Assessing the clinical benefit, safety, and patient-reported outcomes with the use of the PAHcare™ digital platform in pulmonary arterial hypertension: a pilot study.

Introduction: Digital health interventions, particularly mobile health platforms, have shown promise in supporting patients with respiratory conditions, but their application in pulmonary arterial hypertension (PAH) remains limited. We aimed to assess the feasibility, acceptability, and potential clinical benefit of the novel PAHcare™ digital platform as a patient-centred intervention for PAH management through a prospective, single-arm, multicenter pilot study conducted on 53 patients diagnosed with PAH who used the platform for 6 months. Methods: The primary objective was to assess the impact on Health-Related Quality of Life (HRQoL) through questionnaires. Secondary objectives included evaluating clinical outcomes, including disease progression, PAH signs and symptoms, the 6-min walking test, and the patient's symptom perception. Additionally, we assessed patient satisfaction and engagement with the PAHcare™ platform, interaction with health coaches, retention, costs and healthcare resource utilisation (HCRU), and safety through monitoring device incidents. Results: Minimal changes in HRQoL and clinical outcomes were observed over 6 months. A noteworthy 92.4% of patients actively used the platform in the first month, maintaining high usage throughout the study. Patient satisfaction was substantial, with more than half of the patients expressing excellence in service quality, willingness to reuse the platform, and fulfilment of their needs. Health coach interaction was high, with 76% of patients initiating contact within the first week. User retention rates were 70%, with prevalent ongoing usage and interaction with healthcare professionals even after the study. In terms of HCRU and costs, the study showed no significant changes in PAH-related hospital admissions, clinical visits, or tests. Finally, the low number of device-related incidents indicated platform safety. Conclusion: This pilot study provides compelling evidence supporting the feasibility and acceptability of the PAHcare™ digital platform to empower patients to manage their disease and significantly enhance their overall experience with PAH.

Seed shape and size of Silene latifolia, differences between sexes, and influence of the parental genome in hybrids with Silene dioica.

Introduction: Plants undergo various natural changes that dramatically modify their genomes. One is polyploidization and the second is hybridization. Both are regarded as key factors in plant evolution and result in phenotypic differences in different plant organs. In Silene, we can find both examples in nature, and this genus has a seed shape diversity that has long been recognized as a valuable source of information for infrageneric classification. Methods: Morphometric analysis is a statistical study of shape and size and their covariations with other variables. Traditionally, seed shape description was limited to an approximate comparison with geometric figures (rounded, globular, reniform, or heart-shaped). Seed shape quantification has been based on direct measurements, such as area, perimeter, length, and width, narrowing statistical analysis. We used seed images and processed them to obtain silhouettes. We performed geometric morphometric analyses, such as similarity to geometric models and elliptic Fourier analysis, to study the hybrid offspring of S. latifolia and S. dioica. Results: We generated synthetic tetraploids of Silene latifolia and performed controlled crosses between diploid S. latifolia and Silene dioica to analyze seed morphology. After imaging capture and post-processing, statistical analysis revealed differences in seed size, but not in shape, between S. latifolia diploids and tetraploids, as well as some differences in shape among the parentals and hybrids. A detailed inspection using fluorescence microscopy allowed for the identification of shape differences in the cells of the seed coat. In the case of hybrids, differences were found in circularity and solidity. Overal seed shape is maternally regulated for both species, whereas cell shape cannot be associated with any of the sexes. Discussion: Our results provide additional tools useful for the combination of morphology with genetics, ecology or taxonomy. Seed shape is a robust indicator that can be used as a complementary tool for the genetic and phylogenetic analyses of Silene hybrid populations.

Brunn-Minkowski Inequality for θ-Convolution Bodies via Ball's Bodies.

We consider the problem of finding the best function φn:[0,1]→R such that for any pair of convex bodies K,L∈Rn the following Brunn-Minkowski type inequality holds |K+θL|1n≥φn(θ)(|K|1n+|L|1n),where K+θL is the θ-convolution body of K and L. We prove a sharp inclusion of the family of Ball's bodies of an α-concave function in its super-level sets in order to provide the best possible function in the range 34n≤θ≤1, characterizing the equality cases.

International Association for the Study of Lung Cancer Study of Reproducibility in Assessment of Pathologic Response in Resected Lung Cancers After Neoadjuvant Therapy.

