The small intestinal epithelial barrier inputs signals from the gut microbiota in order to balance physiological inflammation and tolerance, and to promote homeostasis. Understanding the dynamic relationship between microbes and intestinal epithelial cells has been a challenge given the cellular heterogeneity associated with the epithelium and the inherent difficulty of isolating and identifying individual cell types. Here, we used single-cell RNA sequencing of small intestinal epithelial cells from germ-free and specific pathogen-free mice to study microbe-epithelium crosstalk at the single-cell resolution. The presence of microbiota did not impact overall cellular composition of the epithelium, except for an increase in Paneth cell numbers. Contrary to expectations, pattern recognition receptors and their adaptors were not induced by the microbiota but showed concentrated expression in a small proportion of epithelial cell subsets. The presence of the microbiota induced the expression of host defense- and glycosylation-associated genes in distinct epithelial cell compartments. Moreover, the microbiota altered the metabolic gene expression profile of epithelial cells, consequently inducing mTOR signaling thereby suggesting microbe-derived metabolites directly activate and regulate mTOR signaling. Altogether, these findings present a resource of the homeostatic transcriptional and cellular impact of the microbiota on the small intestinal epithelium.
Revealing the molecular events associated with reprogramming different somatic cell types to pluripotency is critical for understanding the characteristics of induced pluripotent stem cell (iPSC) therapeutic derivatives. Inducible reprogramming factor transgenic cells or animals—designated as secondary (2°) reprogramming systems—not only provide excellent experimental tools for such studies but also offer a strategy to study the variances in cellular reprogramming outcomes due to different in vitro and in vivo environments. To make such studies less cumbersome, it is desirable to have a variety of efficient reprogrammable mouse systems to induce successful mass reprogramming in somatic cell types. Here, we report the development of two transgenic mouse lines from which 2° cells reprogram with unprecedented efficiency. These systems were derived by exposing primary reprogramming cells containing doxycycline-inducible Yamanaka factor expression to a transient interruption in transgene expression, resulting in selection for a subset of clones with robust transgene response. These systems also include reporter genes enabling easy readout of endogenous Oct4 activation (GFP), indicative of pluripotency, and reprogramming transgene expression (mCherry). Notably, somatic cells derived from various fetal and adult tissues from these 2° mouse lines gave rise to highly efficient and rapid reprogramming, with transgene-independent iPSC colonies emerging as early as 1 wk after induction. These mouse lines serve as a powerful tool to explore sources of variability in reprogramming and the mechanistic underpinnings of efficient reprogramming systems.
Purpose: American Society of Clinical Oncology recommends that older adults with cancer being considered for chemotherapy receive geriatric assessment (GA) and management (GAM), but few randomized controlled trials have examined its impact on quality of life (QOL). Patients and methods: The 5C study was a two-group parallel 1:1 single-blind multicenter randomized controlled trial of GAM for 6 months versus usual oncologic care. Eligible patients were age 70+ years, diagnosed with a solid tumor, lymphoma, or myeloma, referred for first-/second-line chemotherapy or immunotherapy or targeted therapy, and had an Eastern Cooperative Oncology Group performance status of 0-2. The primary outcome QOL was measured with the global health scale of the European Organisation for the Research and Treatment of Cancer QOL questionnaire and analyzed with a pattern mixture model using an intent-to-treat approach (at 6 and 12 months). Secondary outcomes included functional status, grade 3-5 treatment toxicity; health care use; satisfaction; cancer treatment plan modification; and overall survival. Results: From March 2018 to March 2020, 350 participants were enrolled. Mean age was 76 years and 40.3% were female. Fifty-four percent started treatment with palliative intent. Eighty-one (23.1%) patients died. GAM did not improve QOL (global QOL of 4.4 points [95% CI, 0.9 to 8.0] favoring the control arm). There was also no difference in survival, change in treatment plan, unplanned hospitalization/emergency department visits, and treatment toxicity between groups. Conclusion: GAM did not improve QOL. Most intervention group participants received GA on or after treatment initiation per patient request. Considering recent completed trials, GA may have benefit if completed before treatment selection. The COVID-19 pandemic may have affected our QOL outcome and intervention delivery for some participants.
