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Carbonic anhydrase IX (CAIX) is a membrane spanning protein involved in the enzymatic regulation of tumor acid-base balance. CAIX has been shown to be elevated in a number of hypoxic tumor types. The purpose of this study was to determine the efficiency of intact and IgG fragments of cG250 to target CAIX in vivo in a hypoxic tumor model.Conventional biodistribution studies were performed with (111)In-DO3A-cG250, (111)In-DO3A-F(ab')(2)-cG250 and (111)In-DO3A-Fab-cG250. Additional ex vivo analysis of the tumor was performed with markers for tumor hypoxia, blood perfusion and endogenous CAIX expression. All four data sets were digitally correlated to determine the optimal agent for determining hypoxia in a HT29 colon cancer xenograft. The HT29 human colorectal tumor xenografts show strong CAIX expression in hypoxic areas of poor blood perfusion. The intact IgG had an initial high focal uptake at the periphery of these hypoxic regions and penetration into the areas of highest CAIX expression over the 7-day study period. The lower molecular weight antibody fragments had a faster uptake into areas of high CAIX expression, but had a much lower absolute uptake at the optimal imaging times.For the clinical detection of hypoxia induced CAIX using cG250 antibody based agents, imaging with the intact IgG at 7 days post injection would allow for the most sensitive and accurate detection of CAIX.

BackgroundThe digital transformation in health care requires training nursing and health professionals in the digitally competent use of digital assistive technologies (DAT). The continuing education training “Beratende für digitale Gesundheitsversorgung” (“Consultant for Digital Healthcare”) was developed to fill this gap. The effectiveness of the training program will be assessed in this study. ObjectiveThe primary objective is to record and measure the participants’ learning success. We will assess whether the previously defined teaching intentions, learning objectives, competencies, and participants’ expectations have been achieved and whether a transfer of learning occurred. The secondary objective is participant satisfaction and feasibility of the training. The tertiary objective is the successful transfer of DAT by participants in their institutions. MethodsApproximately 65 nursing and health care professionals will participate in the pilot phase of the further training and evaluation process, which is planned in a mixed methods design in a nonsequential manner. The different methods will be combined in the interpretation of the results to achieve a synaptic view of the training program. We plan to conduct pre-post surveys in the form of participant self-assessments about dealing with DAT and content-related knowledge levels. Exploratory individual interviews will also be conducted to build theory, to examine whether and to what extent competence (cognition) has increased, and whether dealing (affect) with DAT has changed. Furthermore, an interim evaluation within the framework of the Teaching Analysis Poll (TAP) will occur. The knowledge thereby gained will be used to revise and adapt the modules for future courses. To assess the transfer success, the participants create a practical project, which is carried out within the training framework, observed by the lecturers, and subsequently evaluated and adapted. ResultsWe expect that the learning objectives for the continuing education training will be met. The attendees are expected to increase their level of digital competence in different skills areas: (1) theoretical knowledge, (2) hands-on skills for planning the application and practical use of DAT, (3) reflective skills and applying ethical and legal considerations in their use, (4) applying all that in a structured process of technology implementation within their practical sphere of work. ConclusionsThe aim of this study and appropriate further training program are to educate nursing and health care professionals in the use of DAT, thereby empowering them for a structured change process toward digitally aided care. This focus gives rise to the following research questions: First, how should further training programs be developed, and which focus is appropriate for addressee-appropriate learning goals, course structure, and general curriculum? Second, how should a training program with this specific content and area be evaluated? Third, what are the conditions to offer a continued program? International Registered Report Identifier (IRRID)PRR1-10.2196/57860

Background A consensus definition for active sacroiliitis by MRI, mentioned in the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), was published in 2009 and included a qualitative and quantitative MRI cut-off component. In 2021, updates to the quantitative component were preliminarily proposed. This post hoc analysis of part A of the phase 3 open-label C-OPTIMISE study (NCT02505542) explores the differences by applying the 2009 and preliminary 2021 inflammatory cut-offs on clinical outcomes of axSpA patients treated with certolizumab pegol.Methods Baseline MRI scans were used to classify 657 patients as MRI+ or MRI– according to the quantitative components of the 2009 and preliminary 2021 MRI cut-offs for inflammatory lesions. Clinical outcomes, including ASAS ≥40% improvement (ASAS40), Ankylosing Spondylitis Disease Activity Score and Bath Ankylosing Spondylitis Disease Activity Index, were reported to week 48.Results Across all analysed outcomes, 2009 MRI+ and preliminary 2021 MRI+ subgroups showed similar results. Notably, clinical outcomes for the discordant group (2009 MRI+but preliminary 2021 MRI– group; 53/657 [8.1%]) were close to those seen in MRI– patients according to either 2009 or preliminary 2021 inflammatory cut-offs, and notably different from the totality of MRI+ subgroups.Conclusion This analysis suggests that the preliminary 2021 cut-offs for MRI inflammatory lesions may slightly increase the specificity of the quantitative part of the 2009 MRI inflammatory lesion definition. The effects of the updated MRI cut-offs need to be assessed on the basis of efficacy outcomes and with the inclusion of aspects of structural changes.Trial registration number NCT02505542.

Introduction This post hoc analysis evaluated the relationship between objective measures of inflammation and clinical outcomes following 12 weeks of certolizumab pegol (CZP) treatment in patients with active axial spondyloarthritis (axSpA).Methods We report the proportion of patients achieving ≥50% and ≥75% improvements in clinical composite outcome measures of disease activity (Axial Spondyloarthritis Disease Activity Score [ASDAS], Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) and objective measures of inflammation (C reactive protein [CRP], Ankylosing Spondylitis spine MRI score [ASspiMRI-a] Berlin score and Spondyloarthritis Research Consortium of Canada [SPARCC] MRI Sacroiliac Joints [SIJ] score) following 12 weeks of CZP treatment. Data from two independent readers over four MRI reading campaigns were pooled using a mixed model with repeated measures for each variable.Results 136 patients (radiographic axSpA [r-axSpA]: 76; non-radiographic axSpA [nr-axSpA]: 60) were included. Following CZP treatment, CRP, ASspiMRI-a Berlin score and SPARCC SIJ score were reduced by ≥50% in most patients (CRP: 136/136 [100.0%]; Berlin: 73/136 [53.7%]; SPARCC SIJ: 71/136 [52.2%]), and often by ≥75%. Less than half of patients with r-axSpA and nr-axSpA showed ≥50% reduction in clinical responses (BASDAI: 64/136 [47.1%]; ASDAS: 66/136 [48.5%]). These results were also observed at the individual patient level; ≥50% improvements in MRI/CRP inflammatory measures did not translate into similar improvements in clinical responses for most patients.Conclusion There is a potential disconnect between objective measures of inflammation and clinical outcome responses in patients with axSpA. The use of only clinical response measures as trial endpoints may underestimate anti-inflammatory treatment effects.Trial registration number NCT01087762.

