The role of T cell stimulated agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) in mediating multiorgan dysfunction in IL-17 induced hypertension during pregnancy.

PROBLEM: Preeclampsia (PE), new-onset hypertension during pregnancy accompanied by organ dysfunction, is associated with chronic inflammation including elevated IL-17, CD4+ T cells, B cells and natural killer (NK) cells. IL-17 can serve as a signal for either the adaptive or innate immune activation. We have previously shown that IL-17 contributes to increased blood pressure in association with elevated TH17 cells, NK cells and B cells secreting angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA) during pregnancy. Moreover, we have shown an important role for CD4+T cells and AT1-AA in multiorgan dysfunction as measured by mitochondrial oxidative stress (mt ROS). However, we do not know the role of adaptive immune cells such as T cells or B cells secreting AT1-AA in mediating the PE phenotype in response to elevated IL-17. METHOD OF STUDY: In order to answer this question, we infused IL-17 (150 pg/day i.p.) into either Sprague Dawley (SD) or athymic nude rats via mini-osmotic pump from gestational day (GD) 14-19 of pregnancy. On GD 19, blood pressure was determined and NK cells, mtROS and respiration and AT1-AA production from B cells were measured. RESULTS: Infusion of IL-17 increased blood pressure in the presence or absence of T cells. Mean arterial pressure (MAP) increased with IL-17 from 98 ± 2 mm Hg (n = 12) to 114 ± 2 (n = 12) in SD rats and from 99 ± 4 mm Hg (n = 7) versus 115 ± 2 mm Hg (n = 7) in athymic nude rats. Similar trends were seen in NK cells and placental mt ROS. Knowing that IL-17 stimulates AT1-AA in SD pregnant rats, we included a group of SD and athymic nude pregnant rats infused with IL-17 and the AT1-AA inhibitor peptide ('n7AAc'). The inhibitor attenuated blood pressure (104.9 ± 3.2, p = .0001) and normalized NK cells and mt function in SD pregnant rats. Importantly, the AT1-AA was not produced in pregnant nude IL-17 treated rats, nor did 'n7AAc' effect MAP, in nude athymic rats. CONCLUSION: These findings suggest two conclusions; one is that IL-17 causes hypertension and multiorgan dysfunction in the absence of T cells and AT1-AA, possibly through its activation of innate cells and secondly, in the presence of T cells, blockade of the AT1-AA attenuates the effect of IL-17. This study indicates the critical effects of elevated IL-17 during pregnancy and suggest treatment modalities to consider for PE women.

Implementing One-at-a-Time Therapy in community addiction and mental health centres: a retrospective exploration of the implementation process and initial outcomes.

BACKGROUND: The Department of Health of the Government of New Brunswick and Regional Health Authorities elected to implement Stepped Care 2.0 (SC2.0) in 2021, and began with One-at-a-Time (OAAT) therapy in Community Addiction and Mental Health Centres (CAMHCs) to facilitate rapid access to addiction and mental healthcare. This study: 1) explicated the process of implementing OAAT therapy as it aligned to evidence-based implementation frameworks and strategies; 2) assessed readiness for change among providers during the implementation; and 3) evaluated initial client and system outcomes. METHODS: The process of implementing OAAT therapy within CAMHCs was documented and retrospectively aligned with the Active Implementation Frameworks-Stages of Implementation, Consolidated Framework for Implementation Research, and incorporated strategies endorsed by the Expert Recommendations for Implementing Change. Providers working in CAMHCs completed online asynchronous courses in OAAT therapy and SC2.0, and were recruited to participate in research on perceptions of organizational readiness. Initial outcomes of the implementation were evaluated through client satisfaction surveys administered in CAMHCs and system performance indicators. RESULTS: Aligning with implementation stages, key strategies included: 1) continuously monitoring readiness and soliciting stakeholder feedback for iterative improvement; 2) building a representative implementation team with engaged leaders; 3) creating a comprehensive implementation plan on staff training, communication, and system changes; and 4) supporting sustainability. Providers who participated in research (N = 170, ~ 50% response rate) agreed that their organization was ready for implementation, and that OAAT therapy delivered within a SC2.0 framework was acceptable, appropriate, and feasible. More than 3,600 OAAT therapy sessions were delivered during the initial implementation stage, and waitlists were reduced by 64.1%. The majority of clients who completed surveys (N = 1240, ~ 35% response rate) reported that their OAAT therapy session was helpful, with a minority reporting that additional intervention was needed. CONCLUSIONS: Thoughtful planning and execution, aligned with evidence-based implementation frameworks and strategies, played an important role in this provincial change initiative. Implementation steps outlined can help inform others looking to enact large-scale change.

