Biomarkers Improve Diagnostics of Sepsis in Adult Patients With Suspected Organ Dysfunction Based on the Quick Sepsis-Related Organ Failure Assessment (qSOFA) Score in the Emergency Department.

OBJECTIVES: Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool. DESIGN: In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission. SETTING: Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin). PATIENTS: One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79-0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively. CONCLUSIONS: Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission.

The effect of romosozumab on bone mineral density depending on prior treatment: a prospective, multicentre cohort study in Switzerland.

This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. INTRODUCTION: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies. METHODS: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients. RESULTS: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level. CONCLUSION: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.

Artery Tertiary Lymphoid Organs Control Aorta Immunity and Protect against Atherosclerosis via Vascular Smooth Muscle Cell Lymphotoxin ß Receptors.

Tertiary lymphoid organs (TLOs) emerge during nonresolving peripheral inflammation, but their impact on disease progression remains unknown. We have found in aged Apoe(-/-) mice that artery TLOs (ATLOs) controlled highly territorialized aorta T cell responses. ATLOs promoted T cell recruitment, primed CD4(+) T cells, generated CD4(+), CD8(+), T regulatory (Treg) effector and central memory cells, converted naive CD4(+) T cells into induced Treg cells, and presented antigen by an unusual set of dendritic cells and B cells. Meanwhile, vascular smooth muscle cell lymphotoxin ß receptors (VSMC-LTßRs) protected against atherosclerosis by maintaining structure, cellularity, and size of ATLOs though VSMC-LTßRs did not affect secondary lymphoid organs: Atherosclerosis was markedly exacerbated in Apoe(-/-)Ltbr(-/-) and to a similar extent in aged Apoe(-/-)Ltbr(fl/fl)Tagln-cre mice. These data support the conclusion that the immune system employs ATLOs to organize aorta T cell homeostasis during aging and that VSMC-LTßRs participate in atherosclerosis protection via ATLOs.

Trajectories of pain and opioid use up to one year after surgery: analysis of a European registry.

BACKGROUND: Long-term opioid use after surgery is a crucial healthcare problem in North America. Data from European hospitals are scarce and differentiation of chronic pain has rarely been considered. METHODS: In a mixed surgical cohort of the PAIN OUT registry, opioid use and chronic pain were evaluated before surgery, and 6 and 12 months after surgery (M6/M12). Subgroups with or without opioid medication and pre-existing chronic pain were analysed. M12-chronic pain was categorised as chronic postsurgical pain (CPSP) meeting the ICD-11 definition, chronic pain related to surgery not meeting the ICD-11 definition, and chronic pain unrelated to surgery. Primary endpoint was the rate of M12 opioid users. Variables associated with M12 opioid use and patient-reported outcomes were evaluated. RESULTS: Of 2326 patients, 5.5% were preoperative opioid users; 4.4% and 3.5% took opioids at M6 and M12 (P<0.001). Chronic pain before operation and at M6/M12 was reported by 41.2%, 41.8%, and 34.7% of patients, respectively (P<0.001). The rate of M12 opioid users was highest in group unrelated (22.3%; related 8.3%, CPSP 1.5%; P<0.001). New opioid users were 1.1% (unrelated 7.1%, related 2.3%, CPSP 0.7%; P<0.001). M12 opioid users reported more pain, pain-related physical and affective interference, and needed more opioids than non-users. The predominant variable associated with M12 opioids was preoperative opioid use (estimated odds ratio [95% confidence interval]: 28.3 [14.1-56.7], P<0.001). CONCLUSIONS: Opioid use was low in patients with CPSP, and more problematic in patients with chronic pain unrelated to surgery. A detailed assessment of chronic pain unrelated or related to surgery or CPSP is necessary. CLINICAL TRIAL REGISTRATION: NCT02083835.

Child abuse and neglect: A comparative study between dental and medical students' competencies in Germany.