NIV-NAVA mode for respiratory support in preterm infants is not well-studied. This study aimed to describe the diaphragmatic function, diaphragmatic excursion (DE), and thickness fraction (DTF), in preterm infants < 30 weeks’ gestation supported by NIV-NAVA compared to NIPPV using bedside ultrasonography. In this consecutive prospective study, DE, diaphragmatic thickness at end of expiration (DTexp), end of inspiration (DTins), and DTF were assessed using bedside ultrasound. Lung aeration evaluation using lung ultrasound score (LUS) was performed for the two groups. Diaphragmatic measurements and LUS were compared for the 2 groups (NIV-NAVA group versus NIPPV group). Statistical analyses were conducted using the SPSS software version 22. Out of 70 infants evaluated, 40 were enrolled. Twenty infants were on NIV-NAVA and 20 infants on NIPPV with a mean [SD] study age of 25.7 [0.9] weeks and 25.1 [1.4] weeks respectively (p = 0.15). Baseline characteristics and respiratory parameters at the time of the scan showed no significant difference between groups. DE was significantly higher in NIV-NAVA with a mean SD of 4.7 (1.5) mm versus 3.5 (0.9) mm in NIPPV, p = 0.007. Additionally, the mean (SD) of DTF for the NIV-NAVA group was 81.6 (30) % vs 78.2 (27) % for the NIPPV group [p = 0.71]. Both groups showed relatively high LUS but no significant difference between groups [12.8 (2.6) vs 12.6 (2.6), p = 0.8]. Conclusion: Preterm infants managed with NIV-NAVA showed significantly higher DE compared to those managed on NIPPV. This study raises the hypothesis that NIV-NAVA could potentially improve diaphragmatic function due to its synchronization with patients’ own breathing. Longitudinal studies to assess diaphragmatic function over time are needed. Trial registry: Clinicaltrials.gov (NCT05079412). Date of registration September 30, 2021. What is Known: • NIV-NAVA utilizes diaphragmatic electrical activity to provide synchronized breathing support. • Evidence for the effect of NIV-NAVA on diaphragmatic thickness fraction (DTF) and excursion (DE) is limited. What is New: • Ultrasonographic assessment of diaphragmatic function (DTF and DE) is feasible. • In preterm infants, DE was significantly higher in infants supported with NIV-NAVA compared to those supported with NIPPV.
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Background Accumulating evidence suggests that the androgen receptor (AR) and its endogenous ligands influence disease progression in breast cancer (BCa). However, AR-mediated changes in BCa differ among the various BCa subtypes according to their hormone receptor profile [i.e., presence/absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2, (HER2)]. Thus, we explored the androgen-regulated transcriptomic changes in the ER ⁺ PR ⁺ HER2 ⁺ BCa cell line, BT-474, and compared them with PR-mediated changes. Methods We performed RNA sequencing analysis in treated BT-474 cells with dihydrotestosterone (DHT) and progesterone. Validation of the top ten differentially androgen-regulated genes and a number of other genes found in enriched signaling pathways was performed by qRT-PCR in BT-474 and other BCa cell lines. In addition, a parallel reaction monitoring targeted proteomic approach was developed to verify selected transcripts at the protein level. Results In total 19,450 transcripts were detected, of which 224 were differentially regulated after DHT treatment. The increased expression of two well-known androgen-regulated genes, KLK2 (p < 0.05) and KLK3 (p < 0.001), confirmed the successful androgen stimulation in BT-474 cells. The transcription factor, ZBTB16, was the most highly upregulated gene, with ~ 1000-fold change (p < 0.001). Pathway enrichment analysis revealed downregulation of the DNA replication processes (p < 0.05) and upregulation of the androgen signaling and fatty acid metabolism pathways (p < 0.05). Changes related to progesterone treatment showed opposite effects in gene expression than DHT treatment. Similar expression profiles were observed among other BCa cell lines expressing high levels of AR (ZR75.1 and MBA-MB-453). The parallel reaction monitoring targeted proteomic analysis further confirmed that altered protein expression (KLK3, ALOX15B) in the supernatant and cell lysate of DHT-treated BT-474 cells, compared to control cells. Discussion Our findings suggest that AR modulates the metabolism of BT-474 cells by affecting the expression of a large number of genes and proteins. Based on further pathway analysis, we suggest that androgen receptor acts as a tumor suppressor in the BT-474 cells.
