Project SATURN- a real-world evidence data collaboration with existing European datasets in Osteogenesis Imperfecta to support future therapies.

Regulatory marketing authorisation is not enough to ensure patient access to new medicinal products. Health Technology Assessment bodies may require data on effectiveness, relative effectiveness, and cost-effectiveness. Healthcare systems may require data on clinical utility, savings, and budget impact. Furthermore, the exact requirements of these bodies vary country by country and sometimes even region to region, resulting in a patchwork of different data requirements to achieve effective, reimbursed patient access to new therapies. In addition, clinicians require data to make informed clinical management decisions. This requirement is of key importance in rare diseases where there is often limited data and clinical experience at the time of regulatory approval.This paper describes an innovative initiative that is called Project SATURN: Systematic Accumulation of Treatment practices and Utilization, Real world evidence, and Natural history data for the rare disease Osteogenesis Imperfecta. The objective of this project is to generate a common core dataset by utilising existing data sources to meet the needs of the various stakeholders and avoiding fragmentation through multiple approaches (e.g., a series of individual national requests/approaches, and unconnected with the regulators' potential requirements). It is expected that such an approach will reduce the time for patient access to life-changing medications. Whilst Project SATURN applies to Osteogenesis Imperfecta, it is anticipated that the principles could also be applied to other rare diseases and reduce the time for patient access to new medications.

Cardiovascular events among recipients of hematopoietic stem cell transplantation-A systematic review and meta-analysis.

Cardiovascular diseases are an emerging cause of mortality and morbidity in survivors of hematopoietic stem cell transplantation (HSCT); however, the incidence of cardiovascular events (CVEs) in this population is not well described. This systematic review summarizes the evidence on the incidence of CVEs in HSCT recipients. Medline and Embase were searched from inception to December 2020. Inclusion criteria were cohort studies and phase 3 randomized controlled trials that reported CVEs among adults who underwent HSCT for hematological malignancies. After reviewing 8386 citations, 57 studies were included. The incidence of CVEs at 100 days was 0.19 (95% CI: 0.17-0.21) per 100 person-days after autologous HSCT and 0.06 (95% CI: 0.05-0.07) per 100 person-days after allogeneic HSCT. This higher incidence after autologous HSCT was driven by reports of arrhythmia from one population-based study in patients with multiple myeloma. The incidence of long-term CVEs was 3.98 (95% CI; 3.44-4.63) per 1000 person-years in survivors of autologous HSCT and 3.06 (95% CI; 2.69-3.48) per 1000 person-years in survivors of allogeneic HSCT. CVEs remain an important but under-reported cause of morbidity and mortality in recipients of HSCT. Future studies are required to better understand the incidence and risk factors for CVEs in HSCT recipients.

Group theory analysis of phonons in monolayer chromium trihalides and their Janus structures.

A contrastive investigation of the symmetry aspects of phonons in monolayer chromium trihalides and their Janus structures Y3-Cr2-X3 (X, Y = F, Cl, Br, I) was presented within group theory. We classified all phonon vibration modes at the Brillouin-zone center (Γ) into irreducible representations. The infrared and Raman activity of optic phonons, Raman tensors, and the possible polarization assignments of Raman active phonons are further predicted. We clarify the discrepancy concerning the Raman and infrared activity of optic modes in monolayer CrI3. It is also found that the Raman and infrared spectra are exclusive for X3-Cr2-X3 but coincident for Janus Y3-Cr2-X3. This distinction plays a vital role in optic spectra identification of the Janus Y3-Cr2-X3 monolayer from the X3-Cr2-X3 monolayer. To demonstrate the origin of phonon chirality and magnetism intuitively, we derive the symmetry-matched phonon eigenfunctions and the corresponding schematic representations of the eigenvectors for both the F3-Cr2-I3 and I3-Cr2-I3 monolayers. Our analysis indicates that the spin-phonon coupling, the magneto-optical effect of infrared and Raman active phonons, and the phonon chirality could be observed in the Janus Y3-Cr2-X3 monolayer more easily than in the X3-Cr2-X3 monolayer. Our results thus provide a detailed guiding map for experimental identification and characterization of the Janus Y3-Cr2-X3 monolayer.

