Efficacy and Safety of Direct Oral Anticoagulants (DOACs) Versus Warfarin in Atrial Fibrillation Patients with Prior Stroke: a Systematic Review and Meta-analysis.

BACKGROUND: The purpose of this meta-analysis was to compare efficacy and safety of direct oral anticoagulants (DOACs) to warfarin for secondary stroke prevention among adult patients with atrial fibrillation and prior stroke. METHODS: Major repositories were screened for randomized controlled trials (RCTs), RCT subgroups, and observational studies (OBSs, divided in claims and non-claims). Occurrences of ischemic stroke or transient ischemic attack, systemic embolism, all-cause mortality, intracranial hemorrhage (ICH), and major bleeding were outcomes of interest. Hazard ratios (HRs) and their confidence intervals (95%CIs) were pooled using random-effects models for each study design. Claims studies were analyzed separately from non-claims, while RCT subgroups were grouped with OBSs (non-claims) as the randomization was broken. RESULTS: Of 8647 articles, 20 were included (one RCT, six RCT subgroups, nine claims, and four non-claims). Comparing DOACs to warfarin, pooled HRs (95%CI) were consistently in favor of DOACs although some did not reach statistical significance: for ischemic stroke, 0.84 (0.66-1.07) in claims; 0.90 (0.77-1.06) in non-claims and RCT subgroups; for systemic embolism, 0.77 (0.62-0.96) in claims; 0.86 (0.77-0.96) in non-claims and RCT subgroups; for all-cause mortality, 0.57 (0.33-0.99) in claims; 0.87 (0.79-0.96) in non-claims and RCT subgroups; for ICH, 0.72 (0.39-1.33) in claims; 0.51 (0.38-0.67) in non-claims and RCT subgroups; and for major bleeding, 0.86 (0.71-1.03) in claims; 0.90 (0.76-1.08) for non-claims and RCT subgroups. CONCLUSION: DOACs were associated with better efficacy and safety profiles than warfarin in atrial fibrillation patients with prior stroke, more specifically a lower risk of systemic embolism, all-cause mortality, and ICH.

Comparing frailty prevalence between countries: validation of the Global Burden of Disease study Frailty Index (GBD-FI) in the survey of health, ageing and retirement in Europe.

BACKGROUND: Accurate comparable prevalence proportions are required to better understand the epidemiology of frailty. Estimates in many countries are missing or incomparable. The Global Burden of Disease Frailty Index (GBD-FI) applies the deficit accumulation model to generate frailty scores from items available in the Global Burden of Disease study. OBJECTIVE: To externally validate the GBD-FI. METHODS: Data were obtained from the Survey of Health Ageing and Retirement in Europe (SHARE). A 20-item modified GBD-FI was compared with established frailty measures: a 70-item frailty index (FI-70), the Clinical Frailty Scale (CFS), Frailty Phenotype (FP) and SHARE-FI. Area under receiver operating characteristic curves (AUC) were fitted to examine diagnostic accuracy for frailty and predictive validity for 2-year mortality. RESULTS: In total, 31,624 participants aged ≥50 years from 15 countries were included. Frailty prevalence was 22% using the GBD-FI (ranging from 8% in Switzerland to 41% in Poland). The GBD-FI had good to excellent diagnostic accuracy for frailty, irrespective of approach; the AUC ranged from 0.86 (95% confidence interval: 0.85-0.87) measuring frailty using the CFS to 0.94 (0.93-0.94) with the FI-70. The GBD-FI had similar accuracy for 2-year mortality (AUC 0.71, 0.69-0.74) compared with the CFS (0.73; P = 0.186), FP (0.73; P = 0.392) and SHARE-FI (0.70; P = 0.255) but lower than the FI-70 (0.76; P < 0.001). CONCLUSION: The GBD-FI demonstrated concurrent and predictive validity, suggesting it is a valid measure of frailty. It has the potential to be an efficient, replicable and consistent approach to comparing frailty between countries and regions across time using GBD data.

Early Metformin in Gestational Diabetes: A Randomized Clinical Trial.