Objectives Symptomatic knee osteoarthritis (OA) frequently co-occurs in individuals with type 2 diabetes mellitus (T2DM). In the context of T2DM, OA is often underdiagnosed and undertreated. To elucidate strategies to improve OA care in persons with T2DM, we assessed their perceptions of the barriers and enablers to seeking and engaging in OA care. Design We conducted semi-structured interviews with 18 individuals with T2DM and symptomatic knee OA in Ontario, Canada. Transcripts were deductively coded using the Theoretical Domains Framework (TDF), an implementation science framework that incorporates theoretical domains of behaviour determinants, which can be linked to behaviour change techniques. Within each of the relevant domains, data were thematically analyzed to generate belief statements. Results Seven of the TDF domains prominently influenced the behaviour to seek and engage in OA care. Participants described insufficient receipt of OA knowledge to fully engage in care (knowledge), feeling incapable of participating in physical activity due to joint pain (beliefs about capabilities), uncertainty about effectiveness of therapies (optimism) and lack of guidance from health care providers and insufficient access to community programs/supports (environmental context and resources). Key enablers were strong social support (social influences), sources of accountability (behavioural regulation) and experiencing benefit from treatment (reinforcement). Participants did not see concomitant T2DM as limiting the desire to seek OA care. Conclusions Among individuals with symptomatic knee OA and T2DM, we identified behavioural determinants of seeking and engaging in OA care. These will be mapped to behavioural change techniques to inform development of a complex intervention.
Purpose Few quality improvement tools specific to patients with persistent or chronic critical illness exist to aid delivery of high-quality care. Using experience-based co-design methods, we sought consensus from key stakeholders on the most important actionable processes of care for inclusion in a quality improvement checklist. Methods Item generation methods: systematic review, semi-structured interviews (ICU survivors and family) members, touchpoint video creation, and semi-structured interviews (ICU clinicians). Consensus methods: modified online Delphi and a virtual meeting using nominal group technique methods. Results We enrolled 138 ICU interprofessional team, patients, and family members. We obtained consensus on a quality improvement checklist comprising 11 core domains: patient and family involvement in decision-making; patient communication; physical comfort and complication prevention; promoting self-care and normalcy; ventilator weaning; physical therapy; swallowing; pharmacotherapy; psychological issues; delirium; and appropriate referrals. An additional 27 actionable processes are contained within 6 core domains that provide more specific direction on the actionable process to be targeted. Conclusions Using a highly collaborative and methodologically rigorous process, we generated a quality improvement checklist of actionable processes to improve patient and family-centred care considered important by key stakeholders. Future research is needed to understand optimal implementation strategies and impact on outcomes and experience.