RUPP Th17s cause hypertension and mitochondrial dysfunction in the kidney and placenta during pregnancy.

BACKGROUND: Preeclampsia (PE), new-onset hypertension (HTN), and organ dysfunction during the second half of pregnancy, is associated with an increase in inflammatory immune cells, including T helper 17 (Th17) cells. Studies have demonstrated that mitochondrial (mt) dysfunction is important in the pathogenesis of PE though causative factors have yet to be fully identified. Although Th17 cells, natural killer (NK) cells, and mt dysfunction contribute to HTN in the reduced uterine perfusion pressure (RUPP) rat model, the role of Th17 cells or IL-17 in mt dysfunction is unknown. Therefore, we hypothesize that RUPP stimulated Th17 cells cause HTN and mt dysfunction, which is alleviated with the blockade of IL-17. METHODS: On gestational day 12 (GD12), RUPP Th17 cells were transferred into normal pregnant (NP) Sprague Dawley rats. A subset of NP + RUPPTh17 rats received IL-17RC (100 pg/day) on GD14-19. Blood pressure (MAP), NK cells, and mt function were measured on GD19 in all groups. RESULTS: MAP increased in response to NP + RUPP Th17 compared to NP rats and was lowered with IL-17RC. Circulating and placental NK cells increased with NP + RUPP Th17 compared to NP and were lowered with IL-17RC. Renal mtROS increased in NP + RUPP Th17 compared to NP and was normalized with IL-17RC. Similar to PE women, placental mtROS decreased in NP + RUPP Th17 and was normalized with IL-17RC. CONCLUSION: Our results indicate that IL-17RC inhibition normalizes HTN, NK cell activation, and multi-organ mt dysfunction caused by Th17 cells stimulated in response to placental ischemia.

Healthcare provider knowledge, beliefs, and attitudes regarding opioids for chronic non-cancer pain in North America prior to the emergence of COVID-19: A systematic review of qualitative research.

Background: Balance between benefits and harms of using opioids for the management of chronic noncancer pain (CNCP) must be carefully considered on a case-by-case basis. There is no one-size-fits-all approach that can be executed by prescribers and clinicians when considering this therapy. Aim: The aim of this study was to identify barriers and facilitators for prescribing opioids for CNCP through a systematic review of qualitative literature. Methods: Six databases were searched from inception to June 2019 for qualitative studies reporting on provider knowledge, attitudes, beliefs, or practices pertaining to prescribing opioids for CNCP in North America. Data were extracted, risk of bias was rated, and confidence in evidence was graded. Results: Twenty-seven studies reporting data from 599 health care providers were included. Ten themes emerged that influenced clinical decision making when prescribing opioids. Providers were more comfortable to prescribe opioids when (1) patients were actively engaged in pain self-management, (2) clear institutional prescribing policies were present and prescription drug monitoring programs were used, (3) long-standing relationships and strong therapeutic alliance were present, and (4) interprofessional supports were available. Factors that reduced likelihood of prescribing opioids included (1) uncertainty toward subjectivity of pain and efficacy of opioids, (2) concern for the patient (e.g., adverse effects) and community (i.e., diversion), (3) previous negative experiences (e.g., receiving threats), (4) difficulty enacting guidelines, and (5) organizational barriers (e.g., insufficient appointment duration and lengthy documentation). Conclusions: Understanding barriers and facilitators that influence opioid-prescribing practices offers insight into modifiable targets for interventions that can support providers in delivering care consistent with practice guidelines.

