The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Streptococcus dysgalactiae subsp. equisimilis infection and its intersection with Streptococcus pyogenes.

SUMMARYStreptococcus dysgalactiae subsp. equisimilis (SDSE) is an increasingly recognized cause of disease in humans. Disease manifestations range from non-invasive superficial skin and soft tissue infections to life-threatening streptococcal toxic shock syndrome and necrotizing fasciitis. Invasive disease is usually associated with co-morbidities, immunosuppression, and advancing age. The crude incidence of invasive disease approaches that of the closely related pathogen, Streptococcus pyogenes. Genomic epidemiology using whole-genome sequencing has revealed important insights into global SDSE population dynamics including emerging lineages and spread of anti-microbial resistance. It has also complemented observations of overlapping pathobiology between SDSE and S. pyogenes, including shared virulence factors and mobile gene content, potentially underlying shared pathogen phenotypes. This review provides an overview of the clinical and genomic epidemiology, disease manifestations, treatment, and virulence determinants of human infections with SDSE with a particular focus on its overlap with S. pyogenes. In doing so, we highlight the importance of understanding the overlap of SDSE and S. pyogenes to inform surveillance and disease control strategies.

Molecular characterization of the interaction between human IgG and the M-related proteins from Streptococcus pyogenes.

Group A Streptococcal M-related proteins (Mrps) are dimeric α-helical-coiled-coil cell membrane-bound surface proteins. During infection, Mrp recruit the fragment crystallizable region of human immunoglobulin G via their A-repeat regions to the bacterial surface, conferring upon the bacteria enhanced phagocytosis resistance and augmented growth in human blood. However, Mrps show a high degree of sequence diversity, and it is currently not known whether this diversity affects the Mrp-IgG interaction. Herein, we report that diverse Mrps all bind human IgG subclasses with nanomolar affinity, with differences in affinity which ranged from 3.7 to 11.1 nM for mixed IgG. Using surface plasmon resonance, we confirmed Mrps display preferential IgG-subclass binding. All Mrps were found to have a significantly weaker affinity for IgG3 (p < 0.05) compared to all other IgG subclasses. Furthermore, plasma pulldown assays analyzed via Western blotting revealed that all Mrp were able to bind IgG in the presence of other serum proteins at both 25 °C and 37 °C. Finally, we report that dimeric Mrps bind to IgG with a 1:1 stoichiometry, enhancing our understanding of this important host-pathogen interaction.

Glycan-Tailored Glycoproteomic Analysis Reveals Serine is the Sole Residue Subjected to O-Linked Glycosylation in Acinetobacter baumannii.

Protein glycosylation is a ubiquitous process observed across all domains of life. Within the human pathogen Acinetobacter baumannii, O-linked glycosylation is required for virulence; however, the targets and conservation of glycosylation events remain poorly defined. In this work, we expand our understanding of the breadth and site specificity of glycosylation within A. baumannii by demonstrating the value of strain specific glycan electron-transfer/higher-energy collision dissociation (EThcD) triggering for bacterial glycoproteomics. By coupling tailored EThcD-triggering regimes to complementary glycopeptide enrichment approaches, we assessed the observable glycoproteome of three A. baumannii strains (ATCC19606, BAL062, and D1279779). Combining glycopeptide enrichment techniques including ion mobility (FAIMS), metal oxide affinity chromatography (titanium dioxide), and hydrophilic interaction liquid chromatography (ZIC-HILIC), as well as the use of multiple proteases (trypsin, GluC, pepsin, and thermolysis), we expand the known A. baumannii glycoproteome to 33 unique glycoproteins containing 42 glycosylation sites. We demonstrate that serine is the sole residue subjected to glycosylation with the substitution of serine for threonine abolishing glycosylation in model glycoproteins. An A. baumannii pan-genome built from 576 reference genomes identified that serine glycosylation sites are highly conserved. Combined this work expands our knowledge of the conservation and site specificity of A. baumannii O-linked glycosylation.

Outcomes of one-stage and two-stage aneurysm repair in arteriovenous fistulae.