Aim To assess central set point of thyroid homeostasis in drug-naïve patients affected by first episode schizophrenia. Methods This cross-sectional study was conducted in Xinxiang city, Henan, China. Patients were drug-naïve patients affected by first episode schizophrenia, aged 14–50 years old and admitted to the “Second Affiliated Hospital of Xinxiang Medical University” from January 2018 to December 2018. Controls were healthy individuals who underwent annual health from Xinxiang city, a community population of the same age and time period. The parameters of “central set point of thyroid homeostasis” were measured by “thyroid-stimulating hormone (TSH) index” and “thyroid feedback quantile-based index”. The parameters were compared between schizophrenia patients and controls. Linear regression models adjusted by age and sex were used to assess the association of schizophrenia with the parameters. Results A total of 235 patients and 121 controls were included in this study. Patients affected by schizophrenia had significantly higher prevalence of hyperthyroxinemia and levels of free T4, “TSH index”, and “thyroid feedback quantile-based index” than controls. After adjusting age and sex, schizophrenia was independently associated with the higher level of “TSH index” (adjusted β 0.33, 95 % confidence interval 0.17, 0.49) and “thyroid feedback quantile-based index” (adjusted β 0.21, 95 % confidence interval 0.12, 0.30). The results with age and sex matched patients and controls were similar to those observed in the overall study population. Conclusion Higher central set point may be the underlying mechanism of thyroid allostatic load in drug-naïve patients affected first episode schizophrenia.
We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of “candidate ciliopathy genes.” From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1 ). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.
Background and Purpose Patients with anal squamous cell carcinoma (SCC) are treated with sphincter-preserving radiation therapy and concurrent chemotherapy, achieving excellent oncologic outcomes. Patients, however, may experience treatment-related morbidity including sexual dysfunction. The objective of this systematic review was to review the literature on sexual dysfunction in female patients treated for anal cancer and to identify knowledge gaps. Materials and Methods This systematic review was registered in PROSPERO prior to initiation. Databases searched included MEDLINE, Embase, PubMed, Cochrane, and Google Scholar. There were no restrictions on the study time period. Studies were limited to English. All study designs were included except review articles, letters to the editor, and case reports with less than ten patients. Results In total, 1801 studies were retrieved and 19 met the inclusion criteria, including: 13 cross-sectional surveys, 3 prospective studies, 1 longitudinal intervention study, 1 retrospective chart review, 1 case control study. Sexual function was assessed using the female sexual functioning index (FSFI), EORTC-QLQ-CR30 and -CR38; response rates were low (<50% in most studies). Sexual dysfunction was reported by up to 85% of women; the most common symptoms being dyspareunia (17-65%), vaginal dryness (22-88%), and loss of libido (38-95%). Gastrointestinal issues, such as bowel problems, and body image concerns additionally affected sexual function and quality of life. Conclusion Sexual dysfunction is a common issue affecting most female patients treated for anal cancer and there is a paucity of evidence on the management of this important survivorship issue. There is additionally a lack of ethnic, economic, and educational diversity and there are no studies addressing the unique needs of LGBTQ individuals - future studies should make a concerted effort to include a diverse patient population.
Introduction À ce jour, la prise en charge diagnostique et thérapeutique des vascularites primitives du système nerveux central (VPSNC) ne repose sur aucune recommandation consensuelle. L’objectif de ce sondage était d’évaluer les habitudes pratiques des médecins prenant en charge des adultes avec une VPSNC, en évaluant les éléments concordants et divergents. Patients et méthodes Après concertation et validation par les investigateurs principaux de cette étude, un sondage comprenant 20 questions était mis en ligne sur la plateforme surveymonkey et accessible pour une durée de 3 mois entre novembre 21 et janvier 22. La diffusion du sondage se faisait via les réseaux de plusieurs sociétés savantes françaises (SNFMI, SFNV) et canadiennes (CNSF, CSC) de médecine interne, neurologie et rhumatologie. Les groupes de recherches