Contexte: L'équilibre entre les avantages et les inconvénients de l'utilisation d'opioïdes pour la prise en charge de la douleur chronique non cancéreuse (CNCP) doit être soigneusement examiné au cas par cas. Il n'existe pas d'approche uniforme pouvant être adoptée par les prescripteurs et les cliniciens lorsqu'ils envisagent cette thérapie.Objectif: L'objectif de cette étude était de recenser les obstacles et les facilitateurs pour la prescription d'opioïdes pour la douleur chronique non cancéreuse par une revue systématique de la littérature qualitative.Méthodes: Six bases de données ont été consultées pour la période allant de leur création jusqu'en juin 2019 afin d'y repérer les rapports d'études qualitatives sur les connaissances, les attitudes, les croyances ou les pratiques des prestataires en matière de prescription d'opioïdes pour la douleur chronique non cancéreuse en Amérique du Nord. Les données ont été extraites, le risque de biais a été évalué et la confiance envers les données probantes a été notée.Résultats: Vingt-sept études faisant état de données provenant de 599 prestataires de soins de santé ont été incluses. Dix thèmes influençant la prise de décision clinique lors de la prescription d'opioïdes ont émergé. Les prestataires étaient plus à l'aise pour prescrire des opioïdes lorsque (1) les patients étaient activement engagés dans la prise en charge de la douleur, (2) des politiques de prescription institutionnelles claires et des programmes de surveillance des médicaments d'ordonnance étaient en place, (3) des relations de longue date et une alliance thérapeutique forte étaient présentes, et (4) du soutien interprofessionnel était disponible. Les facteurs qui réduisaient la probabilité de la prescription d'opioïdes comprenaient (1) l'incertitude à l'égard de la subjectivité de la douleur et de l'efficacité des opioïdes, (2) une préoccupation pour le patient (p. ex., effets indésirables) et la collectivité (p. ex., détournement), (3) des expériences négatives antérieures (p. ex., recevoir des menaces), (4) des difficultés à adopter des lignes directrices et (5) des obstacles organisationnels (p. ex., durée insuffisante des rendez-vous et longueur de la documentation).Conclusions: La compréhension des obstacles et des facilitateurs qui influencent les pratiques de prescription d'opioïdes permet d'avoir un aperçu des cibles modifiables pour les interventions qui peuvent aider les prestataires à fournir des soins conformes aux directives de pratique.

A formal evaluation of The Ottawa Hospital Pain Clinic orientation session: A quality improvement project.

Background: Chronic pain affects approximately one in every five Canadians and has a substantial impact on psychological well-being, relationships, ability to attend work or school, and overall functioning.The Ottawa Hospital Pain Clinic introduced orientation sessions, with the aim of providing new patients with pain education to help prepare patients for engagement with multimodal pain management strategies. This report summarizes the results of a formative evaluation of the orientation session at The Ottawa Hospital Pain Clinic to determine whether patients perceived the orientation session as beneficial. Methods: Interviews were conducted, transcribed, and then thematically analyzed to understand patients' perspectives on the orientation session. Coding was done by two team members using the constant comparison analyses method with key ideas, concepts, and patterns identified and compared to identify similarities. Results: Between September 6 and October 18, 2019, 18 patients attended an orientation session and 12 consented to participation and completed telephone interviews. The six themes identified included (1) feeling of community, (2) participants feeling heard by providers, (3) appreciation of the holistic approach, (4) availability of community resources, (5) barriers to access, and (6) discordant feelings of preparedness for the physician appointment. Conclusion: Results from this evaluation indicate that the orientation session offered at The Ottawa Hospital Pain Clinic improves chronic pain literacy, reduces feeling of isolation, and instills hope. As such, it appears to be a valuable component of pain clinic programs.

Contexte: La douleur chronique touche environ un Canadien sur cinq et a des répercussions sur le bien-être psychologique, les relations, la capacité à aller au travail ou à l'école, et l'ensemble du fonctionnement. La Clinique de la douleur de l'Hôpital d'Ottawa a lancé des séances d'orientation, dans le but de fournir aux nouveaux patients une formation sur la douleur pour les aider à se préparer à adopter des stratégies multimodales de prise en charge de la douleur. Ce rapport résume les résultats d'une évaluation formative de la séance d'orientation à la Clinique de la douleur de l'Hôpital d'Ottawa visant à déterminer si les patients perçoivent la session d'orientation comme bénéfique.Méthodes: Les entrevues ont été menées, transcrites, puis analysées de maniére thématique pour comprendre les points de vue des patients sur la séance d'orientation. Le codage a été effectué par deux membres de l'équipe à l'aide d'une méthode d'analyse par comparaison constante avec des idées, des concepts et des modéles clés répertoriés et par rapport à l'identification de similitudes.Résultats: Entre le 6 septembre et le 18 octobre 2019, 18 patients ont assisté à une séance d'orientation. Parmi ceux-ci, 12 ont accepté de participer et ont complété des entrevues téléphoniques. Les six thémes répertoriés comprenaient (1) le sentiment de communauté, (2) le sentiment des participants d'étre entendus des prestataires, (3) l'appréciation de l'approche holistique, (4) la disponibilité des ressources communautaires, (5) les obstacles à l'accés, et (6) des sentiments discordants de préparation pour le rendez-vous chez le médecin.Conclusion: Les résultats de cette évaluation indiquent que la séance d'orientation offerte à la Clinique de la douleur de l'Hôpital d'Ottawa améliore la littératie en matiére de douleur chronique, réduit le sentiment d'isolement et suscite l'espoir. Ainsi, elle semble étre un élément précieux des programmes de la Clinique de la douleur.