INTRODUCTION: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria. METHODS: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion. RESULTS: Unanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76-0.92) and 0.86 (95% CI: 0.79-0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96-1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89-0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma. CONCLUSIONS: Our study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy.

Consenso colombiano de la enfermedad inflamatoria intestinal pediátrica

está disponible en el texto completo

Introduction: Pediatric ulcerative colitis (CUP), pediatric Crohn's disease (PCD), and pediatric inflammatory bowel disease not classifiable (PIDNCID) have clinical and psychosocial particularities that differentiate them from those of adults and may condition different therapeutic approaches due to possible nutritional, growth and developmental repercussions, representing a challenge for the pediatrician and gastroenterologist. Objective: Develop expert consensus evidence-based recommendations for the timely and safe diagnosis and treatment of Pediatric Inflammatory Bowel Disease (PID) in children under 18 years of age for professionals caring for these patients and healthcare payers. Methodology: Through a panel of experts from the Colombian College of Pediatric Gastroenterology, Hepatology and Nutrition (COLGAHNP) and a multidisciplinary group, 35 questions were asked regarding the clinical picture, diagnosis, and treatment of PID. Through a critical review and analysis of the literature with particular emphasis on the main clinical practice guidelines (CPGs), randomized clinical trials (RCTs), and meta-analyses of the last ten years, from which the experts made 77 recommendations that responded to each of the research questions with their respective practical points. Subsequently, each of the statements was voted on within the developer group, including the statements that achieved > 80%. Results: All statements scored > 80%. PID has greater extension, severity, and evolution towards stenosis, perianal disease, extraintestinal manifestations, and growth retardation compared to adult patients, so its management should be performed by multidisciplinary groups led by pediatric gastroenterologists and prepare them for a transition to adulthood. Porto's criteria allow a practical classification of PID. In CPE, we should use the Paris classification and perform ileocolonoscopy and esophagogastroduodenoscopy, since 50% have upper involvement, using the SES-CD (UCEIS/Mayo in CUP) and taking multiple biopsies. Initial labs should include inflammatory markers and fecal calprotectin and rule out intestinal infections. Treatment, induction, and maintenance of PID should be individualized and decided according to risk stratification. Follow-up should use PCDAI and PUCAI for the last 48 hours. Immunologists and geneticists should evaluate patients with early and infantile PID. Conclusion: A consensus guideline is provided with evidence-based recommendations on timely and safe diagnosis and treatments in patients with ILD.

Widespread distribution and altered pain processing in head and neck cancer survivors at long-term after treatment.

PURPOSE: Radiotherapy (RT) treatment in head and neck cancer (HNC) patients may induce long-term sequels as pain, which nowadays is not fully understand. Therefore, there is a need of characterization of pain features in HNC to enhance after oncology treatment management. Head and neck cancer survivors develop chronic pain after radiotherapy treatment. The purpose of the current study is to evaluate the presence of pain, pain distribution, and pain processing by means of patient reported outcomes and quantitative sensory testing. METHODS: Pain pressure threshold (PPT), temporal summation (TS), Brief Pain Inventory (BPI), Widespread Pain Index (WPI), The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, and EuroQol5D5L were assessed in 20 head and neck cancer survivors (sHNC) and 20 health-related sex and age-matched controls. RESULTS: The sHNC present lower PPT values in both the affected and non-affected side than did the healthy controls, especially in the widespread pain in the body, an altered TS in both affected and non-affected side and lower scores in quality of life and arm dysfunction. CONCLUSIONS: Following radiotherapy treatment after 1 year, sHNC present widespread pain, hypersensitivity in the radiated area, altered pain processing, upper limb affection, and a QoL diminution. These data provide evidence that a peripheral and central sensitization is happening in sHNC. Future efforts should focus on preventing pain after oncologic treatment. The comprehension about pain and its features in sHNC enhance health professional understanding and allows to tailor an optimal patient-targeted pain treatment.

Drugs in Focus: Domperidone.

