem, scope problem, specification problem, and aggregation problem. ObjectiveThis systematic scoping review aims to gain insights into how to define and address well-being in digital health. MethodsWe followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist. Papers were identified from 6 databases and included if they addressed the design or evaluation of digital health and reported the enhancement of patient well-being as their purpose. These papers were divided into design and evaluation papers. We studied how the 4 problems in technology for well-being are considered per paper. ResultsA total of 117 studies were eligible for analysis (n=46, 39.3% design papers and n=71, 60.7% evaluation papers). For the epistemological problem, the thematic analysis resulted in various definitions of well-being, which were grouped into the following seven values: healthy body, functional me, healthy mind, happy me, social me, self-managing me, and external conditions. Design papers mostly considered well-being as healthy body and self-managing me, whereas evaluation papers considered the values of healthy mind and happy me. Users were rarely involved in defining well-being. For the scope problem, patients with chronic care needs were commonly considered as the main users. Design papers also regularly involved other users, such as caregivers and relatives. These users were often not involved in evaluation papers. For the specification problem, most design and evaluation papers focused on the provision of care support through a digital platform. Design papers used numerous design methods, whereas evaluation papers mostly considered pre-post measurements and randomized controlled trials. For the aggregation problem, value conflicts were rarely described. ConclusionsCurrent practice has found pragmatic ways of circumventing or dealing with the problems of digital health for well-being. Major differences exist between the design and evaluation of digital health, particularly regarding their conceptualization of well-being and the types of users studied. In addition, we found that current methodologies for designing and evaluating digital health can be improved. For optimal digital health for well-being, multidisciplinary collaborations that move beyond the common dichotomy of design and evaluation are needed.

Abstract Background Serum free thiols (R-SH, sulfhydryl groups) reliably reflect systemic oxidative stress. Since serum free thiols are rapidly oxidized by reactive species, systemic oxidative stress is generally associated with reduced serum free thiol levels. Free thiols associate with favorable disease outcomes in many patient cohorts, and the current hypothesis is that oxidative stress might also play an important role in cardiovascular disease. In this study, we aimed to establish the role of serum free thiols in the general population by investigating their relationship with the risk of cardiovascular (CV) events and all-cause mortality. Methods Participants (n = 5955) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study from the general population were included. At baseline, serum levels of free thiols were quantified and adjusted to total protein levels. Protein-adjusted serum free thiol levels were studied for their associations with clinical and biochemical parameters, as well as with the risk of CV events and all-cause mortality. Results The mean protein-adjusted serum free thiol level was 5.05 ± 1.02 μmol/g of protein. Protein-adjusted serum free thiols significantly predicted the risk of CV events, even after adjustment for potential confounding factors (hazard ratio [HR] per doubling 0.68 [95% confidence interval [CI] 0.47–1.00], P = 0.048). Similarly, protein-adjusted serum free thiols were significantly predictive of the risk of all-cause mortality (HR per doubling 0.66 [95% CI 0.44–1.00], P = 0.050). Stratified analyses revealed lower HRs for subjects with a lower body mass index (BMI), without hypertension, and without diabetes. Conversely, HRs were lower in subjects with albuminuria. Conclusions In this large population-based cohort study, serum free thiols significantly predicted the risk of CV events and all-cause mortality. Our results highlight the potential significance and clinical applicability of serum free thiols since they are amendable to therapeutic intervention.

Abstract Background and aims Acute appendicitis (AA) is among the most common causes of acute abdominal pain. Diagnosis of AA is still challenging and some controversies on its management are still present among different settings and practice patterns worldwide. In July 2015, the World Society of Emergency Surgery (WSES) organized in Jerusalem the first consensus conference on the diagnosis and treatment of AA in adult patients with the intention of producing evidence-based guidelines. An updated consensus conference took place in Nijemegen in June 2019 and the guidelines have now been updated in order to provide evidence-based statements and recommendations in keeping with varying clinical practice: use of clinical scores and imaging in diagnosing AA, indications and timing for surgery, use of non-operative management and antibiotics, laparoscopy and surgical techniques, intra-operative scoring, and peri-operative antibiotic therapy. Methods This executive manuscript summarizes the WSES guidelines for the diagnosis and treatment of AA. Literature search has been updated up to 2019 and statements and recommendations have been developed according to the GRADE methodology. The statements were voted, eventually modified, and finally approved by the participants to the consensus conference and by the board of co-authors, using a Delphi methodology for voting whenever there was controversy on a statement or a recommendation. Several tables highlighting the research topics and questions, search syntaxes, and the statements and the WSES evidence-based recommendations are provided. Finally, two different practical clinical algorithms are provided in the form of a flow chart for both adults and pediatric (< 16 years old) patients. Conclusions The 2020 WSES guidelines on AA aim to provide updated evidence-based statements and recommendations on each of the following topics: (1) diagnosis, (2) non-operative management for uncomplicated AA, (3) timing of appendectomy and in-hospital delay, (4) surgical treatment, (5) intra-operative grading of AA, (6) ,management of perforated AA with phlegmon or abscess, and (7) peri-operative antibiotic therapy.