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Both anxiety and depression are associated with lower self-perceived health status (HS) in persons with Parkinson's disease (PD). Given the high co-morbidity with depression and other non-motor symptoms, it is unclear whether anxiety disorders, in general, versus specific anxiety subtypes have an independent effect on HS in PD. To examine this question, comprehensive assessments of motor and non-motor symptoms from 249 subjects with idiopathic PD followed in three community-based movement disorders neurology practices were analyzed. HS was measured using the 8-item PD Questionnaire (PDQ-8). Psychiatric diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Stepwise multiple regression analyses were used, with the PDQ-8 score as the dependent variable, to identify independent predictors of HS among motor, psychiatric, and other non-motor variables. Among the anxiety disorders, only anxiety associated with motor fluctuations was an independent predictor of HS after accounting for co-morbid depression and other clinical features. In addition, depressive disorders were also an independent predictor of lower HS. Prevention or treatment of state-dependent anxiety may improve HS in persons with PD. [ABSTRACT FROM AUTHOR]

Bone is a natural mineral-organic nanocomposite protecting internal organs and allowing mobility. Through the ages, numerous strategies have been developed for repairing bone defects and fixing fractures. Several generations of bone repair biomaterials have been proposed, either based on metals, ceramics, glasses, or polymers, depending on the clinical need, the maturity of technologies, and knowledge of the natural constitution of the bone tissue to be repaired. The global trend in bone implant research is shifting toward osteointegrative, bioactive and possibly stimuli-responsive biomaterials and, where possible, resorbable implants that actively promote the regeneration of natural bone tissue. In this mini-review, the fundamentals of bone healing materials and clinical challenges are summarized and commented on with regard to progressing scientific discoveries. The main types of bone-healing materials are then reviewed, and their specific relevance to the field is reminded, with the citation of reference works. In the final part, we highlight the promise of hybrid organic-inorganic bioactive materials and the ongoing research activities toward the development of multifunctional or stimuli-responsive implants. This contribution is expected to serve as a commented introduction to the ever-progressing field of bone regeneration and highlight trends of future-oriented research.

From a game of darts to neurorehabilitation, the ability to explore and fine tune our movements is critical for success. Past work has shown that exploratory motor behaviour in response to reinforcement (reward) feedback is closely linked with the basal ganglia, while movement corrections in response to error feedback is commonly attributed to the cerebellum. While our past work has shown these processes are dissociable during adaptation, it is unknown how they uniquely impact exploratory behaviour. Moreover, converging neuroanatomical evidence shows direct and indirect connections between the basal ganglia and cerebellum, suggesting that there is an interaction between reinforcement-based and error-based neural processes. Here we examine the unique roles and interaction between reinforcement-based and error-based processes on sensorimotor exploration in a neurotypical population. We also recruited individuals with Parkinson's disease to gain mechanistic insight into the role of the basal ganglia and associated reinforcement pathways in sensorimotor exploration. Across three reaching experiments, participants were given either reinforcement feedback, error feedback, or simultaneously both reinforcement & error feedback during a sensorimotor task that encouraged exploration. Our reaching results, a re-analysis of a previous gait experiment, and our model suggests that in isolation, reinforcement-based and error-based processes respectively boost and suppress exploration. When acting in concert, we found that reinforcement-based and error-based processes interact by mutually opposing one another. Finally, we found that those with Parkinson's disease had decreased exploration when receiving reinforcement feedback, supporting the notion that compromised reinforcement-based processes reduces the ability to explore new motor actions. Understanding the unique and interacting roles of reinforcement-based and error-based processes may help to inform neurorehabilitation paradigms where it is important to discover new and successful motor actions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Roth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A large amount of research in orthopedic and maxillofacial domains is dedicated to the development of bioactive 3D scaffolds. This includes the search for highly resorbable compounds, capable of triggering cell activity and favoring bone regeneration. Considering the phosphocalcic nature of bone mineral, these aims can be achieved by the choice of amorphous calcium phosphates (ACPs). Because of their metastable property, these compounds are however to-date seldom used in bulk form. In this work, we used a non-conventional "cold sintering" approach based on ultrafast low-pressure RT compaction to successfully consolidate ACP pellets while preserving their amorphous nature (XRD). Complementary spectroscopic analyses (FTIR, Raman, solid-state NMR) and thermal analyses showed that the starting powder underwent slight physicochemical modifications, with a partial loss of water and local change in the HPO 4 2- ion environment. The creation of an open porous structure, which is especially adapted for non-load bearing bone defects, was also observed. Moreover, the pellets obtained exhibited sufficient mechanical resistance allowing for manipulation, surgical placement and eventual cutting/reshaping in the operation room. Three-dimensional porous scaffolds of cold-sintered reactive ACP, fabricated through this low-energy, ultrafast consolidation process, show promise toward the development of highly bioactive and tailorable biomaterials for bone regeneration, also permitting combinations with various thermosensitive drugs.

From a baby's babbling to a songbird practising a new tune, exploration is critical to motor learning. A hallmark of exploration is the emergence of random walk behaviour along solution manifolds, where successive motor actions are not independent but rather become serially dependent. Such exploratory random walk behaviour is ubiquitous across species' neural firing, gait patterns and reaching behaviour. The past work has suggested that exploratory random walk behaviour arises from an accumulation of movement variability and a lack of error-based corrections. Here, we test a fundamentally different idea-that reinforcement-based processes regulate random walk behaviour to promote continual motor exploration to maximize success. Across three human reaching experiments, we manipulated the size of both the visually displayed target and an unseen reward zone, as well as the probability of reinforcement feedback. Our empirical and modelling results parsimoniously support the notion that exploratory random walk behaviour emerges by utilizing knowledge of movement variability to update intended reach aim towards recently reinforced motor actions. This mechanism leads to active and continuous exploration of the solution manifold, currently thought by prominent theories to arise passively. The ability to continually explore muscle, joint and task redundant solution manifolds is beneficial while acting in uncertain environments, during motor development or when recovering from a neurological disorder to discover and learn new motor actions.