INTRODUCTION: Despite children's right to a non-violent upbringing, they become daily victims of violence. Physical violence concerns mostly the head-especially the orofacial area. Therefore, dentists and paediatricians should be able to suspect possible abuse and to initiate child protection. This study aimed to record and compare the training situation and competencies of dental and medical students at Jena University Hospital regarding child abuse and neglect (CAN). MATERIALS AND METHODS: Using a three-part questionnaire about CAN, 123 medical and 77 dental students were surveyed anonymously after completing all courses on the topic. The question sets included as follows: (1) educational experiences, training content and satisfaction; (2) current knowledge regarding diagnostic, management and legal concerns; (3) self-evaluation, needs of further education and wishes. Reliability of the questionnaire was tested with kappa-statistics and assessed as good. RESULTS: Dental and medical students' overall satisfaction with CAN-related training is low. Although medical students had more knowledge on CAN, all participants showed large deficits. Better diagnostic than management skills were reported in both groups. Only 1.3% dental and 16.3% medical students felt adequately prepared to deal with CAN. 7% of all study participants stated that they can report CAN without any help. 87.0% of medical and 79.2% of dental students expressed a desire for further education. To improve their knowledge, both courses prefer seminars, followed by expert talks, lectures and simulation-based training (SkillsLab). CONCLUSION: Dental and medical students are inadequately prepared to suspect possible abuse and to deal with possible signs of CAN. Mandatory interdisciplinary courses and lectures addressing CAN are recommendable for both medical and dental curricula.

Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis (REMOVE): Results From a Multicenter Randomized Controlled Trial.

BACKGROUND: Cardiac surgery often represents the only treatment option in patients with infective endocarditis (IE). However, IE surgery may lead to a sudden release of inflammatory mediators, which is associated with postoperative organ dysfunction. We investigated the effect of hemoadsorption during IE surgery on postoperative organ dysfunction. METHODS: This multicenter, randomized, nonblinded, controlled trial assigned patients undergoing cardiac surgery for IE to hemoadsorption (integration of CytoSorb to cardiopulmonary bypass) or control. The primary outcome (change in sequential organ failure assessment score [ΔSOFA]) was defined as the difference between the mean total postoperative SOFA score, calculated maximally to the 9th postoperative day, and the basal SOFA score. The analysis was by modified intention to treat. A predefined intergroup comparison was performed using a linear mixed model for ΔSOFA including surgeon and baseline SOFA score as fixed effect covariates and with the surgical center as random effect. The SOFA score assesses dysfunction in 6 organ systems, each scored from 0 to 4. Higher scores indicate worsening dysfunction. Secondary outcomes were 30-day mortality, duration of mechanical ventilation, and vasopressor and renal replacement therapy. Cytokines were measured in the first 50 patients. RESULTS: Between January 17, 2018, and January 31, 2020, a total of 288 patients were randomly assigned to hemoadsorption (n=142) or control (n=146). Four patients in the hemoadsorption and 2 in the control group were excluded because they did not undergo surgery. The primary outcome, ΔSOFA, did not differ between the hemoadsorption and the control group (1.79±3.75 and 1.93±3.53, respectively; 95% CI, -1.30 to 0.83; P=0.6766). Mortality at 30 days (21% hemoadsorption versus 22% control; P=0.782), duration of mechanical ventilation, and vasopressor and renal replacement therapy did not differ between groups. Levels of interleukin-1ß and interleukin-18 at the end of integration of hemoadsorption to cardiopulmonary bypass were significantly lower in the hemoadsorption than in the control group. CONCLUSIONS: This randomized trial failed to demonstrate a reduction in postoperative organ dysfunction through intraoperative hemoadsorption in patients undergoing cardiac surgery for IE. Although hemoadsorption reduced plasma cytokines at the end of cardiopulmonary bypass, there was no difference in any of the clinically relevant outcome measures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03266302.

Comparison of anti-fracture effectiveness of zoledronate, ibandronate and alendronate versus denosumab in a registry-based cohort study.

