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Introduction: Distal radius fractures (DRFs) are very common in older people and often result from low-energy falls in individuals with underlying osteoporosis. Fracture Liaison Services (FLSs) are designed to identify, investigate and treat patients with fragility fractures to prevent further fractures. The aim of this study is to audit an established FLS's current practice in identifying patients aged 50 or older with fragility DRFs against the current BOAST guidelines (stating all patients should be identified), and compare it with the identification rate in an acute hospital in the same region without a dedicated FLS. Methods: All forearm and wrist radiographs of patients aged 50 or older presenting at Addenbrooke's Hospital in the UK between 1st April and 31st July 2020 were assessed to identify patients with DRF. Electronic patient records were investigated to determine mechanism of injury (MoI), age, gender, admission or discharge and follow-up in fracture clinic (FC). Only low-energy MoIs were included. Results: Of 117 DRF patients (males: 8, females: 109; median age: 74yrs, age range: 51-94 yrs), 13 (11%) were not identified by the FLS. FC follow-up was strongly associated with identification by the FLS, with patients not seen in FC more likely to be missed (P < 0.0001). Although the majority of admitted patients were identified (96%), discharge did not appear to increase the risk of being missed (P = 0.163), but half those missed were on no Trauma & Orthopaedics Department list. Conclusion: Addenbrooke's FLS is very successful at identifying DRFs. In comparison, an acute hospital with no FLS reported identifying just 2%. However, this audit highlights opportunities to further enhance FLS detection of fragility fracture patients, particularly those discharged from A&E without follow-up. Improving identification of fragility fractures will undoubtedly be beneficial to patients and financially favourable for the NHS. This study demonstrates the clear benefit of an FLS in identifying patients with fragility fractures. [ABSTRACT FROM AUTHOR]

Introduction: Space weathering refers to the chemical, microstructural, and optical changes on the surfaces of airless planetary bodies caused by high-velocity micrometeoroid impacts and solar wind irradiation [1]. Space weathering may alter the spectral properties of airless surfaces by changing the spectral slope, darkening/brightening, and attenuating absorption bands in the visible and near-infrared. These spectral changes make it difficult to establish a link between meteorites and their parent bodies [2], and accurately characterize the mineralogical composition of these surfaces via remote sensing spectroscopy. Analyses of returned regolith samples and laboratory experiments simulating space weathering processes have concentrated on studying silicate minerals, the most abundant phases in lunar soils and ordinary chondrites. However, little is known about the space weathering of magnetite, which is an important mineral phase in carbonaceous chondrites [3], and that has been identified in returned samples from asteroid Ryugu [4,5,6,7,8], and on the surface of asteroid Bennu through remote sensing observations [9]. To better understand the response of magnetite under space weathering conditions, we simulated micrometeoroid bombardment and solar wind irradiation using pulsed laser and ion irradiation experiments, respectively. Methods: We used synthetic magnetite powders with grain sizes <45 µm that were pressed into pellets at 1500 psi. To reproduce micrometeoroid bombardment on the magnetite pellets, we used pulsed-laser irradiation, employing an Nd-YAG laser with 3.5 mJ per pulse and pulse durations of 4-6 ns. To simulate solar wind irradiation, we performed 1 keV H+ and 4 keV He+ irradiation experiments using fluxes ~1 x 1013 ions/cm2/s and total fluences of 8.7x1017 H+/cm2 and 3.6 × 1016 He+/cm2, equivalent to exposure times of ~750 years at 1 AU at the surface of asteroid Bennu, respectively. In addition, we conducted reflectance spectroscopy measurements in the visible near-infrared region (0.3-2.5 µm) for the laser and ion irradiated pellets. We analyzed the microstructural and chemical properties of individual magnetite grains after pulsed-laser and ion irradiation using transmission electron microscopy (TEM) and energy-dispersive X-ray spectroscopy (EDS). Results and Conclusions: TEM analysis of the pulsed laser irradiated sample reveals the presence of a discontinuous crystalline rim in the outermost part of the magnetite grain with a thickness that varies from 5-15 nm. EDS observations show that this rim is enriched in Fe around 5 at% compared to the unaltered region. The 1 keV H+ irradiated sample exhibits a crystalline rim in the outer 35 nm in the grain enriched ~20 at% in Fe compared to the unirradiated surface. However, we identified an increase of O in the outer 15 nm of the rim likely caused by atmospheric oxidation after the irradiation experiments. The 4 keV He+ irradiated magnetite presents elongated structural defects in the upper 50 nm but no changes in the concentration of O and Fe were identified via EDS. No amorphization was observed in the pulsed laser or ion irradiated samples. Reflectance spectroscopy reveals that the 4 keV He+ irradiated sample is darker than an unirradiated pellet used as a reference, whereas the pulsed laser irradiated magnetite is brighter. However, the most significant change is observed in the 1 keV H+ irradiated sample, which is brighter than the unirradiated pellet in the visible wavelengths, reaching up to 2x the reflectance values of the unirradiated sample at the ~470-570 nm region. These results suggest that under space weathering, the concentrations of O and Fe in magnetite rims are altered along with its reflectance and spectral slope. Preliminary analysis of Ryugu regolith particles show the presence of a layer rich in metallic iron nanoparticles (npFe0) on the surface of a magnetite grain [6], which is consistent with the depletion of O that is observed in our experiments. This loss of O could create a reducing environment for the Fe present in magnetite and promote the development of a metallic iron-rich layer. We expect a similar chemical behavior (depletion of O and enrichment of Fe) on magnetite grains that will be returned from asteroid Bennu. Additionally, the resistance of magnetite to amorphization has been also observed in sulfide minerals from asteroid Itokawa, suggesting that Fe-oxides and sulfide phases are more resistant to solar wind irradiation damage compared to silicate minerals. [ABSTRACT FROM AUTHOR]

