Alterations in tumour metabolism and acid/base regulation result in the formation of a hostile environment, which fosters tumour growth and metastasis. Acid/base homoeostasis in cancer cells is ...governed by the concerted interplay between carbonic anhydrases (CAs) and various transport proteins, which either mediate proton extrusion or the shuttling of acid/base equivalents, such as bicarbonate and lactate, across the cell membrane. Accumulating evidence suggests that some of these transporters interact both directly and functionally with CAIX to form a protein complex coined the 'transport metabolon'. Transport metabolons formed between bicarbonate transporters and CAIX require CA catalytic activity and have a function in cancer cell migration and invasion. Another type of transport metabolon is formed by CAIX and monocarboxylate transporters. In this complex, CAIX functions as a proton antenna for the transporter, which drives the export of lactate and protons from the cell. Since CAIX is almost exclusively expressed in cancer cells, these transport metabolons might serve as promising targets to interfere with tumour pH regulation and energy metabolism. This review provides an overview of the current state of research on the function of CAIX in tumour acid/base transport and discusses how CAIX transport metabolons could be exploited in modern cancer therapy.
A lack of effective therapist training is a major barrier to evidence-based intervention (EBI) delivery in the community. Systematic reviews published nearly a decade ago suggested that traditional ...EBI training leads to higher knowledge but not more EBI use, indicating that more work is needed to optimize EBI training and implementation. This systematic review synthesizes the training literature published since 2010 to evaluate how different training models (workshop, workshop with consultation, online training, train-the-trainer, and intensive training) affect therapists' knowledge, beliefs, and behaviors. Results and limitations for each approach are discussed. Findings show that training has advanced beyond provision of manuals and brief workshops; more intensive training models show promise for changing therapist behavior. However, methodological issues persist, limiting conclusions and pointing to important areas for future research.
Public Health Significance
Therapist training plays a critical role in the implementation of evidence-based interventions. This review provides an update of the past decade of literature related to therapist training in evidence-based interventions and examines five approaches to therapist training: workshops alone, workshops followed by consultation, online training, train-the-trainer, and intensive training. Results suggest that more intensive training models are most likely to facilitate clinician behavior change, although optimal dosage and training content remains unclear. Future work is needed to identify key elements of training to optimize the success of implementation efforts and ensure that treatment-seeking individuals receive effective care.
Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, ...and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders.
Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios ORs = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR 95% CI per 1-kg increase in predicted VAT mass = 1.32 1.06-1.64, P = 0.0130), PCOS (OR 95% CI = 1.15 1.08-1.23, P = 3.24 × 10-05), and pre-eclampsia (OR 95% CI = 3.08 1.98-4.79, P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy.
We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.
Objectives
To review the scientific literature pertaining to the use of hand‐carried and hand‐held ultrasound devices in low‐ and middle‐income countries (LMIC), with a focus on clinical ...applications, geographical areas of use, the impact on patient management and technical features of the devices used.
Methods
The electronic databases PubMed and Google Scholar were searched. No language or date restrictions were applied. Case reports and original research describing the use of hand‐carried ultrasound devices in LMIC were included if agreed upon as relevant by two‐reviewer consensus based on our predefined research questions.
Results
A total of 644 articles were found and screened, and 36 manuscripts were included for final review. Twenty‐seven studies were original research articles, and nine were case reports. Several reports describe the successful diagnosis and management of difficult, often life‐threatening conditions, using hand‐carried and hand‐held ultrasound. These portable ultrasound devices have also been studied for cardiac screening exams, as well as a rapid triage tool in rural areas and after natural disaster. Most applications focus on obstetrical and abdominal complaints. Portable ultrasound may have an impact on clinical management in up to 70% of all cases. However, no randomised controlled trials have evaluated the impact of ultrasound‐guided diagnosis and treatment in resource‐constrained settings. The exclusion of articles published in journals not listed in the large databases may have biased our results. Our findings are limited by the lack of higher quality evidence (e.g. controlled trials).