AIM OF THE STUDY: The purpose of the present study was to evaluate demographic characteristics of inmates in the Canton of Zurich (exposure), and investigate the changes in diseases and drug use between 2015 and 2020 (outcome). METHODS: The study prospectively evaluated 51,989 inmates admitted to the Police Prison Zurich in Switzerland between 1 April 2015 and 31 August 2020 and who were systematically medically assessed. A total of 19,027 (37%) inmates had one or more health conditions, which the authors recorded according to the International Classification of Diseases-10 (ICD-10), in addition to demographic data (country of origin, sex, age, year of imprisonment), as well as details of any drugs used (type and dosage). RESULTS: The 19,027 inmates with medical conditions had a mean age of 35.4±12.5 years (range 10–89) and comprised 16,489 males (87%). The inmates originated from 170 countries, including 4606 from Switzerland (24.2%), 4227 from Eastern Europe (22%) and 3432 from the Middle East & North Africa (18%). A total of 1631 inmates (9%) were enrolled in the medication-assisted treatment (MAT) programme, and 672 patients (4%) received a psychiatric evaluation. The proportions of foreign prisoners did not increase during the study period. There was a significant increase in the use of antipsychotics from year 1 to 5 (y = 0.866x; R2 = 0.902; p = 0.01) and anticonvulsants from year 1 to 4 (y = 1.27x; R2 = 0.823; p = 0.01), and a significant decrease in the use of analgesics from year 2 to 5 (y = -4.42x; R2 = 0.947; p = 0.03) and antianxiety drugs from year 1 to 4 (y = -3.31x; R2 = 0.989; p = 0.005). Inmates from Switzerland were most likely to use antianxiety drugs, while inmates from the Middle East & North Africa were most likely to use antipsychotics (OR 2.09; CI 1.88–2.34) and anticonvulsants (OR 3.52; CI 2.90–4.29), whereas inmates from Latin and North America were most likely to use herbal medicine (OR 1.50; CI 1.05–2.10). CONCLUSIONS: The findings of this study could help anticipate needs of prisons as well as improve treatment of disease and assist with substance use or abuse, particularly in the context of migration.

Objectives Medical overuse exposes patients to unnecessary risks of harm. It is an open question whether and how patients perceive the concept of medical overuse, its causes and negative consequences.Design A qualitative study design, using elements of the Grounded Theory Approach by Strauss and Corbin.Setting Between May 2017 and January 2020, we recruited participants and conducted face-to-face interviews in the participants’ homes. Data collection took place in Bavaria, Germany.Participants We recruited 16 participants (female=8, male=8) with various characteristics for the study. We used different strategies such as flyers in supermarkets, pharmacies, participants spreading information about the study or local multipliers (snowball sampling).Results The participants mostly defined medical overuse as too much being done but understood the concept superficially. During the interviews, most participants could describe examples of medical overuse. They named a variety of direct and indirect drivers with economic factors suspected to be the main driver. As a consequence of medical overuse, participants named the physical and emotional harm (eg, side effects of medication). They found it difficult to formulate concrete solutions. In general, they saw themselves more in a passive role than being responsible for bringing about change and solutions themselves. Medical overuse is a ‘problem of the others’. The participants emphasised that health education is important in reducing medical overuse.Conclusions Medical overuse was little discussed among participants, although many participants reported experiences of too much medicine. Health education and strengthening the patients’ self-responsibility can play a vital role in reducing medical overuse.

A new study reveals how naturally occurring mutations affect the biophysical properties of nucleocapsid proteins in SARS-CoV-2.

Objective There is a paucity of data on long-term clinical responses in patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on their baseline objective signs of inflammation such as MRI or C-reactive protein (CRP) levels. This study reports clinical outcomes up to 3 years of the C-axSpAnd trial, including safety follow-up extension (SFE) from Weeks 52 to 156, stratified by patients’ baseline MRI and CRP status.Methods C-axSpAnd (NCT02552212) was a phase 3, multicentre study that evaluated certolizumab pegol (CZP) in patients with active nr-axSpA who had active sacroiliitis on MRI and/or elevated CRP. In this post hoc analysis, efficacy outcomes are reported to Week 156 of C-axSpAnd for patients stratified according to their MRI and CRP status at Week 0 (MRI+/CRP−, MRI−/CRP+ and MRI+/CRP+).Results Across all outcome measures, including major improvement in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) and Assessment of SpondyloArthritis international Society criteria ≥40% response (ASAS40), outcomes were generally sustained in SFE patients from Week 52 to Week 156. MRI+/CRP+ patients showed numerically higher or comparable responses relative to MRI−/CRP+ and MRI+/CRP− patients at Weeks 52 and 156; however, all three subgroups demonstrated substantial improvements from Week 0 (in CZP-randomised patients, ASDAS-MI at Week 156 [observed case]: MRI+/CRP+: 73.1%, MRI–/CRP+: 52.2%, MRI+/CRP–: 30.4%; ASAS40: MRI+/CRP+: 76.9%, MRI–/CRP+: 62.5%, MRI+/CRP–: 65.2%).Conclusions In patients with nr-axSpA and objective signs of inflammation, long-term clinical outcomes achieved after 1 year were generally sustained at 3 years across MRI+/CRP+, MRI−/CRP+ and MRI+/CRP− subgroups.

Abstract This study aimed to examine the influence of COVID-specific stressors on cross-sectional and longitudinal bereavement outcomes. According to the Dual Process Model of grief these stress-inducing factors can relate to the loss (loss-oriented stressors) or to manage everyday life (restoration-oriented stressors) and require coping in the grief process. A total of 491 participants (94.1% female; 43.92 years on average; 44.4% loss of a parent) were included at the first measurement time point (T0), of whom 99 individuals also participated in a follow-up assessment 6 months later (T1). Participants frequently reported loss-oriented (on average 7.30 out of 21 queried) and restoration-oriented stressors (on average 6.99 out of 19 queried). Cross-sectionally, higher acute grief intensity was associated with a higher number of loss-oriented stressors, poorer mental well-being, and sociodemographic variables. This effect disappeared longitudinally, with only acute grief intensity and poorer mental well-being at T0 predicting higher prolonged grief at T1. Common resilience factors did not buffer the effects of the pandemic on grief. Loss-oriented stressors seem to be especially relevant for understanding grief and might be a mediator of higher long-term grief. The findings suggest that COVID-specific strains need to be specifically taken into account in the support of bereaved individuals.

Abstract Recent developments in deep learning have shown success in accurately predicting the location of biological markers in Optical Coherence Tomography (OCT) volumes of patients with Age-Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). We propose a method that automatically locates biological markers to the Early Treatment Diabetic Retinopathy Study (ETDRS) rings, only requiring B-scan-level presence annotations. We trained a neural network using 22,723 OCT B-Scans of 460 eyes (433 patients) with AMD and DR, annotated with slice-level labels for Intraretinal Fluid (IRF) and Subretinal Fluid (SRF). The neural network outputs were mapped into the corresponding ETDRS rings. We incorporated the class annotations and domain knowledge into a loss function to constrain the output with biologically plausible solutions. The method was tested on a set of OCT volumes with 322 eyes (189 patients) with Diabetic Macular Edema, with slice-level SRF and IRF presence annotations for the ETDRS rings. Our method accurately predicted the presence of IRF and SRF in each ETDRS ring, outperforming previous baselines even in the most challenging scenarios. Our model was also successfully applied to en-face marker segmentation and showed consistency within C-scans, despite not incorporating volume information in the training process. We achieved a correlation coefficient of 0.946 for the prediction of the IRF area.

Abstract As the need for higher data rates for communication increases, the terahertz (THz) band has drawn considerable attention. This spectral region promises a much wider bandwidth and the transmission of large amounts of data at high speeds. However, there are still challenges that need to be addressed before the THz telecommunications technology hits the consumer market. One of the recurring concerns is that THz radiation is greatly absorbed by atmospheric water-vapor. Although many studies have presented the attenuation of THz signals under different atmospheric conditions, these results analyze specific temperature or humidity values, leaving the need for a more comprehensive analysis over a wider range of climate conditions. In this work, we present the first study of the attenuation of THz radiation over a broad range of temperatures and humidity values. It is worth noticing that all of our measurements have been undertaken at atmospheric pressure unlike many previous studies where the pressure was not kept constant for various temperatures. Furthermore, we extend our analysis beyond the impact of absolute humidity on the bit error rate in THz communications. We also discuss the refractivity of the atmosphere, examining its variations across different temperatures and humidity levels. THz propagation is studied using two different measurement systems, a long-path THz time-domain spectrometer as well as a quasi-optic setup with vector network analyze. We also compare the results with the ITU-R P.676-13 propagation model. We conclude that the attenuation at the absorption peaks increases linearly with water content and has no dependence on the temperature, while the refractive index, away from absorption lines, namely at 300 GHz shows a sub-linear increase with humidity.