The newly evolved gene Heterochromatin Protein 6 ( HP6 ), which has been previously classified as essential, challenged the dogma that functions required for viability are only seen in genes with a long evolutionary history. Based on previous RNA-sequencing analysis in Drosophila germ cells, we asked whether HP6 might play a role in germline development. Surprisingly, we found that CRISPR-generated HP6 mutants are viable and fertile. Using previously generated mutants, we identified an independent lethal allele and an RNAi off-target effect that prevented accurate interpretation of HP6 essentiality. By reviewing existing data, we found that the vast majority of young genes that were previously classified as essential were indeed viable when tested with orthologous methods. Together, our data call into question the frequency with which newly evolved genes gain essential functions and suggest that using multiple independent genetic methods is essential when probing the functions of young genes.

Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis., Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19-78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression., Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes ( BRCA1 : n = 170 [10.6%]; BRCA2 : n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years ( n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21-1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years., Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed., Competing Interests: Christopher Schröder reports an institutional grant from Illumina and research grants from BMS Stiftung Immunonkologie outside the submitted work. Julia Gallwas is a member of the academic advisory board of the Bundesaerztekammer and was paid for lectures for Merck Sharp & Dohme and Roche Diagnostics between 2017 and 2019. All other authors have no conflicts to declare., (Copyright © 2023 by The Author(s). Published by S. Karger AG, Basel.)

Background : The Mediterranean diet (MD) is an anti-inflammatory diet linked to improved health-related quality of life (HRQoL). Germline (g) BRCA1/2 mutation carriers have an increased risk of developing breast cancer and are often exposed to severe cancer treatments, thus the improvement of HRQoL is important. Little is known about the associations between dietary intake and HRQoL in this population. Methods : We included 312 g BRCA1/2 mutation carriers from an ongoing prospective randomized controlled lifestyle intervention trial. Baseline data from the EPIC food frequency questionnaire was used to calculate the dietary inflammatory index (DII), and adherence to MD was captured by the 14-item PREDIMED questionnaire. HRQoL was measured by the EORTC QLQ-C30 and LOT-R questionnaires. The presence of metabolic syndrome (MetS) was determined using anthropometric measurements, blood samples and vital parameters. Linear and logistic regression models were performed to assess the possible impact of diet and metabolic syndrome on HRQoL. Results : Women with a prior history of cancer (59.6%) reported lower DIIs than women without it ( p = 0.011). A greater adherence to MD was associated with lower DII scores ( p < 0.001) and reduced odds for metabolic syndrome (MetS) ( p = 0.024). Women with a more optimistic outlook on life reported greater adherence to MD ( p < 0.001), whereas a more pessimistic outlook on life increased the odds for MetS (OR = 1.15; p = 0.023). Conclusions : This is the first study in g BRCA1/2 mutation carriers that has linked MD, DII, and MetS to HRQoL. The long-term clinical implications of these findings are yet to be determined.