OBJECTIVE: Maintenance of long-term arteriovenous access is important in long-term care for patients with end-stage renal disease. Arteriovenous access is associated in the long term with the development of fistula aneurysms (FAs). This study aims to evaluate the outcomes of staged FA treatment in dialysis access arteriovenous fistulae (AVF). METHODS: A retrospective review of all patients over a 12-year period with primary autogenous AVF was undertaken at a single center. Patients undergoing elective open aneurysm repair were identified and were categorized into three groups: single FA repair (single, control group) and staged and unstaged repair of two FAs (staged and unstaged). A staged repair was a procedure in which the initial intent was to treat both aneurysms in the AVF and in which the most symptomatic aneurysm was treated first. When the incision from the first surgery had healed, the second symptomatic aneurysm in the AVF was treated. An unstaged repair was a procedure in which the initial intent was to repair both symptomatic aneurysms simultaneously. All patients had a fistulogram before the FA repair. Thirty-day outcomes, cannulation failure, line placement, reintervention, and functional dialysis (continuous hemodialysis for 3 consecutive months) were examined. RESULTS: Five hundred twenty-seven patients presented with FA that met requirements for open intervention; 44% underwent single FA repair, whereas the remaining 34% and 22% underwent staged and unstaged repair of two FAs, respectively. The majority of patients were diabetic and Hispanic. Ninety-one percent of the patients required percutaneous interventions of the outflow tract (37%) and the central veins (54%). Thirty-day major adverse cardiovascular events were equivalent across all modalities. Thirty-day morbidity and early thrombosis (<18 days) were significantly higher in the unstaged group (4.3%) compared with the two other groups (1.3% and 2.1%, single and staged, respectively), which led to an increased need for a short-term tunneled catheter (8.9%) compared with the two other groups (3.4% and 4.4%, single and staged, respectively), Unstaged repair resulted in an increased incidence of secondary procedures (5.0%) compared with the two other groups (2.6% and 3.1%, single and staged, respectively). Functional dialysis at 5 years was equivalent in the single and staged groups but was significantly decreased in the unstaged group. CONCLUSIONS: Open interventions are successful therapeutic modalities for FAs, but unstaged rather than staged repair of two concurrent FAs results in a higher early thrombosis, an increased secondary intervention rate, and a need for a short-term tunneled central line. Staged and single FA repairs have equivalent results. In the setting of two symptomatic FAs, staged repair is recommended.

Pedal medial arterial calcification influences the outcomes of isolated infra-malleolar interventions for chronic limb-threatening ischemia.

OBJECTIVE: Inframalleolar disease is present in most diabetic patients presenting with tissue loss. Inframalleolar (pedal) artery disease and pedal medial arterial calcification (pMAC) are associated with major amputation in patients with chronic limb-threatening ischemia (CLTI). This study aimed to examine the impact of pMAC on the outcomes after isolated inframalleolar (pedal artery) interventions. METHODS: A database of lower extremity endovascular intervention for patients with tissue loss between 2007 and 2022 was retrospectively queried. Patients with CLTI were selected, and those undergoing isolated inframalleolar intervention on the dorsalis pedis and medial and lateral tarsal arteries and who had foot x-rays were identified. X-rays were assessed blindly for pMAC and scored on a scale of 0 to 5. Patients with concomitant superficial femoral artery and tibial interventions were excluded. Intention to treat analysis by the patient was performed. Amputation-free survival (survival without major amputation) was evaluated. RESULTS: A total of 223 patients (51% female; 87% Hispanic; average age, 66 years; 323 vessels) underwent isolated infra-malleolar intervention for tissue loss. All patients had diabetes, 96% had hypertension, 79% had hyperlipidemia, and 63% had chronic renal insufficiency (55% of these were on hemodialysis). Most of the patients had Wound, Ischemia, and foot Infection (WIfI) stage 3 disease and had various stages of pMAC: severe (score = 5) in 48%, moderate (score = 2-4) in 31%, and mild (score = 0-1) in 21% of the patients. Technical success was 94%, with a median of one vessel treated per patient. All failures were in severe pMAC. Overall, major adverse cardiovascular events was 0.9% at 90 days after the procedure. Following the intervention, most patients underwent a planned forefoot amputation (single digit, multiple digits, ray amputation, or trans-metatarsal amputation). WIfI ischemic grade was improved by 51%. Wound healing at 3 months was 69%. Those not healing underwent below-knee amputations. The overall 5-year amputation-free survival rate was 35% ± 9%. The severity of pMAC was associated with decreased AFS. CONCLUSIONS: Increasing severity of pMAC influences the technical and long-term outcomes of infra-malleolar intervention in diabetes. Severe pMAC is associated with amputation and should be considered as a variable in the shared decision-making of diabetic patients with CLTI.