sur les vascularites français (GFEV, GEFA), canadiens (CVRN, SSVQ) et européens (EUVAS) étaient également sollicités. N’étaient inclus dans l’analyse des résultats que les participants qui (1) étaient impliqués directement dans la prise en charge de ≥ 2 patients avec une VPSNC et (2) avaient répondu intégralement au questionnaire. Via des questions ouvertes ou fermées, le sondage explorait 3 dimensions de la prise en charge des VPSNC : la démarche diagnostique, le traitement, et l’évaluation de l’activité de la maladie au cours du suivi. La concordance inter-évaluateurs pour les questions étalonnées sur une échelle de Likert était calculée en utilisant le test AC2 de Gwet. L’échelle de Landis et Koch était utilisée pour l’interprétation (< 0 : désaccord ; 0–0,2 : accord très faible ; 0,21–0,4 : accord faible ; 0,41–0,6 : accord modéré ; 0,61–0,8 : accord fort ; 0,81–1 : accord presque parfait). Une analyse des réponses était également faite en stratifiant sur l’expérience du participant (± 5 patients pris en charge). Résultats Après exclusion des sondages incomplets et des praticiens n’ayant pris en charge qu’un seul patient (n = 89), un total de 96 questionnaires était analysé. Les participants étaient neurologues (40 %), internistes (35 %), rhumatologues (23 %) et d’autres spécialités (2 %). Ils exerçaient en France et au Canada pour 46 % et 30 % respectivement d’entre eux, principalement dans des établissements universitaires (87 %). En termes de nombre de patients, 51 % déclaraient avoir pris en charge 2 à 5 patients avec une VPSNC. Parmi les réponses intéressantes à rapporter : – une biopsie cérébroméningée était demandée dans 25 % des cas. Le degré de concordance inter-évaluateurs pour déterminer la justification d’une biopsie pour 8 scénarii différents était faible (0,30, IC95 % : 0,23–0,41) ; – la rémission était définie par 57 % des répondeurs comme l’absence de nouvel évènement radio-clinique, tandis que les 43 % autres la définissait comme une amélioration radio-clinique ; – l’induction de la rémission reposait majoritairement sur l’utilisation des glucocorticoïdes (GC) et le cyclophosphamide, et 84 % des participants y recouraient pour plus de la moitié de leurs patients ; – un traitement d’entretien, y compris par un recours prolongé aux GC, était préconisé par 89 % des participants. Les GC étaient maintenus en médiane 12 mois, tandis que azathipoprine, mycophénolate mofetil, méthotrexate ou rituximab étaient maintenus au moins 24 mois en médiane ; – chez des patients en rémission, lors du suivi, nous demandions en quoi 8 différents changements à l’imagerie et/ou à l’analyse du LCR motivaient une intensification du traitement, chez un patient symptomatique ou non. Le degré de concordance inter-évaluateurs était fort (0,66, IC95 % : 0,58–0,80) si le patient était symptomatique et modéré (0,50, IC95 % : 0,45–0,60) s’il ne l’était pas ; – la stratification sur l’expérience révélait que les participants les plus expérimentés réalisaient plus souvent une biopsie cérébroméningée (p < 0,001). Les stratégies thérapeutiques n’étaient pas différentes selon l’expérience. Conclusion Ce sondage de vraie-vie illustre bien les difficultés rencontrées en l’absence de recommandations. Ceci conduit à une variabilité des pratiques, ce qui renforce la nécessité de mener des études méthodologiquement robustes.
Objective To develop and evaluate a storytelling communication facilitation tool designed to help parents overcome barriers to discussing a complex multisystem genetic diagnosis with their affected children, using 22q11.2 deletion syndrome (22q11DS) as an exemplar condition. Methods A story telling communication facilitation tool (SCFT), entitled 22q and Me, was developed for a target audience of children with 22q11DS aged 9 to 12. The SCFT was evaluated by 14 parents to assess usability and utility by comparing responses to survey questions before and after viewing the SCFT, using a Likert scale. Results After viewing 22q and Me, parents reported that barriers to discussion were mitigated. Participants indicated they felt more comfortable and better prepared to talk to their children about 22q11DS and worried less that the diagnosis would affect their children’s self-esteem. Parents described 22q and Me as engaging and able to address parental concerns. Conclusion 22q and Me was found to be an effective tool for increasing parental comfort and ability to talk to their children about their diagnosis of 22q11DS. Innovation This novel storytelling communication facilitation tool can serve as a model for the development of other educational tools geared at facilitating disclosure and discussion of other genetic conditions.