This registry-based study of 3068 patients with osteoporosis compared the anti-fracture effectiveness of denosumab versus bisphosphonates. Denosumab was associated with significantly greater risk reduction than alendronate or ibandronate for vertebral and any fractures. No difference in fracture risk reduction was found between zoledronate and denosumab. PURPOSE: To analyse the fracture risk of patients with osteoporosis receiving bisphosphonates or denosumab in a real-world setting. METHODS: This registry-based cohort study evaluated patients taking denosumab, bisphosphonates or both sequentially. Fractures were analysed using rates, rate ratios and hazard ratios (HR), including both therapies as time-varying co-variates. Fracture risk hazards were adjusted (aHR) for baseline T-Scores and trabecular bone score (TBS) and were additionally analysed with inverse probability treatment weighting. RESULTS: A total of 3068 patients (89% female; median age at treatment onset, 69 years [63 to 76]) received denosumab (median duration 2.8 years, [2.2 to 4.7]), bisphosphonates (3.4 years, [2.1 to 5.7]) or both sequentially. Thus, 11,078 subject-years were assessed for bisphosphonates (41% alendronate, 36% ibandronate, 23% zoledronate) and 4216 for denosumab. Moreover, 48,375 subject-years were observed before treatment onset, in addition to 2593 years of drug holidays. A total of 1481 vertebral fractures (435 under therapy), 1508 non-vertebral fractures (499 under therapy) and 202 hip fractures (67 under therapy) occurred after age 50. The risks of vertebral, non-vertebral and hip fractures were significantly lower under all bisphosphonates, denosumab and drug holidays than before treatment onset (all p < 0.001). After adjusting for age, baseline T-scores and TBS, denosumab was associated with lower risk than alendronate or ibandronate for vertebral fractures (aHR 0.47 (0.35 to 0.64) and 0.70 [0.53 to 0.91], p < 0.001 and p = 0.009, respectively) and any fractures (aHR 0.62 [0.51 to 0.76] and 0.77 [0.64 to 0.92], p < 0.001 and p = 0.004). With propensity weighting, denosumab was associated with a lower hip fracture risk compared to alendronate (HR 0.54 [0.29 to 0.98], p = 0.044). No difference in fracture risk reduction (vertebral, non-vertebral or hip) was found between zoledronate and denosumab. CONCLUSIONS: When adjusting for disease severity, denosumab was associated with significantly greater risk reduction than alendronate and ibandronate for vertebral fractures. No difference in fracture risk reduction was found between zoledronate and denosumab.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

Analgesic use and favourable patient-reported outcome measures after paediatric surgery: an analysis of registry data.

BACKGROUND: Pain after paediatric appendectomy and tonsillectomy is often undertreated. Benchmarking of hospitals could reveal which measures are associated with improved patient- or parent-reported pain-related outcomes. METHODS: A total of 898 anonymised cases from 11 European hospitals participating in PAIN OUT infant were analysed. The children completed a questionnaire on patient-reported outcomes (PROs) 24 h after surgery. According to a composite PRO measure, including pain intensity and pain-related interference, hospitals were allocated to Group I (favourable results), II (average results), and III (unfavourable results). Benchmarking of hospital groups was performed investigating process variables (dosing of non-opioid analgesics, opioids, and dexamethasone) associated with PROs, side-effects, and children's perception of care. Variables associated with PROs were analysed using multinomial regression analysis with the PRO score-related hospital group as a dependent variable (estimated odds ratios [OR], 95% confidence interval [CI]). RESULTS: During the first 24 h after surgery, 1.2 (1.1-1.3) full daily doses of non-opioid analgesics (non-steroidal anti-inflammatory drug [NSAID], paracetamol, metamizole) were administered in group I and 0.7 (0.6-0.8) in group III (P<0.001). Intraoperative dexamethasone was administered to 70.1 and 52.6% of the children in Group I and Group III, respectively (P<0.001). A lower number of full daily doses of non-opioid analgesics: 0.22 [0.15-0.31]), less dexamethasone (0.49 [0.33-0.71]), fewer non-opioid analgesics before the end of surgery (0.37 [0.22-0.62]) and higher opioid doses were associated with hospital allocation to group III vs group I (Nagelkerke's R2=0.433). CONCLUSIONS: The results indicated substantial deficits in the concept, application, and dosing of analgesics in paediatric patients after surgery. Timely administration of adequate analgesic doses can easily be introduced into daily clinical practice. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT02083835.

Amniotic fluid content in children with kidney and urinary tract anomalies determines pre- and postnatal development.