Biomolecular condensation has emerged as a key organizing principle governing the formation of membraneless cellular assemblies. Revealing the mechanism of formation of biomolecular condensates requires the quantitative examination of their growth kinetics. Here, we introduce mass balance imaging (MBI) as a general method to study compositional growth dynamics based on fluorescent images of multicomponent clusters. MBI allows the visualization and measurement of composition-dependent growth rates of biomolecular condensates and other assemblies. We provide a computational pipeline and demonstrate the applicability of our method by investigating cortical assemblies containing N-WASP (WSP-1) and F-actin that appear during oocyte cortex activation in C. elegans. In general, the method can be broadly implemented to identify interactions that underlie growth kinetics of multicomponent assemblies in vivo and in vitro., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Anxiety that occurs in association with on-off dopamine medication fluctuations is a major cause of distress, dysfunction, and lower quality of life in people with Parkinson's disease (PD). However, the association between anxiety and on-off fluctuations is poorly understood and it is difficult to predict which patients will suffer from this atypical form of anxiety. To understand whether fluctuating anxiety in PD exists as part of an endophenotype that is associated with other signs or symptoms, we prospectively assessed the change in anxiety and a battery of clinical variables when transitioning from the off-dopamine medication state to the on state in 200 people with PD. We performed latent profile analysis with observed variables as latent profile indicators measuring the on-off-state difference in anxiety, depression, motor function, daily functioning, and the wearing off questionnaire 19 item scale (WOQ-19) in order to model unobserved (i.e., latent) profiles. A two-class model produced the best fit. The majority of participants, 69%, were categorized as having a 'typical on-off response' compared to a second profile constituting 31% of the sample who experienced a worsening in anxiety in the off state that was three times that of other participants. This profile referred to as "anxious fluctuators" had a Hamilton Anxiety Rating Scale change between the off and on medication state of 10.22(32.85) compared to 3.27 (7.62), higher depression scores, greater disability and was less likely to improve on select WOQ-19 items when in the on-state. Anxious fluctuators were more likely to be male and have a family history of anxiety disorder. Given the adverse impact of this profile we believe it may be important to distinguish patients with a typical on-off response from those with this more problematic course of fluctuations., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: In Germany, record linkage of claims and cancer registry data is cost- and time-consuming, since up until recently no unique personal identifier was available in both data sources. The aim of this study was to evaluate the feasibility and performance of a deterministic linkage procedure based on indirect personal identifiers included in the data sources., Methods: We identified users of glucose-lowering drugs with residence in four federal states in Northern and Southern Germany (Bavaria, Bremen, Hamburg, Lower Saxony) in the German Pharmacoepidemiological Research Database (GePaRD) and assessed colorectal and thyroid cancer cases. Cancer registries of the federal states selected all colorectal and thyroid cancer cases between 2004 and 2015. A deterministic linkage approach was performed based on indirect personal identifiers such as year of birth, sex, area of residence, type of cancer and an absolute difference between the dates of cancer diagnosis in both data sources of at most 90 days. Results were compared to a probabilistic linkage using "direct" personal identifiers (gold standard)., Results: The deterministic linkage procedure yielded a sensitivity of 71.8% for colorectal cancer and 66.6% for thyroid cancer. For thyroid cancer, the sensitivity improved when using only inpatient diagnosis to define cancer in GePaRD (71.4%). Specificity was always above 99%. Using the probabilistic linkage to define cancer cases, the risk for colorectal cancer was estimated 10 percentage points lower than when using the deterministic approach., Conclusions: Sensitivity of the deterministic linkage approach appears to be too low to be considered as reasonable alternative to the probabilistic linkage procedure., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD., Objective: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation., Design: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791)., Setting: Outpatient., Patients: 150 patients with PD and constipation., Intervention: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period., Measurements: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD])., Results: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group ( P  < 0.001). Improvement in secondary end points included SBMs ( P  = 0.002), stool consistency ( P  < 0.001), ease of passage ( P  = 0.006), and laxative use ( P  = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group ( n  = 14) versus 2.0 points in the placebo group ( n  = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group ( n  = 5) and from 6.3 to 4.4 in the placebo group ( n  = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P  < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P  = 0.016)., Limitation: Longer treatment periods need to be investigated in future studies., Conclusion: ENT-01 was safe and significantly improved constipation., Primary Funding Source: Enterin, Inc.

Aim: Since reliable response predictors to platinum-based chemotherapy in ovarian cancer (OC) are scarce, we characterize NCALD as a predictive biomarker. Materials & methods: NCALD mRNA (n = 100) and protein (n = 102) expression was analyzed in OC samples and associated with patient outcome. A stable OC cell line knockdown was generated and cellular response to platinum was explored. Results: High NCALD mRNA and protein expression was significantly associated with longer overall patient survival (p = 0.037/0.002). Knockdown experiments revealed a significant association between cisplatin sensitivity and NCALD expression. Conclusion: Low NCALD expression was associated with reduced sensitivity to platinum-based chemotherapy. NCALD may be a new biomarker candidate to identify patients who might benefit from platinum-based chemotherapy.

A comprehensive small area description of regional variations in outpatient antibiotic prescribing in Germany is lacking. Using the German Pharmacoepidemiological Research Database (GePaRD), a claims database covering ~20% of the German population, we determined the age- and sex-standardized prescription rates of antibiotics (number of outpatient prescriptions per 1000 persons/year). We calculated these prescription rates overall and on the level of 401 German districts for the calendar years 2010 and 2018. In 2018, the standardized prescription rate of antibiotics in the total study population was 23% lower than in 2010 (442 vs. 575 per 1000 persons/year). Among 0-17-year-olds, prescription rates across districts ranged from 312 to 1205 in 2010 and from 188 to 710 in 2018 per 1000 persons/year; among adults (≥18 years), they ranged from 388 to 841 in 2010 and from 300 to 693 in 2018 per 1000 persons/year. Despite the overall decline in outpatient antibiotic prescribing between 2010 and 2018, regional variations at the district level remained high in all age groups in Germany. Identifying reasons that explain the persistently high prescription rates in certain regions will be helpful in designing effective and tailored measures to further improve antibiotic stewardship in these regions.

Background Cardiovascular disease (CVD) is an important cause of morbidity and mortality in breast cancer survivors. Effective screening modalities to identify CVD risk are lacking in this population. Adrenomedullin (ADM) has been suggested as a biomarker for subclinical cardiac dysfunction in the general population. Levels of ADM have been proven to be responsive to lifestyle changes that lead to improved cardiovascular health. As BRCA1/2 mutation carriers are deemed to be at an increased risk for CVD, the aim of this study was to examine plasma ADM levels in a cohort of BRCA mutation carriers and to assess their association with cardiovascular risk factors. Methods Plasma ADM concentrations were measured in 292 female BRCA1/2 mutation carriers with and without a history of breast cancer. Subjects were classified into high versus low ADM levels based on the median ADM level in the entire cohort (13.8 pg/mL). Logistic regression models were used to estimate the odds ratios (OR) of having elevated ADM levels by several cardiovascular risk factors. Results Of all women (median age: 43 years), 57.5% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was three years (range: 0 - 32 years). Women presenting with metabolic syndrome had 22-fold increased odds of having elevated ADM levels (p < 0.001). Elevated ADM levels were associated with lower cardiorespiratory fitness (OR = 0.88, p < 0.001) and several parameters of obesity (p < 0.001). ADM levels were higher in women who have ever smoked (OR = 1.72, p = 0.02). ADM levels were not associated with a previous diagnosis of breast cancer (p = 0.28). Conclusions This is the first study in BRCA mutation carriers that has linked circulating ADM levels to traditional cardiovascular risk factors. The long-term clinical implications of these findings are yet to be determined., Competing Interests: Conflict of Interest JS and OH are employed by Sphingotec GmbH, a company having patent rights in and commercializing the bio-ADM assay. MK and SG received grants from Sphingotec GmbH. JL, MB, CE, SCB, ABE and MH have nothing to disclose., (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 commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has established a multigene panel (TruRisk®) for the analysis of risk genes for familial breast and ovarian cancer., Summary: An interdisciplinary team of experts from the GC-HBOC has evaluated the available data on risk modification in the presence of pathogenic mutations in these genes based on a structured literature search and through a formal consensus process., Key Messages: The goal of this work is to better assess individual disease risk and, on this basis, to derive clinical recommendations for patient counseling and care at the centers of the GC-HBOC from the initial consultation prior to genetic testing to the use of individual risk-adapted preventive/therapeutic measures., Competing Interests: Christopher Schroeder reports research support from Illumina and Bristol Myers Squibb and institutional research support from Novartis., (Copyright © 2021 by S. Karger AG, Basel.)