Importance: Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain. Objective: To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38. Design, Setting, and Participants: Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks' postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria. Interventions: Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care. Main Outcomes And Measures: The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38. Results: Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, -6.9% [95% CI, -15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing >4 kg, a lower proportion in the >90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7. Conclusion and relevance: Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02980276; EudraCT: 2016-001644-19.

Marrow changes and reduced proliferative capacity of mesenchymal stromal cells from patients with "no-option" critical limb ischemia; observations on feasibility of the autologous approach from a clinical trial.

BACKGROUND AIMS: Approximately 1 in 3 patients with critical limb ischemia (CLI) are not suitable for surgical or endovascular revascularization. Those "no-option" patients are at high risk of amputation and death. Autologous bone marrow mesenchymal stromal cells (MSCs) may provide a limb salvage option. In this study, bone marrow characteristics and expansion potentials of CLI-derived MSCs produced during a phase 1b clinical trial were compared with young healthy donor MSCs to determine the feasibility of an autologous approach. Cells were produced under Good Manufacturing Practice conditions and underwent appropriate release testing. METHODS: Five bone marrow aspirates derived from patients with CLI were compared with six young healthy donor marrows in terms of number of colony-forming units-fibroblast (CFUF) and mononuclear cells. The mean population doubling times and final cell yields were used to evaluate expansion potential. The effect of increasing the volume of marrow on the CFUF count and final cell yield was evaluated by comparing 5 CLI-derived MSCs batches produced from a targeted 30 mL of marrow aspirate to five batches produced from a targeted 100 mL of marrow. RESULTS: CLI-derived marrow aspirate showed significantly lower numbers of mononuclear cells with no difference in the number of CFUFs when compared with healthy donors' marrow aspirate. CLI-derived MSCs showed a significantly longer population doubling time and reduced final cell yield compared with young healthy donors' MSCs. The poor growth kinetics of CLI MSCs were not mitigated by increasing the bone marrow aspirate from 30 to 100 mL. CONCLUSIONS: In addition to the previously reported karyotype abnormalities in MSCs isolated from patients with CLI, but not in cells from healthy donors, the feasibility of autologous transplantation of bone marrow MSCs for patients with no-option CLI is further limited by the increased expansion time and the reduced cell yield.

An International Delphi Consensus on Diagnostic Criteria for Buerger's Disease.

BACKGROUND: Buerger's disease (BD) remains a debilitating condition. Despite multiple published diagnostic criteria for BD, none is universally accepted as a gold standard. METHODS: We conducted a 2-round modified Delphi consensus study to establish a consensus on the diagnostic. The questionnaire included statements from several commonly used diagnostic criteria for BD. Qualitative and quantitative analysis methods were performed. An agreement level of 70% was applied. RESULTS: Twenty nine experts from 18 countries participated in this study. Overall, 75 statements were circulated in Round 1. Of these, 28% of statements were accepted. Following comments, 21 statements were recirculated in Round 2 and 90% were accepted. Although more than 90% of the experts did not agree that the diagnosis of BD can be based only on clinical manifestation, none of the nonclinical manifestations of BD were agreed as a part of the diagnostic criteria. There was an agreement that a history of tobacco consumption in any form, not necessarily confined to the current use, should be a part of the diagnostic criteria of BD. The history of thrombophlebitis migrans, even if not present at presentation, was accepted as a clue for BD diagnosis. It was also agreed that discoloration of the toes or fingers could be included in the diagnostic criteria of BD. Experts agreed that histology results could differentiate BD from atherosclerosis obliterans and other types of vasculitis. The presence of corkscrew collaterals on imaging and burning pain reached the agreement at the first round but not at the second. There was no consensus regarding age cut-off, the requirement of normal lipid profile, and normal blood glucose for BD diagnosis. CONCLUSIONS: The present study demonstrated discrepancies in the various published diagnostic criteria for BD and their selective utilization in routine clinical practice worldwide. We propose that all published diagnostic criteria for BD be re-evaluated for harmonization and universal use.

Methodological considerations in injury burden of disease studies across Europe: a systematic literature review.

