Search

Background: Ischemia-reperfusion injury (IRI) inevitably occurs during kidney transplantation and extended ischemia is associated with delayed graft function and poor outcomes. Remote ischemic preconditioning (RIPC) is a simple, noninvasive procedure aimed at reducing IRI and improving graft function. Experimental studies have implicated the kynurenine pathway as a protective mechanism behind RIPC., Methods: First, paired biopsies from 11 living kidney donors were analyzed to characterize the acute transcriptomic response to IRI. Second, 16 living kidney donors were subjected to either RIPC (n = 9) or no pretreatment (n = 7) to evaluate the impact of RIPC on the transcriptomic response to IRI. Finally, the effect of RIPC on plasma metabolites was analyzed in 49 healthy subjects., Results: There was a robust immediate response to IRI in the renal transcriptomes of living-donor kidney transplantation, including activation of the mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) pathways. Preconditioning with RIPC did not significantly alter the transcriptomic response to IRI or the concentration of plasma metabolites., Conclusions: The present data validate living-donor kidney transplantation as a suitable model for mechanistic studies of IRI in human kidneys. The failure of RIPC to alter transcriptomic responses or metabolites in the kynurenine pathway raises the question of the robustness of the standard procedure used to induce RIPC, and might explain the mixed results in clinical trials evaluating RIPC as a method to attenuate IRI., Competing Interests: J.S.R. reports funding from GSK and Sanofi and fees from Travere Therapeutics and Astex. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products associated with this research to declare., (Copyright: © 2024 Nordström et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aimed to investigate how electromyography (EMG) cluster analysis of the rectus femoris (RF) could help to better interpret gait analysis in patients with cerebral palsy (CP). The retrospective gait data of CP patients were categorized into two groups: initial examination (E1, 881 patients) and subsequent examination (E2, 377 patients). Envelope-formatted EMG data of RF were collected. Using PCA and a combined PSO-K-means algorithm, main clusters were identified. Patients were further classified into crouch, jump, recurvatum, stiff and mild gait for detailed analysis. The clusters (labels) were characterized by a significant peak EMG activity during mid-swing (L1), prolonged EMG activity during stance (L2), and a peak EMG activity during loading response (L3). Notably, L2 contained 76% and 92% of all crouch patients at E1 and E2, respectively. Comparing patients with a crouch gait pattern in L2-E1 and L2-E2, two subgroups emerged: patients with persistent crouch (G1) and patients showing improvement at E2 (G2). The minimum activity of RF during 20-45% of the gait was significantly higher (p = 0.025) in G1 than in G2. A greater chance of improvement from crouch gait might be associated with lower RF activity during the stance phase. Using our findings, we could potentially establish an approach to improve clinical decision-making regarding treatment of patients with CP., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Davoudi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18%) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52% were female. Overall FujiLAM sensitivity was 54·4% (95% CI: 48·7-60·0), overall specificity was 85·2% (83·2-87·0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26·5% (95% CI: 17·4%-38·0%) to 73·2% (60·4%-83·0%), and 75·0 (65·0%-82·9%) to 96·5 (92·1%-98·5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423)., Competing Interests: RS, AM, CMD and MR are or were employed by FIND at the time of the study. FIND is a not-for-profit foundation that supports the evaluation of publicly prioritized tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for tuberculosis and other diseases. These agreements strictly define FIND’s independence and neutrality with regard to these private sector companies. TB reports patents in the field of TB detection and is a shareholder of Avelo Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Székely et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The transition of patients between inpatient and outpatient care can lead to adverse events and medication-related problems due to medication and communication errors, such as medication discontinuation, the frequency of (re-)hospitalizations, and increased morbidity and mortality. Older patients with multimorbidity and polypharmacy are particularly at high risk during transitions of care. Previous research highlighted the need for interventions to improve transitions of care in order to support information continuity, coordination, and communication. The HYPERION-TransCare project aims to improve the continuity of medication management for older patients during transitions of care., Methods and Findings: Using a qualitative design, 32 expert interviews were conducted to explore the perspectives of key stakeholders, which included healthcare professionals, patients and one informal caregiver, on transitions of care. Interviews were conducted between October 2020 and January 2021, transcribed verbatim and analyzed using content analysis. We narratively summarized four main topics (stakeholders' tasks, challenges, ideas for solutions and best practice examples, and patient-related factors) and mapped them in a patient journey map. Lacking or incomplete information on patients' medication and health conditions, inappropriate communication and collaboration between healthcare providers within and across settings, and insufficient digital support limit the continuity of medication management., Conclusions: The study confirms that medication management during transitions of care is a complex process that can be compromised by a variety of factors. Legal requirements and standardized processes are urgently needed to ensure adequate exchange of information and organization of medication management before, during and after hospital admissions. Despite the numerous barriers identified, the findings indicate that involved healthcare professionals from both the inpatient and outpatient care settings have a common understanding., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dinh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: For biomedical data-driven research purposes, secondary use of clinical data carries great but largely untapped potential. Physicians' attitudes and their needs towards secondary data use are essential to inform its practical and ethically sound implementation but are currently understudied., Objective: Therefore, the objectives of the study are to assess physicians' (i) general attitudes and concerns, (ii) willingness to adapt workflows and to make data available for secondary use, (iii) group-specific conditions toward implementation of secondary use and associated concerns of physician-scientists and purely clinical physicians., Methods: We developed an online survey based on a literature review and an expert interview study. Physicians in private practice and at two large German university hospitals were surveyed from May 2021 until January 2022., Results: In total, 446 physicians participated in the survey. 96% [380/397] of all physicians reported a positive attitude towards secondary use; 87% [31/397] are in-principle willing to support secondary use of clinical data along with a small proportion of physicians with fundamental reservations. Secondly, the most important conditions for adapting workflows were funding of additional time and effort for research-adequate documentation (71% [286/390]) and the most important condition for providing patients' clinical data was reliable protection of patients' privacy (67% [254/382]). Thirdly, physician-scientists were more likely than purely clinical physicians to request additional funding for research-adequate documentation as a precondition for support (83% vs 69%, P = .002) and the privilege to conduct research with their own patients' clinical data before other researchers are allowed to (43% vs 11%, P < .001); while purely clinical physicians more frequently require reliable protection of patient privacy (76% vs 62%, P = .007) and monetary compensation (45% vs 25%, P < .001)., Conclusion: Since this study presents high in-principle willingness of physicians to support secondary use along with little general concerns, it seems essential to address physicians' group-specific conditions toward secondary use in order to gain their support., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Köngeter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Machine perfusion (MP) is often referred to as one of the most promising advancements in liver transplantation research of the last few decades, with various techniques and modalities being evaluated in preclinical studies using animal models. However, low scientific rigor and subpar reporting standards lead to limited reproducibility and translational potential, hindering progress. This pre-registered systematic review (PROSPERO: CRD42021234667) aimed to provide a thematic overview of the preclinical research landscape on MP in liver transplantation using in vivo transplantation models and to explore methodological and reporting standards, using the ARRIVE (Animal Research: Reporting of In Vivo Experiments) score. In total 56 articles were included. Studies were evenly distributed across Asia, Europe, and the Americas. Porcine models were used in 57.1% of the studies, followed by rats (39.3%) and dogs (3.6%). In terms of graft type, 55.4% of the studies used donation after cardiac death grafts, while donation after brain death grafts accounted for 37.5%. Regarding MP modalities, the distribution was as follows: 41.5% of articles utilized hypothermic MP, 21.5% normothermic MP, 13.8% subnormothermic MP, and 16.9% utilized hypothermic oxygenated MP. The stringent documentation of ARRIVE elements concerning precise experimental execution, group size and selection, the choice of statistical methods, as well as adherence to the principles of the 3Rs, was notably lacking in the majority of publications, with less than 30% providing comprehensive details. Postoperative analgesia and antibiotics treatment were not documented in 82.1% of all included studies. None of the analyzed studies fully adhered to the ARRIVE Guidelines. In conclusion, the present study emphasizes the importance of adhering to reporting standards to promote reproducibility and adequate animal welfare in preclinical studies in machine perfusion. At the same time, it highlights a clear deficiency in this field, underscoring the need for further investigations into animal welfare-related topics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Since computed tomography (CT) is a part of standard diagnostic protocol in pancreatic ductal adenocarcinoma (PDAC), we have evaluated the value of CT for sarcopenia screening in patients with PDAC, intending to expand the diagnostic value of tomographic studies. In our study, we included 177 patients with available CT images. Two groups were formed: Group 1 consisted of 117 patients with PDAC in various locations and stages and Group 2, or the control group, consisted of 60 "nominally healthy" patients with other somatic non-oncological diseases. The body mass index (BMI) was defined as a ratio of patient's weight to the square of their height (kg/m2). CT-based body composition analysis was performed using commercially available software with evaluation of sarcopenia using skeletal muscle index (SMI, cm2/m2). Based on the SMI values, sarcopenia was found in 67.5% of patients (79 out of 117) in the first patient group. It was found more frequently in males (42 out of 56; 75%) than in females (37 out of 61; 60.6%). Additionally, we observed a decrease in muscle mass (hidden sarcopenia) in 79.7% in patients with a normal BMI. Even in overweight patients, sarcopenia was found in 50% (sarcopenic obesity). In patients with reduced BMI sarcopenia was found in all cases (100%). Statistically significant difference of SMI between two groups was revealed for both sexes (p = 0,0001), with no significant difference between groups in BMI. BMI is an inaccurate value for the assessment of body composition as it does not reflect in the details the human body structure. As SMI may correlate with the prognosis, decreased muscle mass- especially "hidden" sarcopenia or sarcopenic obesity- should be reported. The use of CT-based evaluation of sarcopenia and sarcopenic obesity will allow for a better treatment response assessment in patients with cancer cachexia., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Khristenko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Early stages of catastrophes like COVID-19 are often led by chaos and panic. To characterize the initial chaos phase of clinical research in such situations, we analyzed the first surge of more than 1000 clinical trials about the new disease at baseline and after two years follow-up. Our 3 main objectives were: (1) Assessment of spatial and temporal evolution of clinical research of COVID-19 across the globe, (2) Assessment of transparency and quality-trial registration, (3) Assessment of research waste and redundancies., Methods: By entering the keyword "COVID-19" we screened the International Clinical Trials Registry Platform of the WHO and downloaded the search output when our goal of 1000 trials was reached on the 1st of April 2020. Additionally, we verified the integrity of the downloaded data from the meta registry by comparing the data with each individual registration record on their source register. Also, we conducted a follow-up after two years to track their progress., Results: (1) The spatial evolution followed the geographical spread of the disease as expected, however, the temporal development suggested that panic was the main driver for clinical research activities. (2) Trial registrations and registers showed a huge lack of transparency by allowing retrospective registrations and not keeping their registration records up to date. Quality of trial registration seems to have improved over the last decade, yet crucial information still was missing. (3) Research waste and redundancies were present as suggested by discontinuation of trials, preventable flaws in study design, and similar but uncoordinated research topics operationally fragmented in isolated silo-structures., Conclusion: The scientific response mechanism across the globe was intact during the chaos phase. However, supervision, leadership, and accountability are urgently needed to prevent research waste, to ensure effective structure, quality, and validity to ultimately break the "panic-then-forget" cycle in future catastrophes., Competing Interests: Markus Ries is a guest editor of the call for papers “Prediction and Mitigation of Natural Hazards”. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Adami, Ries. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Locomotion is a complex task involving excitatory and inhibitory circuitry in spinal gray matter. While genetic knockouts examine the function of individual spinal interneuron (SpIN) subtypes, the phenotype of combined SpIN loss remains to be explored. We modified a kainic acid lesion to damage intermediate gray matter (laminae V-VIII) in the lumbar spinal enlargement (spinal L2-L4) in female rats. A thorough, tailored behavioral evaluation revealed deficits in gross hindlimb function, skilled walking, coordination, balance and gait two weeks post-injury. Using a Random Forest algorithm, we combined these behavioral assessments into a highly predictive binary classification system that strongly correlated with structural deficits in the rostro-caudal axis. Machine-learning quantification confirmed interneuronal damage to laminae V-VIII in spinal L2-L4 correlates with hindlimb dysfunction. White matter alterations and lower motoneuron loss were not observed with this KA lesion. Animals did not regain lost sensorimotor function three months after injury, indicating that natural recovery mechanisms of the spinal cord cannot compensate for loss of laminae V-VIII neurons. As gray matter damage accounts for neurological/walking dysfunction in instances of spinal cord injury affecting the cervical or lumbar enlargement, this research lays the groundwork for new neuroregenerative therapies to replace these lost neuronal pools vital to sensorimotor function., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2023 Kuehn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Transvenous laser lead extraction (TLE) for cardiac implantable electric devices (CIED) is a challenging procedure especially if performed in octogenarians. In this study we evaluated the safety and efficacy of transvenous laser lead extraction in elderly patients., Methods: This is a retrospective study of octogenarian patients who underwent laser-assisted lead extraction (LLE) (GlideLight laser sheath, Philips, San Diego, USA). 270 Consecutive patients were included. Patients were divided into two groups. Octogenarian group and non-octogenarian group. The Data was gathered from patients treated between September 2013 and January 2020 and is retrospectively analyzed., Results: Of 270 consecutive patients, 38 (14.0%) were 80 years old or more. The total number of the extracted leads was 556 among which 84(15.0%) from the Octogenarian group. From these leads were 155 single coil leads, 82 dual coil leads, 129 right ventricular pacing leads, 155 right atrial leads, and 35 left ventricular leads. In the Octogenarian group the number of removed leads was as follows: 13 single coil leads, 10 dual coil leads, 28 right ventricular pacing leads, 28 right atrial leads and 5 left ventricular leads. No mortality was recorded in the Octogenarian group. One patient in the YG suffered from a superior vena cava tear and one patient suffered from pulmonary embolism., Conclusion: In octogenarian laser assisted lead extraction patients is a safe and effective procedure. No increase in morbidity, mortality or perioperative complication could be recorded in this group. Age should not be a limiting factor to perform this procedure., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Al-Maisary et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Extensive scar tissue formation after peripheral nerve injury or surgery is a common problem. To avoid perineural scarring, implanting a mechanical barrier protecting the nerve from inflammation processes in the perineural environment has shown promising results for functional recovery. This study investigates the potential of an acellular collagen-elastin matrix wrapped around a peripheral nerve after induction of scar tissue formation., Materials and Methods: In the present study, 30 Lewis rats were separated into three groups and sciatic nerve scarring was induced with 2.5% glutaraldehyde (GA-CM) or 2.5% glutaraldehyde with a supplemental FDA-approved acellular collagen-elastin matrix application (GA+CM). Additionally, a sham group was included for control. Nerve regeneration was assessed by functional analysis using the Visual Statisc Sciatic Index (SSI) and MR neurography during the 12-week regeneration period. Histological and histomorphometry analysis were performed to evaluate the degree of postoperative scar tissue formation., Results: Histological analysis showed an extensive scar tissue formation for GA-CM. Connective tissue ratio was significantly (p < 0.009) reduced for GA+CM (1.347 ± 0.017) compared to GA-CM (1.518 ± 0.057). Similarly, compared to GA+CM, MR-Neurography revealed extensive scar tissue formation for GA-CM with a direct connection between nerve and paraneural environment. Distal to the injury site, quantitative analysis presented significantly higher axon density (p = 0.0145), thicker axon diameter (p = 0.0002) and thicker myelinated fiber thickness (p = 0.0008) for GA+CM compared to GA-CM. Evaluation of functional recovery revealed a significantly faster regeneration for GA+CM., Conclusion: The supplemental application of an acellular collagen-elastin matrix showed beneficial effects in histological, radiological, and functional analysis. Therefore, applying a collagen-elastin matrix around the nerve after peripheral nerve injury or surgery may have beneficial effects on preventing scar tissue formation in the long run. This represents a feasible approach to avoid scar tissue formation in peripheral nerve surgery., Competing Interests: MedSkin Solutions Dr. Suwelack funded this research. MedSkin Solutions Dr. Suwelack manufactures the collagen matrix (CM) MatriDerm® that was used in this trial. Implants were provided by MedSkin Solutions Dr. Suwelack free of charge. The study was conceived and designed prior to seeking financial support. With respect to this study, MedSkin Solutions Dr. Suwelack was excluded from any aspect of design, conduct, analysis, write up, or publication of the trial. None of the authors has any personal financial ties to MedSkin Solutions Dr. Suwelack. None of the authors received reimbursements, fees, funding, or salary from MedSkin Solutions Dr. Suwelack. None of the authors hold any stocks or shares. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no further competing interests exist., (Copyright: © 2023 Aman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Breast cancer therapy improved significantly, allowing for different surgical approaches for the same disease stage, therefore offering patients different aesthetic outcomes with similar locoregional control. The purpose of the CINDERELLA trial is to evaluate an artificial-intelligence (AI) cloud-based platform (CINDERELLA platform) vs the standard approach for patient education prior to therapy., Methods: A prospective randomized international multicentre trial comparing two methods for patient education prior to therapy. After institutional ethics approval and a written informed consent, patients planned for locoregional treatment will be randomized to the intervention (CINDERELLA platform) or controls. The patients in the intervention arm will use the newly designed web-application (CINDERELLA platform, CINDERELLA APProach) to access the information related to surgery and/or radiotherapy. Using an AI system, the platform will provide the patient with a picture of her own aesthetic outcome resulting from the surgical procedure she chooses, and an objective evaluation of this aesthetic outcome (e.g., good/fair). The control group will have access to the standard approach. The primary objectives of the trial will be i) to examine the differences between the treatment arms with regards to patients' pre-treatment expectations and the final aesthetic outcomes and ii) in the experimental arm only, the agreement of the pre-treatment AI-evaluation (output) and patient's post-therapy self-evaluation., Discussion: The project aims to develop an easy-to-use cost-effective AI-powered tool that improves shared decision-making processes. We assume that the CINDERELLA APProach will lead to higher satisfaction, better psychosocial status, and wellbeing of breast cancer patients, and reduce the need for additional surgeries to improve aesthetic outcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kaidar-Person et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: We sought to identify trajectories of patient-reported outcomes, specifically physical well-being of the chest (PWBC), in patients who underwent postmastectomy breast reconstruction, and further assessed its significant predictors, and its relationship with health-related quality of life (HRQOL)., Methods: We used data collected as part of the Mastectomy Reconstruction Outcomes Consortium study within a 2-year follow-up in 2012-2017, with 1422, 1218,1199, and 1417 repeated measures at assessment timepoints of 0,3,12, and 24 months, respectively. We performed latent class growth analysis (LCGA) in the implant group (IMPG) and autologous group (AUTOG) to identify longitudinal change trajectories, and then assessed its significant predictors, and its relationship with HRQOL by conducting multinomial logistic regression., Results: Of the included 1424 patients, 843 were in IMPG, and 581 were in AUTOG. Both groups experienced reduced PWBC at follow-up. LCGA identified four distinct PWBC trajectories (χ2 = 1019.91, p<0.001): low vs medium high vs medium low vs high baseline PWBC that was restored vs. not-restored after 2 years. In 76.63%(n = 646) of patients in IMPG and 62.99% (n = 366) in AUTOG, PWBC was restored after two years. Patients in IMPG exhibited worse PWBC at 3 months post-surgery than that in AUTOG. Patients with low baseline PWBC that did not improve at 2-year follow up (n = 28, 4.82% for AUTOG) were characterized by radiation following reconstruction and non-white ethnicity. In IMPG, patients with medium low-restored trajectory were more likely to experience improved breast satisfaction, while patients developing high-restored trajectories were less likely to have worsened psychosocial well-being., Conclusion: Although more women in IMPG experienced restored PWBC after 2 years, those in AUTOG exhibited a more favorable postoperative trajectory of change in PWBC. This finding can inform clinical treatment decisions, help manage patient expectations for recovery, and develop rehabilitation interventions contributing to enhancing the postoperative quality of life for breast cancer patients., Competing Interests: Cai Xu No relationship to disclose. Peiyi Lu No relationship to disclose. André Pfob No relationship to disclose. Andrea L. Pusic Patents, Royalties, Other Intellectual Property: I am a codeveloper of BREAST-Q and receive royalty payments when it is used in for-profit industry-sponsored trials. Jennifer B Hamill No relationship to disclose. Chris Sidey-Gibbons No relationship to disclose. Our competing interests statement does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The internet has become an increasingly important resource for health information, especially for lay people. However, the information found does not necessarily comply with the user's health literacy level. Therefore, it is vital to (1) identify prominent information providers, (2) quantify the readability of written health information, and (3) to analyze how different types of information sources are suited for people with differing health literacy levels., Objective: In previous work, we showed the use of a focused crawler to "capture" and describe a large sample of the "German Health Web", which we call the "Sampled German Health Web" (sGHW). It includes health-related web content of the three mostly German speaking countries Germany, Austria, and Switzerland, i.e. country-code top-level domains (ccTLDs) ".de", ".at" and ".ch". Based on the crawled data, we now provide a fully automated readability and vocabulary analysis of a subsample of the sGHW, an analysis of the sGHW's graph structure covering its size, its content providers and a ratio of public to private stakeholders. In addition, we apply Latent Dirichlet Allocation (LDA) to identify topics and themes within the sGHW., Methods: Important web sites were identified by applying PageRank on the sGHW's graph representation. LDA was used to discover topics within the top-ranked web sites. Next, a computer-based readability and vocabulary analysis was performed on each health-related web page. Flesch Reading Ease (FRE) and the 4th Vienna formula (WSTF) were used to assess the readability. Vocabulary was assessed by a specifically trained Support Vector Machine classifier., Results: In total, n = 14,193,743 health-related web pages were collected during the study period of 370 days. The resulting host-aggregated web graph comprises 231,733 nodes connected via 429,530 edges (network diameter = 25; average path length = 6.804; average degree = 1.854; modularity = 0.723). Among 3000 top-ranked pages (1000 per ccTLD according to PageRank), 18.50%(555/3000) belong to web sites from governmental or public institutions, 18.03% (541/3000) from nonprofit organizations, 54.03% (1621/3000) from private organizations, 4.07% (122/3000) from news agencies, 3.87% (116/3000) from pharmaceutical companies, 0.90% (27/3000) from private bloggers, and 0.60% (18/3000) are from others. LDA identified 50 topics, which we grouped into 11 themes: "Research & Science", "Illness & Injury", "The State", "Healthcare structures", "Diet & Food", "Medical Specialities", "Economy", "Food production", "Health communication", "Family" and "Other". The most prevalent themes were "Research & Science" and "Illness & Injury" accounting for 21.04% and 17.92% of all topics across all ccTLDs and provider types, respectively. Our readability analysis reveals that the majority of the collected web sites is structurally difficult or very difficult to read: 84.63% (2539/3000) scored a WSTF ≥ 12, 89.70% (2691/3000) scored a FRE ≤ 49. Moreover, our vocabulary analysis shows that 44.00% (1320/3000) web sites use vocabulary that is well suited for a lay audience., Conclusions: We were able to identify major information hubs as well as topics and themes within the sGHW. Results indicate that the readability within the sGHW is low. As a consequence, patients may face barriers, even though the vocabulary used seems appropriate from a medical perspective. In future work, the authors intend to extend their analyses to identify trustworthy health information web sites., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zowalla et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Hypercoagulability and thrombo-inflammation are the main reasons for death in COVID-19 patients. It is unclear whether there is a difference between D-dimer levels in patients without or with COVID-19 acute respiratory distress syndrome (ARDS)., Methods: We searched PubMed, EMBASE, and ClinicalTrails.gov databases looking for studies reporting D-dimer levels in patients without or with COVID-19 ARDS. Secondary endpoints included length of hospital stay, and mortality data at the longest follow-up available., Results: We included 12 retrospective and 3 prospective studies with overall 2,828 patients, of whom 1,404 (49.6%) had non-COVID-19 ARDS and 1,424 had COVID-19 ARDS. D-dimer levels were not significantly higher in non-COVID-19 ARDS than in COVID-19 ARDS patients (mean 7.65 mg/L vs. mean 6.20 mg/L MD 0.88 [CI: -0.61 to 2.38] p = 0.25; I² = 85%) while the length of hospital stay was shorter (non-COVID-19 mean 37.4 days vs. COVID-19 mean 48.5 days, MD -10.92 [CI: -16.71 to -5.14] p < 0.001; I² = 44%). No difference in mortality was observed: non-COVID-19 ARDS 418/1167 (35.8%) vs. COVID-19 ARDS 467/1201 (38.8%)., Conclusions: We found no difference in the mean D-dimer levels between non-COVID-19 ARDS and COVID-19 ARDS patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tóth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Anticholinergic burden has been associated with adverse outcomes such as falls. To date, no gold standard measure has been identified to assess anticholinergic burden, and no conclusion has been drawn on which of the different measure algorithms best predicts falls in older patients from general practice. This study compared the ability of five measures of anticholinergic burden to predict falls. To account for patients' individual susceptibility to medications, the added predictive value of typical anticholinergic symptoms was further quantified in this context., Methods and Findings: To predict falls, models were developed and validated based on logistic regression models created using data from two German cluster-randomized controlled trials. The outcome was defined as "≥ 1 fall" vs. "no fall" within a 6-month follow-up period. Data from the RIME study (n = 1,197) were used in model development, and from PRIMUM (n = 502) for external validation. The models were developed step-wise in order to quantify the predictive ability of anticholinergic burden measures, and anticholinergic symptoms. In the development set, 1,015 patients had complete data and 188 (18.5%) experienced ≥ 1 fall within the 6-month follow-up period. The overall predictive value of the five anticholinergic measures was limited, with neither the employed anticholinergic variable (binary / count / burden), nor dose-dependent or dose-independent measures differing significantly in their ability to predict falls. The highest c-statistic was obtained using the German Anticholinergic Burden Score (0.73), whereby the optimism-corrected c-statistic was 0.71 after interval validation using bootstrapping and 0.63 in the external validation. Previous falls and dizziness / vertigo had the strongest prognostic value in all models., Conclusions: The ability of anticholinergic burden measures to predict falls does not appear to differ significantly, and the added value they contribute to risk classification in fall-prediction models is limited. Previous falls and dizziness / vertigo contributed most to model performance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Dinh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Care engagement or active patient involvement in healthcare contributes to the quality of primary care, but organisational preconditions in routine practice need to be aligned. A Maturity Matrix for Care Engagement to assess and discuss these preconditions in the general practice team was developed and tested on feasibility and acceptability in general practice., Methods and Findings: A systematic user-centred approach was applied, starting with a scoping literature search to describe the domains on the horizontal axis of the maturity matrix. The domains and growing steps (vertical axis) were refined by patients (n = 16) and general practice staff (n = 11) in three focus group discussions and reviewed by six experts (local facilitators and scientists). Seven domains could be distinguished: Personalised Care, Shared Decision Making, Self-Management, Patient as Partner, Supportive Means, Patient Environment, and Teamwork among Healthcare Professionals. The growing steps described three to six activities per domain (n = 32 in total) that contribute to care engagement. Local facilitators implemented the tool in two general practice teams according to a user guide, starting with a two-hour kick-off meeting on care engagement. In the next step, practitioners, nurses and assistants in each practice indicated their score on the domains individually. The scores were discussed in the facilitated practice meeting which was aimed at SMART improvement plans. Feasibility and acceptability were assessed in interviews showing that the tool was well received by the pilot practices, although the practice assistants had difficulties scoring some of the activities as they did not always relate to their daily work. An assessment after three months showed changes in practice organisation towards increased care engagement., Conclusions: The maturity matrix on care engagement is a tool to identify the organisational practice maturity for care engagement. Suggested adaptations must be implemented before large-scale testing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wolters et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Artificial Intelligence (AI) systems have demonstrated potential in detecting tuberculosis (TB) associated abnormalities from chest X-ray (CXR) images. Thus, they might provide a solution to radiologist shortages in high TB burden countries. However, the cost of implementing computer-aided detection (CAD) software has thus far been understudied. In this study, we performed a costing analysis of CAD software when used as a screening or triage test for pulmonary TB, estimated the incremental cost compared to a radiologist reading of different throughput scenarios, and predicted the cost for the national scale-up plan in Pakistan., Methods: For the study, we focused on CAD software reviewed by the World Health Organization (CAD4TB, Lunit INSIGHT CXR, qXR) or listed in the Global Drug Facility diagnostics catalogue (CAD4TB, InferRead). Costing information was obtained from the CAD software developers. CAD4TB and InferRead use a perpetual license pricing model, while Lunit and qXR are priced per license for restricted number of scans. A major implementer in Pakistan provided costing information for human resource and software training. The per-screen cost was estimated for each CAD software and for radiologist for 1) active case finding, and 2) facility based CXR testing scenarios with throughputs ranging from 50,000-100,000 scans. Moreover, we estimated the scale-up cost for CAD or radiologist CXR reading in Pakistan based on the National Strategic Plan, considering that to reach 80% diagnostic coverage, 50% of TB patients would need to be found through facility-based triage and 30% through active case finding (ACF)., Results: The per-screen cost for CAD4TB (0.25 USD- 2.33 USD) and InferRead (0.19 USD- 2.78 USD) was lower than that of a radiologist (0.70 USD- 0.93 USD) for high throughput scenarios studied. In comparison, the per-screen cost for Lunit (0.94 USD- 1.69 USD) and qXR (0.95 USD-1.9 USD) were only comparable with that of the radiologists in the highest throughput scenario in ACF. To achieve 80 percent diagnostic coverage at scale in Pakistan, the projected additional cost of deploying CAD software to complement the current infrastructure over a four-year period were estimated at 2.65-19.23 million USD, whereas Human readers, would cost an additional 23.97 million USD., Conclusions: Our findings suggest that using CAD software could enable large-scale screening programs in high TB-burden countries and be less costly than radiologist. To achieve minimum cost, the target number of screens in a specific screening strategy should be carefully considered when selecting CAD software, along with the offered pricing structure and other aspects such as performance and operational features. Integrating CAD software in implementation strategies for case finding could be an economical way to attain the intended programmatic goals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Bashir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Data Sharing is widely recognised as crucial for accelerating scientific research and improving its quality. However, data sharing is still not a common practice. Funding agencies tend to facilitate the sharing of research data by both providing incentives and requiring data sharing as part of their policies and conditions for awarding grants. The goal of our article is to answer the following question: What challenges do international funding agencies see when it comes to their own efforts to foster and implement data sharing through their policies?, Methods: We conducted a series of sixteen guideline-based expert interviews with representatives of leading international funding agencies. As contact persons for open science at their respective agencies, they offered their perspectives and experiences concerning their organisations' data sharing policies. We performed a qualitative content analysis of the interviews and categorised the challenges perceived by funding agencies., Results: We identify and illustrate six challenges surrounding data sharing policies as perceived by leading funding agencies: The design of clear policies, monitoring of compliance, sanctions for non-compliance, incentives, support, and limitations for funders' own capabilities. However, our interviews also show how funders approach potential solutions to overcome these challenges, for example by coordinating with other agencies or adjusting grant evaluation metrics to incentivise data sharing., Discussion and Conclusion: Our interviews point to existing flaws in funders' data sharing policies, such as a lack of clarity, a lack of monitoring of funded researchers' data sharing behaviour, and a lack of incentives. A number of agencies could suggest potential solutions but often struggle with the overall complexity of data sharing and the implementation of these measures. Funders cannot solve each challenge by themselves, but they can play an active role and lead joint efforts towards a culture of data sharing., Competing Interests: The authors have declared that no competing interests exist.