Domperidone is a peripheral dopamine-2 receptor antagonist with prokinetic and antiemetic properties. Its prokinetic effects are mainly manifest in the upper gastrointestinal (GI) tract. Currently its use is restricted to relief of nausea and vomiting in children older than 12 years for a short period of time. However, among (pediatric) gastroenterologists, domperidone is also used outside its authorized indication ("off label") for treatment of symptoms associated with gastro-esophageal reflux disease, dyspepsia, and gastroparesis. Little is known about its efficacy in the treatment of GI motility disorders in children and controversial data have emerged in the pediatric literature. As its use is off label, appropriate knowledge of its efficacy is helpful to support an "off label/on evidence" prescription. Based on this, the purpose of this review is to summarize all evidence on the efficacy of domperidone for the treatment of GI disorders in infants and children and to report an overview of its pharmacological properties and safety profile.

CINSARC in high-risk soft tissue sarcoma patients treated with neoadjuvant chemotherapy: Results from the ISG-STS 1001 study.

BACKGROUND: The Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity. This study aims to assess CINSARC value of in an independent series of high-risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG-STS 1001). PATIENTS AND METHODS: Patients with available pre-treatment samples, treated with 3 cycles of either standard (ST) preoperative or histotype-tailored (HT) chemotherapy, were scored according to CINSARC (low-risk, C1; high-risk, C2). The 10-year overall survival probability (pr-OS) according to SARCULATOR was calculated, and patients were classified accordingly (low-risk, Sarc-LR, 10-year pr-OS>60%; high-risk, Sarc-HR, 10-year pr-OS<60%). Survival functions were estimated using the Kaplan-Meier method and compared using log-rank test. RESULTS: Eighty-six patients were included, 30 C1 and 56 C2, 49 Sarc-LR and 37 Sarc-HR. A low level of agreement between CINSARC and SARCULATOR was observed (Cohen's Kappa = 0.174). The 5-year relapse-free survival in C1 and C2 were 0.57 and 0.55 (p = 0.481); 5-year metastases-free survival 0.63 and 0.64 (p = 0.740); 5-year OS 0.80 and 0.72 (p = 0.460). The 5-year OS in C1 treated with ST and HT chemotherapy was 0.84 and 0.76 (p = 0.251) respectively; in C2 treated it was 0.72 and 0.70 (p = 0.349). The 5-year OS in Sarc-LR treated with S and HT chemotherapy was 0.80 and 0.82 (p = 0.502) respectively; in Sarc-HR it was 0.70 and 0.61 (p = 0.233). CONCLUSIONS: Our results, although constrained by the small size of the series, suggest that CINSARC has weak prognostic power in high-risk, localized STS treated with neoadjuvant chemotherapy.

Hypnotherapy in Pediatric Gastroenterology.

In several countries, gut-directed hypnotherapy is becoming an established and evidence-based treatment in pediatric gastroenterology. This article describes what hypnotherapy is, offers an overview of its effect in gut-brain disorders and explains its potential mode of action. Moreover, the use of hypnotherapy in other areas of pediatric gastroenterology, as a supportive tool to reduce pain, stress, depression, and anxiety and improve quality of life, will be also discussed. Guidance toward implementing hypnotherapy in clinical practice is provided, including examples of how you can explain hypnosis to patients with gastroenterological symptoms.

Best clinical management of tenosynovial giant cell tumour (TGCT): A consensus paper from the community of experts.

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein.

Human Dental Pulp Stem Cells Differentiate into Cementoid-Like-Secreting Cells on Decellularized Teeth Scaffolds.

Periodontitis is a common inflammatory disease that in some cases can cause tooth loss. Cementum is a mineralized tissue that forms part of the insertion periodontium and serves to fix the teeth to the alveolar bone. In addition, it acts as a reservoir of different growth and differentiation factors, which regulate the biology of the teeth. Cementogenesis is a complex process that is still under investigation and involves different factors, including dentin sialophosphoprotein (DSPP). In this work we studied the role of surface microtopography in the differentiation of human dental pulp stem cells (hDPSCs) into cementoid-like secreting cells. We cultured hDPSCs on decellularized dental scaffolds on either dentin or cementum surfaces. Cell morphology was evaluated by light and electron microscopy. We also evaluated the DSPP expression by immunohistochemistry. The hDPSCs that was cultured on surfaces with accessible dentinal tubules acquired an odontoblastic phenotype and emitted characteristic processes within the dentinal tubules. These cells synthesized the matrix components of a characteristic reticular connective tissue, with fine collagen fibers and DSPP deposits. The hDPSCs that was cultured on cementum surfaces generated a well-organized tissue consisting of layers of secretory cells and dense fibrous connective tissue with thick bundles of collagen fibers perpendicular to the scaffold surface. Intra- and intercellular deposits of DSPP were also observed. The results presented here reinforce the potential for hDPSCs to differentiate in vitro into cells that secrete a cementoid-like matrix in response to the physical stimuli related to the microtopography of contact surfaces. We also highlight the role of DSPP as a component of the newly formed matrix.

Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa sobre la importancia, el cribado y la vacunación en pacientes con enfermedad inflamatoria intestinal / Recommendations of the Spanish Group on Crohn's Disease and Ulcerative Colitis on the importance, screening and vaccination in inflammatory bowel disease patients

Los pacientes con enfermedad inflamatoria intestinal (EII) pueden requerir diferentes tratamientos inmunosupresores a lo largo del curso de su enfermedad. Por ello, es fundamental evaluar el estado de inmunización en el momento del diagnóstico o, si no es posible, siempre antes de iniciar un tratamiento inmunosupresor, y administrar las vacunas apropiadas. El objetivo del presente documento es establecer unas recomendaciones claras y concisas sobre la vacunación en pacientes con EII en diferentes escenarios de práctica clínica, incluyendo situaciones especiales como la vacunación en la edad pediátrica, el embarazo, la lactancia o en viajes al extranjero. Se presentan las diferencias entre vacunas inactivadas y atenuadas, los diferentes grados de inmunosupresión y su relación con las pautas de administración de las diferentes vacunas (tanto obligatorias como opcionales) recomendadas a los pacientes con EII. En el documento, se establecen 17 recomendaciones basadas en la evidencia científica disponible y opinión de expertos. En la elaboración de estas recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa ha participado un equipo multidisciplinar con amplia experiencia en EII y vacunación formado por especialistas de gastroenterología, pediatría, enfermería y farmacia.(AU)

Patients with inflammatory bowel disease (IBD) may require different immunosuppressive treatments throughout their illness. It is essential to assess the immunization status of patients at diagnosis or, if this is not possible, at least before the beginning of immunosuppressive therapy and, subsequently, administering the appropriate vaccines. Therefore, the aim of this work is to establish clear and concise recommendations on vaccination in patients with IBD in the different settings of our clinical practice including vaccination in children, during pregnancy, breastfeeding or on trips. This consensus document emphasises the differences between inactivated and attenuated vaccines and the different degrees of immunosuppression and correlates them with the administration of both mandatory and optional vaccines recommended to our patients with IBD. Finally, as a summary, 17 recommendations are established based on the available scientific evidence and expert opinion. A multidisciplinary team with extensive experience in IBD and vaccination, made up of specialists in gastroenterology, paediatrics, nursing and pharmacy, has participated in the preparation of these recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis.

El modelo Clinical outcomes, healthcare resource utilization, and related costs (COHERENT). Aplicación en pacientes con insuficiencia cardiaca / The Clinical outcomes, healthcare resource utilization, and related costs (COHERENT) model. Application in heart failure patients

Introducción y objetivos: Los resultados combinados se utilizan ampliamente, pero tienen diversas limitaciones. El modelo Clinical outcomes, healthcare resource utilization and related costs (COHERENT) es una aproximación nueva para presentar y comparar visualmente todos los componentes de los resultados combinados (incidencia, tiempo, duración) y los costes relacionados. El objetivo es evaluar su utilidad en una cohorte de pacientes. Métodos: Se diseñó un sistema de colores que representa gráficamente el porcentaje de pacientes en cada situación clínica (estado vital y ubicación: domicilio, urgencias, hospital), codificada jerárquicamente, en cada momento del seguimiento. Se aplicó a 1.126 pacientes con insuficiencia cardiaca aguda de 25 hospitales seguidos durante 30 días tras su visita a urgencias, y se calculó el tiempo en cada situación clínica y sus costes sanitarios. Resultados: El modelo ilustra visualmente los componentes del objetivo combinado a los 30 días (el 2,12% en urgencias, el 23,6% en hospitalización índice, el 2,7% en reingresos, el 65,5% vivo en casa y el 6,02% fallecido) y muestra diferencias significativas entre grupos de pacientes, hospitales o sistemas sanitarios. El instrumento también calcula y muestra los costes diarios y acumulados (total, 4.895.070 euros; media, 144,91 euros/paciente/día). Conclusiones: El modelo COHERENT es un nuevo método para mostrar visualmente resultados combinados y sus costes que permite comparar grupos de pacientes y cohortes. El nuevo sistema puede ser útil como un nuevo criterio de valoración para ensayos clínicos o estudios observacionales, y un instrumento para la evaluación comparativa, la planificación clínica, el análisis económico y la implementación de la atención sanitaria basada en valor (AU)