Management of depth to achieve timely arteriovenous fistula utilization.

OBJECTIVE: Failure to achieve timely arteriovenous fistulae (AVFs) utilization due to excessive depth (>6 mm) remains an ongoing concern for dialysis access. This study evaluates the outcomes of radiocephalic (RCF) and brachiocephalic (BCF) fistula elevation required for access utilization. METHODS: A retrospective review of all patients undergoing first-time autologous access over 10 years was undertaken. RCF and BCF were analyzed, and cases of initial access failure due to depth alone were selected for study. Primary and staged brachio-basilic AVF were excluded. Outcomes of early thrombosis, line placement, maturation (successful progression to hemodialysis [HD), reintervention, and functional dialysis (continuous HD for 3 consecutive months) were examined. RESULTS: From January 2012 to December 2022, 1733 patients (67% female; mean age, 61 ± 14 years) underwent autologous AVF placement. Of these, 298 patients (17%) had depth-related AVF access issues (BCF, 71% and RCF, 29%). Nineteen percent of these AVFs underwent a primary balloon-assisted maturation (BAM), and 2% had side branch coil embolization before consideration for elevation. The average time to intervention for depth was 11 ± 4 weeks after primary creation. During elevation, side branch ligation occurred in 38% of cases, and 15% underwent intraoperative BAM, The pre-elevation depth was 8.2 ± 3.1 mm, and the mean post-elevation depth was 4.7 ± 2.9 mm (P = .002). Early thrombosis (<18 days) occurred in 4% of cases. There was no mortality, and the 30-day major adverse cardiac event rate was 2%, with a 30-day morbidity of 5%, which was driven by wound issues. Six percent of the AVFs underwent follow-up BAM within 3 months. Mean maturation of the AVFs was 74% ± 3% vs 72% ± 3% (P = .58) for the elevation vs no-elevation groups at 24 weeks, respectively. However, there was an increase in tunneled central line placement in pre-emptive fistula patients due to the delay in maturation (elevation, 17% vs no-elevation, 8%; P = .008). There was a mean successful access time of 6 ± 3 weeks after elevation (16 ± 4 weeks after access creation). There was a median of 2.4 secondary interventions per year after elevation compared with a median of 2.7 secondary interventions per year without elevation. Mean access functionality was 68% ± 8% vs 75% ± 8% at 3 years for the elevation vs no-elevation groups, respectively (P = .25). CONCLUSIONS: Elevation of deep BCF and RCF occurs late after placement but can be successfully achieved with low morbidity and satisfactory long-term functionality. It results in an increase in tunneled central line placement in pre-emptive fistula patients. Elevation is a valuable adjunct to AVF maturation and enhances an autologous access policy.

Counting the lifetime cost of obesity: Analysis based on national England data.