BACKGROUND: Calculating the disease burden due to injury is complex, as it requires many methodological choices. Until now, an overview of the methodological design choices that have been made in burden of disease (BoD) studies in injury populations is not available. The aim of this systematic literature review was to identify existing injury BoD studies undertaken across Europe and to comprehensively review the methodological design choices and assumption parameters that have been made to calculate years of life lost (YLL) and years lived with disability (YLD) in these studies. METHODS: We searched EMBASE, MEDLINE, Cochrane Central, Google Scholar, and Web of Science, and the grey literature supplemented by handsearching, for BoD studies. We included injury BoD studies that quantified the BoD expressed in YLL, YLD, and disability-adjusted life years (DALY) in countries within the European Region between early-1990 and mid-2021. RESULTS: We retrieved 2,914 results of which 48 performed an injury-specific BoD assessment. Single-country independent and Global Burden of Disease (GBD)-linked injury BoD studies were performed in 11 European countries. Approximately 79% of injury BoD studies reported the BoD by external cause-of-injury. Most independent studies used the incidence-based approach to calculate YLDs. About half of the injury disease burden studies applied disability weights (DWs) developed by the GBD study. Almost all independent injury studies have determined YLL using national life tables. CONCLUSIONS: Considerable methodological variation across independent injury BoD assessments was observed; differences were mainly apparent in the design choices and assumption parameters towards injury YLD calculations, implementation of DWs, and the choice of life table for YLL calculations. Development and use of guidelines for performing and reporting of injury BoD studies is crucial to enhance transparency and comparability of injury BoD estimates across Europe and beyond.

Transcranial Doppler and computed tomography angiography for detecting cerebral vasospasm post-aneurysmal subarachnoid hemorrhage.

Cerebral vasospasm is a life-threatening complication following aneurysmal subarachnoid hemorrhage (aSAH). While digital subtraction angiography (DSA) is the current gold standard for detection, the diagnostic performance of computed tomography angiography (CTA) and transcranial Doppler (TCD) remains controversial. We aimed to summarize the available evidence and provide recommendations for their use based on GRADE criteria. A literature search was conducted for studies comparing CTA or TCD to DSA for adults ≥ 18 years with aSAH for radiographic vasospasm detection. The DerSimonian-Laird random-effects model was used to pool sensitivity and specificity and their 95% confidence intervals (CI) and derive positive and negative pooled likelihood ratios (LR + /LR -). Out of 2070 studies, seven studies (1646 arterial segments) met inclusion criteria and were meta-analyzed. Compared to the gold standard (DSA), CTA had a pooled sensitivity of 82% (95%CI, 68-91%) and a specificity of 97% (95%CI, 93-98%), while TCD had lower sensitivity 38% (95%CI, 19-62%) and specificity of 91% (95%CI, 87-94%). Only the LR + for CTA (27.3) reached clinical significance to rule in diagnosis. LR - for CTA (0.19) and TCD (0.68) approached clinical significance (< 0.1) to rule out diagnosis. CTA showed higher LR + and lower LR - than TCD for diagnosing radiographic vasospasm, thereby achieving a strong recommendation for its use in ruling in or out vasospasm, based on the high quality of evidence. TCDs had very low LR + and a reasonably low LR - , thereby achieving a weak recommendation against its use in ruling in vasospasm and weak recommendation for its use in ruling out vasospasm.

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function.

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.

Prevalence of frailty in 62 countries across the world: a systematic review and meta-analysis of population-level studies.