Purpose: Emerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations., Methods: Serum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups., Results: The lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = - 0.70; q = 0.0018). Baseline physical fitness (assessed as VO 2 peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871)., Conclusion: Findings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL., (© 2021. The Author(s).)

Background: Women with Li-Fraumeni syndrome (LFS) have elevated breast cancer (BC) risk. Optimal BC treatment strategies in this population are yet unknown., Methods: BC subtypes and treatment were retrospectively investigated between December 2016 and January 2019 in a multicentre study. BC risks were evaluated according to the type of surgery., Results: Thirty-five women of our study population (35/44; 79.5%) had developed 36 breast lesions at first diagnosis at a mean age of 34 years. Those breast lesions comprised 32 invasive BCs (89%), three ductal carcinoma in situ alone (8%) and one malignant phyllodes tumour (3%). BCs were mainly high-grade (18/32), of no special type (NST; 31/32), HER2-enriched (11/32) or luminal-B-(like)-type (10/32). Affected women (n = 35) received breast-conserving surgery (BCS, n = 17) or a mastectomy (ME, n = 18) including seven women with simultaneous contralateral prophylactic mastectomy (CPM) at first diagnosis. Nineteen women suffered 20 breast or locoregional axillary lesions at second diagnosis with mean age of 36. Median time between first and second diagnosis was 57 months; median time to contra- and ipsilateral recurrence depended on surgical strategies (BCS: 46 vs. unilateral ME: 93 vs. bilateral ME > 140 months). Women with a primary treatment of solitaire therapeutic ME suffered from contralateral BC earlier compared to those with therapeutic ME and CPM (median: 93 vs. >140 months)., Conclusion: Aggressive BC subtypes occur among women with LFS. Surgical treatment, i.e. ME and CPM, may prolong time to a second BC diagnosis. Conclusion on long-term survival benefit is pending. Individual competing tumour risks and long-term outcomes need to be taken into consideration., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The diagnosis of preeclampsia in China currently relies on limited clinical signs and unspecific laboratory findings. These are inadequate predictors of preeclampsia development, limiting early diagnosis and appropriate management. Previously, the Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia Study (PROGNOSIS) and PROGNOSIS Asia demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio of ≤38 can be used to rule out preeclampsia within 1 week, with negative predictive values of 99.3 and 98.6%, respectively. This is an exploratory sub-analysis of the Chinese cohort ( n = 225) of the PROGNOSIS Asia study. The primary objectives were to assess the predictive performance of using the sFlt-1/PlGF ratio to rule out preeclampsia within 1 week and to rule in preeclampsia within 4 weeks. The sFlt-1/PlGF ratio was also examined for short-term prediction of fetal adverse outcomes, maternal adverse outcomes, and time to delivery. The overall prevalence of preeclampsia was 17.3%. With the use of an sFlt-1/PlGF ratio of ≤38, the negative predictive value for ruling out preeclampsia within 1 week was 97.3% [95% confidence interval (CI), 93.8-99.1], with a sensitivity of 64.3% and specificity of 85.3%. With the use of an sFlt-1/PlGF ratio of >38, the positive predictive value for ruling in preeclampsia within 4 weeks was 35.0% (95% CI, 20.6-51.7), with a sensitivity of 50.0% and specificity of 86.8%. In the analyses of the sFlt-1/PlGF ratio and fetal adverse outcomes, the area under the receiver operating characteristic curve was 92.8% (95% CI, 83.5-98.7) for ruling out fetal adverse outcomes within 1 week and 79.9% (95% CI, 68.1-90.3) for ruling in fetal adverse outcomes within 4 weeks. An sFlt-1/PlGF ratio of >38 increased the likelihood of imminent delivery 3.3-fold compared with a ratio of ≤38 [hazard ratio, 3.3 (95% CI, 2.1-5.1)]. This sub-analysis confirms the high predictive performance of the sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia in Chinese women, which may help prevent unnecessary hospitalization of women with low risk of developing preeclampsia., Competing Interests: AD and SG are employees of Roche Diagnostics GmbH. MH is an employee of Roche Diagnostics International Ltd and holds stock in F. Hoffmann-La Roche. MH also reports being an inventor of patents related to sFlt-1/PlGF or endoglin/PlGF ratio to rule out onset of preeclampsia in pregnant women within a certain time period PCT/EP2013/063115 and the dynamic of sFlt-1 or endoglin/PlGF ratio as indicator for imminent preeclampsia and HELLP syndrome PCT/EP2012/072157. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Huang, Di, Dong, Gou, Shi, Wang, Dietl, Grill and Hund.)