BACKGROUND: Renal oligohydramnios (ROH) describes an abnormally low volume of amniotic fluid (AF) during pregnancy. ROH is mostly caused by congenital fetal kidney anomalies. The ROH diagnosis frequently implies an increased risk of peri- and postnatal fetal mortality and morbidity. The present study aimed to evaluate the impact of ROH on pre-and postnatal development in children with congenital kidney anomalies. METHODS: This retrospective study included 168 fetuses with anomalies in the kidney and urinary tract. Based on the amount of AF measured by ultrasound, patients were divided into three groups: normal amniotic fluid (NAF), amniotic fluid in the lower normal range (LAF), and ROH. These groups were compared with respect to prenatal sonographic parameters, perinatal outcomes, and postnatal outcomes. RESULTS: Among the 168 patients with congenital kidney anomalies, 26 (15%) had ROH, 132 (79%) had NAF, and 10 (6%) had LAF. Of the 26 families affected by ROH, 14 (54%) decided to terminate pregnancy. Of 10 live-born children in the ROH group, 6 (60%) survived the observation time; of these, 5/6 presented with chronic kidney disease, stages I-III, at their last examination. The main differences in postnatal development between the ROH group and the NAF and LAF groups were: restricted height and weight gain, respiratory issues, complicated feeding, and the presence of extrarenal malformations. CONCLUSIONS: ROH is not a mandatory indicator of severe postnatal kidney function impairment. However, children with ROH have complicated peri-and postnatal periods, due to the presence of concomitant malformations, which must be considered in prenatal care. A higher resolution version of the Graphical abstract is available as Supplementary information.

Structural characteristics and contractual terms of specialist palliative homecare in Germany.

BACKGROUND: Multi-professional specialist palliative homecare (SPHC) teams care for palliative patients with complex symptoms. In Germany, the SPHC directive regulates care provision, but model contracts for each federal state are heterogeneous regarding staff requirements, cooperation with other healthcare providers, and financial reimbursement. The structural characteristics of SPHC teams also vary. AIM: We provide a structured overview of the existing model contracts, as well as a nationwide assessment of SPHC teams and their structural characteristics. Furthermore, we explore whether these characteristics serve to find specifc patterns of SPHC team models, based on empirical data. METHODS: This study is part of the multi-methods research project "SAVOIR", funded by the German Innovations Fund. Most model contracts are publicly available. Structural characteristics (e.g. number, professions, and affiliations of team members, and external cooperation) were assessed via an online database ("Wegweiser Hospiz- und Palliativversorgung") based on voluntary information obtained from SPHC teams. All the data were updated by phone during the assessment process. Data were descriptively analysed regarding staff, cooperation requirements, and reimbursement schemes, while latent class analysis (LCA) was used to identify structural team models. RESULTS: Model contracts have heterogeneous contract partners and terms related to staff requirements (number and qualifications) and cooperation with other services. Fourteen reimbursement schemes were available, all combining different payment models. Of the 283 SPHC teams, 196 provided structural characteristics. Teams reported between one and 298 members (mean: 30.3, median: 18), mainly nurses and physicians, while 37.8% had a psychosocial professional as a team member. Most teams were composed of nurses and physicians employed in different settings; for example, staff was employed by the team, in private practices/nursing services, or in hospitals. Latent class analysis identified four structural team models, based on the team size, team members' affiliation, and care organisation. CONCLUSION: Both the contractual terms and teams' structural characteristics vary substantially, and this must be considered when analysing patient data from SPHC. The identified patterns of team models can form a starting point from which to analyse different forms of care provision and their impact on care quality.

[A regional comparison of outcomes quality and costs of general and specialized palliative care in Germany: a claims data analysis]. / Ergebnisqualität und Kosten der allgemeinen und spezialisierten Palliativversorgung in Deutschland im regionalen Vergleich: eine GKV-Routinedatenstudie.

BACKGROUND: The main framework conditions for palliative care are set at the regional level. The scope of the forms of care used (outpatient, inpatient, general, specialized) varies widely. What is the quality of outcomes achieved by the palliative care provided on a federal states level? What are the associated costs of care? METHOD: Retrospective observational study using BARMER claims data from 145,372 individuals who died between 2016 and 2019 and had palliative care in the last year of life. Regional comparison with regard to the following outcomes: proportion of palliative care patients who died in the hospital, potentially burdensome care in the last 30 days of life (ambulance calls, [intensive care] hospitalizations, chemotherapy, feeding tubes, parenteral nutrition), total cost of care (last three months), cost of palliative care (last year), and cost-effectiveness ratios. Calculation of patient/resident characteristic adjusted rates, costs, and ratios. RESULTS: Federal states vary significantly with respect to the outcomes (also adjusted) of palliative care. Palliative care costs vary widely, most strongly for specialized outpatient palliative care (SAPV). Across all indicators and the cost-effectiveness ratio of total cost of care to at-home deaths, Westphalia-Lippe shows favorable results. CONCLUSION: Regions with better quality and more favorable cost (ratios) can provide guidance for other regions. The extent to which the new federal SAPV agreement can incorporate the empirical findings should be reviewed. Patient-relevant outcome parameters should be given greater weight than parameters aiming at structures of care.