Introduction: To support research projects that require medical data from multiple sites is one of the goals of the German Medical Informatics Initiative (MII). The data integration centers (DIC) at university medical centers in Germany provide patient data via FHIR® in compliance with the MII core data set (CDS). Requirements for data protection and other legal bases for processing prefer decentralized processing of the relevant data in the DICs and the subsequent exchange of aggregated results for cross-site evaluation., Methods: Requirements from clinical experts were obtained in the context of the MII use case INTERPOLAR. A software architecture was then developed, modeled using 3LGM2, finally implemented and published in a github repository., Results: With the CDS tool chain, we have created software components for decentralized processing on the basis of the MII CDS. The CDS tool chain requires access to a local FHIR endpoint and then transfers the data to an SQL database. This is accessed by the DataProcessor component, which performs calculations with the help of rules (input repo) and writes the results back to the database. The CDS tool chain also has a frontend module (REDCap), which is used to display the output data and calculated results, and allows verification, evaluation, comments and other responses. This feedback is also persisted in the database and is available for further use, analysis or data sharing in the future., Discussion: Other solutions are conceivable. Our solution utilizes the advantages of an SQL database. This enables flexible and direct processing of the stored data using established analysis methods. Due to the modularization, adjustments can be made so that it can be used in other projects. We are planning further developments to support pseudonymization and data sharing. Initial experience is being gathered. An evaluation is pending and planned.

Background: The mental health benefits of cannabidiol (CBD) are promising but can be inconsistent, in part due to challenges in defining an individual's effective dosage. In schizophrenia, alterations in anandamide (AEA) concentrations, an endocannabinoid (eCB) agonist of the eCB system, reflect positively on treatment with CBD. Here, we expanded this assessment to include eCBs alongside AEA congeners, comparing phytocannabinoids and dosage in a clinical setting., Methods: Liquid chromatography-tandem mass spectrometry quantified changes in serum levels of AEA, 2-arachidonoylglycerol (2-AG), alongside AEA-related compounds oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which were attained from two independent, parallel-designed, clinical trials investigating single, oral CBD (600 or 800 mg), delta-9-tetrahydrocannabinol (Δ 9 -THC, 10 or 20 mg) and combination administration (CBD|800 mg+Δ 9 -THC|20 mg) in healthy volunteers (HVs, n=75). Concentrations were measured at baseline (t=0), 65 and 160 min post administration., Results: CBD-led increases in AEA (1.6-fold), OEA and PEA (1.4-fold) were observed following a single 800 mg (p corr <0.05) but not 600 mg dosage. Declining AEA was observed with Δ 9 -THC at 10 mg (-1.3-fold) and 20 mg (-1.4-fold) but restored to baseline levels by 160 min. CBD+Δ 9 -THC yielded the highest increases in AEA (2.1-fold), OEA (1.9-fold) and PEA (1.8-fold) without reaching a maximal response., Conclusion: CBD-administered effects towards AEA, OEA and PEA are consistent with phase II trials reporting clinical improvement for acute schizophrenia (CBD≥800 mg). Including Δ 9 -THC appears to enhance the CBD-induced response towards AEA and its congeners. Our results warrant further investigations into the potential of these lipid-derived mediators as metabolic measures for CBD dose prescription and co-cannabinoid administration., Competing Interests: Competing interests: FML and DK are shareholders of curantis UG (Ltd.). CR is a shareholder of lero bioscience UG (Ltd.). CR, CB, ID, and AEH are employees of Endosane Pharmaceuticals GmbH. FML received an Investigator Initiated Trial Grant from Endosane Pharmaceuticals GmbH. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Within occupational settings, mental health of employees can be affected by complex interactions between individuals and their work environment. The aim of this cross-sectional analysis was to investigate the association between person-environment fit and mental health in employees. Data of n = 568 participants from the LIFE adult cohort study was analysed, including socio-demographic characteristics, three dimensions of person-environment fit (P-E fit), symptoms of depression and anxiety. Assessment took place between 2017 and 2021. Statistical analysis included descriptive analyses as well as generalized linear regression models adjusted for age, gender, socioeconomic status, marital status, and job status. Correlational analysis revealed significant associations between age, marital status, SES, employment status, symptoms of depression and anxiety and P-E fit. According to regression models, greater perceived fit between person and organization was associated with lower depression scores and lower symptoms of anxiety. Higher perceived fit between demands and abilities was significantly related to lower severity of depression and anxiety. Similarly, participants reporting a higher fit between needs and supplies, exhibited less symptom severity regarding depression and anxiety. These results underline the importance of person-environment fit regarding mental health. Finding ways to obtain an optimal balance should not only be recognized as an important factor for health and well-being, but might also be beneficial for organizations and employers in the long-term., (© 2024. The Author(s).)

Objective: The bejective was to determine health literacy (HL) and care aspects of those affected by Long-COVID., Method: 407 patients with Long-COVID and long-term neuropsychiatric symptoms were interviewed in the LIFE study center. In addition to descriptive analyses, regression models were calculated to examine the relationships between health literacy (HLS-EU-Q16) and various aspects of care (RehaQ-N1)., Results: The results show that 35.8% had problematic and 17.9% had inadequate HL. The majority of subjective needs were unmet and 47.7% of those affected were dissatisfied with the therapy they received., Discussion: Among those affected by Long-COVID, subjective HL is rather reduced. The healthcare system appears to be unprepared for these patients, which is reflected in unmet needs and low treatment satisfaction. This was even more pronounced among those exhibiting lower HL., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Medication analyses by ward pharmacists are an important measure of drug therapy safety (DTS). Medication-related problems (MRPs) are identified and resolved with the attending clinicians. However, staff resources for extended medication analyses and complete documentation are often limited. Until now, data required for the identification of risk patients and for an extended medication analysis often had to be collected from various parts of the institution's internal electronic medical record (EMR). This error-prone and time-consuming process is to be improved in the INTERPOLAR (INTERventional POLypharmacy-Drug interActions-Risks) project using an IT tool provided by the data integration centers (DIC).INTERPOLAR is a use case of the Medical Informatics Initiative (MII) that focuses on the topic of DTS. The planning phase took place in 2023, with routine implementation planned from 2024. DTS-relevant data from the EMR is to be presented and the documentation of MRPs in routine care is to be facilitated. The prospective multicenter, cluster-randomized INTERPOLAR‑1 study serves to evaluate the benefits of IT support in routine care. The aim is to show that more MRPs can be detected and resolved with the help of IT support. For this purpose, six normal wards will be selected at each of eight university hospitals, so that 48 clusters (with a total of at least 70,000 cases) are available for randomization., (© 2024. The Author(s).)