INTRODUCTION: The prevalence of frailty at population level is unclear. We examined this in population-based studies, investigating sources of heterogeneity. METHODS: PubMed, Embase, CINAHL and Cochrane Library databases were searched for observational population-level studies published between 1 January 1998 and 1 April 2020, including individuals aged ≥50 years, identified using any frailty measure. Prevalence estimates were extracted independently, assessed for bias and analysed using a random-effects model. RESULTS: In total, 240 studies reporting 265 prevalence proportions from 62 countries and territories, representing 1,755,497 participants, were included. Pooled prevalence in studies using physical frailty measures was 12% (95% CI = 11-13%; n = 178), compared with 24% (95% CI = 22-26%; n = 71) for the deficit accumulation model (those using a frailty index, FI). For pre-frailty, this was 46% (95% CI = 45-48%; n = 147) and 49% (95% CI = 46-52%; n = 29), respectively. For physical frailty, the prevalence was higher among females, 15% (95% CI = 14-17%; n = 142), than males, 11% (95% CI = 10-12%; n = 144). For studies using a FI, the prevalence was also higher in females, 29% (95% CI = 24-35%; n = 34) versus 20% (95% CI = 16-24%; n = 34), for males. These values were similar for pre-frailty. Prevalence increased according to the minimum age at study inclusion. Analysing only data from nationally representative studies gave a frailty prevalence of 7% (95% CI = 5-9%; n = 46) for physical frailty and 24% (95% CI = 22-26%; n = 44) for FIs. CONCLUSIONS: Population-level frailty prevalence varied by classification and sex. Data were heterogenous and limited, particularly from nationally representative studies making the interpretation of differences by geographic region challenging. Common methodological approaches to gathering data are required to improve the accuracy of population-level prevalence estimates. PROTOCOL REGISTRATION: PROSPERO-CRD42018105431.

Autologous bone marrow mesenchymal stromal cell therapy for "no-option" critical limb ischemia is limited by karyotype abnormalities.

BACKGROUND: Critical limb ischemia (CLI) is the most severe manifestation of peripheral vascular disease. Revascularization is the preferred therapy, but it is not achievable in 25%-40% of patients due to diffuse anatomic distribution of the disease or medical comorbidities. No-option CLI represents an unmet medical need. Mesenchymal stromal cells (MSCs) may provide salvage therapy through their angiogenic and tissue-trophic properties. This article reports a phase 1b clinical study examining the safety and feasibility of intramuscular transplantation of autologous bone-marrow MSCs for patients with no-option CLI. METHODS: Twelve patients were enrolled in the clinical trial, and nine proceeded to bone marrow aspiration and culture expansion of MSCs. RESULTS: A high rate of karyotype abnormality (>30%) was detected in the produced cell batches, resulting in failure of release for clinical administration. Four patients were treated with the investigational medicinal product (IMP), three with a low dose of 20 × 106 MSCs and one with a mid-dose of 40 × 106 MSCs. There were no serious adverse events related to trial interventions, including bone marrow aspiration, IMP injection or therapy. CONCLUSIONS: The results of this trial conclude that an autologous cell therapy approach with MSCs for critical limb ischemia is limited by the high rate of karyotype abnormalities.

The Efficacy of Prophylactic Negative Pressure Wound Therapy for Closed Incisions in Breast Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Negative pressure wound therapy (NPWT) is a promising advance in the management of closed surgical incisions. NPWT application induces several effects locally within the wound including reduced lateral tension and improving lymphatic drainage. As a result, NPWT may improve wound healing and reduce surgical site complications. We aim to evaluate the efficacy of prophylactic application of NPWT in preventing surgical site complications for closed incisions in breast surgery. METHODS: This systematic review was reported according to PRISMA guidelines. The protocol was published in PROSPERO (CRD42018114625). Medline, Embase, CINAHL and Cochrane Library databases were searched for studies which compare the efficacy of NPWT versus non-NPWT dressings for closed incisions in breast surgery. Specific outcomes of interest were total wound complications, surgical site infection (SSI), seroma, haematoma, wound dehiscence and necrosis. RESULTS: Seven studies (1500 breast incisions in 904 patients) met the inclusion criteria. NPWT was associated with a significantly lower rate of total wound complications [odds ratio (OR) 0.36; 95% CI 0.19-069; P = 0.002], SSI (OR 0.45; 95% CI 0.24-0.86; P = 0.015), seroma (OR 0.28; 95% CI 0.13-0.59; P = 0.001), wound dehiscence (OR 0.49; 95% CI 0.32-0.72; P < 0.001) and wound necrosis (OR 0.38; 95% CI 0.19-0.78; P = 0.008). There was no significant difference in haematoma rate (OR 0.8; 95% CI 0.19-3.2; P = 0.75). Statistically significant heterogeneity existed for total wound complications, but no other outcomes. CONCLUSION: Compared with conventional non-NPWT dressings, prophylactic application of NPWT is associated with significantly fewer surgical site complications including SSI, seroma, wound dehiscence and wound necrosis for closed breast incisions.