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial.

BACKGROUND: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. PATIENTS AND METHODS: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. RESULTS: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). CONCLUSION: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Replicating an effective VA program to train and support family caregivers: a hybrid type III effectiveness-implementation design.

BACKGROUND: Caring for a growing aging population using existing long-term care resources while simultaneously supporting and educating family caregivers, is a public health challenge. We describe the application of the Replicating Effective Programs (REP) framework, developed by the Centers for Disease Control Prevention and used in public health program implementation, to scale up an evidence-based family caregiver training intervention in the Veterans Affairs (VA) healthcare system. METHODS: From 2018 to 2020, clinicians at eight VA medical centers received REP-guided implementation including facilitation, technical assistance, and implementation tools to deliver the training program. The project team used the REP framework to develop activities across four distinct phases - (1) pre-conditions, (2) pre-implementation, (3) implementation, and (4) maintenance and evolution - and systematically tracked implementation facilitators, barriers, and adaptations. RESULTS: Within the REP framework, results describe how each medical center adapted implementation approaches to fit local needs. We highlight examples of how sites balanced adaptations and intervention fidelity. CONCLUSIONS: The REP framework shows promise for national expansion of the caregiver training intervention, including to non-VA systems of care, because it allows sites to adapt while maintaining intervention fidelity. TRIAL REGISTRATION: NCT03474380 . Date registered: March 22, 2018.

Moiré Potential, Lattice Corrugation, and Band Gap Spatial Variation in a Twist-Free MoTe2/MoS2 Heterobilayer.

To have a fully first-principles description of the moiré pattern in transition-metal dichalcogenide heterobilayers, we have carried out density functional theory calculations on a MoTe2(9 × 9)/MoS2(10 × 10) stacking, which has a superlattice larger than an exciton yet not large enough to justify a continuum model treatment. Lattice corrugation is found to be significant in both monolayers, yet its effect on the electronic properties is marginal. We reveal that the variation of the average local potential near Mo atoms in both MoTe2 and MoS2 layers displays a conspicuous moiré pattern. They are the intralayer moiré potentials correlating closely with the spatial variation of the valence band maximum and conduction band minimum. The interlayer moiré potential, defined as the difference between the two intralayer moiré potentials, changes roughly in proportion to the band gap variation in the moiré cell. This finding might be instructive in chemical engineering of van der Waals bilayers.

Indicators of long-term return to work after severe traumatic brain injury: A cohort study.

BACKGROUND: Return to work (RTW) is a major objective in the rehabilitation of individuals with severe traumatic brain injury (TBI). Implications for long-term occupational integration (beyond 5 years) have rarely been studied. OBJECTIVE: The objective was to assess long-term RTW and the associated factors after severe TBI. MATERIAL AND METHODS: Retrospective analysis of a cohort of individuals 16 to 60 years old admitted to hospital after severe TBI from 2005 to 2009 and followed prospectively. Medical and occupational data were collected from medical files and by systematic telephone interview to assess outcome at a minimum of 6 years post-trauma. Factors associated with RTW were investigated by multivariable regression analysis, estimating prevalence ratios (PRs) and 95% confidence intervals (CIs). A proportional hazards model was used to study RTW delay, estimating hazard ratios (HRs). RESULTS: Among the 91 individuals included (mean [SD] age 28.5 [11.3] years; 79% male), 63.7% returned to work after a mean of about 20 months, and 57.1% were still working at the time of the survey. Factors significantly associated with RTW on multivariable analysis were higher educational level (adjusted PR, 1.53; 95% CI, 1.15 to 2.03), absence of motor disability (adjusted PR, 1.82; 1.12 to 2.95) and behavioural disorder (adjusted PR, 1.26; 1.01 to 1.60), as well as disabled worker status (adjusted PR, 1.26; 1.01 to 1.60) (likelihood of the multivariate analysis model 53.1). Delayed RTW was associated with health insurance payments (adjusted HR, 0.40; 95% CI, 0.22 to 0.71), motor disability (adjusted HR, 0.34; 0.15 to 0.76), low educational level (adjusted HR, 2.20; 1.06 to 4.56) and moderate disability on the Extended Glasgow Outcome Scale (adjusted HR, 0.49; 0.27 to 0.91) (likelihood of the multivariate analysis model 335.5). CONCLUSION: Individuals with the most severe TBI are able to RTW and remain in work. This study highlights the multiple determinants involved in RTW and the role of socioenvironmental factors.