Conclusions
Hand‐carried and hand‐held ultrasound is successfully being used to triage, diagnose and treat patients with a variety of complaints in LMIC. However, the quality of the current evidence is low. There is an urgent need to perform larger clinical trials assessing the impact of hand‐carried ultrasound in LMIC.
Objectifs
Passer en revue la littérature scientifique portant sur l'utilisation d'appareils d’échographie portatifs dans les pays à faible revenu et à revenu intermédiaire (PFR‐PRI) en mettant l'accent sur les applications cliniques, les zones géographiques d'utilisation, l'impact sur la prise en charge des patients et les caractéristiques techniques des appareils utilisés.
Méthodes
Recherche effectuée dans les bases de données électroniques PubMed et Google Scholar. Aucune restriction linguistique ou de période n'a été appliquée. Les rapports de cas et les recherches originales décrivant l'utilisation d'appareils d’échographie portatifs dans les PFR‐PRI ont été inclus, si trouvés pertinents par le consensus de deux reviewers, basé sur nos questions de recherche prédéfinies.
Résultats
644 articles ont été trouvés et analysés, 36 manuscrits ont été inclus pour analyse finale. 27 études faisaient l'objet d'articles de recherche originale et 9 étaient des rapports de cas. Plusieurs rapports décrivent le diagnostic et la prise en charge avec succès de conditions difficiles, souvent mortelles, en utilisant des appareils d’échographie portatifs. Ces dispositifs d’échographie portatifs ont également été étudiés pour les examens de dépistage cardiaques, ainsi que comme outil de triage rapide dans les zones rurales et à la suite de catastrophes naturelles. La plupart des applications se concentrent sur les plaintes obstétricales et abdominales. L’échographie portative peut avoir un impact sur la prise en charge clinique dans 70% de tous les cas. Cependant, aucun essai contrôlé randomisé n'a évalué l'impact sur le diagnostic et le traitement guidé par l’échographie dans les milieux à ressources limitées. L'exclusion des articles publiés dans des revues ne figurant pas dans les grandes bases de données peut avoir biaisé nos résultats. Nos résultats sont limités par le manque de donnée de meilleure qualité (par ex., les essais contrôlés).
Conclusions
L’échographie portative et réalisée à la main est utilisée avec succès au triage, au diagnostic et pour le traitement des patients avec diverses plaintes dans PFR‐PRI. Cependant, la qualité des données actuelles est faible. Il est urgent de procéder à des essais cliniques de grande envergure évaluant l'impact de l’échographie réalisée à la main dans les PFR‐PRI.
Objetivos
Revisar la literatura científica existente sobre el uso de aparatos portátiles de ultrasonido en países con ingresos bajos y medios (PIBM), con especial atención en las aplicaciones clínicas, las áreas geográficas de uso, el impacto sobre el manejo del paciente y las características técnicas de los aparatos utilizados.
Métodos
Se realizó una búsqueda en las bases de datos electrónicas PubMed y Google Scholar. No se aplicaron restricciones de idioma o fecha. Se incluyeron los informes de casos y artículos originales que describían el uso de aparatos de ultrasonido portátiles en PIBM, si dos revisores estaban de acuerdo sobre su relevancia basándose en las preguntas predefinidas de búsqueda.
Resultados
Se encontraron y revisaron 644 artículos, y se incluyeron 36 manuscritos en la revisión final. 27 estudios eran artículos de investigaciones originales y 9 eran informes de casos. Varios informes describan el diagnóstico exitoso y el manejo de condiciones difíciles, a menudo letales, utilizando equipos portátiles de ultrasonido. Estos equipos también han sido estudiados en pruebas de riesgo cardiaco, al igual que como herramientas de triaje rápido en áreas rurales y después de un desastre natural. La mayoría de las aplicaciones se centran en problemas obstétricos y abdominales. El ultrasonido portátil podría tener un impacto sobre el manejo clínico en hasta un 70% de todos los casos. Sin embargo, ningún ensayo aleatorizado y controlado ha evaluado el impacto del diagnóstico y el tratamiento guiado por ultrasonido en lugares con recursos limitados. Excluir aquellos artículos publicados en revistas que no figuran en las grandes bases de datos podría haber sesgado nuestros resultados. Nuestros hallazgos están limitados por la falta de evidencia de mayor calidad (ej. ensayos controlados).