European Collaborative and Interprofessional Capability Framework for Prevention and Management of Frailty-a consensus process supported by the Joint Action for Frailty Prevention (ADVANTAGE) and the European Geriatric Medicine Society (EuGMS).

BACKGROUND: Interprofessional collaborative practice (ICP) is currently recommended for the delivery of high-quality integrated care for older people. Frailty prevention and management are key elements to be tackled on a multi-professional level. AIM: This study aims to develop a consensus-based European multi-professional capability framework for frailty prevention and management. METHODS: Using a modified Delphi technique, a consensus-based framework of knowledge, skills and attitudes for all professions involved in the care pathway of older people was developed within two consultation rounds. The template for the process was derived from competency frameworks collected in a comprehensive approach from EU-funded projects of the European Commission (EC) supported best practice models for health workforce development. RESULTS: The agreed framework consists of 25 items structured in 4 domains of capabilities. Content covers the understanding about frailty, skills for screening and assessment as well as management procedures for every profession involved. The majority of items focused on interprofessional collaboration, communication and person-centred care planning. DISCUSSION: This framework facilitates clarification of professionals' roles and standardizes procedures for cross-sectional care processes. Despite a lack of evidence for educational interventions, health workforce development remains an important aspect of quality assurance in health care systems. CONCLUSIONS: The multi-professional capability framework for frailty prevention and management incorporated interprofessional collaborative practice, consistent with current recommendations by the World Health Organization, Science Advice for Policy by European Academies and the European Commission.

Defining the characteristics of intermediate care models including transitional care: an international Delphi study.

BACKGROUND: Although there is growing utilisation of intermediate care to improve the health and well-being of older adults with complex care needs, there is no international agreement on how it is defined, limiting comparability between studies and reducing the ability to scale effective interventions. AIM: To identify and define the characteristics of intermediate care models. METHODS: A scoping review, a modified two-round electronic Delphi study involving 27 multi-professional experts from 13 countries, and a virtual consensus meeting were conducted. RESULTS: Sixty-six records were included in the scoping review, which identified four main themes: transitions, components, benefits and interchangeability. These formed the basis of the first round of the Delphi survey. After Round 2, 16 statements were agreed, refined and collapsed further. Consensus was established for 10 statements addressing the definitions, purpose, target populations, approach to care and organisation of intermediate care models. DISCUSSION: There was agreement that intermediate care represents time-limited services which ensure continuity and quality of care, promote recovery, restore independence and confidence at the interface between home and acute services, with transitional care representing a subset of intermediate care. Models are best delivered by an interdisciplinary team within an integrated health and social care system where a single contact point optimises service access, communication and coordination. CONCLUSIONS: This study identified key defining features of intermediate care to improve understanding and to support comparisons between models and studies evaluating them. More research is required to develop operational definitions for use in different healthcare systems.

Pre-frailty as a multi-dimensional construct: A systematic review of definitions in the scientific literature.

There is as yet no widely-accepted definition of pre-frailty. We aimed to identify and examine definitions of pre-frailty in the literature to characterise important features and factors contributing to the construct using a systematic review approach with a qualitative analysis. PubMed, PsycINFO, Embase, Cochrane Library, ASSIA, and CINAHL databases were searched for studies conducted in any settings providing a definition or description of pre-frailty, published in English, between January 2000 and July 2018. Seventy-seven studies met the inclusion criteria. No consensus definition of pre-frailty was evident in the literature. Four main themes were identified using thematic analysis: (1) Pre-frailty as a prodromal, multi-factorial concept; (2) Physical, social, cognitive and nutritional subtypes; (3) Operational definitions; and (4) Outcomes. We propose a comprehensive definition suggesting that pre-frailty is a multi-dimensional concept, an early and reversible risk-state before frailty that can lead to negative healthcare outcomes, which is defined operationally by existing frailty screening and assessment tools.

Computed Tomography Angiography Versus Digital Subtraction Angiography for Postclipping Aneurysm Obliteration Detection.