Two prospective multicenter studies demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio cutoff of ≤38 can rule out preeclampsia within 1 week with a negative predictive value (NPV) of 99.3% (PROGNOSIS) and 98.6% (PROGNOSIS Asia). We report a subanalysis of the Japanese cohort from the PROGNOSIS Asia study. Pregnant women with suspected preeclampsia between gestational weeks 18 + 0 days and 36 + 6 days were enrolled at eight Japanese sites. Primary objectives: Assess the performance of the Elecsys ® sFlt-1/PlGF ratio cutoff ≤38 to rule out preeclampsia within 1 week and of the cutoff >38 to rule in preeclampsia within 4 weeks. Key secondary objectives: Prediction of maternal and fetal adverse outcomes (MAOs/FAOs) and their relationship with duration of pregnancy. Of 192 women enrolled, 180 (93.8%)/175 (91.1%) were evaluable for primary/combined endpoint analyses. Overall preeclampsia prevalence was 13.3%. A sFlt-1/PlGF ratio of ≤38 provided an NPV of 100% (95% confidence interval [CI], 97.5-100) for ruling out preeclampsia within 1 week, and a ratio of >38 provided a positive predictive value of 32.4% (95% CI, 18.0-49.8) for ruling in preeclampsia within 4 weeks. The area under the curve for the prediction of preeclampsia/maternal/fetal adverse outcomes within 1 week was 94.2% (95% CI, 89.3-97.8). After adjusting for gestational age and final preeclampsia status, Cox regression indicated a 2.8-fold greater risk of imminent delivery for women with a sFlt-1/PlGF ratio >38 versus ≤38. This subanalysis of Japanese women with suspicion of preeclampsia showed high predictive value for a Elecsys sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia.

FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion (FUTURE) 3 was a 24-week open-label, prospective, and randomized phase 3 study that assessed the pharmacokinetics of bosentan 2 mg/kg b.i.d. or t.i.d. in children with pulmonary arterial hypertension (PAH). We report findings from a post-hoc analysis that explored the prognostic value of echocardiographic changes during FUTURE 3 in relation to clinical outcomes observed during the 24-week core study and 48-week extension. Patients aged ≥3 months to <12 years ( n = 64) received oral doses of bosentan 2 mg/kg b.i.d. or t.i.d. (1:1) for 24 weeks, after which they were eligible to enter the extension with continued bosentan administration. Echocardiographic evaluations were performed at baseline, Week 12, and 24 of the core study via central reading, and analyzed post-hoc for correlation with clinical outcomes (time to PAH worsening, time to death, and vital status). Sixty-four patients were randomized in the core study [median (IQR) age 3.8 (1.7-7.8) years]; and 58 patients (90.6%) entered the 48-week extension. Most of the patients (68.8%) were receiving ≥1 PAH medication at baseline. Echocardiographic changes during the core study were small but with high variability. There were statistically significant associations at Week 24 between worsening of the parameters, systolic left ventricular eccentricity index (LVEIS) and E/A ratio mitral valve flow, and the outcomes of time to death and time to PAH worsening. Additional studies that utilize simple and reproducible echocardiographic assessments are needed to confirm these findings and subsequently identify potential treatment goals in pediatric PAH., Competing Interests: SG and CL are employed by Actelion Pharmaceuticals Ltd., a Janssen Pharmaceutical Company of Johnson & Johnson, and declare that this study received funding from Actelion Pharmaceuticals Ltd., a Janssen Pharmaceutical Company of Johnson & Johnson. The sponsor was involved in the conception and design of the study, analysis and interpretation of data, critical revision of the manuscript, and approval for submission to the journal. J-CL is employed by Effi-Stat, a contract research organization that received financial support from Janssen Pharmaceutical Companies of Johnson & Johnson for statistical analysis and programming in this study. The disclosures of the remaining authors are as follows: MB has received grants, personal fees, and non-financial support from Janssen Pharmaceutical Companies of Johnson & Johnson, and has received personal fees from Bayer HealthCare Pharmaceuticals LLC, Bristol–Myers Squibb, Eli Lilly and Company, and GlaxoSmithKline. RB's institution (University Medical Center Groningen) contracts with Janssen Pharmaceutical Companies of Johnson & Johnson, and Eli Lilly and Company for RB to be a consultant, and has received research support from Janssen Pharmaceutical Companies of Johnson & Johnson. DB has received personal fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer HealthCare Pharmaceuticals LLC, Bristol–Myers Squibb, Eli Lilly and Company, and Novartis. DI's institution (The University of Colorado) contracts with Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer HealthCare Pharmaceuticals LLC, GlaxoSmithKline, Lilly, and United Therapeutics for DI to be a consultant., (Copyright © 2021 Beghetti, Berger, Bonnet, Grill, Lesage, Lemarie and Ivy.)