Introduction Uncomplicated urinary tract infections (uUTIs) in women are common infections encountered in primary care. Evidence suggests that rapid point-of-care tests (POCTs) to detect bacteria and erythrocytes in urine at presentation may help primary care clinicians to identify women with uUTIs in whom antibiotics can be withheld without influencing clinical outcomes. This pilot study aims to provide preliminary evidence on whether a POCT informed management of uUTI in women can safely reduce antibiotic use.Methods and analysis This is an open-label two-arm parallel cluster-randomised controlled pilot trial. 20 general practices affiliated with the Bavarian Practice-Based Research Network (BayFoNet) in Germany were randomly assigned to deliver patient management based on POCTs or to provide usual care. POCTs consist of phase-contrast microscopy to detect bacteria and urinary dipsticks to detect erythrocytes in urine samples. In both arms, urine samples will be obtained at presentation for POCTs (intervention arm only) and microbiological analysis. Women will be followed-up for 28 days from enrolment using self-reported symptom diaries, telephone follow-up and a review of the electronic medical record. Primary outcomes are feasibility of patient enrolment and retention rates per site, which will be summarised by means and SDs, with corresponding confidence and prediction intervals. Secondary outcomes include antibiotic use for UTI at day 28, time to symptom resolution, symptom burden, number of recurrent and upper UTIs and re-consultations and diagnostic accuracy of POCTs versus urine culture as the reference standard. These outcomes will be explored at cluster-levels and individual-levels using descriptive statistics, two-sample hypothesis tests and mixed effects models or generalised estimation equations.Ethics and dissemination The University of Würzburg institutional review board approved MicUTI on 16 December 2022 (protocol n. 109/22-sc). Study findings will be disseminated through peer-reviewed publications, conferences, reports addressed to clinicians and the local citizen’s forums.Trial registration number ClinicalTrials.gov NCT05667207.

Abstract Background In the course of the SARS-CoV-2 pandemic, multiple vaccines were developed. Little was known about reactogenicity and safety in comparison to established vaccines, e.g. influenza, pneumococcus, or herpes zoster. Therefore, the present study aimed to compare self-reported side effects in persons vaccinated against SARS-CoV-2 with the incidence of side effects in persons receiving one of the established vaccines. Methods A longitudinal observational study was conducted over a total of 124 days using web-based surveys. Persons receiving either a vaccination against SARS-CoV-2 or one of the established vaccines (comparator group) were included. In the first questionnaire (short-term survey), 2 weeks after vaccination, mainly local and systemic complaints were evaluated. The long-term survey (42 days after vaccination) and follow-up survey (124 weeks after vaccination) focused on medical consultations for any reason. Multivariate analyses were conducted to determine the influence of the vaccine type (SARS-CoV-2 vs. comparator) and demographic factors. Results In total, data from 16,636 participants were included. Self-reported reactogenicity was lowest in the comparator group (53.2%) and highest in the ChAdOx1 group (85.3%). Local reactions were reported most frequently after mRNA-1273 (73.9%) and systemic reactions mainly after vector-based vaccines (79.8%). Almost all SARS-CoV-2 vaccines showed increased odds of reporting local or systemic reactions. Approximately equal proportions of participants reported medical consultations. None in the comparator group suspected a link to vaccination, while this was true for just over one in 10 in the mRNA-1273 group. The multivariate analysis showed that people with SARS-CoV-2 vaccination were not more likely to report medical consultations; patients who had received a regimen with at least one ChAdOx1 were even less likely to report medical consultations. Younger age, female gender and higher comorbidity were mostly associated with higher odds of medical consultations. Conclusion The rate of adverse reactions after established vaccinations was roughly comparable to previous studies. Two weeks after vaccination, participants in the SARS-CoV-2 vaccination group reported more local and systemic local reactions than participants in the comparator group. In the further course, however, there were no higher odds of medical consultations in either of the two groups. Thus, altogether, we assume comparable safety. Trial registration DRKS-ID DRKS00025881 and DRKS-ID DRKS00025373.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer characterized by therapy resistance and early metastasis, resulting in a low survival rate. Histone deacetylase (HDAC) inhibitors showed potential for the treatment of hematological malignancies. In PDAC, the overexpression of HDAC 2 is associated with the epithelial–mesenchymal transition (EMT), principally accompanied by the downregulation of the epithelial marker E-cadherin and increased metastatic capacity. The effector cytokine transforming growth factor-β (TGF β) is known to be a major inducer of the EMT in PDAC, leading to high metastatic and invasive potential. In addition, the overexpression of HDAC 6 in PDAC is associated with reduced apoptosis. Here, we have demonstrated that a novel HDAC 2/6 inhibitor not only significantly increased E-cadherin expression in PANC-1 cells (5.5-fold) and in 3D PDAC co-culture spheroids (2.5-fold) but was also able to reverse the TGF-β-induced downregulation of E-cadherin expression. Moreover, our study indicates that the HDAC inhibitor mediated re-differentiation resulting in a significant inhibition of tumor cell invasion by approximately 60% compared to control. In particular, we have shown that the HDAC inhibitor induces both apoptosis (2-fold) and cell cycle arrest. In conclusion, the HDAC 2/6 inhibitor acts by suppressing invasion via upregulating E-cadherin mediated by HDAC 2 blockade and by inducing cell cycle arrest leading to apoptosis via HDAC 6 inhibition. These results suggest that the HDAC 2/6 inhibitor might represent a novel therapeutic strategy for the treatment of PDAC tumorigenesis and metastasis.

Abstract Background Since the beginning of the COVID-19 vaccination campaigns, recommendations regarding the vaccination have been very dynamic. Although the safety and efficacy of different vaccines have been analysed, data were scarce for vaccine regimens combining different vaccines. We therefore aimed to evaluate and compare the perceived reactogenicity and need for medical consultation after the most frequently applied homologous and heterologous COVID-19 vaccination regimens. Methods In an observational cohort study, reactogenicity and safety were assessed within a maximum follow-up time of 124 days using web-based surveys. Reactogenicity was assessed for different vaccination regimens 2 weeks after a vaccination (short-term survey). The following surveys, long-term and follow-up surveys, focused on the utilisation of medical services, including those that were not suspected to be vaccine-related. Results Data of 17,269 participants were analysed. The least local reactions were seen after a ChAdOx1 − ChAdOx1 regimen (32.6%, 95% CI [28.2, 37.2]) and the most after the first dose with mRNA-1273 (73.9%, 95% CI [70.5, 77.2]). Systemic reactions were least frequent in participants with a BNT162b2 booster after a homologous primary immunisation with ChAdOx1 (42.9%, 95% CI [32.1, 54.1]) and most frequent after a ChAdOx1 − mRNA-1273 (85.5%, 95% CI [82.9, 87.8]) and mRNA-1273/mRNA-1273 regimen (85.1%, 95% CI [83.2, 87.0]). In the short-term survey, the most common consequences were medication intake and sick leave (after local reactions 0% to 9.9%; after systemic reactions 4.5% to 37.9%). In the long-term and follow-up surveys, between 8.2 and 30.9% of participants reported consulting a doctor and between 0% and 5.4% seeking hospital care. The regression analyses 124 days after the first and after the third dose showed that the odds for reporting medical consultation were comparable between the vaccination regimens. Conclusions Our analysis revealed differences in reactogenicity between the COVID-19 vaccines and vaccination regimens in Germany. The lowest reactogenicity as reported by participants was seen with BNT162b2, especially in homologous vaccination regimens. However, in all vaccination regimens reactogenicity rarely led to medical consultations. Small differences in seeking any medical consultation after 6 weeks diminished during the follow-up period. In the end, none of the vaccination regimens was associated with a higher risk for medical consultation. Trial registration DRKS DRKS00025881 ( https://drks.de/search/de/trial/DRKS00025373 ). Registered on 14 October 2021. DRKS DRKS00025373 ( https://drks.de/search/de/trial/DRKS00025881 ). Registered on 21 May 2021. Registered retrospectively.