Background and Purpose- Digital subtraction angiography has been used as the gold standard to confirm successful aneurysmal obliteration after aneurysm clipping procedures using titanium or cobalt alloy clips. Computed tomographic angiography is a newer, less invasive imaging technique also used to confirm successful aneurysmal obliteration; however, its use compared with digital subtraction angiography remains controversial. Methods- A comprehensive literature search was conducted on Pubmed, EMBASE, and Cochrane databases through November 6, 2017, for studies that evaluated postclipping aneurysm obliteration with both computed tomographic angiography and digital subtraction angiography. Pooled sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated using the bivariate random-effects model. Results- Out of 6916 studies, 13 studies met inclusion criteria for this meta-analysis. A total of 510 patients with 613 aneurysms were included. Compared with digital subtraction angiography, which detected 87 residual aneurysms, computed tomographic angiography detected 58 resulting in a pooled sensitivity of 69% (95% CI, 54%-81%) and a pooled specificity of 99% (95% CI, 97%-99%). This corresponded to LR+ of 55.5 (95% CI, 23.6-130.9) and LR- of 0.31 (95% CI, 0.20-0.48). Univariate meta-regression revealed that the pooled sensitivity was worse in prospective designs ( P interaction <0.05), and the pooled specificity was better in higher-quality studies and for postoperative aneurysm diameters of <2 mm ( P interaction <0.001 for both). Conclusions- This meta-analysis revealed that computed tomographic angiography had a favorable LR+ but not a favorable LR-. Thus, this imaging modality may be applicable to rule in, but not rule out, residual aneurysms after clipping.

The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1ß.

Myeloid angiogenic cells (MACs) promote revascularization through the paracrine release of angiogenic factors and have been harnessed as therapeutic cells for many ischemic diseases. However, their proangiogenic properties have been suggested to be diminished in diabetes. This study investigates how the diabetic milieu affects the immunophenotype and function of MACs. Both MACs isolated from diabetic conditions and healthy cells exposed to a diabetic environment were used to determine the potential of MACs as a cell therapy for diabetic-related ischemia. MACs were isolated from human peripheral blood and characterized alongside proinflammatory macrophages M (LPS + IFNγ) and proangiogenic macrophages M (IL4). Functional changes in MACs in response to high-d-glucose were assessed using an in vitro 3D-tubulogenesis assay. Phenotypic changes were determined by gene and protein expression analysis. Additionally, MACs from type 1 diabetic (T1D) patients and corresponding controls were isolated and characterized. Our evidence demonstrates MACs identity as a distinct macrophage subtype that shares M2 proangiogenic characteristics, but can be distinguished by CD163hi expression. High-d-glucose treatment significantly reduced MACs proangiogenic capacity, which was associated with a significant increase in IL1ß mRNA and protein expression. Inhibition of IL1ß abrogated the antiangiogenic effect induced by high-d-glucose. IL1ß was also significantly upregulated in MACs isolated from T1D patients with microvascular complications compared to T1D patients without microvascular complications or nondiabetic volunteers. This study demonstrates that Type 1 diabetes and diabetic-like conditions impair the proangiogenic and regenerative capacity of MACs, and this response is mediated by IL-1ß. Stem Cells 2018;36:834-843.