First-principles study on structural, thermal, mechanical and dynamic stability of T'-MoS2.

Using first-principles density functional theory calculations, we investigate the structure, stability, optical modes and electronic band gap of a distorted tetragonal MoS2 monolayer (T'-MoS2). Our simulated scanning tunnel microscopy (STM) images of T'-MoS2 are dramatically similar to those STM images which were identified as K x (H2O) y MoS2 from a previous experimental study. This similarity suggests that T'-MoS2 might have already been experimentally observed, but due to being unexpected was misidentified. Furthermore, we verify the stability of T'-MoS2 from the thermal, mechanical and dynamic aspects, by ab initio molecular dynamics simulation, elastic constants evaluation and phonon band structure calculation based on density functional perturbation theory, respectively. In addition, we calculate the eigenfrequencies and eigenvectors of the optical modes of T'-MoS2 at [Formula: see text] point and distinguish their Raman and infrared activity by pointing out their irreducible representations using group theory. At the same time, we compare the Raman modes of T'-MoS2 with those of H-MoS2 and T-MoS2. Our results provide useful guidance for further experimental identification and characterization of T'-MoS2.

Image-Based Predictive Modeling of Heart Mechanics.

Personalized biophysical modeling of the heart is a useful approach for noninvasively analyzing and predicting in vivo cardiac mechanics. Three main developments support this style of analysis: state-of-the-art cardiac imaging technologies, modern computational infrastructure, and advanced mathematical modeling techniques. In vivo measurements of cardiac structure and function can be integrated using sophisticated computational methods to investigate mechanisms of myocardial function and dysfunction, and can aid in clinical diagnosis and developing personalized treatment. In this article, we review the state-of-the-art in cardiac imaging modalities, model-based interpretation of 3D images of cardiac structure and function, and recent advances in modeling that allow personalized predictions of heart mechanics. We discuss how using such image-based modeling frameworks can increase the understanding of the fundamental biophysics behind cardiac mechanics, and assist with diagnosis, surgical guidance, and treatment planning. Addressing the challenges in this field will require a coordinated effort from both the clinical-imaging and modeling communities. We also discuss future directions that can be taken to bridge the gap between basic science and clinical translation.

Role of Interlayer Coupling on the Evolution of Band Edges in Few-Layer Phosphorene.

Using first-principles calculations, we have investigated the evolution of band edges in few-layer phosphorene as a function of the number of P layers. Our results predict that monolayer phosphorene is an indirect band gap semiconductor and its valence band edge is extremely sensitive to strain. Its band gap could undergo an indirect-to-direct transition under a lattice expansion as small as 1% along the zigzag direction. A semiempirical interlayer coupling model is proposed, which can reproduce the evolution of valence band edges obtained by first-principles calculations well. We conclude that the interlayer coupling plays a dominant role in the evolution of the band edges via decreasing both band gap and carrier effective masses with the increase of phosphorene thickness. Scrutiny of the orbital-decomposed band structure provides a better understanding of the upward shift of the valence band maximum, surpassing that of the conduction band minimum.

Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998).

Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m(2) orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy.

Very-high-risk localized prostate cancer: definition and outcomes.