Abstract Background Student burnout during medical education is a prevalent and critical problem. Burnout has reaching consequences, including negative health outcomes for students, financial loss for schools, and worsened patient care as students transition to practice. Global Health Outreach Experiences (GHOEs), known to enhance cultural awareness and clinical knowledge among medical students, are offered in most programs. Prior studies document that GHOEs benefit physicians suffering from burnout, with effects demonstrating improvement over 6 months. No study, to our knowledge, has assessed the influence GHOEs may have on medical student burnout with a comparable control group. This study examines whether participation in a GHOE, compared to a standard break from school, has a positive effect on burnout. Methods A case control study utilizing the Copenhagen Burnout Inventory was conducted on medical students. 41 students participated in a one-week, spring break GHOE and 252 were randomly selected as non-participating students in a control group. Assessments were gathered 1 week prior, 1 week after, and 10 weeks after spring break. Response across the surveys in chronological order included 22, 20, 19 GHOE and 70, 66, 50 control participants. Results A significant reduction in personal burnout (PB) (P = 0.0161), studies related burnout (SRB) (P = 0.0056), and colleagues related burnout (CRB) (P = 0.0357) was found among GHOE attendees compared to control participants at 10-weeks after spring break. When modeled with potential confounders, CRB and SRB reductions remained significant. Conclusion GHOEs may be a potential tool for institutions to combat burnout rates in their students. The benefits of GHOEs appear to enhance over time.

BackgroundMedical overuse is defined as health care services that exceed the individual needs of patients and when the potential harms of medical interventions exceed their benefits. It has impacts on patients as well as on health care resources. To address medical overuse, it is important to understand the knowledge and experiences of overuse on the side of patients.Research questionsWhat is the citizens' understanding of overuse? How do they assess its relevance, causes, consequences and potential solutions?MethodsA quantitative online survey was conducted. The participants were asked to state what they understand by medical overuse. Statements on causes, consequences and possible solutions were evaluated. Recruitment was carried out via a panel of a market research institute (Schlesinger Group).ResultsThe survey was completed by 406 participants. In terms of age and gender, the sample corresponded to the distribution in the German population. The majority had never heard of medical overuse (58%). About 60% assumed that medical overuse means "too much medicine including overtreatment and overtesting". Medical overuse was mainly suspected for services not covered by the public health insurance system (56%), surgical interventions (45%) and medication prescriptions (37%). Reasons for medical overuse were seen in uncoordinated care and financial incentives, but also in the expectations of patients. The main problem with medical overuse was seen in rising health care costs, while harmful physical and mental consequences for patients were mentioned less often. In order to reduce medical overuse, little importance was attributed to a primary care based system or higher financial contribution of patients. Instead, stricter cost control on the side of physicians and better coordination between care providers were suggested as solutions. Differences in socio-demographic characteristics hardly showed any differences in response behavior.ConclusionMore than half of the respondents had never heard of medical overuse. Overuse was mainly associated with financial causes and consequences. It was not seen that overuse can be harmful for patients directly. The limited awareness of the problem of overuse probably is a barrier to tackling it effectively. Communicating the topic to the public might therefore be an effective start to mitigate medical overuse.Take home messageMany citizens seem not to be familiar with the concept of medical overuse, especially not with the fact that it may directly cause harm to patients. Informing citizens about the harms of medical overuse might be helpful in mitigating it.

BackgroundAn increasing number of mHealth interventions aim to contribute to mental healthcare of which interventions that foster cognitive reappraisal may be particularly effective.ObjectivesTo evaluate the efficacy of mHealth interventions enhancing cognitive reappraisal to improve mental health in adult populations.MethodsThe literature search (four databases) yielded 30 eligible randomized controlled trials (comprising 3,904 participants). We performed a multi-level meta-analysis to examine differences between intervention and comparator conditions at post-intervention assessment. Moderator analyses were conducted for potential moderator variables (e.g., type of comparators).ResultsMost interventions were CBT-based with other training components in addition to cognitive reappraisal. We found preliminary evidence for a small to medium effect favouring mHealth interventions to enhance cognitive reappraisal over comparators, M(SMD) = 0.34, p = .002. When analysing single symptoms, there was evidence for a small to medium effect of mHealth interventions on anxiety and depressive symptoms, but not for psychological distress and well-being. All analyses showed substantial heterogeneity. Moderator analyses revealed evidence for more favourable effects in studies with passive comparators. There was an overall high risk of bias in most of the studies.ConclusionsWe found preliminary evidence for a small to medium effect of mHealth interventions including a cognitive reappraisal component to improve mental health. However, most of the interventions were complex (i.e., reappraisal was provided alongside other components), which prevents us from examining reappraisal-specific effects beyond general mental health promotion in mHealth. Dismantling studies examining the effects of single intervention components are warranted to corroborate these promising results.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=142149, identifier [CRD42019142149].

Spatially resolved metabolomics enables the investigation of tumoral metabolites in situ. Inter- and intratumor heterogeneity are key factors associated with patient outcomes. Adrenocortical carcinoma (ACC) is an exceedingly rare tumor associated with poor survival. Its clinical prognosis is highly variable, but the contributions of tumor metabolic heterogeneity have not been investigated thus far to our knowledge. An in-depth understanding of tumor heterogeneity requires molecular feature-based identification of tumor subpopulations associated with tumor aggressiveness. Here, using spatial metabolomics by high–mass resolution MALDI Fourier transform ion cyclotron resonance mass spectrometry imaging, we assessed metabolic heterogeneity by de novo discovery of metabolic subpopulations and Simpson’s diversity index. After identification of tumor subpopulations in 72 patients with ACC, we additionally performed a comparison with 25 tissue sections of normal adrenal cortex to identify their common and unique metabolic subpopulations. We observed variability of ACC tumor heterogeneity and correlation of high metabolic heterogeneity with worse clinical outcome. Moreover, we identified tumor subpopulations that served as independent prognostic factors and, furthermore, discovered 4 associated anticancer drug action pathways. Our research may facilitate comprehensive understanding of the biological implications of tumor subpopulations in ACC and showed that metabolic heterogeneity might impact chemotherapy.