Introduction and objectives: Composite endpoints are widely used but have several limitations. The Clinical outcomes, healthcare resource utilization and related costs (COHERENT) model is a new approach for visually displaying and comparing composite endpoints including all their components (incidence, timing, duration) and related costs. We aimed to assess the validity of the COHERENT model in a patient cohort. Methods: A color graphic system displaying the percentage of patients in each clinical situation (vital status and location: at home, emergency department [ED] or hospital) and related costs at each time point during follow-up was created based on a list of mutually exclusive clinical situations coded in a hierarchical fashion. The system was tested in a cohort of 1126 patients with acute heart failure from 25 hospitals. The system calculated and displayed the time spent in each clinical situation and health care resource utilization-related costs over 30 days. Results: The model illustrated the times spent over 30 days (2.12% in ED, 23.6% in index hospitalization, 2.7% in readmissions, 65.5% alive at home, and 6.02% dead), showing significant differences between patient groups, hospitals, and health care systems. The tool calculated and displayed the daily and cumulative health care-related costs over time (total, €4 895 070; mean, €144.91 per patient/d). Conclusions: The COHERENT model is a new, easy-to-interpret, visual display of composite endpoints, enabling comparisons between patient groups and cohorts, including related costs. The model may constitute a useful new approach for clinical trials or observational studies, and a tool for benchmarking, and value-based health care implementation (AU)

Quantification of methane emitted by ruminants: a review of methods.

The contribution of greenhouse gas (GHG) emissions from ruminant production systems varies between countries and between regions within individual countries. The appropriate quantification of GHG emissions, specifically methane (CH4), has raised questions about the correct reporting of GHG inventories and, perhaps more importantly, how best to mitigate CH4 emissions. This review documents existing methods and methodologies to measure and estimate CH4 emissions from ruminant animals and the manure produced therein over various scales and conditions. Measurements of CH4 have frequently been conducted in research settings using classical methodologies developed for bioenergetic purposes, such as gas exchange techniques (respiration chambers, headboxes). While very precise, these techniques are limited to research settings as they are expensive, labor-intensive, and applicable only to a few animals. Head-stalls, such as the GreenFeed system, have been used to measure expired CH4 for individual animals housed alone or in groups in confinement or grazing. This technique requires frequent animal visitation over the diurnal measurement period and an adequate number of collection days. The tracer gas technique can be used to measure CH4 from individual animals housed outdoors, as there is a need to ensure low background concentrations. Micrometeorological techniques (e.g., open-path lasers) can measure CH4 emissions over larger areas and many animals, but limitations exist, including the need to measure over more extended periods. Measurement of CH4 emissions from manure depends on the type of storage, animal housing, CH4 concentration inside and outside the boundaries of the area of interest, and ventilation rate, which is likely the variable that contributes the greatest to measurement uncertainty. For large-scale areas, aircraft, drones, and satellites have been used in association with the tracer flux method, inverse modeling, imagery, and LiDAR (Light Detection and Ranging), but research is lagging in validating these methods. Bottom-up approaches to estimating CH4 emissions rely on empirical or mechanistic modeling to quantify the contribution of individual sources (enteric and manure). In contrast, top-down approaches estimate the amount of CH4 in the atmosphere using spatial and temporal models to account for transportation from an emitter to an observation point. While these two estimation approaches rarely agree, they help identify knowledge gaps and research requirements in practice.