Gene therapy for peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD), caused by narrowing of the arteries in the limbs, is increasing in incidence and prevalence as our population is ageing and as diabetes is becoming more prevalent. PAD can cause pain in the limbs while walking, known as intermittent claudication, or can be more severe and cause pain while at rest, ulceration, and ultimately gangrene and limb loss. This more severe stage of PAD is known as 'critical limb ischaemia'. Treatments for PAD include medications that help to reduce the increased risk of cardiovascular events and help improve blood flow, as well as endovascular or surgical repair or bypass of the blocked arteries. However, many people are unresponsive to medications and are not suited to surgical or endovascular treatment, leaving amputation as the last option. Gene therapy is a novel approach in which genetic material encoding for proteins that may help increase revascularisation is injected into the affected limbs of patients. This type of treatment has been shown to be safe, but its efficacy, especially regarding ulcer healing, effects on quality of life, and other symptomatic outcomes remain unknown. OBJECTIVES: To assess the effects of gene therapy for symptomatic peripheral arterial disease. SEARCH METHODS: The Cochrane Vascular Information Specialist searched Cochrane CENTRAL, the Cochrane Vascular Specialised Register, MEDLINE Ovid, Embase Ovid, CINAHL, and AMED, along with trials registries (all searched 27 November 2017). We also checked reference lists of included studies and systematic reviews for further studies. SELECTION CRITERIA: We included randomised and quasi-randomised studies that evaluated gene therapy versus no gene therapy in people with PAD. We excluded studies that evaluated direct growth hormone treatment or cell-based treatments. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, performed quality assessment, and extracted data from the included studies. We collected pertinent information on each study, as well as data for the outcomes of amputation-free survival, ulcer healing, quality of life, amputation, all-cause mortality, ankle brachial index, symptom scores, and claudication distance. MAIN RESULTS: We included in this review a total of 17 studies with 1988 participants (evidence current until November 2017). Three studies limited their inclusion to people with intermittent claudication, 12 limited inclusion to people with varying levels of critical limb ischaemia, and two included people with either condition. Study investigators evaluated many different types of gene therapies, using different protocols. Most studies evaluated growth factor-encoding gene therapy, with six studies using vascular endothelial growth factor (VEGF)-encoding genes, four using hepatocyte growth factor (HGF)-encoding genes, and three using fibroblast growth factor (FGF)-encoded genes. Two studies evaluated hypoxia-inducible factor 1-alpha (HIF-1α) gene therapy, one study used a developmental endothelial locus-1 gene therapy, and the final study evaluated a stromal cell-derived factor-1 (SDF-1) gene therapy. Most studies reported outcomes after 12 months of follow-up, but follow-up ranged from three months to two years.Overall risk of bias varied between studies, with many studies not providing sufficient detail for adequate determination of low risk of bias for many domains. Two studies did not utilise a placebo control, leading to risk of performance bias. Several studies reported in previous protocols or in their Methods sections that they would report on certain outcomes for which no data were then reported, increasing risk of reporting bias. All included studies reported sponsorships from corporate entities that led to unclear risk of other bias. The overall quality of evidence ranged from moderate to very low, generally as the result of heterogeneity and imprecision, with few or no studies reporting on outcomes.Evidence suggests no clear differences for the outcomes of amputation-free survival, major amputation, and all-cause mortality between those treated with gene therapy and those not receiving this treatment (all moderate-quality evidence). Low-quality evidence suggests improvement in complete ulcer healing with gene therapy (odds ratio (OR) 2.16, 95% confidence interval (CI) 1.02 to 4.59; P = 0.04). We could not combine data on quality of life and can draw no conclusions at this time regarding this outcome (very low-quality evidence). We included one study in the meta-analysis for ankle brachial index, which showed no clear differences between treatments, but we can draw no overall association (low-quality evidence). We combined in a meta-analysis pain symptom scores as assessed by visual analogue scales from two studies and found no clear differences between treatment groups (very low-quality evidence). We carried out extensive subgroup analyses by PAD classification, dosage schedule, vector type, and gene used but identified no substantial differences. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows no clear differences in amputation-free survival, major amputation, and all-cause mortality between those treated with gene therapy and those not receiving gene therapy. Some evidence suggests that gene therapy may lead to improved complete ulcer healing, but this outcome needs to be explored with improved reporting of the measure, such as decreased ulcer area in cm², and better description of ulcer types and healing. Further standardised data that are amenable to meta-analysis are needed to evaluate other outcomes such as quality of life, ankle brachial index, symptom scores, and claudication distance.

Focused Versus Bilateral Parathyroid Exploration for Primary Hyperparathyroidism: A Systematic Review and Meta-analysis.