Objectives Functioning of older adults needs to be adequately described before it can become the focus of care. The International Classification of Functioning, Disability and Health (ICF) provides a basis for describing functioning. As the ICF is too extensive for daily practice in primary care, there is a need for a reduced number of categories. The aim is to develop an ICF-subset for community-dwelling older adults aged 75 and above in primary care.Design The scientific basis for decision-making in our consensus study was laid by four preparatory studies, identifying potentially relevant ICF categories from four perspectives (research, patients’, experts’ and clinical perspective). The results of the preparatory phase were discussed by an international expert panel in a consensus study following the Nominal Group Technique (NGT).Setting An international 1-day online consensus conference.Participants International experts (n=7) participated in the consensus conference, meeting the following criteria: extensive expertise in the field of the ICF and/or caring for older adults, and being fluent in English.Results Each preparatory study yielded a different number of categories with some overlaps but also differences. The expert panel decided to: (1) restrict the subset to second-level categories and reduce the number of categories from the preparatory phase, (2) limit the subset to the component activities and participation and (3) weight the patients’ perspective as the most relevant one.Conclusions By using consensus techniques and the NGT, the process led to 51 second-level ICF categories to describe the functioning of community-dwelling older adults. The decisions made in the consensus conference emphasised the importance of considering the individual life situation from a more holistic perspective and addressing functioning as a focus of care. Next, the 51 categories will contribute to the development of an ICF-based questionnaire.

Abstract Large epidemiological studies such as the UK Biobank (UKBB) or German National Cohort (NAKO) provide unprecedented health-related data of the general population aiming to better understand determinants of health and disease. As part of these studies, Magnetic Resonance Imaging (MRI) is performed in a subset of participants allowing for phenotypical and functional characterization of different organ systems. Due to the large amount of imaging data, automated image analysis is required, which can be performed using deep learning methods, e. g. for automated organ segmentation. In this paper we describe a computational pipeline for automated segmentation of abdominal organs on MRI data from 20,000 participants of UKBB and NAKO and provide results of the quality control process. We found that approx. 90% of data sets showed no relevant segmentation errors while relevant errors occurred in a varying proportion of data sets depending on the organ of interest. Image-derived features based on automated organ segmentations showed relevant deviations of varying degree in the presence of segmentation errors. These results show that large-scale, deep learning-based abdominal organ segmentation on MRI data is feasible with overall high accuracy, but visual quality control remains an important step ensuring the validity of down-stream analyses in large epidemiological imaging studies.

Introduction General practitioners often criticise clinical trials for their poor applicability in primary care, which may at least partially explain why their engagement in primary care research remains limited. In order to enhance primary care research, the German government has funded six regional practice based research networks (PBRNs). Within the Bavarian PBRN (BayFoNet), two cluster-randomised pilot trials will be conducted. This paper presents the protocol of the process evaluation accompanying both trials, which aims to explore relevance, feasibility, acceptability and credibility of clinical research in primary care from the perspectives of BayFoNet researchers, general practitioners, and patients.Methods and analysis The BayFoNet will be established by recruiting general practices (GPs) as prospective research collaborators in two cluster randomised pilot trials. Research teams will provide training in good clinical practice, and support practices in patient recruitment, data collection and documentation. Our process evaluation explores barriers and facilitators in the set up of the BayFoNet PBRN and both cluster randomised pilot trials, under the application of the consolidated framework for implementation research and the theoretical domains framework. In a mixed-methods concept, we will use qualitative and quantitative approaches to evaluate both pilot cluster-randomised trials as well as the BayFoNet itself: focus groups with researchers, semi-structured interviews with general practitioners and questionnaires for patients participating in the pilot cluster-randomised trials at three different time points.Ethics and dissemination Research ethical approval for this study was granted by the Ethics Committee of the Medical Department, Ludwig-Maximilians-University Munich (AZ 21-1135). Results will be published in international peer-reviewed journals and summaries will be provided to the funders of the study as well as other PBRNs, GP teams and patients.Trial registration numbers DRKS00028805, NCT05667207.

Introduction Pain is the main symptom of osteoarthritis (OA) with approximately 50% of patients reporting moderate-to-severe pain. Total knee replacement (TKR) is the ultimate treatment option to alleviate pain in knee OA. Nevertheless, TKR does not provide complete relief for all as approximately 20% of patients experience chronic postoperative pain. Painful peripheral stimuli may alter the central nociceptive pathways leading to central sensitisation that can influence treatment response in patients with OA. Currently, there is no objective protocol for detecting whether a patient will respond to a given treatment. Therefore, there is a need for a better mechanistic understanding of individual factors affecting pain relief, consequently informing personalised treatment guidelines. The purpose of this research is to examine the feasibility of conducting a full-scale mechanistic clinical trial in painful knee OA investigating the analgesic response to intra-articular bupivacaine between those with or without evidence of central sensitisation.Methods and analysis The Understanding Pain mechanisms in KNEE osteoarthritis (UP-KNEE) study is a feasibility, double-blinded, placebo-controlled randomised parallel study in participants with radiographically defined knee OA and with self-reported chronic knee pain. The study involves the following assessments: (1) a suite of psychometric questionnaires; (2) quantitative sensory testing; (3) magnetic resonance imaging (MRI) scan of the knee and brain; (4) a 6-minute walk test; and (5) an intra-articular injection of bupivacaine or placebo (sodium chloride 0.9%) into the index knee. Assessments will be repeated post intra-articular injection apart from the MRI scan of the knee. Our aim is to provide proof of concept and descriptive statistics to power a future mechanistic trial.Ethics and dissemination Ethical approval was obtained from the Health Research Authority (HRA) (REC: 20/EM/0287). Results will be disseminated via peer-reviewed journals and scientific conferences. The results will also be shared with lay audiences through relevant channels, such as Pain Centre Versus Arthritis website and patient advocacy groups.Trial registration number NCT05561010.

Introduction People in need of care or support are severely affected by the COVID-19 pandemic. We lack valid data of long-term assessments. We present a register study to detect the physical and psychosocial impact of the COVID-19 pandemic on people in need of care or support in Bavaria, Germany. To describe the persons’ life conditions comprehensively, we assess the perspectives and needs of the respective care teams too. Results will serve as evidence-based source to manage the pandemic and long-term prevention strategies.Methods and analysis The ‘Bavarian ambulatory COVID-19 Monitor’ is a multicentre registry including a purposive sample of up to 1000 patient–participants across three study sites in Bavaria. The study group consists of 600 people in need of care with a positive SARS-CoV-2 PCR test. Control group 1 comprises 200 people in need of care with a negative SARS-CoV-2 PCR test, while control group 2 comprises 200 people with a positive SARS-CoV-2 PCR test but are not in need of care. We assess the clinical course of infection, psychosocial aspects and care needs using validated measures. Follow-up is every 6 months for up to 3 years. Additionally, we assess up to 400 people linked to these patient–participants (caregivers, general practitioners (GPs)) for their health and needs. Main analyses are stratified by level of care I–V (I=minor/V=most severe impairment of independence), inpatient/outpatient care setting, sex and age. We use descriptive and inferential statistics to analyse cross-sectional data and changes over time. In qualitative interviews with 60 stakeholders (people in need of care, caregivers, GPs, politicians), we explore interface problems of different functional logics, of everyday and professional perspectives.Ethics and dissemination The Institutional Review Board of the University Hospital LMU Munich (#20-860) and the study sites (Universities of Wurzburg and Erlangen) approved the protocol. We disseminate the results by peer-reviewed publications, international conferences, governmental reports, etc.