Background: SARS-CoV-2 has been spreading worldwide since late 2019. Before vaccines became available, exclusively non-pharmaceutical measures were used to prevent transmission of infection. Despite the fact that vaccinations are now available, it is still important to identify relevant transmission routes in order to contain the COVID-19- or further pandemics. Therefore, this study aims to systematically analyse data from the largest public health department in Germany to determine the significance of the various known and unknown transmission situations in terms of the proportion of infections., Methods: All infections in Cologne were systematically recorded by the local health department. In addition to clinical data, the transmission situations were recorded and categorised as pertaining to social contact, work contact, travellers, health care workers, users of educational institutions, visitors of community institutions, infection in the context of medical treatment, and unknown infection., Findings: The analysis included 25,966 persons. A transmission situation could be identified in 82.7% of the cases (n = 21,477). Most persons (42.1%) were infected due to social contact, primarily within their own household. Another 22.3% were infected at their place of work; this was particularly common among staff members of medical facilities, nursing homes and educational institutions. In 17.3% of the cases, the transmission situation remained unknown; the cases with unknown transmission situation were slightly more often symptomatic (75.2%) than the cases with known transmission situation (69.4%)., Interpretation: Considering that during the study period the leading strains were the wild-type and alpha-variant transmission rather occurred during scenarios involving close contacts than in anonymous situations. Presumably, however, the findings can be transferred to the new variants. Therefore, in order to prevent transmission, besides vaccination regular antigen tests and/or appropriate protective measures remain relevant until this pandemic has subsided., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The COVID-19 pandemic has imposed severe challenges on medical education at German university hospitals. In this first German nationwide expert survey, we addressed the responsible university teaching coordinators in obstetrics and gynecology departments and investigated their experiences during the pandemic as well as their opinions on future developments, especially with regard to the broader implementation of e-learning in the standard curriculum., Methods: The questionnaire included 42 items and was disseminated among teaching coordinators at all 41 departments of obstetrics and gynecology at German university hospitals via an email that included a weblink to the online survey provider. Responses were collected between 19 April and 7 June 2021., Results: In total, 30 responses were collected from 41 departments across Germany and their respective teaching coordinators in obstetrics and gynecology. The general opinion of the medical teaching provided during the pandemic was positive, whereas the teaching quality in practical skills was considered inferior and not equivalent to the standard face-to-face curriculum. Lectures and seminars had to be substituted by remote-learning alternatives, while clinical clerkships were reduced in length and provided less patient contact. Students in their final year experienced only a few differences in the clinical and teaching routine. Teaching coordinators in obstetrics and gynecology stated that they intend to incorporate more e-learning into the curriculum in the future., Conclusion: The medical educators' views presented here may help to complement the already-thoroughly investigated experiences of students under the restrictions of the COVID-19 pandemic. Medical educators in obstetrics and gynecology at German university hospitals have successfully established online and hybrid teaching alternatives to their standard face-to-face courses. Building on recent experiences, digitalization could help to improve future medical education., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following potential competing interests: Niklas Amann, Florian Recker, and Martin Weiss are members of the “Junges Forum in der DGGG” (i.e., the official German organization and interest group of physicians in training in OB/GYN within the German Society for Gynecology and Obstetrics). This does not alter our adherence to PLOS ONE policies on sharing data and material.