Reconstruction of evolutionary changes in fat and toxin consumption reveals associations with gene losses in mammals: A case study for the lipase inhibitor PNLIPRP1 and the xenobiotic receptor NR1I3.

The inactivation of ancestral protein-coding genes (gene loss) can be associated with phenotypic modifications. Within placental mammals, repeated losses of PNLIPRP1 (gene inhibiting fat digestion) occurred preferentially in strictly herbivorous species, whereas repeated NR1I3 losses (gene involved in detoxification) occurred preferentially in strictly carnivorous species. It was hypothesized that lower fat contents of herbivorous diets and lower toxin contents of carnivorous diets cause relaxed selection pressure on these genes, resulting in the accumulation of mutations and ultimately to convergent gene losses. However, because herbivorous and carnivorous diets differ vastly in their composition, a fine-grained analysis is required for hypothesis testing. We generated a trait matrix recording diet and semi-quantitative estimates of fat and toxin consumption for 52 placental species. By including data from 31 fossil taxa, we reconstructed the ancestral diets in major lineages (grundplan reconstruction). We found support that PNLIPRP1 loss is primarily associated with low levels of fat intake and not simply with herbivory/carnivory. In particular, PNLIPRP1 loss also occurred in carnivorous lineages feeding on a fat-poor diet, suggesting that the loss of this gene may be beneficial for occupying ecological niches characterized by fat-poor food resources. Similarly, we demonstrated that carnivorous species are indeed less exposed to diet-related toxins, suggesting that the loss of NR1I3 and related genes (NR1I2 and UGT1A6) resulted from relaxed selection pressure. This study illustrates the need of detailed phenotype studies to obtain a deeper understanding of factors underlying gene losses and to progress in understanding genomic causes of phenotypic variation in mammals.

Bone Mass Gains After One Denosumab Injection Followed by Zoledronate.

Denosumab discontinuation can lead to bone loss despite subsequent bisphosphonate therapy. This bone loss is more severe in patients treated with denosumab for longer than 3 years. We aimed to evaluate the bone mass changes after only a single denosumab injection followed by zoledronate administration. We screened all of our patients who received a single denosumab injection and who were included in the osteoporosis register from the Swiss Society of Rheumatology between August 1, 2010, and January 31, 2022. This case series assessed the outcome of patients who were consecutively treated with one denosumab injection followed by a single infusion of zoledronate 6 months later. Bone mineral density (BMD) and bone turnover markers (BTM) changes were analysed before therapy and 18 months later. Percentage BMD changes and T-scores were compared with those of registered patients who received 2.5 years of denosumab treatment and one subsequent infusion of zoledronate. Thirty-two patients (31 female, 1 male) received a single denosumab injection and one zoledronate infusion 6 months later. BTM decreased significantly in this period (p = 0.035). Percentage BMD changes from baseline to 1 year after zoledronate treatment were 7.6% [IQR 3.2, 9.4] at the lumbar spine, 3.5% [1.8, 5.9] at the total hip and 4.6% [1.3, 6.0] at the femoral neck. In contrast, percentage changes from baseline in 110 patients with 2.5 years of denosumab treatment and one zoledronate infusion were 5.6% [3.0, 9.1], 2.3% [0.2, 4.9] and 2.3% [-0.9, 4.7], respectively. Differences between the 2 groups were significant at the lumbar spine (p = 0.014), total hip (p = 0.010) and femoral neck (p = 0.010). A single denosumab injection followed by zoledronate led to a remarkable gain of BMD at the lumbar spine and hip within a short time. This observation could help to identify a new short treatment sequence for patients with osteoporosis.

Predictors of a successful vaginal delivery in women with type 1 diabetes: a retrospective analysis of 20 years.