Purpose: TP53germline (g) mutations, associated with the Li-Fraumeni syndrome (LFS), have rarely been reported in the context of hereditary breast and ovarian cancer (HBOC). The prevalence and cancer risks in this target group are unknown and counseling remains challenging. Notably an extensive high-risk surveillance program is implemented, which evokes substantial psychological discomfort. Emphasizing the lack of consensus about clinical implications, we aim to further characterize TP53g mutations in HBOC families., Methods: Next-generation sequencing was conducted on 1876 breast cancer (BC) patients who fulfilled the inclusion criteria for HBOC., Results: (Likely) pathogenic variants in TP53 gene were present in 0.6% of the BC cohort with higher occurrence in early onset BC < 36 years. (1.1%) and bilateral vs. unilateral BC (1.1% vs. 0.3%). Two out of eleven patients with a (likely) pathogenic TP53g variant (c.542G > A; c.375G > A) did not comply with classic LFS/Chompret criteria. Albeit located in the DNA-binding domain of the p53-protein and therefore revealing no difference to LFS-related variants, they only displayed a medium transactivity reduction constituting a retainment of wildtype-like anti-proliferative functionality., Conclusion: Among our cohort of HBOC families, we were able to describe a clinical subgroup, which is distinct from the classic LFS-families. Strikingly, two families did not adhere to the LFS criteria, and functional analysis revealed a reduced impact on TP53 activity, which may suit to the attenuated phenotype. This is an approach that could be useful in developing individualized screening efforts for TP53g mutation carrier in HBOC families. Due to the low incidence, national/international cooperation is necessary to further explore clinical implications. This might allow providing directions for clinical recommendations in the future.

Telomerase catalyzes chromosome end replication in stem cells and other long-lived cells. Mutations in telomerase or telomere-related genes result in diseases known as telomeropathies. Telomerase is recruited to chromosome ends by the ACD/TPP1 protein (TPP1 hereafter), a component of the shelterin complex that protects chromosome ends from unwanted end joining. TPP1 facilitates end protection by binding shelterin proteins POT1 and TIN2. TPP1 variants have been associated with telomeropathies but remain poorly characterized in vivo. Disease variants and mutagenesis scans provide efficient avenues to interrogate the distinct physiological roles of TPP1. Here, we conduct mutagenesis in the TIN2- and POT1-binding domains of TPP1 to discover mutations that dissect TPP1's functions. Our results extend current structural data to reveal that the TPP1-TIN2 interface is more extensive than previously thought and highlight the robustness of the POT1-TPP1 interface. Introduction of separation-of-function mutants alongside known TPP1 telomeropathy mutations in mouse hematopoietic stem cells (mHSCs) lacking endogenous TPP1 demonstrated a clear phenotypic demarcation. TIN2- and POT1-binding mutants were unable to rescue mHSC failure resulting from end deprotection. In contrast, TPP1 telomeropathy mutations sustained mHSC viability, consistent with their selectively impacting end replication. These results highlight the power of scanning mutagenesis in revealing structural interfaces and dissecting multifunctional genes.

Background: Germline BRCA1/2 mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)-involved in tumorigenesis and obesity-related diseases-are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC., Methods: The stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors., Results: At SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L, p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = - 0.435; CI - 0.653 to - 0.151; p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061-0.544; p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: - 37.9, p = 0.097/0.080) in multivariate analysis., Conclusion: Our results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.

Background: Treatment of patients with luminal metastatic breast cancer (MBC) has become even more complex over the last few years as molecular profiling has begun to alter disease management. It is well accepted that MBC is not curable but is treatable. Today we are able to prolong progression-free survival and partly overall survival with targeted and more individual treatment strategies adjusted according to the molecular subtype., Summary: Genetic and genomic testing has become therapeutically relevant in luminal MBC and is therefore an integral component within the treatment spectrum. By now, germline testing of BRCA 1 and BRCA 2 and somatic testing for PIK3CA mutations are inevitable elements in disease management and the current state of the art in luminal MBC patients. Furthermore, testing of ESR1 resistance mutation, ERBB2 mutation, microsatellite instability, and neurotrophic tyrosine receptor kinase (NTRK) gene fusion (mainly in secretory breast cancer) has recently gained increasing attention. However, based on the expanding role of personalized medicine, clinicians are now faced with substantial new challenges and possibly unsuspected possibilities. The following review summarizes current developments in genetic and genomic testing in luminal MBC., Key Messages: In luminal MBC genomics have become an integral component within the spectrum of oncological treatment establishing novel therapeutic facilities. Further developments in treatment personalization adjusted according to the molecular subtype should become increasingly important in order to enhance the progress of de-escalation of chemotherapy in luminal MBC. However, based on the expanding role of personalized medicine, clinicians are now faced with substantial new challenges and possibly unsuspected possibilities., Competing Interests: The authors have no conflict of interests to declare., (Copyright © 2021 by S. Karger GmbH, Freiburg.)

Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific ribonuclease affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of dyskeratosis congenita mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pinpoint disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In late stage drug development, the experimental drug is tested in a diverse study population within the relevant indication. In order to receive marketing authorization, robust evidence for the therapeutic efficacy is crucial requiring investigation of treatment effects in well-defined subgroups. Conventionally, consistency analyses in subgroups have been performed by means of interaction tests. However, the interaction test can only reject the null hypothesis of equivalence and not confirm consistency. Simulation studies suggest that the interaction test has low power but can also be oversensitive depending on sample size-leading in combination with the actually ill-posed null hypothesis to findings regardless of clinical relevance. In order to overcome these disadvantages in the setup of binary endpoints, we propose to use a consistency test based on the interval inclusion principle, which is able to reject heterogeneity and confirm consistency of subgroup-specific treatment effects while controlling the type I error. This homogeneity test is based upon the deviation between overall treatment effect and subgroup-specific effects on the odds ratio scale and is compared with an equivalence test based on the ratio of both subgroup-specific effects. Performance of these consistency tests is assessed in a simulation study. In addition, the consistency tests are outlined for the relative risk regression. The proposed homogeneity test reaches sufficient power in realistic scenarios with small interactions. As expected, power decreases for unbalanced subgroups, lower sample sizes, and narrower margins. Severe interactions are covered by the null hypothesis and are more likely to be rejected the stronger they are., (© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Aims: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects., Methods: Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods., Results: Bioequivalence of macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies., Conclusion: The FDC-2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Li-Fraumeni syndrome (LFS) is a high-risk cancer predisposition syndrome caused by pathogenic germline variants of TP53. Cancer surveillance has noted a significant survival advantage in individuals with LFS; however, little is known about the feasibility, acceptance, and psychosocial effects of such a program., Methods: Pathogenic TP53 germline variant carriers completed a 7-part questionnaire evaluating sociodemographics, cancer history, surveillance participation, reasons for nonadherence, worries, and distress adapted from the Cancer Worry Scale. Counselees' common concerns and suggestions were assessed in MAXQDA Analytics Pro 12., Results: Forty-nine participants (46 females and 3 males), aged 40.0 ± 12.6 years, formed the study population; 43 (88%) had a personal cancer history (including multiple cancers in 10 [20%]). Forty-three individuals participated (88%) in surveillance during the study or formerly. Willingness to undergo surveillance was influenced by satisfaction with genetic testing and counseling (P = .019 [Fisher-Yates test]) but not by sociodemographics, cancer history, or distress level. Almost one-third of the participants reported logistical difficulties in implementing surveillance because of the high frequency of medical visits, scheduling difficulties, and the travel distance to their surveillance providers. Self-reported distress and perceived emotional burden for family members and partners were moderate (median for self-reported distress, 3.3; median for perceived emotional burden, 3.0). For both, the interquartile range was moderate to very high (2.7-3.7 and 3.0-3.7, respectively)., Conclusions: Individuals with LFS require efficient counseling as well as an accessible, well-organized, interdisciplinary, standardized surveillance program to increase adherence and psychological coping., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Cells respond to biophysical and biochemical signals. We developed a composite filament from collagen and silica particles modified to interact with collagen and/or present a laminin epitope (IKVAV) crucial for cell-matrix adhesion and signal transduction. This combines scaffolding and signaling and shows that local tuning of collagen organization enhances cell differentiation.

Aim: We assessed the suitability of a biomarker panel to improve early detection and individual risk assessment in breast cancer (BC) patients. Materials & methods: PENK, pro-SP, hGH and CA15-3 of 204 BC patients and 68 healthy controls were measured. Results: PENK and human growth hormone concentrations were significantly lower and pro-SP values higher in BC patients compared with controls. C-index increased from 0.628 for CA15-3 alone to 0.754 when all three biomarkers were added to the model. Conclusion: This biomarker panel may improve early detection of BC and influence the assessment of breast imaging. It might be useful for a risk-adapted cancer surveillance or primary prevention program by a more precise determination of an individualized BC risk.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., (© 2019 Wiley Periodicals, Inc.)

Current diagnostic criteria have limited clinical value for prediction of preeclampsia and fetal adverse outcomes. The prediction of short-term outcome in pregnant women with suspected preeclampsia study in Asia (PROGNOSIS Asia) was a prospective, multicenter study designed to investigate the value of the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio for predicting adverse outcomes in pregnant Asian women with suspected preeclampsia. Seven hundred sixty-four pregnant women at gestational week 20+0 days (18+0 days in Japan) to 36+6 days were enrolled at 25 sites in Asia. The primary objectives were to demonstrate the value of the sFlt-1/PlGF ratio for ruling out preeclampsia within 1 week and ruling in preeclampsia within 4 weeks. The value of the ratio for predicting fetal adverse outcomes was also assessed. Seven hundred patients were evaluable for primary end point analysis. The prevalence of preeclampsia was 14.4%. An sFlt-1/PlGF ratio of ≤38 had a negative predictive value of 98.6% (95% CI, 97.2%-99.4%) for ruling out preeclampsia within 1 week, with 76.5% sensitivity and 82.1% specificity. The positive predictive value of a ratio of >38 for ruling in preeclampsia within 4 weeks was 30.3% (95% CI, 23.0%-38.5%), with 62.0% sensitivity and 83.9% specificity. An sFlt-1/PlGF ratio of ≤38 had a negative predictive value of 98.9% (95% CI, 97.6%-99.6%) for ruling out fetal adverse outcomes within 1 week and a ratio of >38 had a positive predictive value of 53.5% (95% CI, 45.0%-61.8%) for ruling in fetal adverse outcomes within 4 weeks. The sFlt-1/PlGF ratio cutoff of 38 demonstrated clinical value for the short-term prediction of preeclampsia in Asian women with suspected preeclampsia, potentially helping to prevent unnecessary hospitalization and intervention.