Introduction: Multiple camera systems are widely used for 3D-motion analysis. Due to increasing accuracies these camera systems gained interest in biomechanical research areas, where high precision measurements are desirable. In the current study different measurement systems were compared regarding their measurement accuracy., Materials and Methods: Translational and rotational accuracy measurements as well as the zero offset measurements of seven different measurement systems were performed using two reference devices and two different evaluation algorithms. All measurements were performed in the same room with constant temperature at the same laboratory. Equal positions were measured with the systems according to a standardized protocol. Measurement errors were determined and compared., Results: The highest measurement errors were seen for a measurement system using active ultrasonic markers, followed by another active marker measurement system (infrared) having measurement errors up to several hundred micrometers. The highest accuracies were achieved by three stereo camera systems, using passive 2D marker points having errors typically below 20 μm., Conclusions: This study can help to better assess the results obtained with different measurement systems. With the focus on the measurement accuracy, only one aspect in the selection of a system was considered. Depending on the requirements of the user, other factors like measurement frequency, the maximum analyzable volume, the marker type or the costs are important factors as well., Competing Interests: [I have read the journal’s policy and the authors of this manuscript have the following competing interests: [Sebastian Jaeger reports grants from B Braun Aesculap, Johnson & Johnson Depuy Synthes, Heraeus Medical, Waldemar Link, Peter Brehm, Ceramtec, Implantcast, Mathys Orthopaedie GmbH and Zimmer Biomet that are not related to the current study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”]

Objectives: This comparative study aimed to evaluate intraoral digital photography (IODP) as assessment-tool for DMFT and number of implants (IMPL) compared to clinical diagnosis (CLIN) in an elderly population with high restorative status. Secondary research questions were whether an additional evaluation of panoramic radiographs (PAN-X) or raters' clinical experience influence the agreement., Methods: Fifty patients (70.98±7.60 years) were enrolled for standardized CLIN and IODP. The clinical reference examiner and ten blinded raters evaluated the photographs without and with a PAN-X regarding DMFT and IMPL. CLIN were used as reference standard and differences to IODP and IODP-PAN-X findings were analysed descriptively. To assess intra-rater agreement, pairwise Gwet's AC1s of the three diagnostic methods CLIN, IODP and IODP+PAN-X were calculated., Results: Compared to a DMFT of 22.10±3.75 (CLIN), blinded raters evaluated a DMFT of 21.54±3.40 (IODP) and 22.12±3.45 (IODP+PAN-X). Mean values for "Decayed" were 0.18±0.52 (CLIN), 0.45±0.46 (IODP) and 0.48±0.47 (IODP-PAN-X), while 11.02±5.97 (CLIN), 10.66±5.78 (IODP) and 10.93±5.91 (IODP+PAN-X) were determined for "Missing" and 10.90±5.61 (CLIN), 10.43±4.85 (IODP) and 10.71±5.11 (IODP+PAN-X) for "Filled". IMPL were 0.78±2.04 (CLIN), 0.58±1.43 (IODP), 0.78±2.04 (IODP+PAN-X). Gwet's AC1 using the mode of the blinded raters' assessment of "Decayed", "Missing" and IMPL compared to CLIN ranged from 0.81 to 0.89 (IODP) and 0.87 to 1.00 (IODP+PAN-X), while for "Filled" and DMFT they were 0.29 and 0.36 (IODP) as well as 0.33 and 0.36 (IODP+PAN-X), respectively. Clinical experience did not influence the agreement., Conclusions: Assessment of "Decayed", "Missing" and IMPL by IODP showed almost perfect agreement, whereas of "Filled" and DMFT revealed fair to moderate agreement with clinical findings. Additional PAN-X-evaluation increased agreement compared to IODP-diagnostics alone. IODP for the assessment of DMFT and IMPL might be a suitable method in large-scale epidemiological studies, considering high agreement in total values and miscellaneous agreement at patient-level., Competing Interests: The authors have declared that no competing interests exist.

Light chain amyloidosis is one of the most common forms of systemic amyloidosis. The disease is caused by the misfolding and aggregation of immunoglobulin light chains to insoluble fibrils. These fibrils can deposit in different tissues and organs such as heart and kidney and cause organ impairments that define the clinical presentation. In this study, we present an overview of IGLV-IGLJ and IGLC germline utilization in 85 patients classified in three clinically important subgroups with dominant cardiac, renal as well as cardiac and renal involvement. We found that IGLV3 was the most frequently detected IGLV-family in patients with dominant cardiac involvement, whereas in renal patients IGLV1 were most frequently identified. For patients with dominant heart and kidney involvement IGLV6 was the most frequently detected IGLV-family. In more detailed analysis IGLV3-21 was observed as the most dominant IGLV-subfamily for patients with dominant heart involvement and IGLV1-44 as the most frequent IGLV-subfamily in the group of patients with dominant kidney involvement. For patients with dominant heart and kidney involvement IGLV6-57 was the most frequently detected IGLV-subfamily. Additionally, we were able to show an exclusive linkage between IGLJ1 and IGLC1 as well as between IGLJ2 and IGLC2 in the fully assembled IGL mRNA., Competing Interests: The authors have declared that no competing interests exist.