The Medical Informatics Initiative (MII) funded by the Federal Ministry of Education and Research (BMBF) 2016-2027 is successfully laying the foundations for data-based medicine in Germany. As part of this funding, 51 new professorships, 21 junior research groups, and various new degree programs have been established to strengthen teaching, training, and continuing education in the field of medical informatics and to improve expertise in medical data sciences. A joint decentralized federated research data infrastructure encompassing the entire university medical center and its partners was created in the form of data integration centers (DIC) at all locations and the German Portal for Medical Research Data (FDPG) as a central access point. A modular core dataset (KDS) was defined and implemented for the secondary use of patient treatment data with consistent use of international standards (e.g., FHIR, SNOMED CT, and LOINC). An officially approved nationwide broad consent was introduced as the legal basis. The first data exports and data use projects have been carried out, embedded in an overarching usage policy and standardized contractual regulations. The further development of the MII health research data infrastructures within the cooperative framework of the Network of University Medicine (NUM) offers an excellent starting point for a German contribution to the upcoming European Health Data Space (EHDS), which opens opportunities for Germany as a medical research location., (© 2024. The Author(s).)

Aims/hypothesis: As the prevalence of insulin resistance and glucose intolerance is increasing throughout the world, diabetes-induced eye diseases are a global health burden. We aim to identify distinct optical bands which are closely related to insulin and glucose metabolism, using non-invasive, high-resolution spectral domain optical coherence tomography (SD-OCT) in a large, population-based dataset., Methods: The LIFE-Adult-Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. Cross-sectional, standardised phenotyping included the assessment of various metabolic risk markers and ocular imaging, such as SD-OCT-derived thicknesses of ten optical bands of the retina. Global and Early Treatment Diabetic Retinopathy Study (ETDRS) subfield-specific optical retinal layer thicknesses were investigated in 7384 healthy eyes of 7384 participants from the LIFE-Adult-Study stratified by normal glucose tolerance, prediabetes (impaired fasting glucose and/or impaired glucose tolerance and/or HbA 1c 5.7-6.4% [39-47 mmol/mol]) and diabetes. The association of optical retinal band characteristics with different indices of glucose tolerance (e.g. fasting glucose, area under the glucose curve), insulin resistance (e.g. HOMA2-IR, triglyceride glucose index), or insulin sensitivity (e.g. estimated glucose disposal rate [eGDR], Stumvoll metabolic clearance rate) was determined using multivariable linear regression analyses for the individual markers adjusted for age, sex and refraction. Various sensitivity analyses were performed to validate the observed findings., Results: In the study cohort, nine out of ten optical bands of the retina showed significant sex- and glucose tolerance-dependent differences in band thicknesses. Multivariable linear regression analyses revealed a significant, independent, and inverse association between markers of glucose intolerance and insulin resistance (e.g. HOMA2-IR) with the thickness of the optical bands representing the anatomical retinal outer nuclear layer (ONL, standardised β=-0.096; p<0.001 for HOMA2-IR) and myoid zone (MZ; β=-0.096; p<0.001 for HOMA2-IR) of the photoreceptors. Conversely, markers of insulin sensitivity (e.g. eGDR) positively and independently associated with ONL (β=0.090; p<0.001 for eGDR) and MZ (β=0.133; p<0.001 for eGDR) band thicknesses. These global associations were confirmed in ETDRS subfield-specific analyses. Sensitivity analyses further validated our findings when physical activity, neuroanatomical cell/tissue types and ETDRS subfield categories were investigated after stratifying the cohort by glucose homeostasis., Conclusions/interpretation: An impaired glucose homeostasis associates with a thinning of the optical bands of retinal ONL and photoreceptor MZ. Changes in ONL and MZ thicknesses might predict early metabolic retinal alterations in diabetes., (© 2024. The Author(s).)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics., Methods: We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups., Results: We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10 -6 ), including the PCSK9 gene locus and five other lipid loci: APOB, TM6SF2, FADS1/FADS2, JMJD1C, and HP/HPR. The interaction analysis revealed eight loci with sex- and/or statin-interactions. At the PCSK9 gene locus, there were four independent signals, one with a significant sex-interaction showing stronger effects in men (rs693668). Regarding statin treatment, there were two significant interactions in PCSK9 missense mutations: rs11591147 had stronger effects in statin-free individuals, and rs11583680 had stronger effects in statin-treated individuals. Besides replicating known loci, we detected two novel genome-wide significant associations: one for statin-treated individuals at 6q11.1 (within KHDRBS2) and one for males at 12q24.22 (near KSR2/NOS1), both with significant interactions. In the MR of PCSK9 on LDL-C, we observed significant causal estimates within all subgroups, but significantly stronger causal effects in statin-free subjects compared to statin-treated individuals., Conclusions: We performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors., (© 2024. The Author(s).)