BACKGROUND: Focused exploration (FE) and bilateral parathyroid exploration (BE) are the standard surgical options for patients with primary hyperparathyroidism. However, the relative risk of recurrence, persistence, overall failure, reoperation, and any complications associated with either surgical approach is unclear. This study compared the outcomes and complication rates after FE and BE for patients with primary hyperparathyroidism. METHODS: PubMed and Embase were searched for studies comparing these outcomes between FE and BE. A meta-analysis was performed using RevMan 5.3 software. Published data were pooled using the DerSimonian random-effect model, and results were presented as odds ratio (OR) or mean difference with 95% confidence interval (CI). RESULTS: A total of 12,743 patients from 19 studies were included in this meta-analysis. In comparison with BE, the FE arm had comparable rates of recurrence (OR 1.08; 95% CI 0.59-2.00; p = 0.80; n = 9 studies), persistence (OR 0.89; 95% CI 0.58-1.35; p = 0.58; n = 13), overall failure (OR 0.88; 95% CI 0.58-1.34; p = 0.56; n = 13), and reoperation (OR 1.05; 95% CI 0.25-4.32; p = 0.95, n = 4). The operative time was significantly shorter (mean difference = -39.86; 95% CI -53.05 to -26.84; p < 0.01, n = 9), with a lower overall complication rate in the FE arm (OR  0.35; 95% CI 0.15-0.84; p = 0.02; n = 12). The latter was attributed predominantly to a lower risk of transient hypocalcemia (OR  0.36; 95% CI 0.14-0.90; p = 0.03; n = 9). There was a significant heterogeneity among these studies for all outcomes except for disease recurrence. CONCLUSIONS: Compared with BE, FE has similar recurrence, persistence, and reoperation rates but significantly lower overall complication rates and shorter operative time.

Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely Ill hospitalized medical patients: a systematic review and meta-analysis of randomized controlled trials.

Extended-duration pharmacological thromboprophylaxis, for at least 28 days, is effective for the prevention of symptomatic venous thromboembolism (VTE) in high-risk surgical patients but is of uncertain benefit in hospitalized medical patients. We aimed to evaluate the efficacy and safety of extended-duration thromboprophylaxis in hospitalized medical patients. We conducted a systematic PubMed, Medline and EMBASE literature search until June 2016 and a meta-analysis of randomized controlled trials which compared extended-duration with short-duration thromboprophylaxis in hospitalized medical patients. Four randomized controlled trials comparing extended-duration prophylaxis (24-47 days) with short-duration prophylaxis (6-14 days) in a total of 34,068 acutely ill hospitalized medical patients were included. When compared with short-duration prophylaxis, extended-duration prophylaxis was associated with a decrease in symptomatic proximal or distal deep vein thrombosis (DVT) [relative risk (RR) = 0.52; 95% confidence interval (Cl): 0.35-0.77: p = 0.001; absolute risk reduction (ARR) = 0.32%, number needed to treat (NNT) = 313], and symptomatic non-fatal pulmonary embolism (RR = 0.61; 95% Cl 0.38-0.99: p = 0.04; ARR = 0.16%; NNT = 625), an increase in major bleeding (RR = 2.08; 95% Cl 1.50-2.90: p < 0.0001, absolute risk increase = 0.41%, number needed to harm = 244), and no significant reduction in VTE-related mortality (RR = 0.69; 95% Cl 0.45-1.06: p = 0.09) or all-cause mortality (RR = 1.00; 95% CI 0.89-1.12; p = 0.95). There was heterogeneity for major bleeding due to results from the APEX trial (no difference between betrixaban and enoxaparin). Compared with short-duration thromboprophylaxis, extended-duration treatment reduces the risk for symptomatic DVT and non-fatal pulmonary embolism. Extended treatment with apixaban, enoxaparin and rivaroxaban but not betrixaban increases the risk for major bleeding.

The potential of cell-based therapy for diabetes and diabetes-related vascular complications.

Cell therapy has enormous potential for the treatment of conditions of unmet medical need. Cell therapy may be applied to diabetes mellitus in the context of beta cell replacement or for the treatment of diabetic complications. A large number of cell types including hematopoietic stem cells, mesenchymal stem cells, umbilical cord blood, conditioned lymphocytes, mononuclear cells, or a combination of these cells have been shown to be safe and feasible for the treatment of patients with diabetes mellitus. The first part of this review article will focus on the current perspective of the role of embryonic stem cells and inducible pluripotent stem cells for beta cell replacement and the current clinical data on cell-based therapy for the restoration of normoglycemia. The second part of this review will highlight the therapeutic role of MSCs in islet cells cotransplantation and the management of diabetes related vascular complications.