Objective: The relevance of communication in medical education is continuously increasing. At the Medical Faculty of Hamburg, the communication curriculum was further developed and optimized during this project. This article aims to describe the stakeholders' perceived challenges and supporting factors in the implementation and optimization processes., Methods: The initial communication curriculum and its development after a one-year optimization process were assessed with a curricular mapping. A SWOT analysis and group discussions were carried out to provide information on the need for optimization and on challenges the different stakeholders faced., Results: The curricular mapping showed that the communication curriculum is comprehensive, coherent, integrated and longitudinal. In both the implementation and the project-related optimization processes, support from the dean, cooperation among all stakeholders and structural prerequisites were deemed the most critical factors for successfully integrating communication content into the curriculum., Conclusion: The initiative and support of all stakeholders, including the dean, teachers and students, were crucial for the project's success., Practice Implications: Although the implementation of a communication curriculum is recommended for all medical faculties, their actual implementation processes may differ. In a "top-down" and "bottom-up" approach, all stakeholders should be continuously involved in the process to ensure successful integration., Competing Interests: The authors have declared that no competing interests exist.

As the epidemiological transition progresses throughout sub-Saharan Africa, life lived with diseases is an increasingly important part of a population's burden of disease. The burden of disease of climate-sensitive health outcomes is projected to increase considerably within the next decades. Objectively measured, reliable population health data is still limited and is primarily based on perceived illness from recall. Technological advances like non-invasive, consumer-grade wearable devices may play a vital role in alleviating this data gap and in obtaining insights on the disease burden in vulnerable populations, such as heat stress on human cardiovascular response. The overall goal of this study is to investigate whether consumer-grade wearable devices are an acceptable, feasible and valid means to generate data on the individual level in low-resource contexts. Three hundred individuals are recruited from the two study locations in the Nouna health and demographic surveillance system (HDSS), Burkina Faso, and the Siaya HDSS, Kenya. Participants complete a structured questionnaire that comprises question items on acceptability and feasibility under the supervision of trained data collectors. Validity will be evaluated by comparing consumer-grade wearable devices to research-grade devices. Furthermore, we will collect demographic data as well as the data generated by wearable devices. This study will provide insights into the usage of consumer-grade wearable devices to measure individual vital signs in low-resource contexts, such as Burkina Faso and Kenya. Vital signs comprising activity (steps), sleep (duration, quality) and heart rate (hr) are important measures to gain insights on individual behavior and activity patterns in low-resource contexts. These vital signs may be associated with weather variables-as we gather them from weather stations that we have setup as part of this study to cover the whole Nouna and Siaya HDSSs-in order to explore changes in behavior and other variables, such as activity, sleep, hr, during extreme weather events like heat stress exposure. Furthermore, wearable data could be linked to health outcomes and weather events. As a result, consumer-grade wearables may serve as a supporting technology for generating reliable measurements in low-resource contexts and investigating key links between weather occurrences and health outcomes. Thus, wearable devices may provide insights to better inform mitigation and adaptation interventions in these low-resource settings that are direly faced by climate change-induced changes, such as extreme weather events., Competing Interests: The authors have declared that no competing interests exist.

Background: The coronavirus disease 2019 (COVID-19) pandemic led to far-reaching restrictions of social and professional life, affecting societies all over the world. To contain the virus, medical schools had to restructure their curriculum by switching to online learning. However, only few medical schools had implemented such novel learning concepts. We aimed to evaluate students' attitudes to online learning to provide a broad scientific basis to guide future development of medical education., Methods: Overall, 3286 medical students from 12 different countries participated in this cross-sectional, web-based study investigating various aspects of online learning in medical education. On a 7-point Likert scale, participants rated the online learning situation during the pandemic at their medical schools, technical and social aspects, and the current and future role of online learning in medical education., Results: The majority of medical schools managed the rapid switch to online learning (78%) and most students were satisfied with the quantity (67%) and quality (62%) of the courses. Online learning provided greater flexibility (84%) and led to unchanged or even higher attendance of courses (70%). Possible downsides included motivational problems (42%), insufficient possibilities for interaction with fellow students (67%) and thus the risk of social isolation (64%). The vast majority felt comfortable using the software solutions (80%). Most were convinced that medical education lags behind current capabilities regarding online learning (78%) and estimated the proportion of online learning before the pandemic at only 14%. In order to improve the current curriculum, they wish for a more balanced ratio with at least 40% of online teaching compared to on-site teaching., Conclusion: This study demonstrates the positive attitude of medical students towards online learning. Furthermore, it reveals a considerable discrepancy between what students demand and what the curriculum offers. Thus, the COVID-19 pandemic might be the long-awaited catalyst for a new "online era" in medical education., Competing Interests: The authors have declared that no competing interests exist.

Objective: We undertook a systematic review of the literature to explore the prevalence of post-traumatic stress disorder (PTSD) in Palestinian children and adolescents exposed to political violence. This is the first systematic review and meta-analysis of the prevalence of PTSD in this population., Methods: PubMed, Embase, PsycInfo, Google Scholar and Cochrane library were searched until June 2020. To estimate the prevalence of PTSD, sub-group and meta-analysis were conducted., Results: The search resulted in 2786 studies, of which 28 articles representing 32 samples with a total of 15,121 participants from Gaza Strip and West Bank met either the DSM-4 or DSM-5 criteria and were included. The pooled prevalence of PTSD was 36% (95% CI 30-41%; I2 98.6%) and ranged from 6% to 70%. Sub-group analysis showed that the PTSD prevalence did not differ according to region (West Bank, Gaza Strip) and tended to decrease after including only studies using a representative sample (p<0.001), and among those with low risk of bias (p<0.001). Visual inspection of the included studies revealed significant discrepancies in study design and assessment measures., Conclusion: We identified high prevalence of PTSD among Palestinian children and adolescents exposed to political violence. However, the pooled results should be interpreted with caution, due to the high heterogeneity and risk of bias in the included studies. These limitations also reflect the challenge in conceptualizing and measuring PTSD in the Palestinian context with a background of continuous and cumulative trauma. Understanding the contextual factors and developing locally adapted survey measures are of relevance to future research, public health planning, and the provision of mental healthcare in Palestine., Competing Interests: The authors have declared that no competing interests exist.

Background: Most data on COVID-19 was collected in hospitalized cases. Much less is known about the spectrum of disease in entire populations. In this study, we examine a representative cohort of primarily symptomatic cases in an administrative district in Southern Germany., Methods: We contacted all confirmed SARS-CoV-2 cases in the administrative district. Consenting participants answered a retrospective survey either via a telephone, electronically or via mail. Clinical and sociodemographic features were compared between hospitalized and non-hospitalized patients. Additionally, we assessed potential risk factors for hospitalization and time to hospitalization in a series of regression models., Results: We included 897 participants in our study, 69% out of 1,305 total cases in the district with a mean age of 47 years (range 2-97), 51% of which were female and 47% had a pre-existing illness. The percentage of asymptomatic, mild, moderate (leading to hospital admission) and critical illness (requiring mechanical ventilation) was 54 patients (6%), 713 (79%), 97 (11%) and 16 (2%), respectively. Seventeen patients (2%) died. The most prevalent symptoms were fatigue (65%), cough (62%) and dysgeusia (60%). The risk factors for hospitalization included older age (OR 1.05 per year increase; 95% CI 1.04-1.07) preexisting lung conditions (OR 3.09; 95% CI 1.62-5.88). Female sex was a protective factor (OR 0.51; 95% CI 0.33-0.77)., Conclusion: This representative analysis of primarily symptomatic COVID-19 cases confirms age, male sex and preexisting lung conditions but not cardiovascular disease as risk factors for severe illness. Almost 80% of infection take a mild course, whereas 13% of patients suffer moderate to severe illness., Trial Registration: German Clinical Trials Register, DRKS00022926. URL: https://www.drks.de/drks&#95;web/setLocale&#95;EN.do., Competing Interests: The authors have declared that no competing interests exist.

Background: COVID-19 has been reported in over 40million people globally with variable clinical outcomes. In this systematic review and meta-analysis, we assessed demographic, laboratory and clinical indicators as predictors for severe courses of COVID-19., Methods: This systematic review was registered at PROSPERO under CRD42020177154. We systematically searched multiple databases (PubMed, Web of Science Core Collection, MedRvix and bioRvix) for publications from December 2019 to May 31st 2020. Random-effects meta-analyses were used to calculate pooled odds ratios and differences of medians between (1) patients admitted to ICU versus non-ICU patients and (2) patients who died versus those who survived. We adapted an existing Cochrane risk-of-bias assessment tool for outcome studies., Results: Of 6,702 unique citations, we included 88 articles with 69,762 patients. There was concern for bias across all articles included. Age was strongly associated with mortality with a difference of medians (DoM) of 13.15 years (95% confidence interval (CI) 11.37 to 14.94) between those who died and those who survived. We found a clinically relevant difference between non-survivors and survivors for C-reactive protein (CRP; DoM 69.10 mg/L, CI 50.43 to 87.77), lactate dehydrogenase (LDH; DoM 189.49 U/L, CI 155.00 to 223.98), cardiac troponin I (cTnI; DoM 21.88 pg/mL, CI 9.78 to 33.99) and D-Dimer (DoM 1.29mg/L, CI 0.9 to 1.69). Furthermore, cerebrovascular disease was the co-morbidity most strongly associated with mortality (Odds Ratio 3.45, CI 2.42 to 4.91) and ICU admission (Odds Ratio 5.88, CI 2.35 to 14.73)., Discussion: This comprehensive meta-analysis found age, cerebrovascular disease, CRP, LDH and cTnI to be the most important risk-factors that predict severe COVID-19 outcomes and will inform clinical scores to support early decision-making., Competing Interests: I have read the journal’s policy and none of the authors of this manuscript have a competing interest.