The role of immune cells and mediators in preeclampsia.

Preeclampsia is a hypertensive disorder of major concern in pregnancy than can lead to intrauterine growth restriction, placental abruption and stillbirth. The pathophysiology of preeclampsia is multifactorial, including not only kidney dysfunction but also endothelial dysfunction, as the maternal endothelium becomes exposed to placental factors that are released into the circulation and increase systemic levels of vasoconstrictors, oxidative stress, anti-angiogenic factors and inflammatory mediators. Importantly, inflammation can lead to insufficient placental perfusion and low birthweight in offspring. Various innate and adaptive immune cells and mediators have been implicated in the development of preeclampsia, in which oxidative stress is associated with activation of the maternal inflammatory response. Immune cells such as regulatory T cells, macrophages, natural killer cells, and neutrophils are known to have major causative roles in the pathology of preeclampsia, but the contributions of additional immune cells such as B cells, inflammatory cytokines and anti-angiotensin II type 1 receptor autoantibodies are also now recognized. Immunological interventions, therefore, have therapeutic potential in this disease. Here, we provide an overview of the immune responses that are involved in the pathogenesis of preeclampsia, including the role of innate and adaptive immune cells and mediators.

B2 cells contribute to hypertension and natural killer cell activation possibly via AT1-AA in response to placental ischemia.

Preeclampsia, new onset hypertension during pregnancy, is associated with activated T helper cells (Th) and B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA). The reduced uterine perfusion pressure (RUPP) model of placental ischemia recapitulates these characteristics. We have shown that Th-B cell communication contributes to AT1-AA and symptoms of preeclampsia in the RUPP rat. B2 cells are classical B cells that communicate with Th cells and are then transformed into memory B cells. We hypothesize that B2 cells cause hypertension, natural killer (NK) cell activation, and complement activation during pregnancy through the production of AT1-AA. To test this hypothesis, total splenic B cells and B2 cells were isolated from normal pregnant (NP) or RUPP rats on gestational day (GD)19 and adoptively transferred into GD12 NP rats. A group of recipient rats was treated with a specific inhibitor peptide of AT1-AA. On GD19, mean arterial pressure was measured, tissues were collected, activated NK cells were measured by flow cytometry, and AT1-AA was measured by cardiomyocyte assay. NP recipients of RUPP B cells or RUPP B2 cells had increased mean arterial pressure, AT1-AA, and circulating activated NK cells compared with recipients of NP B cells. Hypertension in NP recipients of RUPP B cells or RUPP B2 was attenuated with AT1-AA blockade. This study demonstrates that B cells and B2 cells from RUPP rats cause hypertension and increased AT1-AA and NK cell activation in response to placental ischemia during pregnancy.NEW & NOTEWORTHY This study demonstrates that placental ischemia-stimulated B2 cells induce hypertension and circulating natural killer cell activation and angiotensin II type 1 receptor production in normal pregnant rats.

Extension for Community Healthcare Outcomes (ECHO) Chronic Pain & Opioid Stewardship in Northwestern Ontario: A Thematic Analysis of Patient Cases.

Background: Chronic pain (CP) is a debilitating disease that reduces quality of life, decreases productivity, and has become a primary cause of health care resource consumption. Despite this, many Canadian family physicians have received little formal education in managing CP, making it one of the most challenging areas of practice in primary care. Project Extension for Community Healthcare Outcomes Chronic Pain & Opioid Stewardship St. Joseph's Care Group (Project ECHO-SJCG) is an evidence-based educational program connecting community-based health care providers (HCPs) with an interprofessional team by videoconference to learn about management of CP in rural, remote, and underserved areas. Aims: To explore key learning points from cases presented at Project ECHO-SJCG, identify and analyze themes and improve future sessions of continuing professional development for HCPs. Methods: We completed a thematic analysis of forty cases and key learning points using the constant comparison method. We also summarized descriptive statistics for patient and provider characteristics. Results: Forty cases were presented by 31 HCPs, who received suggestions focused on assessment and diagnosis, pharmacological and non-pharmacological pain symptom management, interventional management, attention to biopsychosocial factors, and appropriate referral to other HCPs. Conclusion: Project ECHO-SJCG cases allow HCPs to gain a broad knowledge base to evaluate and manage CP in their practice. Identified themes highlight common gaps in HCPs' knowledge and will guide future sessions.