Objectives This study aims to evaluate whether the use of thyroid ultrasound (US) early in the work-up of suspected thyroid disorders triggers cascade effects of medical procedures and to analyse effects on morbidity, healthcare usage and costs.Study design Retrospective analysis of claims data from ambulatory care (2012–2017).Setting Primary care in Bavaria, Germany, 13 million inhabitants.Participants Patients having received a thyroid stimulating hormone (TSH) test were allocated to (1) observation group: TSH test followed by an early US within 28 days or (2) control group: TSH test, but no early US. Propensity score matching was used adjusting for socio-demographic characteristics, morbidity and symptom diagnosis (N=41 065 per group after matching).Primary and secondary outcome measures Using cluster analysis, groups were identified regarding frequency of follow-up TSH tests and/or US and compared.Results Four subgroups were identified: cluster 1: 22.8% of patients, mean (M)=1.6 TSH tests; cluster 2: 16.6% of patients, M=4.7 TSH tests; cluster 3: 54.4% of patients, M=3.3 TSH tests, 1.8 US; cluster 4: 6.2% of patients, M=10.9 TSH tests, 3.9 US. Overall, reasons that explain the tests could rarely be found. An early US was mostly found in clusters 3 and 4 (83.2% and 76.1%, respectively, were part of the observation group). In cluster 4 there were more women, thyroid-specific morbidity and costs were higher and the early US was more likely to be performed by specialists in nuclear medicine or radiologists.Conclusion Presumably unnecessary tests in the field of suspected thyroid diseases seem to be frequent, contributing to cascades effects. Neither German nor international guidelines provide clear recommendations for or against US screening. Therefore, guidelines on when to apply US and when not are urgently needed.

Abstract Background Even though a plethora of systemic therapies have been proposed for necrobiotic xanthogranuloma (NXG), there is no systematic review on this topic in literature. Objective To review all existing literature on the systemic therapy of NXG in order to identify the most effective therapies. Methods All reported papers in the literature were screened for systemic treatments of NXG. Papers without proper description of the therapies, papers describing topical therapy, and articles without assessment of effectiveness were excluded. Subsequently, we analyzed 79 papers and a total of 175 cases. Results The most effective treatments for NXG are intravenous immunoglobulins (IVIG), corticosteroids, and combination therapies including corticosteroids. Conclusions Corticosteroids and IVIG should therefore be considered first-line treatments in patients with NXG.

Abstract A new integrated lens-antenna is designed and implemented for a nanocontact based terahertz (THz) photomixer. The new design replaces the standard conventional bulky silicon lens, which normally no THz photomixer can avoid. The Fresnel Zone Plate is used to design the new lens-antenna and is simulated by the MIT open-source tool called Meep. The final design showed, with only two simple fabrication technology processing steps (standard optical lithography) that the lens-antenna can be monolithically integrated with the THz nanophotomixer. With its compact design, the THz measurements showed a comparable behavior to the conventional bulky silicon lens, therefore it would be ready for photonic integrated circuits based THz systems.

Aging is an important risk factor for disease, leading to morphological change that can be assessed on Computed Tomography (CT) scans. We propose a deep learning model for automated age estimation based on CT- scans of the thorax and abdomen generated in a clinical routine setting. These predictions could serve as imaging biomarkers to estimate a "biological" age, that better reflects a patient's true physical condition. A pre-trained ResNet-18 model was modified to predict chronological age as well as to quantify its aleatoric uncertainty. The model was trained using 1653 non-pathological CT-scans of the thorax and abdomen of subjects aged between 20 and 85 years in a 5-fold cross-validation scheme. Generalization performance as well as robustness and reliability was assessed on a publicly available test dataset consisting of thorax-abdomen CT-scans of 421 subjects. Score-CAM saliency maps were generated for interpretation of model outputs. We achieved a mean absolute error of 5.76 ± 5.17 years with a mean uncertainty of 5.01 ± 1.44 years after 5-fold cross-validation. A mean absolute error of 6.50 ± 5.17 years with a mean uncertainty of 6.39 ± 1.46 years was obtained on the test dataset. CT-based age estimation accuracy was largely uniform across all age groups and between male and female subjects. The generated saliency maps highlighted especially the lumbar spine and abdominal aorta. This study demonstrates, that accurate and generalizable deep learning-based automated age estimation is feasible using clinical CT image data. The trained model proved to be robust and reliable. Methods of uncertainty estimation and saliency analysis improved the interpretability.

Objectives Direct oral anticoagulants (DOACs) were introduced based on randomised controlled trials (RCTs) comparing them to vitamin-K-antagonist (VKA) warfarin. In Germany, almost exclusively phenprocoumon is used as VKA. RCTs with phenprocoumon being absent we analysed the benefits and harms of DOACs and phenprocoumon for patients with atrial fibrillation (AF) in a real-world setting.Design In a retrospective observational cohort study, claims data covering inpatient and outpatient care from 2015 to 2019 were analysed by Cox regression and propensity score matching (PSM).Setting Data from a group of small-sized to medium-sized health insurance companies in Germany.Participants We analysed datasets of 71 961 patients with AF and first prescription of phenprocoumon (n=20 179) or DOAC in standard dose (n=51 782). Patients with reduced dose of DOACs were excluded (n=21 724).Outcome measures Outcomes were thromboembolic events, major bleeding and death during a 12-month follow-up period.Results The regression analysis widely showed similarity between phenprocoumon and standard dose DOACs regarding effectiveness and safety. There were only three statistically significant differences: a lower bleeding risk with composite DOACs and apixaban (HR (95% CI) = 0.67 (0.59 to 0.76) and 0.54 (0.46 to 0.63), respectively) and a higher risk of death with rivaroxaban (1.21 (1.10 to 2.34)). The analysis after PSM was consistent with the first two results regarding composite DOACs and apixaban (number needed to treat, NNT 101 and 78) and showed a lower bleeding risk with rivaroxaban (NNT 156). Absolute differences were small.Conclusions The small superiority or non-inferiority of DOACs over warfarin seen in the RCTs might not translate into relevant advantages of DOACs over phenprocoumon. To confirm the hypothesis, an RCT with phenprocoumon is needed. Next to the safety and effectiveness assessments other factors might also play a substantial role in the decision on the right OAC for stroke prevention.

BackgroundThe international collaboration study PRICOV-19 -Primary Health Care in times of COVID-19 aims to assess the impact of the COVID-19 pandemic on the organisation of primary health care. The German part focuses on the subjective perceptions of general practitioners on primary health care and the impact of political measures during the second wave of the COVID-19 pandemic. Within this survey, the "open text field" of the questionnaire was utilised remarkably frequently and extensively by the respondents. It became clear that the content that was named needed to be analysed in an exploratory manner. Accordingly, this paper addresses the following question: What preoccupies general practitioners in Germany during COVID-19 that we have not yet asked them enough?MethodsThe data collection took place throughout Germany from 01.02.2021 to 28.02.2021with a quantitative online questionnaire consisting of 53 items arranged across six topics as well as an "open text field" for further comments. The questionnaire's open text field was analysed following the premises of the qualitative content analysis.ResultsThe topics discussed by the respondents were: insufficient support from health policies, not being prioritised and involved in the vaccination strategy, feeling insufficient prepared, that infrastructural changes and financial concerns threatened the practice, and perceiving the own role as important, as well as that health policies affected the wellbeing of the respondents. One of the main points was the way general practitioners were not sufficiently acknowledged for their contribution to ensuring high-quality care during the pandemic.DiscussionGerman general practitioners perceived their work and role as highly relevant during the COVID-19 pandemic. In controversy with their perception, they described political conditions in which they were the ones who contributed significantly to the fight against the pandemic but were not given enough recognition.