Telomerase replicates chromosome ends in germ and somatic stem cells to facilitate their continued proliferation. Telomerase action depends on the telomeric protein TPP1, which recruits telomerase to telomeres and facilitates processive DNA synthesis. Here, we identify separation-of-function long (TPP1-L) and short (TPP1-S) isoforms of TPP1 that appear to be generated from separate transcripts and differ only in 86 amino acids at their N terminus. Although both isoforms retain the ability to recruit telomerase, only TPP1-S facilitates efficient telomere synthesis. We find that TPP1-S is the predominant isoform in somatic cells, and strikingly, TPP1-L is the major isoform in differentiated male germ cells. We observed that TERT expression persists in these germ cells, suggesting that TPP1-L could restrain telomerase in this context. We show how differential expression of TPP1 isoforms determines telomerase function and demonstrate how alternative transcription start sites allow one gene to perform distinct functions in different biological contexts., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is generally elevated some time before and at the clinical onset of pre-eclampsia. The PROGNOSIS study validated a sFlt-1/PlGF ratio cut-off of ≤ 38 to rule out the onset of pre-eclampsia within 1 week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt-1/PlGF ratio to rule out the onset of pre-eclampsia for up to 4 weeks, and to assess the value of repeat measurements., Methods: This was an exploratory post-hoc analysis of data from the PROGNOSIS study performed in pregnant women aged ≥ 18 years with suspected pre-eclampsia, who were at 24 + 0 to 36 + 6 weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt-1 and PlGF levels were measured using Elecsys® sFlt-1 and PlGF immunoassays. Whether the sFlt-1/PlGF ratio cut-off of ≤ 38 used to rule out the onset of pre-eclampsia within 1 week could predict the absence of pre-eclampsia 2, 3, and 4 weeks post-baseline was assessed. The value of repeat sFlt-1/PlGF testing was assessed by examining the difference in sFlt-1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre-eclampsia or adverse fetal outcome., Results: On analysis of 550 women, sFlt-1/PlGF ratio ≤ 38 ruled out the onset of pre-eclampsia 2 and 3 weeks post-baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre-eclampsia within 4 weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre-eclampsia, those who developed pre-eclampsia had significantly larger median increases in sFlt-1/PlGF ratio at 2 weeks (∆, 31.22 vs 1.45; P < 0.001) and at 3 weeks (∆, 48.97 vs 2.39; P < 0.001) after their initial visit. Women who developed pre-eclampsia and/or adverse fetal outcome compared with those who did not had a significantly greater median increase in sFlt-1/PlGF ratio over the same period (∆, 21.22 vs 1.40; P < 0.001 at 2 weeks; ∆, 34.95 vs 2.30; P < 0.001 at 3 weeks)., Conclusion: The Elecsys® immunoassay sFlt-1/PlGF ratio can help to rule out the onset of pre-eclampsia for 4 weeks in women with suspected pre-eclampsia. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology., (© 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.)

Background: Cadazolid is a novel quinoxolidinone antibiotic developed for treating Clostridium difficile infection. We aimed to investigate the safety and efficacy of cadazolid compared with vancomycin in patients with C difficile infection., Methods: IMPACT 1 and IMPACT 2 were identically designed, multicentre, double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. IMPACT 1 was done in Australia, Brazil, Canada, France, Germany, Italy, the Netherlands, Peru, Poland, Romania, Spain, and the USA, and IMPACT 2 was done in Argentina, Belgium, Brazil, Canada, Chile, Croatia, Czech Republic, Greece, Hungary, Israel, Romania, Slovakia, South Korea, the UK, and the USA. Patients (aged 18 years or older) with mild-to-moderate or severe C difficile infection (diarrhoea with positive glutamate dehydrogenase and toxin A or B enzyme immunoassays) were randomly assigned (1:1) with a randomisation list stratified by centre and C difficile infection episode type (block size of four), and allocation was masked to investigators and participants. Patients received either oral cadazolid 250 mg twice daily with vancomycin-matching placebo capsule four times daily or oral vancomycin 125 mg four times a day with cadazolid-matching placebo suspension twice daily for 10 days, with 30 days of follow-up. The primary efficacy outcome was non-inferiority (margin -10%) of cadazolid versus vancomycin for clinical cure in the modified intention-to-treat and per-protocol populations. Clinical cure was defined as resolution of diarrhoea with no additional treatment for C difficile infection. These trials are registered with ClinicalTrials.gov, numbers NCT01987895 (IMPACT 1) and NCT01983683 (IMPACT 2)., Findings: Between March 28, 2014, and March 24, 2017, for IMPACT 1, and Dec 13, 2013, and May 2, 2017, for IMPACT 2, 1263 participants were randomly assigned to receive cadazolid (306 in IMPACT 1 and 298 in IMPACT 2) or vancomycin (326 in IMPACT 1 and 311 in IMPACT 2). In the modified intention-to-treat population in IMPACT 1, 253 (84%) of 302 had clinical cure in the cadazolid group versus 271 (85%) of 318 in the vancomycin group. In IMPACT 2, 235 (81%) of 290 versus 258 (86%) of 301 had clinical cure. In the per-protocol population, 247 (88%) of 282 versus 264 (92%) of 288 had clinical cure in IMPACT 1 and 214 (87%) of 247 versus 237 (92%) of 259 in IMPACT 2. Non-inferiority for clinical cure to vancomycin was shown in IMPACT 1 but not in IMPACT 2 (IMPACT 1 treatment difference: -1·4 [95% CI -7·2 to 4·3] for modified intention to treat and -4·1 [-9·2 to 1·0] for per protocol; IMPACT 2: -4·7 [-10·7 to 1·3] for modified intention to treat and -4·9 [-10·4 to 0·6] for per protocol). The safety and tolerability profiles of the two antibiotics were similar., Interpretation: Cadazolid was safe and well tolerated but did not achieve its primary endpoint of non-inferiority to vancomycin for clinical cure in one of two phase 3 C difficile infection trials. Therefore, further commercial development of cadazolid for C difficile infection is unlikely., Funding: Actelion Pharmaceuticals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)