BACKGROUND: Outcomes in men with National Comprehensive Cancer Network (NCCN) high-risk prostate cancer (PCa) can vary substantially-some will have excellent cancer-specific survival, whereas others will experience early metastasis even after aggressive local treatments. Current nomograms, which yield continuous risk probabilities, do not separate high-risk PCa into distinct sub-strata. Here, we derive a binary definition of very-high-risk (VHR) localized PCa to aid in risk stratification at diagnosis and selection of therapy. METHODS: We queried the Johns Hopkins radical prostatectomy database to identify 753 men with NCCN high-risk localized PCa (Gleason sum 8-10, PSA >20 ng ml(-1), or clinical stage ≥T3). Twenty-eight alternate permutations of adverse grade, stage and cancer volume were compared by their hazard ratios for metastasis and cancer-specific mortality. VHR criteria with top-ranking hazard ratios were further evaluated by multivariable analyses and inclusion of a clinically meaningful proportion of the high-risk cohort. RESULTS: The VHR cohort was best defined by primary pattern 5 present on biopsy, or ≥5 cores with Gleason sum 8-10, or multiple NCCN high-risk features. These criteria encompassed 15.1% of the NCCN high-risk cohort. Compared with other high-risk men, VHR men were at significantly higher risk for metastasis (hazard ratio 2.75) and cancer-specific mortality (hazard ratio 3.44) (P<0.001 for both). Among high-risk men, VHR men also had significantly worse 10-year metastasis-free survival (37% vs 78%) and cancer-specific survival (62% vs 90%). CONCLUSIONS: Men who meet VHR criteria form a subgroup within the current NCCN high-risk classification who have particularly poor oncological outcomes. Use of these characteristics to distinguish VHR localized PCa may help in counseling and selection optimal candidates for multimodal treatments or clinical trials.

Expression patterns of Oct4, Cdx2, Tead4, and Yap1 proteins during blastocyst formation in embryos of the marsupial, Monodelphis domestica Wagner.

The marsupial blastocyst forms in an entirely different manner from its eutherian counterpart, involving cell-zona rather than cell-cell adhesion during the 8- to-16-cell transition. While the eutherian blastocyst consists of a spherical trophoblast completely enveloping a pluripotent inner cell mass, or pluriblast, the marsupial blastocyst forms initially as a bowl-shaped monolayer of cells lining the zona pellucida at the embryonic pole (ep). This monolayer contains a small patch of centrally positioned pluriblast cells edged with trophoblast cells that later coalesce at the abembryonic pole. Using immunocytochemistry, we examined the localization of the proteins Oct4, Cdx2, Tead4, Sox2, and Yap1 in opossum embryos to determine if their temporal expression pattern differed from that in the mouse, given the important differences in cell behavior preceding blastocyst formation in these mammals. Our results indicate that these proteins are expressed in similar temporal patterns despite the topological differences between mouse and opossum cleavage-stage embryos and blastocysts. That the Hippo-pathway protein Yap1 localized specifically around the approximately 128-cell stage to opossum trophoblast nuclei but remained in the cytoplasm of pluriblast cells suggests that this transcriptional regulator participates in allocating cells to the trophoblast lineage, as it does in mouse. Interestingly, in both mouse and opossum embryos, expression of the pluripotency marker Oct4 persisted after Cdx2, which signals trophoblast specification, began to be expressed in trophoblast cells. This and the observation that Cdx2 is present in opossum embryos well before blastomere-zona adhesion even occurs suggests that the proteins studied may have other roles in early mammalian embryonic development.

Learning chronobiology by improving Wikipedia.

Although chronobiology is of growing interest to scientists, physicians, and the general public, access to recent discoveries and historical perspectives is limited. Wikipedia is an online, user-written encyclopedia that could enhance public access to current understanding in chronobiology. However, Wikipedia is lacking important information and is not universally trusted. Here, 46 students in a university course edited Wikipedia to enhance public access to important discoveries in chronobiology. Students worked for an average of 9 h each to evaluate the primary literature and available Wikipedia information, nominated sites for editing, and, after voting, edited the 15 Wikipedia pages they determined to be highest priorities. This assignment (http://www.nslc.wustl.edu/courses/Bio4030/wikipedia_project.html) was easy to implement, required relatively short time commitments from the professor and students, and had measurable impacts on Wikipedia and the students. Students created 3 new Wikipedia sites, edited 12 additional sites, and cited 347 peer-reviewed articles. The targeted sites all became top hits in online search engines. Because their writing was and will be read by a worldwide audience, students found the experience rewarding. Students reported significantly increased comfort with reading, critiquing, and summarizing primary literature and benefited from seeing their work edited by other scientists and editors of Wikipedia. We conclude that, in a short project, students can assist in making chronobiology widely accessible and learn from the editorial process.