Background: Meniscal root tears can lead to early knee osteoarthritis and pain. This study aimed (1) to compare clinical and radiological outcomes between patients who underwent arthroscopic meniscal root repair after meniscal root tears and those who received non-surgical treatment, and (2) to identify whether baseline MRI findings could be potential predictors for future treatment strategies., Methods: Patients with meniscal root tears were identified from our picture archiving and communication system from 2016 to 2020. Two radiologists reviewed radiographs and MRI studies using Kellgren-Lawrence (KL) grading and a modified Whole Organ MRI Scoring (WORMS) at baseline and follow-up. The median (interquartile range [IQR]) of follow-up radiographs and MRI studies were 134 (44-443) days and 502 (260-1176) days, respectively. MR images were assessed for root tear-related findings. Pain scores using visual analogue scale (VAS) and management strategies (non-surgical vs. arthroscopic root repair) were also collected. Chi-squared tests and independent t-tests were used to assess differences regarding clinical and imaging variables between treatment groups. Logistic regression analyses were performed to evaluate the associations between baseline MRI findings and each future treatment., Results: Ninety patients were included. VAS pain scores were significantly (p < 0.01) lower after arthroscopic repair compared to conservative treatment (1.27±0.38vs.4±0.52) at the last follow-up visit with median (IQR) of 325 (180-1391) days. Increased meniscal extrusion (mm) was associated with higher odds of receiving non-surgical treatment (OR = 1.65, 95%CI 1.02-2.69, p = 0.04). The odds of having arthroscopic repair increased by 19% for every 1 mm increase in the distance of the tear from the root attachment (OR = 1.19, 95% CI: 1.05-1.36, p < 0.01). The odds of undergoing arthroscopic repair were reduced by 49% for every 1 mm increase in the extent of meniscal extrusion (OR = 0.51, 95% CI: 0.29-0.91, p = 0.02) as observed in the baseline MRI., Conclusions: Patients who underwent arthroscopic repair had lower pain scores than patients with conservative treatment in the follow-up. Distance of the torn meniscus to the root attachment and the extent of meniscal extrusion were significant predictors for arthroscopic repair in the next three weeks (time from the baseline MRI to the surgery date)., (© 2024. The Author(s).)

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research., (© 2024. The Author(s).)

Purpose: In patients with peritoneal metastasis (PM) from gastric cancer (GC), chemotherapy is the treatment of choice. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are still being debated. This randomized, controlled, open-label, multicenter phase III trial (EudraCT 2006-006088-22; ClinicalTrials.gov identifier: NCT02158988) explored the impact on overall survival (OS) of HIPEC after CRS., Patients and Methods: Adult patients with GC and histologically proven PM were randomly assigned (1:1) to perioperative chemotherapy and CRS alone (CRS-A) or CRS plus HIPEC (CRS + H). HIPEC comprised mitomycin C 15 mg/m 2 and cisplatin 75 mg/m 2 in 5 L of saline perfused for 60 minutes at 42°C. The primary end point was OS; secondary endpoints included progression-free survival (PFS), other distant metastasis-free survival (MFS), and safety. Analyses followed the intention-to-treat principle., Results: Between March 2014 and June 2018, 105 patients were randomly assigned (53 patients to CRS-A and 52 patients to CRS + H). The trial stopped prematurely because of slow recruitment. In 55 patients, treatment stopped before CRS mainly due to disease progression/death. Median OS was the same for both groups (CRS + H, 14.9 [97.2% CI, 8.7 to 17.7] months v CRS-A, 14.9 [97.2% CI, 7.0 to 19.4] months; P = .1647). The PFS was 3.5 months (95% CI, 3.0 to 7.0) in the CRS-A group and 7.1 months (95% CI, 3.7 to 10.5; P = .047) in the CRS + H group. The CRS + H group showed better MFS (10.2 months [95% CI, 7.7 to 14.7] v CRS-A, 9.2 months [95% CI, 6.8 to 11.5]; P = .0286). The incidence of grade ≥3 adverse events (AEs) was similar between groups (CRS-A, 38.1% v CRS + H, 43.6%; P = .79)., Conclusion: This study showed no OS difference between CRS + H and CRS-A. PFS and MFS were significantly better in the CRS + H group, which needs further exploration. HIPEC did not increase AEs.

Objective: Hysteroscopy and fractional curettage are commonly utilized techniques for the diagnosis of postmenopausal abnormal uterine bleeding and histopathological verification of primary endometrial cancer (EC). This study delves into the clinical significance of procuring preoperative endocervical tissue in conjunction with corpus fractions through fractional curettage., Design: This retrospective study encompassed a cohort of 84 patients diagnosed with T1 stage EC and 55 patients diagnosed with T2 stage EC, who underwent primary treatment between the years 2011 and 2021 at the University Hospital Frankfurt or Jung-Stilling Hospital Siegen., Materials, Setting, Methods: Among the postoperative T2 stage EC patients, a stratification was performed based on preoperative endocervical curettage (ECC) results obtained through fractional curettage. Categorical and continuous variables were compared utilizing the Pearson χ2 test, while for multivariate analyses and regression modeling, the Kaplan-Meier method and Cox regression models were respectively employed., Results: The median age of patients with pT2 stage EC was 64 years (range: 38-85). A predominant majority of these patients exhibited the endometrioid subtype of EC (90.9%). Upon conducting comparative analysis between groups, a notably higher frequency of laparotomies was observed (p = 0.002) among patients in whom preoperatively detected positive ECC was evident. The detection performance of fractional curettage in identifying positive ECC yielded a sensitivity of 70.9% and a specificity of 73.8%. In multivariate analysis, age at diagnosis (p = 0.022), positive ECC observed during fractional curettage (p = 0.036), and the FIGO stage (p = 0.036) emerged as prognostic determinant for progression-free survival. Independent prognostic factors for overall survival (OS) were age at diagnosis (p = 0.003), positive ECC (p = 0.008), histological grading (p = 0.016), and the FIGO stage (p = 0.022). A significant difference in OS was evident between patients characterized by preoperative negative ECC and those displaying positive ECC (81.8 vs. 59.5 months, p = 0.019)., Limitations: Limitations include the retrospective design of the study as well as a small number of patients., Conclusions: Preoperative determination of endocervical involvement of primary T2 stage EC could be a prognostic indicator in decision-making to treat EC. The conduct of prospective trials is necessary to definitively establish the routine application and associated benefits of fractional curettage in the context of primary EC., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated., Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured., Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10 -8 , explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice., Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Investigating the cross talk of different omics layers is crucial to understand molecular pathomechanisms of metabolic diseases like obesity. Here, we present a large-scale association meta-analysis of genome-wide whole blood and peripheral blood mononuclear cell (PBMC) gene expressions profiled with Illumina HT12v4 microarrays and metabolite measurements from dried blood spots (DBS) characterized by targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) in three large German cohort studies with up to 7706 samples. We found 37,295 associations comprising 72 amino acids (AA) and acylcarnitine (AC) metabolites (including ratios) and 8579 transcripts. We applied this catalogue of associations to investigate the impact of associating transcript-metabolite pairs on body mass index (BMI) as an example metabolic trait. This is achieved by conducting a comprehensive mediation analysis considering metabolites as mediators of gene expression effects and vice versa. We discovered large mediation networks comprising 27,023 potential mediation effects within 20,507 transcript-metabolite pairs. Resulting networks of highly connected (hub) transcripts and metabolites were leveraged to gain mechanistic insights into metabolic signaling pathways. In conclusion, here, we present the largest available multi-omics integration of genome-wide transcriptome data and metabolite data of amino acid and fatty acid metabolism and further leverage these findings to characterize potential mediation effects towards BMI proposing candidate mechanisms of obesity and related metabolic diseases. KEY MESSAGES: Thousands of associations of 72 amino acid and acylcarnitine metabolites and 8579 genes expand the knowledge of metabolome-transcriptome associations. A mediation analysis of effects on body mass index revealed large mediation networks of thousands of obesity-related gene-metabolite pairs. Highly connected, potentially mediating hub genes and metabolites enabled insight into obesity and related metabolic disease pathomechanisms., (© 2023. The Author(s).)