On the one hand, sustained β-adrenergic stress is a hallmark of heart failure (HF) and exerts maladaptive cardiac remodelling. On the other hand, acute β-adrenergic stimulation maintains cardiac function under physiological stress. However, it is still incompletely understood to what extent the adaptive component of β-adrenergic signaling contributes to the maintenance of cardiac function during chronic β-adrenergic stress. We developed an experimental catecholamine-based protocol to distinguish adaptive from maladaptive effects. Mice were for 28 days infused with 30 mg/kg body weight/day isoproterenol (ISO) by subcutaneously implanted osmotic minipumps ('ISO on'). In a second and third group, ISO infusion was stopped after 26 days and the mice were observed for additional two or seven days without further ISO infusion ('ISO off short', 'ISO off long'). In this setup, 'ISO on' led to cardiac hypertrophy and slightly improved cardiac contractility. In stark contrast, 'ISO off' mice displayed progressive worsening of left ventricular ejection fraction that dropped down below 40%. While fetal and pathological gene expression (increase in Nppa, decrease in Myh6/Myh7 ratios, increase in Xirp2) was not induced in 'ISO on', it was activated in 'ISO off' mice. After ISO withdrawal, phosphorylation of phospholamban (PLN) at the protein kinase A (PKA) phosphorylation site Ser-16 dropped down to 20% as compared to only 50% at the Ca2+/Calmodulin-dependent kinase II (CaMKII) phosphorylation site Thr-17 in 'ISO off' mice. PKA-dependent cardioprotective production of the N-terminal proteolytic product of histone deacetylase 4 (HDAC4-NT) was reduced in 'ISO off' as compared to 'ISO on'. Taken together, these data indicate that chronic ISO infusion induces besides maladaptive remodelling also adaptive PKA signalling to maintain cardiac function. The use of the 'ISO on/off' model will further enable the separation of the underlying adaptive from maladaptive components of β-adrenergic signalling and may help to better define and test therapeutic targets downstream of β-adrenergic receptors., Competing Interests: Johannes Backs and Matthias Dewenter collaborate with the Lead Discovery Center (LDC) Dortmund to develop CaMKII (Calmodulin-dependent Kinase II)-HDAC4 (histone deacetylase 4) inhibitory compounds. Johannes Backs is scientific cofounder of Artemes Bio, holds a patent on “ABHD5 and partial HDAC4 fragments and variants as a therapeutic approach for the treatment of cardiovascular diseases“, and received personal fees from Bayer outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Diagnostics are essential for controlling the pandemic. Identifying a reliable and fast diagnostic device is needed for effective testing. We assessed performance and ease-of-use of the Abbott PanBio antigen-detecting rapid diagnostic test (Ag-RDT)., Methods: This prospective, multi-centre diagnostic accuracy study enrolled at two sites in Germany. Following routine testing with reverse-transcriptase polymerase chain reaction (RT-PCR), a second study-exclusive swab was performed for Ag-RDT testing. Routine swabs were nasopharyngeal (NP) or combined NP/oropharyngeal (OP) whereas the study-exclusive swabs were NP. To evaluate performance, sensitivity and specificity were assessed overall and in predefined sub-analyses accordingly to cycle-threshold values, days after symptom onset, disease severity and study site. Additionally, an ease-of-use assessment (EoU) and System Usability Scale (SUS) were performed., Results: 1108 participants were enrolled between Sept 28 and Oct 30, 2020. Of these, 106 (9.6%) were PCR-positive. The Abbott PanBio detected 92/106 PCR-positive participants with a sensitivity of 86.8% (95% CI: 79.0% - 92.0%) and a specificity of 99.9% (95% CI: 99.4%-100%). The sub-analyses indicated that sensitivity was 95.8% in Ct-values <25 and within the first seven days from symptom onset. The test was characterized as easy to use (SUS: 86/100) and considered suitable for point-of-care settings., Conclusion: The Abbott PanBio Ag-RDT performs well for SARS-CoV-2 testing in this large manufacturer independent study, confirming its WHO recommendation for Emergency Use in settings with limited resources., Competing Interests: The authors have declared that no competing interests exist.

We investigate the feasibility of molecular-level sample classification of sepsis using microarray gene expression data merged by in silico meta-analysis. Publicly available data series were extracted from NCBI Gene Expression Omnibus and EMBL-EBI ArrayExpress to create a comprehensive meta-analysis microarray expression set (meta-expression set). Measurements had to be obtained via microarray-technique from whole blood samples of adult or pediatric patients with sepsis diagnosed based on international consensus definition immediately after admission to the intensive care unit. We aggregate trauma patients, systemic inflammatory response syndrome (SIRS) patients, and healthy controls in a non-septic entity. Differential expression (DE) analysis is compared with machine-learning-based solutions like decision tree (DT), random forest (RF), support vector machine (SVM), and deep-learning neural networks (DNNs). We evaluated classifier training and discrimination performance in 100 independent iterations. To test diagnostic resilience, we gradually degraded expression data in multiple levels. Clustering of expression values based on DE genes results in partial identification of sepsis samples. In contrast, RF, SVM, and DNN provide excellent diagnostic performance measured in terms of accuracy and area under the curve (>0.96 and >0.99, respectively). We prove DNNs as the most resilient methodology, virtually unaffected by targeted removal of DE genes. By surpassing most other published solutions, the presented approach substantially augments current diagnostic capability in intensive care medicine., Competing Interests: The authors have declared that no competing interests exist.

Background: The implantation of cardiac implantable electronic devices (CIED) has increased in the last decades with improvement in the quality of life of patients with cardiac rhythm disorders. The presence of bilateral subclavian, innominate or superior vena cava obstruction is a major limitation to device revision and/or upgrade., Methods and Material: This is retrospective study of patients who underwent laser-assisted lead extraction (LLE) (GlideLight laser sheath, Spectranetics Corporation, Colorado Springs, USA) with lead revision or upgrade using the laser sheath as a guide rail. Patients with known occlusion, severe stenosis or functional obstruction of the venous access vessels with indwelling leads were included in this study., Results: 106 patients underwent percutaneous LLE with lead revision and/or upgrade. Preoperative known complete occlusion or severe stenosis of access veins was present in 23 patients (21.5%). More patients with implantable cardioverter-defibrillator (ICD) underwent LLE (64.1%) than patients with CRT-Ds (24.5%) and pacemaker patients (11.3%). In total 172 leads were extracted: 79 (45.9%) single-coil defibrillator leads, 35 (20.3%) dual-coil defibrillator leads, 31 (18.0%) right atrial leads, 24 (13.9%) right ventricular leads and three (1.7%) malfunctional coronary sinus left ventricular pacing leads. The mean age of leads was 99.2±65.6 months. The implantation of new leads after crossing the venous stenosis/obstruction was successful in 98 (92.4%) cases. Postoperative complications were pocket hematoma in two cases and wound infection in one case. No peri-operative and no immediate postoperative death was recorded. One intraoperative superior vena cava tear was treated by immediate thoracotomy and surgical repair., Conclusion: In a single-center study on LLE in the presence of supra-cardiac occlusion of the central veins for CIED lead upgrade and revision we could demonstrate a low procedural complication rate with no procedural deaths. Most of the leads could be completely extracted to revise or upgrade the system. Our study showed a low complication rate, with acceptable mortality rates., Competing Interests: The authors have declared that no competing interests exist.

Objective: The objective of this study is to characterize and describe meaningful moments in the context of systemic psychotherapy, from the point of view of patients and their therapists, after the end of therapy. The therapy studied is a manualized, monitored systemic therapy for social anxiety disorder., Method: Semi-structured follow-up interviews were conducted separately with five patients and their therapists (N = 10). Methodological triangulation was used: Grounded theory was used to code the transcripts as described by Charmaz. Then the passages of the selected code "meaningful moment" were evaluated using thematic comparison, in line with Meuser & Nagel., Findings: Three categories involving meaningful moments were identified: (1) meeting other patients in group therapy session, (2) therapeutic resource orientation and (3) recognizing oneself in a diagnosis or pattern of behaviour. These categories emerged as contexts related to the occurrence of meaningful moments from a subjective perspective., Discussion: Meaningful moments seem to be consistently related to the therapist input and to specific interventions or settings, both from the perspective of the patients and the therapists. Two tandems each described a coincident moment. One central aspect of all 14 moments is that the patients and therapists described patients being able to acquire another outlook on themselves., Competing Interests: The authors have declared that no competing interests exist.

Background: Postoperative abdominal infections belong to the most common triggers of sepsis and septic shock in intensive care units worldwide. While monocytes play a central role in mediating the initial host response to infections, sepsis-induced immune dysregulation is characterized by a defective antigen presentation to T-cells via loss of Major Histocompatibility Complex Class II DR (HLA-DR) surface expression. Here, we hypothesized a sepsis-induced differential occupancy of the CCCTC-Binding Factor (CTCF), an architectural protein and superordinate regulator of transcription, inside the Major Histocompatibility Complex Class II (MHC-II) region in patients with postoperative sepsis, contributing to an altered monocytic transcriptional response during critical illness., Results: Compared to a matched surgical control cohort, postoperative sepsis was associated with selective and enduring increase in CTCF binding within the MHC-II. In detail, increased CTCF binding was detected at four sites adjacent to classical HLA class II genes coding for proteins expressed on monocyte surface. Gene expression analysis revealed a sepsis-associated decreased transcription of (i) the classical HLA genes HLA-DRA, HLA-DRB1, HLA-DPA1 and HLA-DPB1 and (ii) the gene of the MHC-II master regulator, CIITA (Class II Major Histocompatibility Complex Transactivator). Increased CTCF binding persisted in all sepsis patients, while transcriptional recovery CIITA was exclusively found in long-term survivors., Conclusion: Our experiments demonstrate differential and persisting alterations of CTCF occupancy within the MHC-II, accompanied by selective changes in the expression of spatially related HLA class II genes, indicating an important role of CTCF in modulating the transcriptional response of immunocompromised human monocytes during critical illness., Competing Interests: The authors have declared that no competing interests exist.