Conclusiones
El uso de equipos de ultrasonido portátiles es exitoso para realizar el triaje, diagnóstico y tratamiento de pacientes con una variedad de problemas en PIBM. Sin embargo, la calidad de la evidencia actualmente disponible es baja. Existe una necesidad urgente de realizar ensayos clínicos grandes para evaluar el impacto de equipos de ultrasonido portátiles en PIBM.
Abstract
Phenotypic definition of helper ILC1 and NK cells is problematic due to overlapping markers. Recently we showed the identification of cytotoxic ILC3s characterized by expression of CD94. ...Here we analyse CD127+ ILCs and NK cells in intestinal lamina propria from healthy donors and Crohn’s disease patients and identify two populations of CD127+CD94+ ILCs, designated population A and B, that can be distinguished on the expression of CD117, CD18 and cytotoxic molecules. Population B expresses granulysin, a cytotoxic molecule linked to bacterial lysis and/or chemotaxis of monocytes. Granulysin protein is secreted by population B cells upon stimulation with IL-15. Activation of population B in the presence of TGF-β strongly reduces the expression of cytotoxic effector molecules of population B. Strikingly, samples from individuals that suffer from active Crohn’s disease display enhanced frequencies of granulysin-expressing effector CD127+CD94+ ILCs in comparison to controls. Thus this study identifies group 1 ILC populations which accumulate in inflamed intestinal tissue of Crohn’s disease patients and may play a role in the pathology of the disease.
To assess patient response rates to medical therapies used to treat endometriosis-associated pain.
A systematic review with the use of Medline and Embase.
Not applicable.
Women receiving medical ...therapy to treat endometriosis.
None.
The proportions of patients who: experienced no reduction in endometriosis-associated pain symptoms; had pain symptoms remaining at the end of the treatment period; had pain recurrence after treatment cessation; experienced an increase or no change in disease score during the study; were satisfied with treatment; and discontinued therapy owing to adverse events or lack of efficacy. The change in pain symptom severity experienced during and after treatment, as measured on the visual analog scale, was also assessed.
In total, 58 articles describing 125 treatment arms met the inclusion criteria. Data for the response of endometriosis-associated pain symptoms to treatment were presented in only 29 articles. The median proportions of women with no reduction in pain were 11%–19%; at the end of treatment, 5%–59% had pain remaining; and after follow-up, 17%–34% had experienced recurrence of pain symptoms after treatment cessation. After median study durations of 2–24 months, the median discontinuation rates due to adverse events or lack of efficacy were 5%–16%.
Few studies of medical therapies for endometriosis report outcomes that are relevant to patients, and many women gain only limited or intermittent benefit from treatment.
Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic ...profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.
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•LLPCs import more glucose than do short-lived plasma cells (SLPCs)•LLPCs primarily use glucose to glycosylate antibodies•Under metabolic stress, LLPCs but not SLPCs divert glucose to form pyruvate•Genetic ablation of mitochondrial pyruvate import shortens the lifespan of LLPCs
Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs), but specific pathways that allow LLPC persistence are unknown. Bhattacharya and colleagues show that LLPCs import and use glucose for antibody glycosylation, but in times of metabolic stress, they divert glucose to generate pyruvate for survival.
Over twenty years have passed since Nelson and Winter put the concept of routines firmly at the center of the analysis of organizational and economic change. A growing number of researchers have ...followed their example since. However, researchers have not always had the same idea of what routines are and what effect they have on organizations. Over time, this has left the literature on routines riddled with ambiguities. For researchers who want to apply the concept of routines in their research, it is not easy to get an overview of the current thinking about routines and their effects. This article offers a systematic review of the literature that has contributed to the theoretical development of the concept of routines, and of the empirical literature that has applied the concept of routines.
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