Background: So far, previous research suggests positive effects of mental demands at the workplace. However, it may depend on how stressfull these demands are perceived on an individual level., Objective: The aim was to build on previous research by investigating how mental demands are related to stress, overload, and work discontent and whether this relationship is mediated by individuals resources, such as resilience., Method: A sub-sample of the LIFE Adult Cohort (n = 480) was asked to answer questions on sociodemographic characteristics, objective stress (using the Trier Inventory of Chronic Stress (TICS)), and perceptions of stress with regard to verbal and executive mental demands at work., Results: According to generalized linear regression models, higher verbal as well as executive mental demands were associated with higher levels of chronic stress, work overload and discontent. Higher levels of resilience were associated with lower levels of these outcomes. Analyses regarding interaction effects revealed that the interaction between resilience and perceived stress of verbal mental demands was significant only in terms of work overload., Conclusion: Higher perceived stressfulness of mental demands was associated with higher chronic stress, work overload and work discontent. Therefore, mental demands should be targeted by occupational interventions that aim to improve job conditions and employees' overall well-being. Besides resilience, other potential influencers or personal resources should be focused on in future studies to develop interventions., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: Obesity is a major global health problem which can be targeted with new mechanistic diverse pharmacological interventions. Here we evaluate a new long-acting secretin receptor agonist as a potential treatment for obesity., Methods: BI-3434 was designed as a secretin analog with stabilized peptide backbone and attached fatty acid-based half-life extension group. The peptide was evaluated in vitro for its ability to stimulate cAMP accumulation in a cell line stably expressing recombinant secretin receptor. On the functional level, stimulation of lipolysis in primary adipocytes after treatment with BI-3434 was determined. The ability of BI-3434 to activate secretin receptor in vivo was assessed in a cAMP reporter CRE-Luc mouse model. Furthermore, a diet-induced obesity mouse model was used to test the effects of BI-3434 on body weight and food intake following repeated daily subcutaneous administration alone and in combination with a GLP-1R agonist., Results: BI-3434 potently activated human secretin receptor. However, lipolysis was only weakly induced in primary murine adipocytes. BI-3434 had an extended half-life compared to endogenous secretin and activated target tissues like pancreas, adipose tissue, and stomach in vivo. BI-3434 did not lower food intake in lean or diet-induced obese mice, but it increased energy expenditure after daily administration. This led to a loss of fat mass, which did not translate in a significant effect on body weight. However, treatment in combination with a GLP-1R agonist led to a synergistic effect on body weight loss., Conclusions: BI-3434 is a highly potent and selective agonist of secretin receptor with an extended pharmacokinetic (PK) profile. Increased energy expenditure after daily treatment with BI-3434 suggests that secretin receptor is involved in metabolic regulation and energy homeostasis. Targeting secretin receptor alone may not be an efficient anti-obesity treatment, but could be combined with anorectic principles like GLP-1R agonists., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Boehringer Ingelheim Pharma GmbH&Co.KG. Published by Elsevier GmbH.. All rights reserved.)

UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18-60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19)., Competing Interests: L. Thurner has received travel grants from Abbvie, Janssen and EUSA-Pharm, and has indicated consultancy for Takeda, Astra-Zeneca, Merck, EUSA-pharm. DK-M has received personal fees from Novartis, Astra-Zeneca, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, and nonfinancial support from Gilead Sciences, Janssen-Cilag, Takeda, Novartis. AV has received honoraria from Roche, Amgen, Kite, Gilead, Novartis, Bristol-Myers Squibb and has indicated a membership of the advisory board of Roche, Amgen, Kite, Gilead, Novartis, Bristol-Myers Squibb. UBK has received honoraria and advisory fees from Roche, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Gilead, Hexal, Pfizer, Astra- Zeneca, Pentixapharm, Amgen, Novartis, MSD and has received clinical study support for Celgene, Takeda, BMS, Roche, Astra-Zeneca, Novartis, MSD, Janssen-Cilag, Pfizer. MN has received travel grants from Roche, Celgene and MSD and personal fees from Roche, Celgene, MSD, Janssen, Amgen, Incyte and Abbvie. FG participates in advisory board of Roche, Boehringer Ingelheim, Abbvie, Merck, Takeda, MSD, Sanofi, Pfizer, Novartis, Amgen and Janssen. RT has received grants from Atara and Roche and travel support from Roche, Atara, Celgene, Janssen and Abbvie; he has indicated a membership of the advisory board of Atara and Abbvie and has indicated consultancy for s Atara. PdNB has indicated consultancy for Roche, Incyte and Novartis. FM has received travel grants from Roche, Takeda, Janssen and Gilead and has indicated consultancy and advisory role for Roche, Gilead, Janssen, MSD, Takeda and Novartis. SS has received grants from Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys and has indicated consultancy for for Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys; he has received drug/equipment supplied by entity from Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys. VP has received grants from Deutsche Krebshilfe (German Cancer Aid), Chugai, Abbvie, Amgen, Roche and Bristol Myers Squibb. GH has received grants from Roche and Bristol Myers Squibb and personal fees from Bristol Myers Squibb, Roche, Amgen, Spectrum and MSD. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

UNFOLDER (NCT00278408, EUDRACT 2005-005218-19) is a phase-3 trial in patients with aggressive B-cell lymphoma and intermediate prognosis, including primary mediastinal B-cell lymphoma (PMBCL). In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. Response was assessed according to the standardized criteria from 1999, which did not include F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET) scans. Primary end point was event-free survival (EFS). A subgroup of 131 patients with PMBCLs was included (median age, 34 y; 54% female, 79% elevated lactate dehydrogenase (LDH), 20% LDH >2× upper limit of normal [ULN], and 24% extralymphatic involvement). Eighty-two (R-CHOP-21: 43 and R-CHOP-14: 39) patients were assigned to radiotherapy and 49 (R-CHOP-21: 27, R-CHOP-14: 22) to observation. The 3-year EFS was superior in radiotherapy arm (94% [95% confidence interval (CI), 89-99] versus 78% [95% CI, 66-89]; P = 0.0069), due to a lower rate of partial responses (PRs) (2% versus 10%). PR triggered additional treatment, mostly radiotherapy (n = 5; PR: 4; complete response/unconfirmed complete response: 1). No significant differences were observed in progression-free survival (PFS) (95% [95% CI, 90-100] versus 90% [95% CI, 81-98]; P = 0.25) nor in overall survival (OS) (98% [95% CI, 94-100] versus 96% [95% CI, 90-100]; P = 0.64). Comparing R-CHOP-14 and R-CHOP-21, EFS, PFS, and OS were not different. A prognostic marker for adverse outcome was elevated LDH >2× ULN (EFS: P = 0.016; PFS: P = 0.0049; OS: P = 0.0014). With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%., Competing Interests: GH has received grants from Roche and Bristol-Myers Squibb and personal fees from Bristol-Myers Squibb, Roche, Amgen, Spectrum and MSD. L Thurner has received travel grants from Abbvie, Janssen and EUSA-Pharm, and has indicated consultancy for Takeda, Astra-Zeneca, Merck, EUSA-pharm. VP has received grants from Deutsche Krebshilfe (German Cancer Aid), Chugai, Abbvie, Amgen, Roche, and Bristol-Myers Squibb. AV has received honoraria from Roche, Amgen, Kite, Gilead, Novartis, Bristol-Myers Squibb and has indicated a membership of the advisory board of Roche, Amgen, Kite, Gilead, Novartis, Bristol-Myers Squibb. MN has received travel grants from Roche, Celgene, and MSD and personal fees from Roche, Celgene, MSD, Janssen, Amgen, Incyte, and Abbvie. FG participates in advisory board of Roche, Boehringer Ingelheim, Abbvie, Merck, Takeda, MSD, Sanofi, Pfizer, Novartis, Amgen, and Janssen. PdNB has indicated consultancy for Roche, Incyte, and Novartis. SS has received grants from Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys and has indicated consultancy for for Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys; he has received drug/equipment supplied by entity from Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Objectives: To assess the perceived state of diversity in Radiology Residency Programs in the United States and to evaluate the level of acceptance for diversity, equity, and inclusion (DEI) initiatives., Methods: An electronic survey was conducted of the Radiology Residency Programs in the United States in December 2021 and January 2022. Respondents were recruited by email sent to the members of the Association of University Radiologists who were Radiology Residency Program Directors. Quantitative and Qualitative analyses were performed., Results: Of the 198 emails sent out to the Radiology Program Directors, 53 completed surveys were returned (response rate of 27%). Although some progress has been made in increasing the number of women and Asians in Academic Radiology, there is persisting imbalance of the numbers of African American and Latinx radiologists which comprise far less than 25% of the physician workforce. Nearly half of the respondents reported having a Vice Chair of DEI. Three themes emerged from the qualitative analysis. Most respondents agreed that diversity should be considered when recruiting faculty and residents. Many noted a strong commitment to DEI but they felt there was room for improvement in formalizing efforts to aid in recruitment of underrepresented minorities. Diversity education was more likely mandatory for residents and optional for faculty., Conclusion: Academic Radiology programs are recognizing the value of internal DEI leadership roles. Radiologists are implementing DEI initiatives and making intentional changes in the recruitment of diverse radiologists. More concerted efforts are needed to increase the low numbers of African American and Latinx radiologists. Effective evaluation metrics for various DEI programs are needed to assess how successful these endeavors are in creating lasting changes., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the feasibility and repeatability of IOLMaster 700 biometry measurements in an adult population. Furthermore, to assess the value of the Quality Indicators (QIs) provided by the device., Method: As part of the large population-based Leipzig Research Centre for Civilization Diseases (LIFE) Adult-Study, randomly selected participants from Leipzig, Germany were evaluated with the ZEISS IOLMaster 700. Age range was 26-85 years, with 53% of participants above 70 years of age. Axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT) and keratometry (K) were assessed in 1767 right eyes. Measurements were repeated twice and in a subset of 1331 eyes, three times. Measurement feasibility was evaluated for three levels; successful, with warnings and failed, using the inbuilt QIs. Repeatability was assessed as within-subject standard deviation (SD) and repeatability limits were calculated., Results: First measurement success rate for phakic eyes was over 99% for AL, CCT, ACD, over 98% for LT and over 97% for K. K had 16% eyes with warnings and the recommendation to repeat the measurement. Excluding the measurements with warnings resulted in a reduction of mean SD for AL from 48 to 4 μm and for mean K from 0.08 to 0.04 D. Repeatability for phakic eyes was 8 μm for AL, CCT, ACD and LT and 2.3 μm for CCT; 0.07 D and 0.12 D for mean K and delta K, respectively, for phakic cases without warnings (two measurements)., Conclusions: In our population-based sample, the IOLMaster 700 collected data for AL, CCT, ACD, LT and K from the vast majority of eyes. Considering the built-in QIs improved the measurement variability substantially. Repeatability measurements indicate that clinically meaningful changes can be detected reliably with this instrument., (© 2023 The Authors. Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.)