Contexte: La douleur chronique est une maladie débilitante qui réduit la qualité de vie et diminue la productivité. En outre, elle est devenue une cause principale de consommation des ressources en soins de santé. Malgré cela, de nombreux médecins de famille canadiens ont reçu peu d'éducation conventionnelle sur la prise en charge de la douleur chronique, ce qui en fait l'un des domaines de pratique les plus difficiles en soins primaires.Le Projet de vulgarisation pour des résultats de santé communautaires ­ Gestion des opioïdes et de la douleur chronique du St. Joseph' s Care Group (projet ECHOSJCG) est un programme éducatif fondé sur les données probantes qui met les prestataires de soins de santé communautaires en relation avec une équipe interprofessionnelle par vidéoconférence pour en apprendre davantage sur la prise en charge de la douleur chronique dans les zones rurales, éloignées et mal desservies.Objectifs: Explorer les principaux points d'apprentissage à partir des cas présentés au projet ECHO-SJCG, recenser et analyser les thèmes et améliorer les futures sessions de développement professionnel continu pour les professionnels de la santé.Méthodes: Nous avons effectué une analyse thématique de quarante cas et points d'apprentissage clés à l'aide de la méthode de comparaison constante. Nous avons également résumé les statistiques descriptives pour le patient et le prestataire.Résultats: Quarante cas ont été présentés par 31 professionnels de la santé ayant reçu des suggestions axées sur l'évaluation et le diagnostic, la prise en charge des symptômes de douleur pharmacologique et non pharmacologique, la prise en charge interventionnelle, l'attention aux facteurs biopsychosociaux et l'orientation appropriée vers d'autres professionnels de la santé.Conclusions: Les cas du projet ECHO-SJCG permettent aux professionnels de la santé d'acquérir une large base de connaissances pour l'évaluation et la prise en charge de la douleur chronique dans leur pratique. Les thèmes recensés mettent en évidence les lacunes communes dans les connaissances des professionnels de la santé et orienteront les sessions futures.

A Systematic Review of Salt Taste Function and Perception Impairments in Adults with Chronic Kidney Disease.

Individuals with chronic kidney disease (CKD) experience physiological changes that likely impair salt taste function and perception. Sodium restriction is a cornerstone of CKD management but dietary sodium plays an important role in food enjoyment and may interfere with compliance to this intervention. Therefore, confirming that taste deficits are present in CKD will improve our understanding of how taste deficits can affect intake, and inform dietary counselling in the future. A systematic review was conducted. Studies that included adults with CKD and healthy controls, and assessed salt taste sensitivity, perceived intensity, and/or hedonic ratings were included. Study quality was assessed using the Academy of Nutrition and Dietetics Evidence Analysis Library Quality Criteria Checklist: Primary Research. Of the 16 studies, the majority reported decreased salt taste sensitivity, but no consistent differences in intensity or hedonic ratings were observed. Higher recognition thresholds in CKD patients were associated with higher sodium intake, but results should be interpreted with caution as the measures used were subject to error in this population. In conclusion, salt taste sensitivity is decreased in CKD, but intensity and hedonic evaluations appear to be more robust. Given that hedonic assessments are better predictors of intake, and that salt taste preferences can be changed over time, dietary counselling for low-sodium intake is likely to be effective for this population.

The SSLepR mutant rat represents a novel model to study obesity-induced renal injury before puberty.

Prepubertal obesity (PPO) has emerged as a major health problem over the past few decades and is a risk factor for the development of proteinuria. The current study investigated whether the development of renal injury in the obese SSLepR mutant strain occurs before puberty. When determining the temporal changes in serum sex hormones in female and male SS and SSLepR mutant rats between 4 and 10 wk of age, we only observed significant increases in estradiol and testosterone levels in female and male SS rats at 10 wk of age than at 4 wk of age. The results suggest that studying both strains between 4 and 8 wk of age is appropriate to study the effects of PPO on renal injury in this model. Proteinuria was significantly higher in SSLepR mutant rats as opposed to the values observed in SS rats at 8 wk of age, and we did not observe any sex differences in proteinuria in either strain. The kidneys from the SSLepR mutant rats displayed significant glomerular and tubular injury and renal fibrosis versus the values measured in SS rats without any sex differences. Overall, we observed increased immune cell infiltration in the kidneys from SSLepR mutant rats compared with SS rats. Interestingly, female SSLepR mutant rats displayed significant increases in not only M1 macrophages (proinflammatory) but also M2 macrophages (anti-inflammatory) versus male SSLepR mutant rats. These results suggest the SSLepR mutant rat may be a useful model to study early progression of obesity-related renal injury before the onset of puberty.

Placental CD4+ T cells from preeclamptic patients cause autoantibodies to the angiotensin II type I receptor and hypertension in a pregnant rat model of preeclampsia.

Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4+ T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4+ T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4+ T cells from normal pregnant (NP) women. However, the role of PE CD4+ T cells to cause AT1-AA as a mechanism of hypertension is not known. Aim: Our goal was to determine if PE CD4+ T cells stimulate AT1-AA in pregnant nude-athymic rats. CD4+ T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4+ T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4+ T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained MAP [114 ± 1 mmHg (n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4+ T cells compared to NP nude + NP CD4+ T cells [98 ± 2 mmHg (n = 7, P < 0.05) and 1.3 ± 0.9 bpm (n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4+ T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4+ T cells. These results show that placental CD4+ T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy.

Progesterone Induced Blocking Factor Reduces Hypertension and Placental Mitochondrial Dysfunction in Response to sFlt-1 during Pregnancy.

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1), and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that blocks inflammatory processes and we have previously shown PIBF to lower mean arterial blood pressure (MAP) and sFlt-1 in a rat model of PE. Infusion of sFlt-1 causes hypertension and many characteristics of PE in pregnant rodents, however, its role in causing mt dysfunction is unknown. Therefore, we hypothesize that PIBF will improve mt function and MAP in response to elevated sFlt-1 during pregnancy. We tested our hypothesis by infusing sFlt-1 via miniosmotic pumps in normal pregnant (NP) Sprague-Dawley rats (3.7 µg·kg-1·day-1) on gestation days (GD) 13-19 in the presence or absence of PIBF (2.0 µg/mL) injected intraperitoneally on GD 15 and examined mean arterial blood pressure (MAP) and placental mt ROS on GD 19. sFlt-1 increased MAP to 112 + 2 (n = 11) compared to NP rats (98 + 2 mmHg, n = 15, p < 0.05), which was lowered in the presence of sFlt-1 (100 + 1 mmHg, n = 5, p < 0.05). Placental mtATP was reduced in sFlt-1 infused rats versus NP controls, but was improved with PIBF. Placental mtROS was elevated with sFlt-1 compared to NP controls, but was reduced with PIBF. Sera from NP + sFlt-1 increased endothelial cell mtROS, which was attenuated with PIBF. These data demonstrate sFlt-1 induced HTN during pregnancy reduces placental mt function. Importantly, PIBF improved placental mt function and HTN, indicating the efficacy of improved progesterone signaling as potential therapeutics for PE.

Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia.

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). PE is characterized by new-onset hypertension during pregnancy and organ dysfunction and increasing evidence indicates that proinflammatory cytokines cause hypertension and mitochondrial (mt) dysfunction during pregnancy. The reduced uterine perfusion pressure (RUPP) model of placental ischemia is a rat model of PE that we commonly use in our laboratory and we have previously shown that low doses of recombinant IL-2 can decrease blood pressure in RUPP rats. The objective of this study was to determine the effects of a low dose of recombinant IL-2 on multi-organ mt dysfunction in the RUPP rat model of PE. We tested our hypothesis by infusing recombinant IL-2 (0.05 ng/mL) into RUPP rats on GD14 and examined mean arterial pressure (MAP), renal, placental and endothelial cell mt function compared to control RUPP. MAP was elevated in RUPP rats (n = 6) compared to controls (n = 5) (122 ± 5 vs. 102 ± 3 mmHg, p < 0.05), but was reduced by administration of LD recombinant IL-2 (107 ± 1 vs. 122 ± 5 mmHg, n = 9, p < 0.05). Renal, placental and endothelial mt ROS were significantly increased in RUPP rats compared to RUPP+ IL-2 and controls. Placental and renal respiration rates were reduced in RUPP rats compared to control rats but were normalized with IL-2 administration to RUPPs. These data indicate that low-dose IL-2 normalized multi-organ mt function and hypertension in response to placental ischemia.

CD4+ T cells cause renal and placental mitochondrial oxidative stress as mechanisms of hypertension in response to placental ischemia.