AIM: Obesity has a significant impact on all-cause mortality rate and overall health care resource use (HCRU). These outcomes are also strongly linked to age, sex and local deprivation of the population. We aimed to establish the lifetime costs of obesity by demographic group/geographic area using published mortality rates and HCRU use for integrated care boards (ICB) in England in the context of costs of therapeutic intervention. METHODS: Population and expected mortality rates by age, sex and deprivation were obtained from national data. Obesity class prevalence was taken from the health of the nation study. The published impact of obesity by age, group, sex and deprivation on mortality and HCRU were applied to estimate life years lost and lifetime HCRU [by sex, age band and body mass index (BMI) class for each ICB]. The year 2019 was chosen as the study basis data to avoid influences of COVID-19 pandemic on obesity rates with application of 2022/23 HCRU values. Outcomes including prevalence, deaths, life years lost, HCRU and lifetime HCRU were compared by age and sex groups across four BMI classes normal/underweight (BMI <25 kg/m2 ), overweight (25-29.9 kg/m2 ), obese class I and II (30-39.9 kg/m2 ), and obese class III (≥40), with benchmarking being set against all population being BMI <25 kg/m2 overall and by each of the 42 ICBs. We also associated future life with deaths to provide an estimate of 'future life years lost' occurring each year. RESULTS: Total population aged >16 years was 45.4 million (51% female). PREVALENCE: 13.7 million (28% of the total adult population) had a BMI ≥30 mg/m2 and BMI ≥40 kg/m2 were 1.50 million (12%) of these 1.0 million (68%) were female and of these 0.6 million 40% were women aged 16-49 years. In addition, 35% of those with a BMI ≥40 kg/m2 were in the top deprivation quintile (i.e. overall 20%). Mortality was based on expected deaths of 518K/year, and modelling suggested that if a BMI <25 kg/m2 was achieved in all individuals, the death rate would fall by 63K to 455K/year for the English population (12% reduction). For those with a BMI ≥40 kg/m2 the predicted reduction was 12K deaths (54% lower); while in those aged 16-49 years with a BMI ≥40 kg/m2 72% of deaths were linked to obesity. For future life years lost, we estimated 2.5 years were lost in people with BMI 30-39.9 kg/m2 6.7 years when BMI ≥40 kg/m2 . However, for those aged 16-49 years with a BMI ≥40 kg/m2 , 8.3 years were lost. HCRU, for weight reduction, the annual HCRU decrease from BMI ≥40 kg/m2 to BMI 30-39.9 kg/m2 was £342 per person and from BMI 30-39.9 to 25-29.9 kg/m2 the reduction was £316/person. However, lifetime costs were similar because of reduced life expectancy for obese individuals. In quality adjusted life years (QALY), overall, 791 689 future life years were lost (13.1% of all) in people with BMI ≥25 kg/m2 and were related to excess weight. When the NICE £30 000 per QALY value was applied to the estimated total 791 689 future life years lost then the potential QALY value reduction lost was equivalent to £24 billion/year or £522/person in the obese population. For morbidly obese men and women the potential QALY value lost was £2864/person/year. Regarding geography, across the 42 ICBs, we observed significant variation in the prevalence of BMI ≥40 (1.8%-4.3%), excess mortality (11.6%-15.4%) and HCRU linked to higher BMI (7.2%-8.8%). The areas with the greatest impact on HCRU were in the north-west, north-east and Midlands of England, while the south shows less impact. CONCLUSION: The expected increases in annual HCRU because of obesity, when considered over a lifetime, are being mitigated by the increased mortality of obese individuals. Our data suggest that simple short-term HCRU reduction brought about through BMI reduction will be insufficient to fund additional specialist weight reduction interventions. The HRCUs associated with BMI are not in most cases related to short-term health conditions. They are a cumulative result over a number of years, so for age 16-49 years reducing BMI from ≥40 to 30-39.9 kg/m2 might show an annual decrease in HCRU/person by £325/year for women and £80/year for men but this might not have immediately occurred within that year. For those aged >70 years reducing BMI from ≥40 to 30-39.9 kg/m2 might show an annual decrease in HCRU/person by £777/year for women and £796/year for men but also may not be manifest within that year. However, for the morbidly obese men and women, the potential QALY value lost was £2864 per person per year with the potential for these funds to be applied to intensive weight management programmes, including pharmacotherapy.

Quantifying the Value of Reduced Health Disparities: Low-Dose Computed Tomography Lung Cancer Screening of High-Risk Individuals Within the United States.