(1) Background: Several lines of evidence established a link between high-risk (HR) sexual behavior (SB), the persistence of human papillomavirus (HPV) DNA in saliva, and the presence of oncogenic HR-HPV subtypes in oropharyngeal squamous cell carcinoma (OPSCC). A highly influential case-control study by D'Souza et al. comparing OPSCC patients and ENT patients with benign diseases (hospital controls) established HR-SB as a putative etiological risk factor for OPSCC. Aiming to replicate their findings in a nested case-control study of OPSCC patients and propensity score (PS)-matched unaffected controls from a large population-based German cohort study, we here demonstrate discrepant findings regarding HR-SB in OPSCC. (2) Methods: According to the main risk factors for HNSCC (age, sex, tobacco smoking, and alcohol consumption) PS-matched healthy controls invited from the population-based cohort study LIFE and HNSCC (including OPSCC) patients underwent interviews, using AUDIT and Fagerström, as well as questionnaires asking for SB categories as published. Afterwards, by newly calculating PSs for the same four risk factors, we matched each OPSCC patient with two healthy controls and compared responses utilizing chi-squared tests and logistic regression. (3) Results: The HNSCC patients and controls showed significant differences in sex distribution, chronologic age, tobacco-smoking history (pack years), and alcohol dependence (based on AUDIT score). However, PS-matching decreased the differences between OPSCC patients and controls substantially. Despite confirming that OPSCC patients were more likely to self-report their first sexual intercourse before age 18, we found no association between OPSCC and HR-SB, neither for practicing oral-sex, having an increased number of oral- or vaginal-sex partners, nor for having casual sex or having any sexually transmitted disease. (4) Conclusions: Our data, by showing a low prevalence of HR-SB in OPSCC patients, confirm findings from other European studies that differ substantially from North American case-control studies. HR-SB alone may not add excess risk for developing OPSCC.

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10 -8 ) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Family history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment., Methods: Analyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses., Results: Higher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%-12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect., Discussion: The present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent., Competing Interests: HG has received travel grant and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. The authors KB, AAK, RTM, SW, FS declare that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflict of interest., (© 2023 Streit, Völker, Klinger-König, Zillich, Frank, Reinhard, Foo, Witt, Sirignano, Becher, Obi, Riedel, Do, Castell, Hassenstein, Karch, Stang, Schmidt, Schikowski, Stahl-Pehe, Brenner, Perna, Greiser, Kaaks, Michels, Franzke, Peters, Fischer, Konzok, Mikolajczyk, Führer, Keil, Fricke, Willich, Pischon, Völzke, Meinke-Franze, Hoffmann, Löffler, Wirkner, Berger, Grabe and Rietschel.)

The largest publicly funded project to generate a German-language medical text corpus will start in mid-2023. GeMTeX comprises clinical texts from information systems of six university hospitals, which will be made accessible for NLP by annotation of entities and relations, which will be enhanced with additional meta-information. A strong governance provides a stable legal framework for the use of the corpus. State-of-the art NLP methods are used to build, pre-annotate and annotate the corpus and train language models. A community will be built around GeMTeX to ensure its sustainable maintenance, use, and dissemination.

Background: Despite standard treatments including chemoradiotherapy with temozolomide (TMZ) (STUPP protocol), the prognosis of glioblastoma patients remains poor. AGuIX nanoparticles have a high radiosensitizing potential, a selective and long-lasting accumulation in tumors and a rapid renal elimination. Their therapeutic effect has been proven in vivo on several tumor models, including glioblastoma with a potential synergetic effect when combined with TMZ based chemoradiotherapy, and they are currently evaluated in 4 ongoing Phase Ib and II clinical trials in 4 indications (brain metastases, lung, pancreatic and cervix cancers) (> 100 patients received AGuIX). Thus, they could offer new perspectives for patients with newly diagnosed glioblastoma. The aim of this study is to determine the recommended dose of AGuIX as a radiosensitizer in combination with radiotherapy and TMZ during the concurrent radio-chemotherapy period for phase II (RP2D) and to estimate the efficacy of the combination., Methods: NANO-GBM is a multicenter, phase I/II, randomized, open-label, non-comparative, therapeutic trial. According to a dose escalation scheme driven by a TITE-CRM design, 3 dose levels of AGuIX (50, 75 and 100 mg/kg) will be tested in phase I added to standard concomitant radio-chemotherapy. Patients with grade IV glioblastoma, not operated or partially operated, with a KPS ≥ 70% will be eligible for the study. The primary endpoints are i) for phase I, the RP2D of AGuIX, with DLT defined as any grade 3-4 NCI-CTCAE toxicity and ii) for phase II, the 6-month progression-free survival rate. The pharmacokinetics, distribution of nanoparticles, tolerance of the combination, neurological status, overall survival (median, 6-month and 12-month rates), response to treatment, and progression-free survival (median and 12-month rates) will be assessed as secondary objectives. Maximum sixty-six patients are expected to be recruited in the study from 6 sites., Discussion: The use of AGuIX nanoparticles could allow to overpass the radioresistance to the reference treatment of newly diagnosed glioblastomas that have the poorest prognosis (incomplete resection or biopsy only)., Trial Registration: Clinicaltrials.gov: NCT04881032 , registered on April 30, 2021. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°Eudra CT 2020-004552-15., Protocol: version 3, 23 May 2022., (© 2023. The Author(s).)