Patients with the renal phosphate–wasting disease X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of XLH, are characterized by loss-of-function mutations in phosphate-regulating endopeptidase homolog X-linked (PHEX), leading to excessive secretion of the bone-derived phosphotropic hormone FGF23. The mineralization defect in patients with XLH and Hyp mice is caused by a combination of hypophosphatemia and local accumulation of mineralization-inhibiting molecules in bone. However, the mechanism by which PHEX deficiency regulates bone cell metabolism remains elusive. Here, we used spatial metabolomics by employing matrix-assisted laser desorption/ionization (MALDI) Fourier-transform ion cyclotron resonance mass spectrometry imaging (MSI) of undecalcified bone cryosections to characterize in situ metabolic changes in bones of Hyp mice in a holistic, unbiased manner. We found complex changes in Hyp bone metabolism, including perturbations in pentose phosphate, purine, pyrimidine, and phospholipid metabolism. Importantly, our study identified an upregulation of several biochemical pathways involved in intra- and extracellular production of the mineralization inhibitor pyrophosphate in the bone matrix of Hyp mice. Our data emphasize the utility of MSI–based spatial metabolomics in bone research and provide holistic in situ insights as to how Phex deficiency–induced changes in biochemical pathways in bone cells are linked to impaired bone mineralization.

Introduction Disordered eating behaviours (DEB) and eating disorders (ED) are among the most common mental health comorbidities of type 1 diabetes. However, research on diabetes-specific risk and protective factors is limited. To this end, comprehensive characterisations of DEB and ED in type 1 diabetes, as well as longitudinal research on the course of DEB and ED, are needed to gain more insight. The ‘Disordered eating behaviours and eating disorders in diabetes type I’ (DEBBI) study aims to describe DEB/ED and their correlates in people with type 1 diabetes, to identify key diabetes-specific, psychosocial risk and protective factors, and to describe the course of DEB over time.Methods and analysis The DEBBI study is a longitudinal online survey with follow-up assessments after 6, 12 and 18 months, targeted at adults who have been diagnosed with type 1 diabetes for at least 12 months. The survey covers data on diabetes diagnosis and self-management (eg, diabetes treatment and complications), lifestyle (eg, eating habits, physical activity), psychosocial well-being (eg, anxiety, depressive symptoms) and demographic and medical information. It includes validated instruments and self-generated items. One key aspect of the data analysis will be latent profile analyses to determine latent subtypes of DEB manifestation in people with type 1 diabetes and their courses over time, including data on the clinical picture and symptoms, behaviours and diabetes-specific complications.Ethics and dissemination The study protocol was approved by the Ethics Committee of the State Medical Chamber of Rhineland-Palatine, Germany (ID 2021-16040). Participants give informed written consent before starting the survey. The DEBBI study will provide more clarity in the so far inconsistent empirical evidence base and will help to inform research on prevention and intervention strategies that are tailored to diabetes-specific needs.Trial registration number The study is registered with DRKS German Clinical Trials Register (DRKS00028833).

Introduction: Optical Coherence Tomography (OCT) and OCT Angiogram (OCT-A) are non invasive techniques for imaging the microvasculature of retina and choroid. OCT is a method of analysing the in-vivo retinal architecture. OCT uses low coherence interferometry to create a cross-sectional map of the retina with a resolution of 10-15 µm. Swept Source OCT utilises light source of 1050 nm wavelength and can reproducibly measure choroidal thickness. OCT-A uses the principle of motion contrast, where the moving red blood cells are traced to depict vessels through different segments of the retina. The same tissue area is imaged repeatedly and differences are analysed between scans to detect area with high flow rates, low flow and no flow at all. Only a few studies have been reported on baseline choroidal thickness and retinal vessel parameters in children. This study was conducted to measure these parameters using Swept source OCT in normal children. Aim: To measure retinal vasculature parameters and choroidal thickness using OCT and OCT-A in normal children. Materials and Methods: A cross-sectional study was conducted on 68 children between 5-15 years of age in Department of Ophthalmology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India between February to July 2018, after obtaining the ethical clearance from the Institutional Review Board. The children were divided into two groups, 5-10 years and >10-15 years. Children with Best Corrected Visual Acuity (BCVA) 25 mm, any systemic disease or ocular pathology were excluded. All underwent comprehensive ophthalmic examination along with fundus photography, OCT and OCTA imaging. Retinal artery and vein calibre at the disc margin and Subfoveal Choroidal Thickness (SFCT) were measured. Measurement of Foveal Avascular Zone (FAZ) both superficial and deep, Vascular Density (VD) of perifoveal, papillary and peripapillary area were obtained from OCT-A. T-test was used to compare the parameters with p-value 10-15 years at the superior disc margin with p-value of (0.4403). There was no statistical difference retinal vessel caliber between the two groups. The mean SFCT in the 5-10 years group was 344.42±86.77 µm and 343.40± 93.56 µm in the other with a p value 0.9474. The mean superficial FAZ (SFAZ) was 189.79±117.11 µm2 in the first group and 264.88±169.91 µm2 in the second group, (p=0.0034). There was no statistical difference among these parameters between the two groups except SFAZ. Conclusion: Present study describes the normative data on retinal vasculature parameters and choroidal thickness in Indian paediatric population aged 5-15 years using OCT and OCT-A. The study findings will further help in screening and monitoring the subjects in this age group.

Aflatoxins are among the main carcinogens threatening food and feed safety while imposing major detection challenges to the agrifood industry. Today, aflatoxins are typically detected using destructive and sample-based chemical analysis that are not optimally suited to sense their local presence in the food chain. Therefore, we pursued the development of a non-destructive optical sensing technique based on fluorescence spectroscopy. We present a novel compact fluorescence sensing unit, comprising both ultraviolet excitation and fluorescence detection in a single handheld device. First, the sensing unit was benchmarked against a validated research-grade fluorescence setup and demonstrated high sensitivity by spectrally separating contaminated maize powder samples with aflatoxin concentrations of 6.6 µg/kg and 11.6 µg/kg. Next, we successfully classified a batch of naturally contaminated maize kernels within three subsamples showing a total aflatoxin concentration of 0 µg/kg, 0.6 µg/kg and 1647.8 µg/kg. Consequently, our novel sensing methodology presents good sensitivity and high potential for integration along the food chain, paving the way toward improved food safety.

Once human photoreceptors die, they do not regenerate, thus, photoreceptor transplantation has emerged as a potential treatment approach for blinding diseases. Improvements in transplant organization, donor cell maturation, and synaptic connectivity to the host will be critical in advancing this technology for use in clinical practice. Unlike the unstructured grafts of prior cell-suspension transplantations into end-stage degeneration models, we describe the extensive incorporation of induced pluripotent stem cell (iPSC) retinal organoid–derived human photoreceptors into mice with cone dysfunction. This incorporative phenotype was validated in both cone-only as well as pan-photoreceptor transplantations. Rather than forming a glial barrier, Müller cells extended throughout the graft, even forming a series of adherens junctions between mouse and human cells, reminiscent of an outer limiting membrane. Donor-host interaction appeared to promote polarization as well as the development of morphological features critical for light detection, namely the formation of inner and well-stacked outer segments oriented toward the retinal pigment epithelium. Putative synapse formation and graft function were evident at both structural and electrophysiological levels. Overall, these results show that human photoreceptors interacted readily with a partially degenerated retina. Moreover, incorporation into the host retina appeared to be beneficial to graft maturation, polarization, and function.

Abstract In this paper we analyse the performance of machine learning methods in predicting patient information such as age or sex solely from retinal imaging modalities in a heterogeneous clinical population. Our dataset consists of N = 135,667 fundus images and N = 85,536 volumetric OCT scans. Deep learning models were trained to predict the patient’s age and sex from fundus images, OCT cross sections and OCT volumes. For sex prediction, a ROC AUC of 0.80 was achieved for fundus images, 0.84 for OCT cross sections and 0.90 for OCT volumes. Age prediction mean absolute errors of 6.328 years for fundus, 5.625 years for OCT cross sections and 4.541 for OCT volumes were observed. We assess the performance of OCT scans containing different biomarkers and note a peak performance of AUC = 0.88 for OCT cross sections and 0.95 for volumes when there is no pathology on scans. Performance drops in case of drusen, fibrovascular pigment epitheliuum detachment and geographic atrophy present. We conclude that deep learning based methods are capable of classifying the patient’s sex and age from color fundus photography and OCT for a broad spectrum of patients irrespective of underlying disease or image quality. Non-random sex prediction using fundus images seems only possible if the eye fovea and optic disc are visible.