PURPOSE: To evaluate the independent factors associated with the success of a trial of vaginal birth (TVB) in women with type 1 diabetes. Despite all therapeutic efforts and technological innovations, rates of caesarean sections (CS) in pregnant women with type 1 diabetes remain unchanged above 60%. Our aim was to point out influencing factors to improve the quality of antepartum counseling. METHODS: We performed a retrospective cohort study of 195 pregnancies with type 1 diabetes treated between 2000 and 2019. After exclusions, 118 women with near-term singleton pregnancies intended vaginal birth (TVB). Group differences between CS and successful vaginal delivery were analyzed. Multivariate logistic regression was performed by including clinical and metabolic variables to determine the independent effects on a successful vaginal delivery. Subgroup analysis for nulliparous women. RESULTS: Of 118 women with TVB, 67 (56.8%) were delivered vaginally. History of previous vaginal delivery (OR 10.29; CI 2.39; 44.30), HbA1c changes during pregnancy (per % increase; OR 0.59; CI 0.36; 0.96) and gestational weight gain (per kg; OR 0.87; CI 0.80; 0.96) were independent predictors for a successful vaginal delivery. In nulliparous women, the duration of diabetes was independently and negatively associated with vaginal delivery. CONCLUSION: Provided data can help to improve antepartum counseling in type 1 diabetic patients. It seems that women with type 1 diabetes should avoid postponing pregnancy and childbirth.

Shear bond strength after using sealant before bonding: a systematic review and meta-analysis of in vitro studies.

OBJECTIVES: Decalcification during orthodontic treatment is significantly increased. To prevent this negative impact, new treatments with sealants before bonding brackets are commonly been used. This systematic review discusses current knowledge on shear bond strength when using sealant before bonding. MATERIALS AND METHODS: A systematic review and meta-analysis were performed to identify studies that address shear bond strength after using a sealant before bonding brackets. The search was carried out using common electronic databases in addition to individual searches. Both screening and study eligibility analysis were performed according to PRISMA and Cochrane Guidelines for systematic reviews. Several terms describing shear bond strength after using a sealant before bonding brackets were searched. Particular attention was paid to bond failure and bracket loss. For the statistical outcome, all results were shown in a forest plot based on standardized mean differences (SMD) with a random-effects model to respect heterogeneity of these studies. To assess the heterogeneity of the different trials, I2-value and the Q-Test were performed. RESULTS: The initial search identified 416 studies. After a thorough selection process, a total of 15 articles met the inclusion criteria. All 15 articles reported results of in vitro studies. Papers were divided into four subgroups according to their used product: ProSeal, Transbond bonding, the combination of Transbond bonding and ProSeal and Clearfil Protect Bond. The results of this review demonstrate a high heterogeneity of the studies. The SMD of the examined 15 articles show nearly no difference between the control and the intervention groups in shear bond strength (p < 0.0001; OR - 0.12; Cl - 0.47-0.23). Forest plots for comparison of the subgroups depict no difference in shear bond strength as well. CONCLUSIONS: This meta-analysis concludes that there is no additive benefit for shear bond strength when using sealant before bonding. However, additional randomized controlled studies should be performed to analyze impact of sealants on bonding strength and bracket loss in more detail. CLINICAL RELEVANCE: Using sealants before orthodontic bonding does not reduce shear bond strength.

Elevated Levels of Toxic Bile Acids in Serum of Cystic Fibrosis Patients with CFTR Mutations Causing Pancreatic Insufficiency.

Hepatobiliary involvement is a hallmark in cystic fibrosis (CF), as the causative CF Transmembrane Conductance Regulator (CFTR) defect is expressed in the biliary tree. However, bile acid (BA) compositions in regard to pancreatic insufficiency, which is present at an early stage in about 85% of CF patients, have not been satisfactorily understood. We assess the pattern of serum BAs in people with CF (pwCF) without CFTR modulator therapy in regard to pancreatic insufficiency and the CFTR genotype. In 47 pwCF, 10 free and 12 taurine- and glycine-conjugated BAs in serum were prospectively assessed. Findings were related to genotype, pancreatic insufficiency prevalence (PIP)-score, and hepatic involvement indicated by serum liver enzymes, as well as clinical and ultrasound criteria for CF-related liver disease. Serum concentrations of total primary BAs and free cholic acid (CA) were significantly higher in pwCF with higher PIP-scores (p = 0.025, p = 0.009, respectively). Higher total BAs were seen in pwCF with PIP-scores ≥0.88 (p = 0.033) and with pancreatic insufficiency (p = 0.034). Free CA was higher in patients with CF-related liver involvement without cirrhosis, compared to pwCF without liver disease (2.3-fold, p = 0.036). pwCF with severe CFTR genotypes, as assessed by the PIP-score, reveals more toxic BA compositions in serum. Subsequent studies assessing changes in BA homeostasis during new highly effective CFTR-modulating therapies are of high interest.