OBJECTIVE: This study aimed to measure the value of increasing lung cancer screening rates for high-risk individuals and its impact on health disparities. METHODS: The model estimated changes in health economic outcomes if low-dose computed tomography screening increased from current to 100% compliance, following clinical guidelines. Current low-dose computed tomography screening rates were estimated by income, education, and race, using 2017-2019 Behavioral Risk Factor Surveillance System data. The model contained a decision tree module to segment the population by screening outcomes and a Markov chain module to estimate cancer progression over time. Model parameters included information on survival, quality of life, and costs related to cancer diagnosis, treatment, and adverse events. Distributional cost-effectiveness analysis estimated the net monetary value from reduced health disparities-measured using quality-adjusted life expectancy-across income, education, and race groups. Outcomes were assessed over 30 years. RESULTS: Lung cancer screening eligibility using US Preventive Services Task Force guidelines was higher for individuals with income <$15 000 (47.2%) and without a high-school education (46.1%) than individuals with income >$50 000 (16.6%) and with a college degree (13.5%), respectively. Increasing lung cancer screening to 100% compliance was cost-effective ($64 654 per quality-adjusted life-year) and produced economic value by up to $560 per person ($182.1 billion for United States overall). Up to 32.2% of the value was due to reductions in health disparities. CONCLUSIONS: Significant value in increasing lung cancer screening rates derived from reducing health disparities. Policy makers and clinicians may not be appropriately prioritizing cancer screening if value from reducing health disparities is unconsidered.

Comparison of Open and Endovascular Aneurysm Repair in Native Arteriovenous Fistulas.

BACKGROUND: Arteriovenous accesses develop aneurysms (FA) during their active use, resulting in pain, erosion, bleeding, and difficulty in cannulation. This study aims to evaluate the outcomes of open and endovascular management of single FA in arteriovenous fistulas (AVF). METHODS: A retrospective review of all upper extremity primary AVFs over 12 years was undertaken at a single center. Patients undergoing elective open and endovascular repair of a single FA were identified. Thirty-day outcomes, cannulation failure, line placement, re-intervention, and functional dialysis (continuous hemodialysis) for 3 consecutive months were examined. RESULTS: Three hundred and seventy nine patients presented with a single FA that met the requirements for intervention: 126 (33%) underwent endovascular repair, and the remainder 253 (67%) underwent open repair. Preoperative fistulogram identified anatomically significant issues in 91% of the cases, and these were treated by balloon angioplasty: 10% within the fistula tract, 44% within the outflow tract, and 47% in the central veins. In open repair, 57% underwent plication, 35% underwent resection and re-anastomosis, and the remainder (8%) underwent interposition grafting. In endovascular repair, successful placement of a stent was achieved in all cases with 1 ± 2 (mean ± standard deviation [SD]) covered stents (diameter: 6 -8 mm) placed, achieving successful exclusion of the FA. The combination of early thrombosis and cannulation failures led to the greater need for a tunneled central line in endovascular repair (6.5% vs. 2.4%; endovascular versus open repair; P = 0.04). As a result, the mean time for establishing renewed access in the index AVF was significantly higher in endovascular repair (2 ± 3 vs. 2 ± 2 weeks, mean ± SD; endovascular open repair versus open repair; P = 0.001). In follow-up, there were more secondary interventions per year in the endovascular compared to open repair groups (3.1 vs. 1.4 secondary interventions per year; endovascular versus open repair; P = 0.04). Median functional dialysis durations were superior in the open repair (48 ± 6%, mean + standard error) compared to the endovascular repair at 5 years. (26 ± 7%; P = 0.03). CONCLUSIONS: Open repair results in a more rapid return to access use, lower need for a tunneled central line, lower secondary re-intervention rates, and superior functional dialysis durations compared to endovascular repair. Open FA repair should be considered for symptomatic single FA repairs before endovascular FA repair.

Extracorporal Membrane Oxygenation in Massive Pulmonary Embolism.

BACKGROUND: Massive pulmonary embolism (MPE) carries significant 30-day mortality risk, and a change in societal guidelines has promoted the increasing use of extracorporeal membrane oxygenation (ECMO) in the immediate management of MPE-associated cardiovascular shock. This narrative review examines the current status of ECMO in MPE. METHODS: A literature review was performed from 1982 to 2022 searching for the terms "Pulmonary embolism" and "ECMO," and the search was refined by examining those publications that covered MPE. RESULTS: In the patient with MPE, veno-arterial ECMO is now recommended as a bridge to interventional therapy. It can reliably decrease right ventricular overload, improve RV function, and allow hemodynamic stability and restoration of tissue oxygenation. The use of ECMO in MPE has been associated with lower mortality in registry reviews, but there has been no significant difference in outcomes between patients treated with and without ECMO in meta-analyses. Applying ECMO is also associated with substantial multisystem morbidity due to systemic inflammatory response, bleeding with coagulopathy, hemorrhagic stroke, renal dysfunction, and acute limb ischemia, which must be factored into the outcomes. CONCLUSIONS: The application of ECMO in MPE should be combined with an aggressive interventional pulmonary interventional program and should strictly adhere to the current selection criteria.