Background: Hospital readmissions place a major burden on patients and health care systems worldwide, but little is known about patterns and timing of readmissions in Germany., Methods: We used German health insurance claims (AOK, 2011-2016) of patients ≥ 65 years hospitalized for acute myocardial infarction (AMI), heart failure (HF), a composite of stroke, transient ischemic attack, or atrial fibrillation (S/AF), chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, or osteoporosis to identify hospital readmissions within 30 or 90 days. Readmissions were classified into all-cause, specific, and non-specific and their characteristics were analyzed., Results: Within 30 and 90 days, about 14-22% and 27-41% index admissions were readmitted for any reason, respectively. HF and S/AF contributed most index cases, and HF and COPD accounted for most all-cause readmissions. Distributions and ratios of specific to non-specific readmissions were disease-specific with highest specific readmissions rates among COPD and AMI., Conclusion: German claims are well-suited to investigate readmission causes if longer periods than 30 days are evaluated. Conditions closely related with the primary disease are the most frequent readmission causes, but multiple comorbidities among readmitted cases suggest that a multidisciplinary care approach should be implemented vigorously addressing comorbidities already during the index hospitalization., Competing Interests: The authors have declared that no competing interests exist.

Background: Keeping up motivation to learn when socially isolated during a pandemic can be challenging. In medical schools, the COVID-19 pandemic required a complete switch to e-learning without any direct patient contact despite early reports showing that medical students preferred face-to-face teaching in clinical setting. We designed close to real-life patient e-learning modules to transmit competency-based learning contents to medical students and evaluated their responses about their experience., Methods: Weekly e-learning cases covering a 10-week leading symptom-based curriculum were designed by a team of medical students and physicians. The internal medicine curriculum (HeiCuMed) at the Heidelberg University Medical School is a mandatory part of clinical medical education in the 6th or 7th semester. Case-design was based on routine patient encounters and covered different clinical settings: preclinical emergency medicine, in-patient and out-patient care and follow-up. Individual cases were evaluated online immediately after finishing the respective case. The whole module was assessed at the end of the semester. Free-text answers were analyzed with MaxQDa following Mayring`s principles of qualitative content analyses., Results: N = 198 students (57.6% female, 42.4% male) participated and 1252 individual case evaluations (between 49.5% and 82.5% per case) and 51 end-of-term evaluations (25.8% of students) were collected. Students highly appreciated the offer to apply their clinical knowledge in presented patient cases. Aspects of clinical context, interactivity, game-like interface and embedded learning opportunities of the cases motivated students to engage with the asynchronously presented learning materials and work through the cases., Conclusions: Solving and interpreting e-learning cases close to real-life settings promoted students' motivation during the COVID-19 pandemic and may partially have compensated for missing bedside teaching opportunities., Competing Interests: Regarding competing interests by performing this work for my Master of Medical Education degree I am happy to confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials. On behalf of all authors I can declare that no other competing interests are present.

Study Design: Chart reviews were combined with neurological and functional outcome data obtained from the prospective European Multicenter Study on Spinal Cord Injury (EMSCI, www.emsci.org)., Objectives: To determine if strict physical isolation of multidrug-resistant organisms (MDRO)-positive patients negatively affects neurological recovery and functional outcome in the first year after acute spinal cord injury (SCI)., Setting: SCI Center Heidelberg University Hospital., Methods: Individuals with acute (< 6 weeks) traumatic or ischemic SCI were included. During primary comprehensive care, isolated MDRO-positive patients (n = 13) were compared with a MDRO-negative control group (n = 13) matched for functional (Spinal Cord Independence Measure-SCIM) and neurological impairment (motor scores based on the International Standards for Neurological Classification of Spinal Cord Injury-ISNCSCI) at an early stage up to 40 days after SCI. SCIM scores and motor scores were obtained at 12 weeks (intermediate stage) and 24 or 48 weeks (late stage) after SCI., Results: Isolated MDRO-positive (median duration of hospitalization: 175 days, 39% of inpatient stay under isolation measures) and non-isolated MDRO-negative (median duration of hospitalization: 161 days) patients showed functional and neurological improvements, which were not statistically different between groups at the intermediate and late stage., Conclusion: Prolonged isolation due to MDRO colonization for over a third of the inpatient comprehensive care period does not appear to impair neurological recovery and functional outcome within the first year after SCI., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Loss of body weight is often seen in pancreatic cancer and also predicts poor prognosis. Thus, maintaining muscle mass is an essential treatment goal. The primary aim was to investigate whether progressive resistance training impacts muscle and adipose tissue compartments. Furthermore, the effect of body composition on overall survival (OS) was investigated., Methods: In the randomized SUPPORT-study, 65 patients were assigned to 6-month resistance training (2x/week) or a usual care control group. As secondary endpoint, muscle strength of the upper and lower extremities was assessed before and after the intervention period. Routine CT scans were assessed on lumbar L3/4 level for quantification of total-fat-area, visceral-fat-area, subcutaneous-fat-area, intramuscular-fat-area, visceral-to-subcutaneous fat ratio (VFR), muscle-area (MA), muscle-density and skeletal-muscle-index (SMI). OS data were retrieved., Results: Of 65 patients, 53 had suitable CT scans at baseline and 28 completed the intervention period with suitable CT scans. There were no significant effects observed of resistance training on body composition (p>0.05; effect sizes ω2p <0.02). Significant moderate to high correlations were found between MA and muscle strength parameters (r = 0.57-0.85; p<0.001). High VFR at baseline was a predictor of poor OS (VFR≥1.3 vs. <1.3; median OS 14.6 vs. 45.3 months; p = 0.012). Loss of muscle mass was also a predictor of poor OS (loss vs. gain of SMI; median OS 24.6 vs. 50.8 months; p = 0.049)., Conclusion: There is anabolic potential in patients with resectable pancreatic cancer. A progressive resistance training may help patients to maintain their muscle mass and avoid muscle depletion. CT-quantified muscle mass at the level of L3/4 showed a good correlation to muscle strength. Therefore, maintaining muscle mass and muscle strength through structured resistance training could help patients to maintain their physical functioning. A high VFR at baseline and a high loss of muscle mass are predictors of poor OS. Registered on ClinicalTrials.gov (NCT01977066)., Competing Interests: The authors have declared that no competing interests exist.

Objective: To report the clinical and MRI-based volumetric mid-term outcome after image guided percutaneous sclerotherapy (PS) of venous malformations (VM) of the head and neck., Methods: A retrospective analysis of a prospectively maintained database was performed, including patients with VM of the head and neck who were treated with PS. Only patients with available pre- and post-interventional MRI were included into this study. Clinical outcome, which was subjectively assessed by the patients, their parents (for paediatric patients) and/or the physicians, was categorized as worse, unchanged, minor or major improvement. Radiological outcome, determined by MRI-based volumetric measurements, was categorized as worse (>10% increase), unchanged (≤10% increase to <10% decrease), minor (≥10% to <25% decrease), intermediate (≥25% to <50% decrease) or major improvement (≥50% decrease)., Results: Twenty-seven patients were treated in 51 treatment sessions. After a mean follow-up of 31 months, clinical outcome was worse for 7.4%, unchanged for 3.7% of the patients, while there was minor and major improvement for 7.4% and 81.5%, respectively. In the volumetric imaging analysis 7.4% of the VMs were worse and 14.8% were unchanged. Minor improvement was observed in 22.2%, intermediate improvement in 44.4% and major improvement in 11.1%. The rate of permanent complications was 3.7%., Conclusion: PS can be an effective therapy to treat the symptoms of patients with VMs of the head and neck and to downsize the VMs. MRI-based volumetry can be used to objectively follow the change in size of the VMs after PS. Relief of symptoms frequently does not require substantial volume reduction., Competing Interests: DFV: has received travel support outside this work from MicroVention, Stryker and Johnson & Johnson; MB: reports board membership: DSMB Vascular Dynamics; consultancy: Roche, Guerbet, Codman; grants/grants pending: DFG, Hopp Foundation, Novartis, Siemens, Guerbet, Stryker, Covidien; payment for lectures (including service on speakers bureaus): Novartis, Roche, Guerbet, Teva, Bayer, Codman; MAM: has received consulting honoraria, speaker honoraria, and travel support outside this work from Codman, Covidien/Medtronic, MicroVention, Phenox, and Stryker. These competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have nothing to disclosure.

Although malaria mortality among children under five years of age is high, the characteristics of their infection patterns are not well described. The aim of this study was to examine the longitudinal sequence pattern of Plasmodium falciparum infections in the first year of life within a birth cohort in Kintampo, Ghana (N = 1855). Infants were monitored at home with monthly sampling and also at the clinic for any febrile illness between 2008 and 2011. Light microscopy was performed on monthly scheduled visits and febrile ill visits over twelve months of follow-ups (n = 19231). Microscopy-positive visits accompanied with or without symptoms were rare during the first five months of life but were common from six to twelve months of age. Among 1264 infants with microscopy data over a minimum of eight monthly visits and also throughout in sick visits, some were microscopy negative (36%), and others positive: only-symptomatic (35%), alternating (22%) and only-asymptomatic (7%). The median age of microscopic infection was seven months for the alternating group and eight months for both the only-symptomatic and only-asymptomatic groups. The alternating group had the highest cumulative incidence of microscopic infections, the lowest age at first infection and 87 different infection patterns. Parasite densities detected by microscopy were significantly higher for symptomatic versus asymptomatic infection. We conclude that infants in malaria endemic areas experience diverse infection profiles throughout their first year of life. Further investigations should include submicroscopic reservoir and may shed more light on the factors that determine susceptibility to malaria during infancy., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: The incidence of hepatitis E virus (HEV)-infections in industrialized nations has been increasing over the past years. Patients suffering from inflammatory bowel diseases (IBD) may be more prone to transmission. Data on HEV seroprevalence in IBD patients is scarce and has not been reported in German IBD patients. The German Health Examination Survey for Adults 2008-2011, which included 4.422 samples, found a HEV seroprevalence of 16.8%, increasing with age. The aim of the present study was to determine the seroprevalence of anti-HEV IgG in a German cohort of IBD patients, and to explore which parameters have an impact on HEV seroprevalence., Material and Methods: This is an uncontrolled, cross-sectional, retrospective monocentric study. Among the patients visiting the IBD outpatient clinic between 25 January, 2019 and 24 September, 2019, 328 patients with Crohn's disease (CD) and 150 patients with ulcerative colitis (UC) were included in the study. IgG antibodies against HEV were determined by enzyme-linked immunosorbent assay. Positive antibody titers were verified using immunoblot analysis. Medical records were reviewed for demographic and clinical parameters to identify potential risk factors for HEV infection., Results: The prevalence of anti-HEV IgG antibodies was 17.4% in CD patients and 24.7% in UC patients. No patient with positive HEV PCR was detected. Greater age of CD und UC patients and longer duration of anti-interleukin 12/23 treatment in CD patients were associated with higher anti-HEV IgG antibody rates., Conclusions: In summary, we conclude that patients with UC have a higher anti-HEV IgG antibody prevalence than the general population in Germany, and that immunosuppressive therapy may carry no higher risk for HEV infection., Competing Interests: Annika Gauss received travel fees from Abbvie and Janssen, speaker’s fees from Janssen, MSD, Tillotts, and Takeda, and consultation fees from Janssen and AMGEN; Peter Hoffmann received travel fees from Abbvie and Janssen and speaker’s fees from Janssen; which might lead to a conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have no conflicts of interest to declare.