The reduced uterine perfusion pressure (RUPP) rat model and normal pregnant (NP) rat recipients of RUPP CD4+ T cells recapitulate many characteristics of preeclampsia such as hypertension and oxidative stress. We have shown an important hypertensive role for natural killer (NK) cells to cause mitochondrial dysfunction in RUPP rats; however, the role for RUPP CD4+ T cells to stimulate NK cells is unknown. Therefore, we hypothesized that RUPP-induced CD4+ T cells activate NK cells to cause mitochondrial dysfunction/reactive oxygen species (ROS) as mechanisms of hypertension during pregnancy. We tested our hypothesis by adoptive transfer of RUPP CD4+ T cells into NP rats or by inhibiting the activation of RUPP CD4+ T cells with Orencia (abatacept) and examining hypertension, NK cells, and mitochondrial function. RUPP was performed on gestation day (GD) 14, and splenic CD4+ T cells were isolated on GD 19 and injected into NP rats on GD 13. In a separate group of rats, Orencia was infused and the RUPP procedure was performed. Mean arterial pressure and placental and renal mitochondrial ROS increased in RUPP (n = 7, P < 0.05) and NP + RUPP CD4+ T-cell recipients (n = 13, P < 0.05) compared with control NP (n = 7) and NP + NP CD4+ T-cell recipients (n = 5) but was reduced with Orencia (n = 13, P < 0.05). Placental and renal respiration was reduced in RUPP (n = 6, P < 0.05) and NP + RUPP CD4+ T-cell recipients (n = 6, state 3 P < 0.05) compared with NP (n = 5) and NP + NP CD4+ T-cell recipients (n = 5) but improved with Orencia (n = 9, n = 8 P < 0.05). These data indicate that CD4+ T cells, independent of NK cells, cause mitochondrial dysfunction/ROS contributing to hypertension in response to placental ischemia during pregnancy.

Twelve tips for teaching medical students online under COVID-19.

Universities worldwide are pausing in an attempt to contain COVID-19's spread. In February 2019, universities in China took the lead, cancelling all in-person classes and switching to virtual classrooms, with a wave of other institutes globally following suit. The shift to online platform poses serious challenges to medical education so that understanding best practices shared by pilot institutes may help medical educators improve teaching. Provide 12 tips to highlight strategies intended to help on-site medical classes moving completely online under the pandemic. We collected 'best practices' reports from 40 medical schools in China that were submitted to the National Centre for Health Professions Education Development. Experts' review-to-summary cycle was used to finalize the best practices in teaching medical students online that can benefit peer institutions most, under the unprecedented circumstances of the COVID-19 outbreak. The 12 tips presented offer-specific strategies to optimize teaching medical students online under COVID-19, specifically highlighting the tech-based pedagogy, counselling, motivation, and ethics, as well as the assessment and modification. Learning experiences shared by pilot medical schools and customized properly are instructive to ensure a successful transition to e-learning.

Comparison of the formation, adipogenic maturation, and retention of human adipose-derived stem cell spheroids in scaffold-free culture techniques.

While three-dimensional spheroids outperform traditional two-dimensional monolayer culture for human adipose-derived stem cells (hASCs), there is not a consensus on the most successful method for enhancing their adipogenic differentiation and minimizing the loss of physiologically relevant, fatty spheroids during culture. To this end, we compared three culture methods, namely, elastin-like polypeptide-polyethyleneimine (ELP-PEI) coated surfaces, ultra-low attachment static culture, and suspension culture for their ability to form and retain productive hASC spheroids. The ELP-PEI coatings used the ELP conjugated to two molecular weights of PEI (800 or 25,000 g/mol). FTIR spectroscopy, atomic force microscopy, and contact angle goniometry revealed that the ELP-PEI coatings had similar chemical structures, surface topography, and hydrophobicity. Time-lapse microscopy showed that increasing the PEI molecular weight resulted in smaller spheroids. Measurement of triglyceride content showed that the three methods induced comparable differentiation of hASCs toward the adipogenic lineage. DNA content and morphometric analysis revealed merging of spheroids to form larger spheroids in the ultra-low attachment static culture and suspension culture methods. In contrast, the retention of hASC spheroid sizes and numbers with a regular spheroid size (~100 µm) were best atop the ELP-PEI800 coatings. Overall, this research shows that the spheroid culture atop the ELP-PEI coatings is a suitable cell culture model for future studies involving long-term, three-dimensional culture of mature adipocytes derived from hASCs.

The impact of a complex workplace dietary intervention on Irish employees' off-duty dietary intakes.