Influence of a Novel Morphology-Driven Classification on Limb Salvage after Isolated Tibial Intervention for Chronic Limb Threatening Ischemia.

BACKGROUND: Infra-popliteal interventions for chronic limb-threatening ischemia (CLTI) can be impacted by the morphology of the tibial vessels. The aim of this study was to examine the impact of a novel morphology-driven classification on the outcomes of isolated tibial intervention for CLTI. METHODS: A database of patients undergoing isolated tibial interventions for CLTI at a single center between 2010 and 2020 was retrospectively queried. Patients with isolated Infra-popliteal disease were identified, and their anatomy was scored as present or absent for lesion calcification (1 point), target vessel diameter<3.0 mm (1 point), lesion length>300mm (1 point) and poor pedal runoff score (1 point). Patients were then divided into three groups: low-risk (0 or 1 points), moderate-risk (2 points), and high-risk (3 or 4 points). Intention to treat analysis by the patient was performed. Limb-based patency (the absence of reintervention, occlusion, critical stenosis (>70%), or hemodynamic compromise with ongoing symptoms of CLTI as it related to the patency of the preoperatively determined target artery pathway) was assessed. Patient-orientated outcomes of amputation-free survival (AFS; survival without major amputation) and freedom from major adverse limb events (MALE; Above ankle amputation of the index limb or major re-intervention (new bypass graft, jump/interposition graft revision) were evaluated. RESULTS: 1607 patients (55% male, average age 60 years, 3846 vessels) underwent tibial intervention for CLTI. The majority of the patients were diabetic and of Hispanic. origin Morphologically, 27%, 31%, and 42% of the vessels were categorized as low risk, moderate risk, and high risk, respectively. There was a significant worsening of the infra-popliteal Global Limb Anatomic Staging System (GLASS) grading as the morphological risk increased. The 30-day major adverse cardiac events (MACE) were equivalent across the groups and were under the stated objective performance goal (OPG) of ≤10%. In contrast, both the 30-day MALE and the 30-day Major Amputations were significantly different across the groups, with the low-risk group remaining under the OPG of ≤9% and ≤4%, respectively, while the moderate-risk and high-risk exceeded the goal threshold. For the OPG. Freedom from MALE was 60±5%, 46±5%, and 22±9% at 5 years for low-, moderate-, and high-risk groups, respectively (mean ± SEM; p =0.008. Overall amputation-free survival (AFS) was 55±5%, 37±6%, and 18±7% at 5 years for low-, moderate-, and high-risk groups, respectively (mean ± SEM; p=0.003). CONCLUSIONS: Tibial anatomic morphology impacts isolated tibial endovascular intervention with adverse morphology associated with poorer short and long-term outcomes. Risk stratification based on anatomic predictors should be an additional consideration as one intervenes on infra-popliteal vessels for CLTI.