Abstract Magnetic resonance imaging (MRI) of the brain combined with voxel-based morphometry (VBM) revealed changes in gray matter volume (GMV) in various disorders. However, the cellular basis of GMV changes has remained largely unclear. We correlated changes in GMV with cellular metrics by imaging mice with MRI and two-photon in vivo microscopy at three time points within 12 weeks, taking advantage of age-dependent changes in brain structure. Imaging fluorescent cell nuclei allowed inferences on (i) physical tissue volume as determined from reference spaces outlined by nuclei, (ii) cell density, (iii) the extent of cell clustering, and (iv) the volume of cell nuclei. Our data indicate that physical tissue volume alterations only account for 13.0% of the variance in GMV change. However, when including comprehensive measurements of nucleus volume and cell density, 35.6% of the GMV variance could be explained, highlighting the influence of distinct cellular mechanisms on VBM results.

Sarcoidosis is a systemic inflammatory disease, characterised by granuloma formation upon an unknown trigger in genetically predisposed individuals. The inflammation is characterised by an activation of both the innate immune system, with macrophages differentiating into epitheloid cells and dendritic cells, and the adaptive immune system, particularly T helper (Th) 1 and Th17 cells. Since all organs can be affected to varying extents, clinical presentation is often diverse. Most commonly, the lungs, lymph nodes, skin and eyes are involved, whereas cardiac, renal and neurological manifestations are less common but associated with higher morbidity. Depending on the clinical symptoms, a detailed evaluation including thorough clinical examination, imaging and laboratory tests should explore all possible organ involvements. In some patients, fatigue manifests as a para-sarcoidosis symptom impacting quality of life, even if sarcoidosis is in remission. Some acute syndromic presentations, such as Löfgren’s syndrome, have a good prognosis and are commonly self-limiting. If possible, a topical treatment, for example for cutaneous sarcoidosis or bronchial involvement, should be applied. Treatment of severe cases with persisting disease activity necessitates long-term immunosuppressive drugs, with glucocorticoids as the first-line option. Steroid-sparing and second-line drugs include methotrexate, azathioprine, mycophenolate mofetil and immunomodulators such hydroxychloroquine, with the latter being first-line therapy in cutaneous sarcoidosis. Tumour necrosis factor-alpha inhibitors (particularly adalimumab and infliximab) are used as third-line agents but are administered earlier in cases of persistent disease activity, severe organ-involvement or intolerance to conventional drugs. Treatment decisions should be based on a multidisciplinary approach, depending on organ involvement and treatment tolerability. Para-sarcoidosis manifestations, particularly fatigue, should also be carefully addressed, where the patient could also be enrolled in multidimensional rehabilitation programmes. With various organ involvement and different phenotypes, larger studies including real-world data from registries are necessary to evaluate different sarcoidosis endotypes and preferential treatment pathways.

BackgroundPatient decisions to take preventative treatments for osteoporosis depend on their perceptions of fracture risk, medication effect sizes (ES) of benefits and harms. However, physicians and lay persons may have differing perceptions of risks and medication efficacy. Both tend to overestimate medication benefits. This study surveyed at what risk physicians would prescribe and lay persons would be willing to take bisphosphonates, the minimum ES both groups do demand and the physicians estimates of the actual benefit of bisphosphonates.DesignCross-sectional online questionnaire survey.MethodsRespondents were confronted with a case vignette with an osteoporotic patient (10-year femoral fracture risk: 32%). They were asked at what threshold of 10-year-risk of femoral neck fracture they would prescribe or take a drug. They were asked for the minimum ES (absolute risk reduction, ARR) they demand from bisphosphonates to prescribe or take them. Physicians were asked to provide their estimate of the actual ARR of bisphosphonates.Results114 physicians and 140 lay persons answered (convenience sample/snowball distribution). The 10-year-risk threshold of lay persons (Mdnlay = 60%) willing to take medication was twice as high as the physicians' threshold (Mdnphy = 30%) to prescribe it (p < .001). The median minimum ARR physicians demanded for bisphosphonates prescription was 17%, whereas lay persons demanded 22% (p < .001). Physicians estimated the actual ARR of bisphosphonates to be 12%. This estimated effect size was below their own minimum threshold for prescription.ConclusionsLay persons tolerate a higher fracture risk and demand a larger benefit of antiosteoporotic medication for fracture prevention than physicians. Physicians demand higher minimum benefits than their own estimates which in turn are above the benefit evidence suggests. Physicians should be more familiar with ES of antiosteoporotic drugs concerning patient outcomes and actively advise lay persons before preventive treatment decisions are taken.

Abstract In renal tumors, suspicious for renal cell carcinoma, where there is any doubt and discrepancy between morphology and immune profile, we recommend performing further immunohistochemical staining for pan‐cytokeratin, S100, NSE, and inhibin‐alpha. Thus, follow‐up overtreatment can be avoided in cases of benign kidney tumors.

To address the continued rise of multi-drug-resistant microorganisms, the development of novel drugs with new modes of action is urgently required. While humans biosynthesize the essential isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via the established mevalonate pathway, pathogenic protozoa and certain pathogenic eubacteria use the less well-known methylerythritol phosphate pathway for this purpose. Important pathogens using the MEP pathway are, for example, Plasmodium falciparum, Mycobacterium tuberculosis, Pseudomonas aeruginosa and Escherichia coli. The enzymes of that pathway are targets for antiinfective drugs that are exempt from target-related toxicity. 2C-Methyl-D-erythritol 4-phosphate (MEP), the second enzyme of the non-mevalonate pathway, has been established as the molecular target of fosmidomycin, an antibiotic that has so far failed to be approved as an anti-infective drug. This review describes the development and anti-infective properties of a wide range of fosmidomycin derivatives synthesized over the last four decades. Here we discuss the DXR inhibitor pharmacophore, which comprises a metal-binding group, a phosphate or phosphonate moiety and a connecting linker. Furthermore, non-fosmidomycin-based DXRi, bisubstrate inhibitors and several prodrug concepts are described. A comprehensive structure–activity relationship (SAR) of nearly all inhibitor types is presented and some novel opportunities for further drug development of DXR inhibitors are discussed.

The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization’s (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by medical agencies to treat drug-resistant TB. Therefore, the development of novel antimycobacterial drug candidates to combat the threat of drug-resistant TB is urgent. In this work, we developed and optimized a total synthesis of the antimycobacterial natural flavonoid chlorflavonin by selective ruthenium(II)-catalyzed ortho-C(sp2)-H-hydroxylation of a substituted 3′-methoxyflavonoid skeleton. We extended our methodology to synthesize a small compound library of 14 structural analogs. The new analogs were tested for their antimycobacterial in vitro activity against Mycobacterium tuberculosis (Mtb) and their cytotoxicity against various human cell lines. The most promising new analog bromflavonin exhibited improved antimycobacterial in vitro activity against the virulent H37Rv strain of Mtb (Minimal Inhibitory Concentrations (MIC90) = 0.78 μm). In addition, we determined the chemical and metabolic stability as well as the pKa values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure–activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives.