A rapid review protocol of physiotherapy and occupational therapy telerehabilitation to inform ethical and equity concerns.

Background: Telerehabilitation (TR) has emerged as a feasible and promising approach for delivering rehabilitation services remotely, utilizing technology to bridge the gap between healthcare providers and patients. As new modalities of virtual care and health technologies continue to emerge, it is crucial to stay informed about the growing landscape of virtual care to ensure that telehealth service delivery is ethical and equitable, and improves the quality of services and patient outcomes. Objective: The primary objective of this article is to present the protocol of a rapid review to examine the equity-related aspects surrounding the implementation of TR. This includes a comprehensive analysis of the ethical dimensions and fairness concerns linked to this practice. Methods: A rapid review protocol was developed in accordance with Cochrane Rapid Reviews Methods Guidance. Medline and EMBASE databases were searched between January 2010 and March 2023. Study selection and data extraction will be conducted in two phases (Phase I) by two independent reviewers and subsequently (Phase II) by a single reviewer. Our study will utilize the PROGRESS-Plus and Equitable virtual rehabilitation in the metaverse era framework to identify dimensions where potential inequities may exist within TR interventions. Results: This rapid review is anticipated to enhance our knowledge of TR in the fields of physiotherapy and occupational therapy, with a specific focus on its influence on ethical and equitable practices and providing a foundation for informed decision-making and improved patient care. Conclusion: This rapid review will contribute to the advancement of our understanding of TR within physiotherapy and occupational therapy. Through synthesizing existing evidence, this study not only addresses current gaps in knowledge but also offers valuable insights for future research and clinical practice in TR services.

Comparison of Clinical Outcomes Between Antegrade and Retrograde Techniques for Chronic Total Occlusion Revascularizations: A Systematic Review and Meta-Analysis.

Chronic total occlusions (CTOs) present significant challenges in interventional cardiology. This meta-analysis aims to compare the efficacy and safety of retrograde versus antegrade techniques in CTO percutaneous coronary intervention (PCI). A systematic review and meta-analysis were conducted following PRISMA guidelines. Electronic databases were searched through June 20, 2024. Studies comparing outcomes between antegrade and retrograde methods for CTO-PCI were included. Primary outcomes were procedural and technical success. Secondary outcomes included major adverse cardiac events (MACE), all-cause mortality, and myocardial infarction. The final analysis included seventeen studies. The antegrade approach showed a 5% higher likelihood of technical success (OR: 1.05, 95% CI: 1.02-1.09) and 14% higher odds of procedural success (OR: 1.14, 95% CI: 1.10-1.19) compared to the retrograde approach. The antegrade group also demonstrated lower risks of MACE, all-cause mortality, and myocardial infarction (RR: 0.40, 95% CI: 0.26-0.63). This meta-analysis suggests that the antegrade approach in CTO-PCI is associated with higher success rates and lower risks of adverse outcomes compared to the retrograde approach. However, the retrograde technique remains crucial for complex lesions and patients with multiple comorbidities.

Protective effect of rupatadine on testicular ischemia/reperfusion injury in rats: Modulation of IL-6/STAT3, Akt/ mTOR signaling pathways.

BACKGROUNDS & AIM: Spermatic cord rotation is a common problem in the field of urology, that finally results in necrosis of testicular tissue as well as male infertility. Rupatadine (RUP); a second-generation antihistaminic drug; demonstrated to have a possible protective effect in variable ischemia/reperfusion (I/R) rat models, but its role has not been studied yet in testicular I/R model. MATERIAL & METHODS: The present study investigated RUP ability to ameliorate testicular I/R injury. The study includes four groups (6 rats/group); sham group, sham group pretreated with RUP (6 mg/kg/day; orally) for 14 days, I/R group, and RUP-I/R pretreated group. KEY FINDINGS: The results demonstrated that I/R significantly lowered serum testosterone level and testicular tissue content of reduced glutathione. Besides, a significant elevation in malondialdehyde level, hypoxia-inducible factor-1, signal transducers and activators of transcription-3 (STAT-3), interleukin-6 (IL-6), histamine, and platelet activating factor levels along with an inhibition in testicular tissue level of vascular endothelial growth factor-A (VEGF-A) with an evident increase in caspase-3 immunoexpression in germ cells. Also, I/R significantly lowered p-AKT and mTOR testicular expression. While, RUP-I/R pretreated group showed a reversal in the testicular I/R damaging effects in a significant manner in the all the aforementioned parameters. CONCLUSION: Based on these findings; RUP was proved to have a possible protective effect in testicular I/R injury via its antioxidant effect and its ability to modulate IL-6/STAT3, Akt/ mTOR inflammatory signaling pathways with improvement in the testicular VEGF-A level.

Efficacy of Nicorandil in Preventing Myocardial Injury and Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention (PCI): A Systematic Review and Meta-Analysis.

Percutaneous coronary intervention (PCI) is a common procedure for treating coronary artery disease, but it carries a risk of periprocedural myocardial injury (PMI). This meta-analysis evaluated the efficacy of nicorandil, a hybrid compound with nitrate-like and potassium channel-opening properties, in preventing PMI during PCI. A comprehensive literature search identified 14 studies involving 1,762 patients, with 882 receiving nicorandil and 880 in the control group. The analysis revealed that nicorandil significantly reduced the incidence of PMI (RR: 0.73, 95% CI: 0.61-0.86) and major adverse cardiovascular events (MACE) (RR: 0.76, 95% CI: 0.58-0.99) compared to the control group. Nicorandil's cardioprotective effects are attributed to its ability to improve coronary blood flow, precondition the myocardium, and reduce oxidative stress and inflammation. These findings suggest that nicorandil could be a valuable adjunctive therapy during PCI, potentially improving patient outcomes. However, the study had limitations, including variations in drug administration methods and a lack of individual-level data for subgroup analysis. Future research should focus on optimizing dosing regimens and administration timing and comparing nicorandil's effectiveness with other cardioprotective agents.

The psychometric properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system in neurorehabilitation populations: a systematic review.

OBJECTIVE: To systematically review the literature of existing evidence on the measurement properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system among neurorehabilitation populations. DATA SOURCES: The Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) guided this systematic review in which we searched nine electronic databases and registries, and hand-searched reference lists of included articles. STUDY SELECTION: Two independent reviewers screened selected articles and extracted data from 28 included studies. DATA EXTRACTION: COSMIN's approach guided extraction and synthesizing measurement properties evidence (insufficient, sufficient), and the modified GRADE approach guided synthesizing evidence quality (very-low, low, moderate, high) by diagnosis. DATA SYNTHESIS: Neuro-QoL has sufficient measurement properties when used by individuals with Huntington's disease, Multiple Sclerosis, Parkinson's disease, stroke, lupus, cognitive decline, and amyotrophic lateral sclerosis. The strongest evidence is for the first four conditions, where test-retest reliability, construct validity, and responsiveness are nearly always sufficient (GRADE: moderate-high). Structural validity is assessed only in multiple sclerosis and stroke but is often insufficient (GRADE: moderate-high). Criterion validity is sufficient in some stroke and Huntington's disease domains (GRADE: high). Item response theory analyses were reported for some stroke domains only. There is limited, mixed evidence for responsiveness and measurement error (GRADE: moderate-high), and no cross-cultural validity evidence CONCLUSIONS: Neuro-QoL domains can describe and evaluate patients with Huntington's disease, multiple sclerosis, Parkinson's disease, and stroke, but predictive validity evidence would be beneficial. In the other conditions captured in this review, a limited number of Neuro-QoL domains have evidence for descriptive use only. For these conditions, further evidence of structural validity, measurement error, cross-cultural validity and predictive validity would enhance the use and interpretation of Neuro-QoL.

Sonophoresis mediated diffusion of caffeine loaded Transcutol® enriched cerosomes for topical management of cellulite.

The goal of this research was to augment the deposition of caffeine loaded Transcutol® enriched cerosomes (TECs) gel for efficient topical treatment of cellulite utilizing the sonophoresis technique. Caffeine-loaded TECs were prepared using thin film hydration method applying 23 factorial design to study the impact of different factors, each with two levels on the entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of the formulated TECs. The studied factors were cetyl trimethyl ammonium bromide (CTAB) amount (mg) (X1), phosphatidylcholine (PC) amount (mg) (X2), and Transcutol® amount (mg) (X3). Design-Expert® software was utilized to determine the optimum TECs formulation. Afterward, the optimum TECs formulation was loaded into a gel and subjected to extra investigations. The optimum TECs formulation was (TEC5) which was prepared using 10 mg of CTAB, 150 mg of PC, and 10 mg of Transcutol®. TEC5 presented EE% of 87.44 ± 0.14 %, PS of 308.60 ± 13.38 nm, PDI of 0.455 ± 0.030, and ZP of 50.20 ± 1.55 mV. TEC5 had a fiber-like morphology, with elongated tubules of ceramide. Further, the optimum TECs formulation showed a high stability profile. Moreover, an in vivo dermatokinetic study showed superior deposition of caffeine from TEC5 gel coupled with the sonophoresis on rat skin compared to TEC5 gel and caffeine gel. Moreover, the histopathological study of TEC5 on rat skin confirmed the non-irritant nature of TEC 5 gel mediated by ultrasonic waves through the skin. Overall, the outcomes exposed the obvious superiority of sonophoresis delivered TECs-gel for topical delivery of caffeine for cellulite management.

View-shuffled clustering via the modified Hungarian algorithm.

In the majority of existing multi-view clustering methods, the prerequisite is that the data have the correct cross-view correspondence. However, this strong assumption may not always hold in real-world applications, giving rise to the so-called View-shuffled Problem (VsP). To address this challenge, we propose a novel multi-view clustering method, namely View-shuffled Clustering via the Modified Hungarian Algorithm (VsC-mH). Specifically, we first establish the cross-view correspondence of the shuffled data utilizing strategies of the global alignment and modified Hungarian algorithm (mH) based intra-category alignment. Subsequently, we generate the partition of the aligned data employing matrix factorization. The fusion of these two processes facilitates the interaction of information, resulting in improved quality of both data alignment and partition. VsC-mH is capable of handling the data with alignment ratios ranging from 0 to 100%. Both experimental and theoretical evidence guarantees the convergence of the proposed optimization algorithm. Extensive experimental results obtained on six practical datasets demonstrate the effectiveness and merits of the proposed method.

Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture.

While guided human cortical organoid (hCO) protocols reproducibly generate cortical cell types at one site, variability in hCO phenotypes across sites using a harmonized protocol has not yet been evaluated. To determine the cross-site reproducibility of hCO differentiation, three independent research groups assayed hCOs in multiple differentiation replicates from one induced pluripotent stem cell (iPSC) line using a harmonized miniaturized spinning bioreactor protocol across 3 months. hCOs were mostly cortical progenitor and neuronal cell types in reproducible proportions that were consistently organized in cortical wall-like buds. Cross-site differences were detected in hCO size and expression of metabolism and cellular stress genes. Variability in hCO phenotypes correlated with stem cell gene expression prior to differentiation and technical factors associated with seeding, suggesting iPSC quality and treatment are important for differentiation outcomes. Cross-site reproducibility of hCO cell type proportions and organization encourages future prospective meta-analytic studies modeling neurodevelopmental disorders in hCOs.

Age-related increase of CD38 directs osteoclastogenic potential of monocytic myeloid-derived suppressor cells through mitochondrial dysfunction in male mice.

An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic-MDSCs (M-MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M-MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M-MDSCs were not increased in bone marrow, however M-MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M-MDSCs in bone marrow, these M-MDSCs had significantly higher osteoclastogenic potential and greater demineralization activity. Intriguingly, osteoclast progenitors from aged bone marrow M-MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was 8-fold increase in Cd38 mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database, and confirmed by qRT-PCR. CD38 regulates NAD+ availability, and 78c, a small molecule inhibitor of CD38, reduced the mitochondrial oxygen consumption rate and glucose metabolism and inhibited the osteoclastogenic potential of aged mice bone marrow-derived M-MDSCs. These results indicate that the age-related increase in Cd38 expression in M-MDSCs bias the transcriptome of M-MDSCs towards osteoclastogenesis. This enhanced understanding of the mechanistic underpinnings of M-MDSCs and their osteoclastogenesis during aging could lead to new therapeutic approaches for age-related bone loss and promote healthy aging.

Melatonin-induced symptomatic bradycardia in an otherwise healthy male: a case report.

Melatonin, a pineal gland hormone closely associated with the circadian rhythm, has been trending over the past years as an over-the-counter medication to aid with sleep disturbances. Although generally believed to be safe, recent studies show negative inotropic and chronotropic effects on the heart rate and blood pressure in humans. Several studies suggested that melatonin induces cardiac vagal tone and affects heart rate and mean arterial pressure. Limited literature is currently available on the effects of melatonin beyond its sleep function. We present a case of a healthy 22-year-old male who visited the emergency department reporting palpitations and dizziness following the ingestion of 20 mg of melatonin. Subsequent examinations revealed marked bradycardia. Fortunately, the patient experienced spontaneous resolution of the bradycardia without necessitating intervention after a few hours of observation, and he was observed and discharged.

Acute massive posterior stroke with tonsillar herniation in a scuba diver.

A transient female passenger in her 40s presented to the emergency department (ED) exhibiting drowsiness post-scuba diving. Despite normal initial vitals, she reported dizziness, sleepiness, and occipital headache. A computed tomography (CT) scan showed a severe posterior circulation acute infarction affecting various brain regions, resulting in significant mass effects and complications like 4th ventricle compression, cerebellar tonsillar herniation, and hydrocephalus. Extensive diagnostic tests, blood workup, and stroke evaluations revealed normal findings, except for an incidental patent foramen ovale (PFO). Collaboration with neurosurgery led to her transfer for life-saving extraventricular drain (EVD) insertion and posterior fossa decompression. Treatment included right-side EVD insertion, suboccipital craniectomy, and foramen magnum decompression. Postoperatively, she was extubated the next day, alert, without focal neurological deficits. Upon EVD removal, a repeat CT head scan showed regression of mass effect. She was discharged home safely after 16 days, fully ambulating.

Translation and linguistic validation of 24 PROMIS item banks into French.

PURPOSE: The Patient-Reported Outcome Measurement Information System (PROMIS®) was developed to provide reliable, valid, and normed item banks to measure health. The item banks provide standardized scores on a common metric allowing for individualized, brief assessment (computerized adaptive tests), short forms (e.g. heart failure specific), or profile assessments (e.g. PROMIS-29). The objective of this study was to translate and linguistically validate 24 PROMIS adult item banks into French and highlight cultural nuances arising during the translation process. METHODS: We used the FACIT translation methodology. Forward translation into French by two native French-speaking translators was followed by reconciliation by a third native French-speaking translator. A native English-speaking translator fluent in French then completed a back translation of the reconciled version from French into English. Three independent reviews by bilingual translators were completed to assess the clarity and consistency of terminology and equivalency across the English source and French translations. Reconciled versions were evaluated in cognitive interviews for conceptual and linguistic equivalence. RESULTS: Twenty-four adult item banks were translated: 12 mental health, 10 physical health, and two social health. Interview data revealed that 577 items of the 590 items translated required no revisions. Conceptual and linguistic differences were evident for 11 items that required iterations to improve conceptual equivalence and two items were revised to accurately reflect the English source. CONCLUSION: French translations of 24 item banks were created for routine clinical use and research. Initial translation supported conceptual equivalence and comprehensibility. Next steps will include validation of the item banks.

Diabetic microenvironment deteriorates the regenerative capacities of adipose mesenchymal stromal cells.

BACKGROUND: Type 2 diabetes is an endocrine disorder characterized by compromised insulin sensitivity that eventually leads to overt disease. Adipose stem cells (ASCs) showed promising potency in improving type 2 diabetes and its complications through their immunomodulatory and differentiation capabilities. However, the hyperglycaemia of the diabetic microenvironment may exert a detrimental effect on the functionality of ASCs. Herein, we investigate ASC homeostasis and regenerative potential in the diabetic milieu. METHODS: We conducted data collection and functional enrichment analysis to investigate the differential gene expression profile of MSCs in the diabetic microenvironment. Next, ASCs were cultured in a medium containing diabetic serum (DS) or normal non-diabetic serum (NS) for six days and one-month periods. Proteomic analysis was carried out, and ASCs were then evaluated for apoptosis, changes in the expression of surface markers and DNA repair genes, intracellular oxidative stress, and differentiation capacity. The crosstalk between the ASCs and the diabetic microenvironment was determined by the expression of pro and anti-inflammatory cytokines and cytokine receptors. RESULTS: The enrichment of MSCs differentially expressed genes in diabetes points to an alteration in oxidative stress regulating pathways in MSCs. Next, proteomic analysis of ASCs in DS revealed differentially expressed proteins that are related to enhanced cellular apoptosis, DNA damage and oxidative stress, altered immunomodulatory and differentiation potential. Our experiments confirmed these data and showed that ASCs cultured in DS suffered apoptosis, intracellular oxidative stress, and defective DNA repair. Under diabetic conditions, ASCs also showed compromised osteogenic, adipogenic, and angiogenic differentiation capacities. Both pro- and anti-inflammatory cytokine expression were significantly altered by culture of ASCs in DS denoting defective immunomodulatory potential. Interestingly, ASCs showed induction of antioxidative stress genes and proteins such as SIRT1, TERF1, Clusterin and PKM2. CONCLUSION: We propose that this deterioration in the regenerative function of ASCs is partially mediated by the induced oxidative stress and the diabetic inflammatory milieu. The induction of antioxidative stress factors in ASCs may indicate an adaptation mechanism to the increased oxidative stress in the diabetic microenvironment.

Application of simultaneous uncertainty quantification and segmentation for oropharyngeal cancer use-case with Bayesian deep learning.

BACKGROUND: Radiotherapy is a core treatment modality for oropharyngeal cancer (OPC), where the primary gross tumor volume (GTVp) is manually segmented with high interobserver variability. This calls for reliable and trustworthy automated tools in clinician workflow. Therefore, accurate uncertainty quantification and its downstream utilization is critical. METHODS: Here we propose uncertainty-aware deep learning for OPC GTVp segmentation, and illustrate the utility of uncertainty in multiple applications. We examine two Bayesian deep learning (BDL) models and eight uncertainty measures, and utilize a large multi-institute dataset of 292 PET/CT scans to systematically analyze our approach. RESULTS: We show that our uncertainty-based approach accurately predicts the quality of the deep learning segmentation in 86.6% of cases, identifies low performance cases for semi-automated correction, and visualizes regions of the scans where the segmentations likely fail. CONCLUSIONS: Our BDL-based analysis provides a first-step towards more widespread implementation of uncertainty quantification in OPC GTVp segmentation.

Radiotherapy is used as a treatment for people with oropharyngeal cancer. It is important to distinguish the areas where cancer is present so the radiotherapy treatment can be targeted at the cancer. Computational methods based on artificial intelligence can automate this task but need to be able to distinguish areas where it is unclear whether cancer is present. In this study we compare these computational methods that are able to highlight areas where it is unclear whether or not cancer is present. Our approach accurately predicts how well these areas are distinguished by the models. Our results could be applied to improve the computational methods used during radiotherapy treatment. This could enable more targeted treatment to be used in the future, which could result in better outcomes for people with oropharyngeal cancer.

Implementation of an integrated primary care prevention and management program for chronic low back pain (LBP): patient-reported outcomes and predictors of pain interference after six months.

BACKGROUND: Integrated primary care programs for patients living with chronic pain which are accessible, interdisciplinary, and patient-centered are needed for preventing chronicity and improving outcomes. Evaluation of the implementation and impact of such programs supports further development of primary care chronic pain management. This study examined patient-reported outcomes among individuals with low back pain (LBP) receiving care in a novel interdisciplinary primary care program. METHODS: Patients were referred by primary care physicians in four regions of Quebec, Canada, and eligible patients received an evidence-based interdisciplinary pain management program over a six-month period. Patients were screened for risk of chronicity. Patient-reported outcome measures of pain interference and intensity, physical function, depression, and anxiety were evaluated at regular intervals over the six-month follow-up. A multilevel regression analysis was performed to evaluate the association between patient characteristics at baseline, including risk of chronicity, and change in pain outcomes. RESULTS: Four hundred and sixty-four individuals (mean age 55.4y, 63% female) completed the program. The majority (≥ 60%) experienced a clinically meaningful improvement in pain intensity and interference at six months. Patients with moderate (71%) or high risk (81%) of chronicity showed greater improvement in pain interference than those with low risk (51%). Significant predictors of improvement in pain interference included a higher risk of chronicity, younger age, female sex, and lower baseline disability. CONCLUSION: The outcomes of this novel LBP program will inform wider implementation considerations by identifying key components for further effectiveness, sustainability, and scale-up of the program.

Impact of Obesity-Related Endoplasmic Reticulum Stress on Cancer and Associated Molecular Targets.

Obesity, characterized by excessive body fat, is closely linked to endoplasmic reticulum (ER) stress, leading to insulin resistance and type 2 diabetes. Inflammatory pathways like c-Jun N-terminal kinase (JNK) worsen insulin resistance, impacting insulin signaling. Moreover, ER stress plays a substantial role in cancer, influencing tumor cell survival and growth by releasing factors like vascular endothelial growth factor (VEGF). The unfolded protein response (UPR) is pivotal in this process, offering both pro-survival and apoptotic pathways. This review offers an extensive exploration of the sophisticated connection between ER stress provoked by obesity and its role in both the onset and advancement of cancer. It delves into the intricate interplay between oncogenic signaling and the pathways associated with ER stress in individuals who are obese. Furthermore, this review sheds light on potential therapeutic strategies aimed at managing ER stress induced by obesity, with a focus on addressing cancer initiation and progression. The potential to alleviate ER stress through therapeutic interventions, which may encompass the use of small molecules, FDA-approved medications, and gene therapy, holds great promise. A more in-depth examination of pathways such as UPR, ER-associated protein degradation (ERAD), autophagy, and epigenetic regulation has the potential to uncover innovative therapeutic approaches and the identification of predictive biomarkers.

WITHDRAWN: Resveratrol-based Delivery Systems as Contemporary Nominees for Combating Pulmonary Diseases: A Comprehensive Review

Since the authors are not responding to the editor's requests to fulfill the editorial requirement, therefore, the article has been withdrawn of the journal "Current Drug Delivery".Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Sustainability of an outcome measure in outpatient stroke rehabilitation: A realist evaluation.

RATIONALE: Only half of newly implemented evidence-based practices are sustained. Though poor sustainment can lead to negative consequences for clinical teams, organizations and patients, the causal explanations of sustainment are largely unknown. AIMS AND OBJECTIVES: We aimed to ascertain how (mechanisms) and in what circumstances (context) a newly implemented outcome measure in rehabilitation was sustained or not (outcome). METHODOLOGY: Informed by an integrated knowledge translation approach, we conducted a realist evaluation using a mixed method, embedded single case study design with data collection up to 18 months following the implementation of the Mayo-Portland Adaptability Inventory - version 4 (MPAI-4), a rehabilitation outcome measure. Quantitative data (survey and patient charts) was analysed using descriptive statistics, then integrated with qualitative data (interviews with 10 key informants) and analysed using inductive and deductive retroduction. We integrated the data to develop a case description and ultimately, to refine the programme theory to better understand the sustainability of the MPAI-4. RESULTS: We linked context, mechanisms and outcomes, and also emphasized sustainability strategies in 18 explanations of how sustainability works. These explanations provide evidence for four overarching patterns: (1) implementation and sustainability phases are interconnected, (2) outcomes build on each other recursively, with patient benefits as the keystone outcome, (3) sustainment is achieved to varying levels across different sustainability outcomes [e.g., high level (e.g., rate of MPAI-4 scoring: 77.7%) to low level (e.g., rate of MPAI-4 application to clinical decision-making: 3.7%)] and (4) the work of sustaining the MPAI-4 is shared amongst different stakeholders. CONCLUSION: Implementation teams can draw from this programme theory to improve the sustainment of outcomes measures while researchers could continue to refine the theory. Continued investigation of sustainability, including diverse and continuous sustainability outcomes, is needed to understand how to maintain improvements in quality of care and patient outcomes.

Susceptible bacteria can survive antibiotic treatment in the mammalian gastrointestinal tract without evolving resistance.

Antibiotic resistance and evasion are incompletely understood and complicated by the fact that murine interval dosing models do not fully recapitulate antibiotic pharmacokinetics in humans. To better understand how gastrointestinal bacteria respond to antibiotics, we colonized germ-free mice with a pan-susceptible genetically barcoded Escherichia coli clinical isolate and administered the antibiotic cefepime via programmable subcutaneous pumps, allowing closer emulation of human parenteral antibiotic dynamics. E. coli was only recovered from intestinal tissue, where cefepime concentrations were still inhibitory. Strikingly, "some" E. coli isolates were not cefepime resistant but acquired mutations in genes involved in polysaccharide capsular synthesis increasing their invasion and survival within human intestinal cells. Deleting wbaP involved in capsular polysaccharide synthesis mimicked this phenotype, allowing increased invasion of colonocytes where cefepime concentrations were reduced. Additionally, "some" mutant strains exhibited a persister phenotype upon further cefepime exposure. This work uncovers a mechanism allowing "select" gastrointestinal bacteria to evade antibiotic treatment.

The cross talk between type II diabetic microenvironment and the regenerative capacities of human adipose tissue-derived pericytes: a promising cell therapy.

BACKGROUND: Pericytes (PCs) are multipotent contractile cells that wrap around the endothelial cells (ECs) to maintain the blood vessel's functionality and integrity. The hyperglycemia associated with Type 2 diabetes mellitus (T2DM) was shown to impair the function of PCs and increase the risk of diabetes complications. In this study, we aimed to investigate the deleterious effect of the diabetic microenvironment on the regenerative capacities of human PCs. METHODS: PCs isolated from human adipose tissue were cultured in the presence or absence of serum collected from diabetic patients. The functionality of PCs was analyzed after 6, 14, and 30 days. RESULTS: Microscopic examination of PCs cultured in DS (DS-PCs) showed increased aggregate formation and altered surface topography with hyperbolic invaginations. Compared to PCs cultured in normal serum (NS-PCs), DS-PCs showed more fragmented mitochondria and thicker nuclear membrane. DS caused impaired angiogenic differentiation of PCs as confirmed by tube formation, decreased VEGF-A and IGF-1 gene expression, upregulated TSP1, PF4, actin-related protein 2/3 complex, and downregulated COL21A1 protein expression. These cells suffered more pronounced apoptosis and showed higher expression of Clic4, apoptosis facilitator BCl-2-like protein, serine/threonine protein phosphatase, and caspase-7 proteins. DS-PCs showed dysregulated DNA repair genes CDKN1A, SIRT1, XRCC5 TERF2, and upregulation of the pro-inflammatory genes ICAM1, IL-6, and TNF-α. Further, DS-treated cells also showed disruption in the expression of the focal adhesion and binding proteins TSP1, TGF-ß, fibronectin, and PCDH7. Interestingly, DS-PCs showed resistance mechanisms upon exposure to diabetic microenvironment by maintaining the intracellular reactive oxygen species (ROS) level and upregulation of extracellular matrix (ECM) organizing proteins as vinculin, IQGAP1, and tubulin beta chain. CONCLUSION: These data showed that the diabetic microenvironment exert a deleterious effect on the regenerative capacities of human adipose tissue-derived PCs, and may thus have possible implications on the vascular complications of T2DM. Nevertheless, PCs have shown remarkable protective mechanisms when initially exposed to DS and thus they could provide a promising cellular therapy for T2DM.