Factors that influence the choice of seeking treatment at polyclinics.

INTRODUCTION: Patients in Singapore can choose their primary care provider on a per-episode basis and pay out-of-pocket for services rendered. The infrastructure of subsidised and private primary care sector facilities differs. Onsite ancillary services are available in subsidised facilities, allowing for convenience of routine investigations, while private clinics are usually standalone practices. This study sought to examine the factors influencing patients' choice of polyclinic. METHODS: This was a cross-sectional survey of a convenient sample of 484 random patients who sought treatment at a polyclinic located in a new housing estate from 24-27 June 2008. RESULTS: The response rate was 85.4% (n = 409). 38.1% of the patients were male. Mean age was 36.2 years. Only 13.8% had a regular private family physician, while 37.3% were followed up at polyclinics. Patients on regular polyclinic follow-up were more likely to be older (p < 0.001), unemployed, retirees or housewives (p < 0.001) and were seeking treatment for chronic diseases (p < 0.001). Geographical convenience (p = 0.002), low cost of consultation (p = 0.024), and onsite laboratory (p = 0.001) and imaging services (p = 0.018) significantly influenced those on regular polyclinic follow-up to attend the polyclinic. CONCLUSION: Affordability, convenience of travel and onsite laboratory facilities influence patients' choice of seeking treatment at polyclinics. Further research examining whether the overall convenience of onsite ancillary services influences patients' choice of primary care provider would be useful in redesigning private primary care infrastructure to enhance patient convenience and encourage more patients to have a regular private family physician.

Ibipinabant attenuates ß-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight.

AIM: To test the antidiabetic efficacy of ibipinabant, this new cannabinoid receptor 1 (CB1) antagonist was compared with food-restriction-induced weight loss, rosiglitazone (4 mg/kg) and rimonabant (3 and 10 mg/kg), using parameters of glycaemic control in male Zucker diabetic fatty (ZDF) rats. METHODS: Body weight, food and water intake, fasted and non-fasted glucose and insulin, glucose tolerance and glycosylated haemoglobin (HbA1c) were all assessed over the course of the 9-week study. Pancreatic insulin content and islet area were also evaluated. RESULTS: At the end of the study, vehicle-treated ZDF rats were severely hyperglycaemic and showed signs of ß-cell decline, including dramatic reductions in unfasted insulin levels. Ibipinanbant (10 mg/kg) reduced the following relative to vehicle controls: fasting glucose (-61%), glucose excursion area under the curve (AUC) in an oral glucose tolerance test (OGTT, -44%) and HbA1c (-50%). Furthermore, non-fasting insulin, islet area and islet insulin content were all increased (71, 40 and 76%, respectively) relative to vehicle controls by the end of the study. All of these effects were similar to those of rimonabant and rosiglitazone, where ibipinabant was slightly more effective than rimonabant at the lowest dose and somewhat less effective than rosiglitazone at all doses. These antidiabetic effects appear independent of weight loss because none of the parameters above were consistently improved by the comparable weight loss induced by food restriction. CONCLUSIONS: Ibipinabant may have weight loss-independent antidiabetic effects and may have the potential to attenuate ß-cell loss in a model of progressive ß-cell dysfunction.

Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1.

MicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3'-untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression- and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.

The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment.

Although age-related macular degeneration (AMD) is not a classic inflammatory disease like uveitis, inflammation has been found to have an important role in disease pathogenesis and progression. Innate immunity and autoimmune components, such as complement factors, chemokines, cytokines, macrophages, and ocular microglia, are believed to be heavily involved in AMD development. Targeting these specific inflammatory molecules has recently been explored in an attempt to better understand and treat AMD. Although antivascular endothelial growth factor therapy is the first line of defence against neovascular AMD, anti-inflammatory agents such as corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressive agents (eg, methotrexate and rapamycin), and biologics (eg, infliximab, daclizumab, and complement inhibitors) may provide an adjunct or alternative mechanism to suppress the inflammatory processes driving AMD progression. Further investigation is required to evaluate the long-term safety and efficacy of these drugs for both neovascular and non-neovascular AMD.