[Patient group-specific data sovereignty needs and acceptance of electronic health records]. / Patientengruppenspezifische Datenhoheitsbedürfnisse und Akzeptanz der elektronischen Patientenakte.

BACKGROUND AND AIM: People in Germany are very sensitive about their health data. The electronic health record (ePA) also raises questions about the patient's need for data sovereignty and acceptance. The possibility of selectively withholding data stored in the ePA from physicians who continue to treat the patient (opt-out) and the patient's prior knowledge of the ePA could influence the need for data sovereignty and acceptance of the ePA. The aim of this explorative study is to investigate these influences for three patient groups: "acute patients," "diabetes type 2 patients," and "palliative patients," as differences are expected between these groups. MATERIALS AND METHODS: From August to October 2019, a quantitative survey was conducted among 140 patients in the abovementioned groups. RESULTS: Of the respondents, 76.0% supported the selective opt-out option and stated that this would increase their willingness to participate in the ePA. Specifically, 81.1% of acute care patients, 80.6% of palliative care patients, and 65.6% of type 2 diabetes patients made this statement. Differences between groups were not significant. A general prior knowledge of the ePA was related to a higher need for data sovereignty - 43.2% of those who had never heard of the ePA rollout would occasionally hide their health data from other physicians, compared with 54.5% who knew of the rollout. DISCUSSION: Consideration of the data sovereignty needs of patients in the further establishment of the ePA is recommended. The selective opt-out option can contribute to acceptance. Knowledge of the ePA should be expanded, especially in the doctor-patient discussion, to enable an informed decision.

Microglia-mediated phagocytosis of apoptotic nuclei is impaired in the adult murine hippocampus after stroke.

Following stroke, neuronal death takes place both in the infarct region and in brain areas distal to the lesion site including the hippocampus. The hippocampus is critically involved in learning and memory processes and continuously generates new neurons. Dysregulation of adult neurogenesis may be associated with cognitive decline after a stroke lesion. In particular, proliferation of precursor cells and the formation of new neurons are increased after lesion. Within the first week, many new precursor cells die during development. How dying precursors are removed from the hippocampus and to what extent phagocytosis takes place after stroke is still not clear. Here, we evaluated the effect of a prefrontal stroke lesion on the phagocytic activity of microglia in the dentate gyrus (DG) of the hippocampus. Three-months-old C57BL/6J mice were injected once with the proliferation marker BrdU (250 mg/kg) 6 hr after a middle cerebral artery occlusion or sham surgery. The number of apoptotic cells and the phagocytic capacity of the microglia were evaluated by means of immunohistochemistry, confocal microscopy, and 3D-reconstructions. We found a transient but significant increase in the number of apoptotic cells in the DG early after stroke, associated with impaired removal by microglia. Interestingly, phagocytosis of newly generated precursor cells was not affected. Our study shows that a prefrontal stroke lesion affects phagocytosis of apoptotic cells in the DG, a region distal to the lesion core. Whether disturbed phagocytosis might contribute to inflammatory- and maladaptive processes including cognitive impairment following stroke needs to be further investigated.

Exploring the ontogenetic development of the inner ear in Aardvarks.

The aardvark is the last living Tubulidentata, an order of afrotherian mammals. Afrotheria is supported strongly by molecular analyses, yet sparingly by morphological characters. Moreover, the biology of the aardvark remains incompletely known. The inner ear, and its ontogeny in particular, has not been studied in details yet, though it bears key ecomorphological characters and phylogenetical signal. The aim of this study is to decipher and discuss the ontogenetic development of the different areas of the inner ear of Orycteropus afer. We focused in particular on their relative size and morphological rates of development. Specimens were scanned with 3D imaging techniques. 3D and 2D geometric morphometrics coupled with qualitative descriptions of the petrosal ossification allowed us to evidence several stages through development. Based on our sample, the cochlea is the first structure of the inner ear to reach adult size, but it is the last one to acquire its adult morphology close to parturition. In contrast, after a delayed growth spurt, the semicircular canals reach their mature morphology before the cochlea, concomitantly with the increase of petrosal ossification. The ontogeny of the aardvark inner ear shows similarities with that of other species, but the apex of the cochlea presents some autapomorphies. This work constitutes a first step in the study of the ontogeny of this sensorial organ in Afrotheria.