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants ( path&#95;MMR ) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time., Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path&#95;MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender., Findings: Gynaecological cancers were more frequent than colorectal cancers in path&#95;MSH2, path&#95;MSH6 and path&#95;PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path&#95;MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path&#95;MMR carriers undergoing colonoscopy surveillance, particularly path&#95;MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers., Interpretation: In path&#95;MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome., Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017., Competing Interests: R.B. has received honoraria for lectures and advisory boards from AbbVie, Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Illumina, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, and Targos MP Inc. R.B. is a Co-Founder and Scientific Advisor for Targos Mol. Pathology Inc. Kassel/Germany. T.T.S. is the CEO and co-owner of Healthfund Finland Oy and reports consultation fees from Boehringer Ingelheim Finland and Amgen. FB is supported by JANSSEN PHARMACEUTICALS (clinical trial for Familial Adenomatous polyposis). RH is supported by the 10.13039/501100002424Fujifilm Germany and Janssen-Pharmaceuticals. LK is consultant of Sandoz, Novartis and Abbott. GM reports consultancy fees from Johnson & Johnson., (© 2023 The Author(s).)

Exposure to environmental factors is generally expected to cause degradation in perovskite films and solar cells. Herein, we show that films with certain defect profiles can display the opposite effect, healing upon exposure to oxygen under illumination. We tune the iodine content of methylammonium lead triiodide perovskite from understoichiometric to overstoichiometric and expose them to oxygen and light prior to the addition of the top layers of the device, thereby examining the defect dependence of their photooxidative response in the absence of storage-related chemical processes. The contrast between the photovoltaic properties of the cells with different defects is stark. Understoichiometric samples indeed degrade, demonstrating performance at 33% of their untreated counterparts, while stoichiometric samples maintain their performance levels. Surprisingly, overstoichiometric samples, which show low current density and strong reverse hysteresis when untreated, heal to maximum performance levels (the same as untreated, stoichiometric samples) upon the photooxidative treatment. A similar, albeit smaller-scale, effect is observed for triple cation and methylammonium-free compositions, demonstrating the general application of this treatment to state-of-the-art compositions. We examine the reasons behind this response by a suite of characterization techniques, finding that the performance changes coincide with microstructural decay at the crystal surface, reorientation of the bulk crystal structure for the understoichiometric cells, and a decrease in the iodine-to-lead ratio of all films. These results indicate that defect engineering is a powerful tool to manipulate the stability of perovskite solar cells., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The COVID-19 pandemic has led to contentious discourse regarding unproven COVID-19 therapies (UCTs),(e.g. ivermectin). Despite recommendations against it, ivermectin remains, in some areas, highly demanded. The goal of this study is to understand patient and provider perspectives about UCTs (e.g., ivermectin) and how responses to requests for UCTs impact healthcare distrust. This mixed methods observational study was conducted in a rural healthcare system in the Southern United States. Adults (n = 26) with a history of COVID-19 or clinicians (n = 8) from the same system were interviewed using questionnaires assessing healthcare distrust and qualitatively interviewed exploring perceptions about UCTs. Patient themes were: 1) Importance of anecdotal stories for decision-making; 2) Use of haphazard approaches to 'research'; 3) Strong distrust of government and healthcare organizations; 4) Inherent trust in local healthcare; 5) Decision-making as weighing pros/cons; and 6) Feeling a right to try medications. High survey medians indicated high distrust with differences of 8.5 points for those who requested/used ivermectin versus those who did not (p = 0.027). Clinician themes were: 1) Frustration when patients trust social media over clinicians; 2) Acceptance of community beliefs about UCTs; 3) Distrust originating outside of the healthcare system; 4) Feeling torn about prescribing UCTs to build trust; and 5) Variable educational strategies. When clinicians are perceived as aligned with government, this may void patients' trust of clinicians. Clinicians should leverage trust in local healthcare and distance themselves from distrusted information sources. Ethical questions arise regarding appropriateness of acquiescing to patient requests for ivermectin for building trust., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery., Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism., Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., (© 2022. The Author(s).)

Background: Clinical trials, epidemiological studies, clinical registries, and other prospective research projects, together with patient care services, are main sources of data in the medical research domain. They serve often as a basis for secondary research in evidence-based medicine, prediction models for disease, and its progression. This data are often neither sufficiently described nor accessible. Related models are often not accessible as a functional program tool for interested users from the health care and biomedical domains., Objective: The interdisciplinary project Leipzig Health Atlas (LHA) was developed to close this gap. LHA is an online platform that serves as a sustainable archive providing medical data, metadata, models, and novel phenotypes from clinical trials, epidemiological studies, and other medical research projects., Methods: Data, models, and phenotypes are described by semantically rich metadata. The platform prefers to share data and models presented in original publications but is also open for nonpublished data. LHA provides and associates unique permanent identifiers for each dataset and model. Hence, the platform can be used to share prepared, quality-assured datasets and models while they are referenced in publications. All managed data, models, and phenotypes in LHA follow the FAIR principles, with public availability or restricted access for specific user groups., Results: The LHA platform is in productive mode (https://www.health-atlas.de/). It is already used by a variety of clinical trial and research groups and is becoming increasingly popular also in the biomedical community. LHA is an integral part of the forthcoming initiative building a national research data infrastructure for health in Germany., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)