Background: The high-fidelity ORSIM (Airway Simulation Ltd) and the low-fidelity wooden-block fiber-optic task trainers allow users to familiarize themselves with the psychomotor skills required to manipulate the fiber-optic scope. Methods: This single-center study aimed to compare residents' performance of fiber-optic intubation after 2 different types of task training. Twenty-four residents with experience of <8 fiber-optic intubations were randomized to either the ORSIM or a wooden-block task trainer. In a single teaching session, the resident performed 20 fiber-optic intubations on their assigned task trainer. This implied simulator competence. In the 4 months after this training, all subjects then attempted to perform a fiber-optic intubation on an American Society of Anesthesiologists (ASA) I or II anesthetized patient whose airway was preoperatively assessed as normal. The primary outcome was the cumulative sum (CUSUM) learning curves obtained as the residents trained on their respective task trainers. Secondary outcomes included: the mean time (in seconds) to perform each of the 20 fiber-optic intubations on their assigned task trainer, the total simulator training time, global rating scale score, checklist score, and time to carina when performing fiber-optic intubation on the patient. Results: The CUSUM analysis showed that the ORSIM group achieved simulator competence faster. The mean time to perform fiber-optic intubation was shorter in the ORSIM group. A 2-way analysis of variance (ANOVA) test suggests that the combined effect of group (wooden-block or ORSIM) and time is statistically significant (P < .05).Total training time (mean, 899 s ± 440 s vs 1358 s ± 405 s; 95% confidence interval [CI], 100.46-818.54; P = .01) was also significantly better in the ORSIM group.No significant difference was found between the 2 groups (P > 0) in terms of global rating scale, checklist score, and time to reach the carina (P >.05) when performing the fiber-optic intubation on the patient. Conclusions: ORSIM showed superiority in terms of the CUSUM learning curve in reaching competence faster in fewer attempts. There was no statistically significant difference in residents' performance when translated to clinical practice on a patient. This information should assist course directors when choosing task trainers for fiber-optic intubation training programs.
Objectives ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. Methods This study retrospectively analyzed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. Results Data from 1441 patients were analyzed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n = 224) than during follow-up (n = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n = 168) and visual impairment (n = 195). Conclusion Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy.
Background: Guidelines advocate for minimization of physical restraint (PR) use in intensive care units (ICU). Interprofessional team perspectives on PR practices can inform the design and implementation of successful PR minimization interventions. Aim: To identify ICU staff perspectives of contextual influences on PR practices and minimization strategies. Study design: A qualitative descriptive study in a single ICU in Toronto, Canada. Methods: One-on-one semi-structured interviews were conducted with 14 ICU staff. A deductive content analysis of interviews was undertaken using the integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) framework. Results: Five themes were developed: risk-averse culture, leadership, practice monitoring and feedback processes, environmental factors, and facilitation. Participants described a risk-averse culture where prophylactic application of PR for intubated patients was used to prevent unplanned extubation thereby avoiding blame from colleagues. Perceived absence of leadership and interprofessional team involvement situated nurses as the primary decision-maker for restraint application and removal. Insufficient monitoring of restraint practices, lack of access to restraint alternatives, and inability to control environmental contributors to delirium and agitation further increased PR use. Recommendations as to how to minimize restraint use included a nurse facilitator to advance leadership-team collaboration, availability of restraints alternatives, and guidance on situations for applying and removing restraints. Conclusions: This analysis of contextual influences on PR practices and minimization using the i-PARIHS framework revealed potentially modifiable barriers to successful PR minimization, including a lack of leadership involvement, gaps in practice monitoring, and collaborative decision-making processes. A team approach to changing behaviour and culture should be considered for successful implementation and sustainability of PR minimization. Relevance to practice: The establishment of an interprofessional facilitation team that addresses risk-averse culture and promotes collaboration among ICU stakeholders will be crucial to the success of any approach to restraint minimization.
The majority of nucleated somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs). The process of reprogramming involves epigenetic remodelling to turn on pluripotency-associated genes and turn off lineage-specific genes. Some evidence shows that iPSCs retain epigenetic marks of their cell of origin and this “epigenetic memory” influences their differentiation potential, with a preference towards their cell of origin. Here, we reprogrammed proximal tubule cells (PTC) and tail tip fibroblasts (TTF), from a reprogrammable mouse to iPSCs and differentiated the iPSCs to renal progenitors to understand if epigenetic memory plays a role in renal differentiation. This model allowed us to eliminate experimental variability due to donor genetic differences and transfection of the reprogramming factors such as copy number and integration site. In this study we demonstrated that early passage PTC iPSCs and TTF iPSCs expressed low levels of renal progenitor genes and high levels of pluripotency-associated genes, and the transcriptional levels of these genes were not significantly different between PTC iPSCs and TTF iPSCs. We used ChIP-seq of H3K4me3, H3K27me3, H3K36me3 and global DNA methylation profiles of PTC iPSCs and TTF iPSCs to demonstrate that global epigenetic marks were not different between the cells from the two different sets of tissue samples. There were also no epigenetic differences observed when kidney developmental genes and pluripotency-associated genes were closely examined. We did observe that during differentiation to renal progenitor cells the PTC iPSC-derived renal cells expressed higher levels of three renal progenitor genes compared to progenitors derived from TTF iPSCs but the underlying DNA methylation and histone methylation patterns did not suggest an epigenetic memory basis for this.
Importance Accruing evidence suggests that gestational hypertensive disorders (GHTD) and gestational diabetes (GD) are each associated with an increased risk of cardiovascular disease (CVD). However, the extent to which the co-occurrence of GHTD and GD is associated with the risk of CVD remains largely unknown. Objective To estimate the individual and joint associations of GHTD and GD with incident CVD. Design, Setting, and Participants This population-based cohort study used the Ministry of Health and Long-Term Care of Ontario (Canada) health care administrative databases. All women in Ontario with a GHTD and/or GD diagnosis, and a live-birth singleton delivery between July 1, 2007, and March 31, 2018, were considered for inclusion. Women with pregravid diabetes, hypertension, or cardiovascular disease were excluded. Statistical analysis was performed from November 2021 to September 2022. Exposures GD and/or GHTD, defined using diagnosis coding. Main Outcomes and Measures Individual and joint associations of GHTD and GD with incident CVD (including a composite of myocardial infarction, acute coronary syndrome, stroke, coronary artery bypass grafting, percutaneous coronary intervention, or carotid endarterectomy), estimated using Cox regression models, adjusting for relevant cardiometabolic risk factors. The follow-up extended from the index pregnancy until March 31, 2020. Results Among 886 295 eligible women (mean [SD] age, 30 [5.6] years; 43 861 [4.9%] with isolated GHTD, 54 061 [6.1%] with isolated GD, and 4975 [0.6%] with GHTD and GD), there were 1999 CVD events over 12 years of follow-up. In the early postpartum phase (first 5 years post partum), there was no association of co-occurrence of GTHD and GD (adjusted hazard ratio [aHR], 1.42, 95% CI, 0.78-2.58) or GD alone (aHR, 0.80; 95% CI, 0.60-1.06) with CVD; there was an association between isolated GTHD and incident CVD compared with no GTHD and no GD (aHR, 1.90; 95% CI, 1.51-2.35). In the late postpartum period (after the initial 5 years post partum), compared with no GD and no GHTD, isolated GHTD (aHR, 1.41, 95% CI, 1.12-1.76) and co-occurrence of GHTD and GD (aHR, 2.43, 95% CI, 1.60-3.67) were each associated with a higher risk of incident CVD. There was no association between isolated GD and incident CVD. Conclusions and Relevance In this cohort study, GHTD was associated with a high risk of CVD post partum, and the co-occurrence of GD and GHTD was associated with a much greater postpartum CVD risk. These findings suggest that CVD preventive care is particularly needed in the aftermath of combined GD and GHTD.
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