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor., Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry)., Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8)., Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk., Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci., Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Leidos Biomedical Research Inc. and Information Management Services, Inc. provided salaries for authors J.M., E.K., C.L.D., L.B., K.J., M.M., K.W., and W.Z. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Introduction: A unilateral transfemoral amputation (TFA) has a major impact on function. A leg-length discrepancy is the primary structural change, accompanied by the loss of lower-limb muscle volume and function. Prostheses can help individuals with a TFA to regain function, but such individuals still do not reach the functional level of unimpaired peers and exhibit gait deviations. This study gives insight into the causality between residual limb strength and gait deviations in individuals with a TFA., Methods: A convenient sample of 13 male individuals with a TFA (38.0 ± 12.6y; 179.7cm ± 6.5cm; 82.9kg ± 12.4kg) was recruited for this study. One participant with TFA was excluded, as he differed from the rest of the cohort, in residual limb length and the use of walking aids. A cohort of 18 unimpaired subjects served as a reference group (REF; nine females; 44y ± 13y; 174cm ± 9cm; 71kg ± 12kg). All participants underwent a conventional clinical gait analysis using a marker based 3D motion capture system and force platforms. Kinematics and kinetics were determined utilizing standard modelling methods. All subjects underwent a strength test, using a custom-made device to determine isometric moments of the hip joint in abduction, adduction, extension, and flexion. Peak values for maximum isometric moments for each movement direction and selected kinematic and kinetic values were derived from the results. Differences between subjects with TFA and unimpaired were compared using a Mann-Whitney U Test and associations between groups by Spearman's rank correlation., Results: The participants with a TFA showed a significantly lower maximum isometric moment for hip abduction (0.85 vs. 1.41 Nm/kg p < .001), adduction (0.87 vs. 1.37 Nm/kg p = .001) and flexion (0.93 vs. 1.63 Nm/kg p = .010) compared to the reference group. Typically reported gait deviations in people with a TFA were identified, i.e. significant lower cadence and increased step width. We further identified altered coronal plane hip and trunk kinematics, with significantly higher ranges of motion during involved side stance-phase. Gait kinetics of individuals with a TFA showed significantly lower peak values during stance for hip abduction, adduction and extension moments in comparison to the reference group. We identified a moderate negative correlation between maximum isometric moment for hip abduction and trunk obliquity range of motion (ρ = -0.45) for participants with a TFA, which was not significant (p = 0.14)., Conclusion: We showed that there are strength deficits in individuals with TFA and, that there are moderate correlations between gait deviations, i.e. lateral trunk lean during involved side stance and isometric hip abductor moment. The relation between maximum moments during gait and the corresponding maximum isometric moment may therefore be helpful to detect strength related compensation mechanisms. However, the moderate, non-significant correlation between lateral trunk lean and isometric hip abductor moment was the only one which corresponded directly to a gait deviation. Thus results must be interpreted with care. This study suggests that gait deviations in individuals with TFA are multifactorial and cannot be exclusively explained by their strength deficits. Future studies should explore the relationship between strength with kinematics and kinetics during gait in this population., Competing Interests: The authors have read the journal’s policy and have the following competing interests: Guenther Bionics GmbH is owned by MG, who was involved in study design and data collection prior to establishing the company. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Objectives: To systematically evaluate the influence of acquisition settings in conjunction with raw-data based iterative image reconstruction (IR) on lung densitometry based on multi-row detector computed tomography (CT) in an anthropomorphic chest phantom., Materials and Methods: Ten porcine heart-lung explants were mounted in an ex vivo chest phantom shell, six with highly and four with low attenuating chest wall. CT (Somatom Definition Flash, Siemens Healthineers) was performed at 120kVp and 80kVp, each combined with current-time products of 120, 60, 30, and 12mAs, and was reconstructed with filtered back projection (FBP) and IR (Safire, Siemens Healthineers). Mean lung density (LD), air density (AD) and noise were measured by semi-automated region-of interest (ROI) analysis, with 120kVp/120 mAs serving as the standard of reference., Results: Using IR, noise in lung parenchyma was reduced by ~ 31% at high attenuating chest wall and by ~ 22% at low attenuating chest wall compared to FBP, respectively (p<0.05). IR induced changes in the order of ±1 HU to mean absolute LD and AD compared to corresponding FBP reconstructions which were statistically significant (p<0.05)., Conclusions: Densitometry is influenced by acquisition parameters and reconstruction algorithms to a degree that may be clinically negligible. However, in longitudinal studies and clinical research identical protocols and potentially other measures for calibration may be required., Competing Interests: The authors have declared that no competing interest exist.

Background: With more than 18 million annual new cases, cancer belongs to the major challenges of modern healthcare. Surgical resection of solid tumours under general anaesthesia is the prime therapy. Different aspects of anaesthesia are under discussion to independently influence the long-term outcome of cancer patients. Most recently, the commonly used volatile anaesthetics like sevoflurane have entered the spotlight, as retrospective studies suggest a detrimental outcome in certain cancer aetiologies with sparse mechanistic understanding. Our objective was to investigate this concept in a murine melanoma model, herein comparing the consequence of inhalative and injection anesthesia on tumour composition and growth., Methods: We used a murine model of malignant melanoma in male, adult C57BL/6 mice (n = 92), induced by the subcutaneous injection of B16-F10 cells. We either exposed the melanoma cells to sevoflurane before implantation or subjected the animals to single or double anaesthesia with either volatile or injection drugs. After a maximum follow-up of 4 weeks, leucocytes within the tumour microenvironment (TME) were comprehensively analysed by flow cytometry with focus on tumor-associated macrophages (TAM)., Results: We found that exposure of melanoma cells to sevoflurane before implantation induced long-lasting transcriptome changes and aggravated tumour growth, without extensive changes of the TME. Contrastingly, both a single and double anaesthesia with sevoflurane led to a significant reduction of TAMs (injection vs. sevoflurane: 2,0 vs. 0.3% and 1.2 vs. 0.6%, respectively), whilst increasing PD-L1 expression on the remaining cells (mean fluorescent intensity injection vs. sevoflurane: 3,804 vs. 7,143 and 9,090 vs. 32,228, respectively). No changes in tumour growth were observed in these groups., Conclusion: In sharp contrast to the detrimental impact of sevoflurane on patients' outcome reported in retrospective clinical studies, we propose here that sevoflurane might actually exert a beneficial effect by decreasing TAMs within the TME, rendering the tumour again susceptible for cytotoxic T cells and immunotherapies. Further research is warranted to delineate, how these results translate into the clinic., Competing Interests: The authors have declared that no competing interests exist.

Along with increasing amounts of big data sources and increasing computer performance, real-world evidence from such sources likewise gains in importance. While this mostly applies to population averaged results from analyses based on the all available data, it is also possible to conduct so-called personalized analyses based on a data subset whose observations resemble a particular patient for whom a decision is to be made. Claims data from statutory health insurance companies could provide necessary information for such personalized analyses. To derive treatment recommendations from them for a particular patient in everyday care, an automated, reproducible and efficiently programmed workflow would be required. We introduce the R-package SimBaCo (Similarity-Based Cohort generation) offering a simple, but modular, and intuitive framework for this task. With the six built-in R-functions, this framework allows the user to create similarity cohorts tailored to the characteristics of particular patients. An exemplary workflow illustrates the distinct steps beginning with an initial cohort selection according to inclusion and exclusion criteria. A plotting function facilitates investigating a particular patient's characteristics relative to their distribution in a reference cohort, for example the initial cohort or the precision cohort after the data has been trimmed in accordance with chosen variables for similarity finding. Such precision cohorts allow any form of personalized analysis, for example personalized analyses of comparative effectiveness or customized prediction models developed from precision cohorts. In our exemplary workflow, we provide such a treatment comparison whereupon a treatment decision for a particular patient could be made. This is only one field of application where personalized results can directly support the process of clinical reasoning by leveraging information from individual patient data. With this modular package at hand, personalized studies can efficiently weight benefits and risks of treatment options of particular patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Communication is a core competence in medical care. Failure of physicians to properly communicate inherent risks of medical interventions has been linked with inadequate training at school. This study analyses a medical curriculum for assessing the content and quality of teaching risk communication to students., Methods: A checklist based on the national guidelines of core competencies on risk communication required of physicians was developed. Participant observers surveyed all teaching sessions at a medical school during a semester to record the frequency, characteristics and clinical context used by lectures during classes. Data were analyzed using statistical and descriptive methods to determine the prevalence and quality of teaching content., Results: 231 teaching sessions were surveyed. The inter-rater reliability was 81%. Lecturers mentioned topics of risk communication in 61.5% of teaching sessions (83.7% in surgery, 43.3% in internal medicine) but core biostatistics concepts were not discussed in more than 80% of these sessions. Important topics such as patient safety and preventable diseases were underrepresented. Risk communication was mainly taught in large-group, theoretical sessions and rarely with supplementary teaching material (7.4%). Students asked questions in 15.2% of courses, more often in surgery classes than in internal medicine., Conclusion: Statistical and clinical topics relevant for teaching risk communication to medical students are not only underrepresented but also minimally explained by lecturers. Supplementary material on risk communication is rarely provided to students during classes. High-resource demanding, small-group teaching formats are not necessarily interactive as students ask few questions., Competing Interests: The authors have declared that no competing interests exist.