There is a need to accurately and precisely quantify greenhouse gas (GHG) emissions, specifically methane (CH4), to ensure correct reporting of GHG inventories and, perhaps more importantly, determine how to best mitigate CH4 emissions. The objective of this study was to review existing methods and methodologies to quantify and estimate CH4 emissions from ruminants. Historically, most techniques were developed for specific purposes that may limit their widespread use on commercial farms and for inventory purposes and typically required frequent calibration and equipment maintenance. Whole animal and head respiration chambers, spot sampling techniques, and tracer gas methods can be used to measure enteric CH4 from individual animals, but each technique has its own inherent limitations. The measurement of CH4 emissions from manure depends on the type of storage, animal housing, CH4 concentration inside and outside the boundaries of the area of interest, and ventilation rate, which is likely the most complex variable creating many uncertainties. For large-scale areas, aircraft, drones, and satellites have been used in association with the tracer flux method, inverse modeling, imagery, and LiDAR (Light Detection and Ranging), but research is lagging in validating these methods. Bottom-up approaches to estimating CH4 emissions rely on empirical or mechanistic modeling to quantify the contribution of individual sources. Top-down approaches estimate the amount of CH4 in the atmosphere using spatial and temporal models to account for transportation from an emitter to an observation point.

Granulocyte and monocyte/macrophage apheresis in paediatric patients with ulcerative colitis: a case series in Spain.

Paediatric ulcerative colitis (UC) can cause malnutrition and growth retardation but its treatment can be limited by the potential adverse events of corticosteroids and anti-TNF agents in children. However, adsorptive granulocyte monocyte/macrophage apheresis (GMA) using Adacolumn® reduces intestinal inflammation through multiple immunomodulatory effects. This case series shows the safety and efficacy of GMA in paediatric UC, illustrating several GMA uses: in chronically active UC, for corticosteroid reduction in steroid-dependent UC, in UC with secondary loss of response to anti-TNF therapy, as bridge therapy in UC with failure of anti-TNF therapy, and to substitute toxic drug treatments.

What Clinical Trials Are Needed for Treatment of Leiomyosarcoma?

OPINION STATEMENT: Leiomyosarcoma is one of the most common subtypes of soft tissue sarcomas accounting for approximately 20% of sarcomas. As leiomyosarcoma patients frequently develop metastatic disease, effective systemic therapies are needed to improve clinical outcomes. The overall activity of the currently available conventional systemic therapies and the prognosis of patients with advanced and/or metastatic disease are poor. As such, the treatment of this patient population remains challenging. As a result, there is a clear unmet medical need, and designing and performing meaningful clinical studies are of utmost importance to improve the prognosis of this patient group. Therefore, the aim of this review is to briefly summarize state-of-the-art treatments for leiomyosarcoma patients and to describe trial characteristics needed for informative clinical studies.

Impact of a pharmacist driven anticoagulation reversal program at a large academic medical center.

In major/life-threatening bleeding, administration of timely and appropriate reversal agents is imperative to reduce morbidity and mortality. Due to complexities associated with the use of reversal agents, a clinical pharmacist-driven anticoagulation reversal program (ARP) was developed. The goal of this program was to ensure appropriateness of reversal agents based on the clinical scenario, optimize selection and avoid unintended consequences. This study describes the impact of a pharmacist-driven anticoagulation program on patient outcomes and cost. A single center retrospective chart review of adult patients whom the ARP was consulted from October 2018 to January 2020 was performed. Patients were included in the efficacy analysis if they were > 18 years of age and presented with acute bleeding. Patients were excluded from the efficacy analysis if the recommended reversal agent was not administered, if a repeat head CT was not available for patients who presented with intracranial hemorrhage (ICH), or if the patient was not bleeding. All patients were included in the economic evaluation. The primary outcome was the percentage of patients who achieved effective hemostasis within 24 h of anticoagulation reversal. Secondary outcomes include incidence of thromboembolic events, in-hospital mortality, and cost avoidance. One hundred twenty-one patients were evaluated by the ARP with 92 patients included in the efficacy analysis. The primary sites of bleeding were ICH in 46% and gastrointestinal (GI) in 29%. Hemostasis was achieved in 84% of patients. Thrombotic events occurred in 7.4% of patients and in-hospital mortality was 26.4%. Total cost avoidance was $1,005,871.78. To our knowledge, this is the first study to evaluate the impact of a pharmacist-driven ARP on clinical and economic outcomes. Implementation of a pharmacist-driven ARP was associated with favorable outcomes and cost savings.

Genetic insights into biological mechanisms governing human ovarian ageing.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.