The effect of exercise on vascular health in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease. This increased risk cannot be fully explained by traditional risk factors such as hypertension. Endothelial dysfunction and arterial stiffness have been suggested as factors that explain some of the increased risk and are independently associated with important cardiovascular outcomes in patients with CKD. Studies in other disease populations have shown the positive effects of exercise on vascular dysfunction. The aim of this review was to determine whether exercise training interventions improve measures of vascular function and morphology in patients across the spectrum of CKD and which exercise training interventions are most efficacious. A systematic search of Medline, Embase, and the Cochrane Central Register identified 25 randomized controlled trials. Only randomized control trials using an exercise intervention with a nonexercising control group and at least one measure of vascular function or morphology were included. Participants were patients with nondialysis CKD or transplant patients or those requiring dialysis therapy. A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A meta-analysis was completed for pulse wave velocity, augmentation index, and measures of endothelium-dependent vasodilation. Data from 25 studies with 872 participants showed that exercise training reduced pulse wave velocity and augmentation index but had no effect on endothelium-dependent vasodilation. Subgroup analyses suggested that exercise interventions of at least moderate intensity were more likely to be effective. Limitations included the absence of observational studies or other interventions aimed at increasing habitual physical activity. Further studies are warranted to investigate which are the most effective exercise interventions.NEW & NOTEWORTHY A thorough systematic review and meta-analysis of the effects of exercise training on measures of vascular function in patients with chronic kidney disease, including arterial stiffness and endothelial function, were conducted. Subgroup analyses investigated how differences in exercise training, according to frequency, intensity, type, and timing, have an impact on the efficacy of the intervention.

Promiscuous evolution of Group A Streptococcal M and M-like proteins.

Group A Streptococcus (GAS) M and M-like proteins are essential virulence factors and represent the primary epidemiological marker of this pathogen. Protein sequences encoding 1054 M, Mrp and Enn proteins, from 1668 GAS genomes, were analysed by SplitsTree4, partitioning around medoids and co-occurrence. The splits network and groups-based analysis of all M and M-like proteins revealed four large protein groupings, with multiple evolutionary histories as represented by multiple edges for most splits, leading to 'M-family-groups' (FG) of protein sequences: FG I, Mrp; FG II, M protein and Protein H; FG III, Enn; and FG IV, M protein. M and Enn proteins formed two groups with nine sub-groups and Mrp proteins formed four groups with ten sub-groups. Discrete co-occurrence of M and M-like proteins were identified suggesting that while dynamic, evolution may be constrained by a combination of functional and virulence attributes. At a granular level, four distinct family-groups of M, Enn and Mrp proteins are observable, with Mrp representing the most genetically distinct of the family-group of proteins. While M and Enn protein families generally group into three distinct family-groups, horizontal and vertical gene flow between distinct GAS strains is ongoing.

Contact force and catheter stability are predictive metrics of successful pulmonary vein isolation with high-power short duration ablation in atrial fibrillation.

INTRODUCTION: Preliminary data suggest that high power short duration (HPSD) ablation for pulmonary vein isolation (PVI) are safe. Limited data are available on its effectiveness. Aim was to evaluate HPSD ablation in atrial fibrillation ablation using a novel Qdot Micro catheter. METHODS AND RESULTS: Prospective multicenter study evaluating safety and efficacy of PVI with HPSD ablation. First pass isolation (FPI) and sustained PVI was assessed. If FPI was not achieved additional ablation index (AI)-guided ablation with 45 W was performed and metrics predictive of this were determined. Sixty-five patients and 260 veins were treated. Procedural and LA dwell time was 93.9 ± 30.4 and 60.5 ± 23.1 min, respectively. FPI was achieved in 47 (72.3%) patients and 231 veins (88.8%) with an ablation duration of 4.6 ± 1.0 min. Twenty-nine veins required additional AI-guided ablation to achieve initial PVI with 24 anatomical sites ablated with the right posterior carina being the most common site (37.5%). A contact force of ≥8 g (area under the curve [AUC]: 0.81; p < 0.001) and catheter position variation of ≤1.2 mm (AUC: 0.79; p < 0.001) with HPSD were strongly predictive of not requiring additional AI-guided ablation. Out of the 260 veins, only 5 (1.9%) veins showed acute reconnection. HPSD ablation was associated with shorter procedure times (93.9 vs. 159.4 min; p < 0.001), ablation times (6.1 vs. 27.7 min; p < 0.001), and lower rates of PV reconnection (9.2% vs. 30.8%; p = 0.004) compared to moderate power cohort. CONCLUSIONS: HPSD ablation is an effective ablation modality which results in effective PVI whilst maintaining a safety profile. Its superiority needs to be evaluated in randomized controlled trials.

Obesity drives secondary procedures to achieve access maturation in end-stage renal disease.