A paucity of evidence exists regarding the impact of workplace dietary interventions on employees' off-duty dietary intakes. This study assessed the impact of workplace dietary interventions that included nutrition education and environmental dietary modification both alone and in combination on employees' dietary intakes inside (on-duty) and outside (off-duty) of work. A pre-post study on employees' on and off-duty dietary intakes was undertaken. Data were obtained from a complex workplace dietary intervention study (Food Choice at Work Trial). Four manufacturing workplaces were allocated to: Control (n = 111), nutrition education (n = 226), environmental dietary modification (n = 113) and nutrition education and environmental dietary modification combined (n = 400) (2013-14). Seven- to nine-month follow-up data were obtained for 517 employees (61% response) [Control (n = 67), Education (n = 107), Environment (n = 71) and Combined (n = 272)]. Dietary intakes were measured using 24-h dietary recalls. Differences between on and off-duty mean dietary intakes were compared and regression analyses adjusted for potential confounders. Significant reductions in on-duty intakes of total fat (-14.2 g/day, p = 0.000), saturated fat (-7 g/day, p = 0.000), salt (-1.4 g/day, p = 0.000) and total sugars (-8.9 g/day, p = 0.003) were observed in the Combined and in the Environment [total fat (-11.4 g/d, p = 0.017) and saturated fat (-8.8 g/day, p = 0.000)]. In the Combined, significant changes were also observed in off-duty intakes of total fat (-10.0 g/day, p = 0.001), saturated fat (-4.2 g/day, p = 0.001), salt (-0.7 g/day, p = 0.020) and total sugars (-8.1 g/day, p = 0.020). Food service can have a positive impact in our everyday environments, including inside and outside of work. Dietary interventions combining nutrition education and environmental dietary modification can improve employees' on and off-duty dietary intakes.

Analysis of the Regulatory Divergence of Comparative Dissolution Requirements for Post-Approval Manufacturing Changes of Modified Release Solid Oral Dosage Forms.

This manuscript discusses global regulatory divergence of dissolution requirements for modified release solid oral dosage forms and the obstacles that must be addressed to be compliant with evolving guidance and legislation. The proliferation of local guidance documents, changing regulatory expectations, and increased legal enforcement has resulted in mismatched country-specific dissolution testing requirements and similarity criteria, and heightens industry's challenges with registration of modified release solid oral dosage forms. The lack of global harmonization and the complexity added by minor regional adaptations contributes to inefficiencies and hinders industry's goal of developing and delivering medicines. Awareness of country-specific similarity requirements and alignment between industry leaders and regulators is needed to facilitate global harmonization which will enable delivering new and improved medicines. The purpose of this manuscript is to compare and contrast in vitro conditions stated in local regulatory guidelines, raise awareness of the need to work toward harmonization of global requirements, and propose an initial study design toward that aspiration.

A new approach to study the sex differences in adipose tissue.

Obesity is one of the most invaliding and preventable diseases in the United States. Growing evidence suggests that there are sex differences in obesity in human and experimental animals. However, the specific mechanisms of this disease are unknown. Consequently, there is any particular treatment according to the sex/gender at this time. During the last decade, we observe a rise in the study of adipocyte and the possible mechanisms involved in the different roles of the fat. Furthermore, the effect of sex steroids on the adipocyte is one of the fields that need elucidation. Supporting evidence suggests that sex steroids play an essential role not only in the fat distribution, but also, in its metabolism, proliferation, and function. Thus, using in vitro and in vivo studies will contribute to our fight against this critical health public problem encompassing both sexes. In the present review, we discuss some of the recent advances in the adipocytes and the effect of the sex steroids on the adipose tissue. Also, we propose a new alternative to study the role of sex steroids on adipocyte biology through human adipose-derived stem cells.

An evaluation and exploration of Irish food-service businesses' uptake of and attitudes towards a voluntary government-led menu energy (calorie) labelling initiative.

OBJECTIVE: To investigate the uptake of and attitudes towards a voluntary government-led energy (calorie) menu labelling initiative in Ireland among a representative sample of food-service businesses and to inform further actions that may need to be undertaken to facilitate successful implementation. DESIGN: A mixed-methods approach, incorporating a national telephone survey, structured observation visits and semi-structured interviews. SETTING: Twenty-six counties in the Republic of Ireland. SUBJECTS: A random selection of food-service businesses (n 604) participated in the telephone survey. Businesses which indicated that they did display calories were selected to participate in structured observation visits (n 42), along with a random sample (n 38) of businesses that did not display calories. A purposive sample of thirteen food-service business owners who participated in the telephone survey participated in semi-structured interviews. RESULTS: In the telephone survey, 7 % (n 42) of food businesses reported displaying calories and the observation visits revealed that of these businesses, 10 % (n 4) were not displaying calorie information. Three major themes emerged from the semi-structured interviews: uncertainty, impact on business and consumer nutrition knowledge. Participants expressed concerns regarding inaccuracies in the calorie information, cost and time implications, mistrust in the food-service industry and poor nutritional knowledge among consumers. These concerns impeded the implementing of calorie menu labelling. CONCLUSIONS: A multifactorial approach that incorporates guidance and support (training/tax incentives), practical assistance (user-friendly calorie calculation software), a reasonable legislative structure and a standardised monitoring system is needed to facilitate the successful implementation of calorie menu labelling.