BACKGROUND: Establishing long-term arteriovenous access is an important component in the long-term care of a patient with end-stage renal disease. The increasing frequency of obesity is reported to impact the access management of end-stage renal disease patients. This study aims to evaluate the outcomes of arteriovenous fistulae (AVF) in obese and nonobese patients. METHODS: A retrospective review of all patients over ten years with primary autogenous AVF (radiocephalic, brachiocephalic, and brachial-basilic) was undertaken at a single center. Patients were subcategorized by body mass index into nonobese, class I, II, and III obesity. Outcomes of maturation (successful progression to hemodialysis), reintervention, functional dialysis (continuous hemodialysis for 3 consecutive months), and patency were examined. RESULTS: From January 1999 to December 2019, 2311 patients (67% female; mean age, 61 ± 15 years) underwent primary AVF placement (12% radiocephalic, 53% brachiocephalic, and 35% brachial basilic). Forty-one percent were nonobese, 29% had class I obesity, 19% had class II obesity, and 11% had class III obesity. The majority of patients were diabetic and Hispanic. The 30-day major adverse cardiovascular event rate was elevated in class II (0.20%) and class III (0.50%) obesity compared with class I obesity (0.15%) and nonobese (0.05%). The 30-day morbidity rate was higher in all classes of obesity (0.5% vs0.3% vs 0.2% vs 0.05% for class III vs class II vs class I obesity and nonobese, respectively). Early thrombosis was significantly increased in class II (9%) and class III obesity (12%) compared with class I obesity (5%) and nonobese (3%). There was a two-fold increase in procedures to effect maturation in class II (51%) and class III (74%) obesity compared with class I obesity (22%) and nonobese (34%). Secondary patency at 3 years was significantly lower in class III (62 ± 4%) and class II (79 ± 3%) compared with class I obesity (87 ± 2%) and nonobese (93 ± 4%). All classes of obesity required significantly more secondary Interventions per year compared with nonobese (3.9 vs 3.1 vs 2.5 vs 1.4 secondary interventions per year for class III vs class II vs class I obesity and nonobese, respectively). CONCLUSIONS: Advancing obesity class is associated with an increased number of procedures to achieve AVF maturation and is associated with poorer patency and functionality as the category of obesity advances.

An analysis of vascular surgery education publications reveals an educational shortage.

BACKGROUND: As vascular surgery training continues to evolve with the growth of integrated vascular surgery residency (0+5) programs and the consolidation of fellowship programs, optimizing all aspects of the education for vascular surgery trainees, both fellows and 0+5 residents, has become increasingly important. In the present study, we aimed to determine the prevalence, quality, and content of vascular surgery education publications across journals. METHODS: Journal websites (n = 26) and PubMed were queried to identify vascular surgery education publications from 2012 to 2021. The publications were organized into 11 content categories: (1) curriculum, (2) simulation, (3) trainee assessment, (4) program evaluation, (5) wellness/burnout, (6) diversity/inclusion, (7) mentorship/career, (8) case outcomes, (9) perceptions of training, (10) social media, and (11) other. Publication interactivity and quality were measured via PlumX data and Medical Education Research Study Quality Instrument scores. The data were analyzed via univariate analysis and linear regression. RESULTS: A total of 115 vascular surgery education publications (0.2% [interquartile range (IQR), 0.04%-0.5%] of total publications) were identified from the selected journals. The Journal of Vascular Surgery had the highest proportion (0.8%) of vascular surgery education publications, followed by the Journal of Surgical Education (0.7%) and Annals of Vascular Surgery (0.6%). Vascular surgery journals constituted most (79%) of the publications. Of the authors, 15% (IQR, 0%-25%) had a master's or doctorate degree in education. Senior authors were more often identified as male gender (77%), and more first authors (41%) were identified as female gender. An interactivity analysis showed that there were 10.3 citations (IQR, 12), 33.1 captures (IQR, 34), and 8.4 social media interactions (IQR 14) per publication. The educational quality had a median Medical Education Research Study Quality Instrument score of 11 (IQR, 9-12.5), with 49% of publications having a score greater than the median. Publications on training (44% curriculum and 20% simulation) were significantly more frequent than other topics (P < .001), with no change in the publication content over 10 years (P = .29). The volume of vascular surgery education publications did not change during the study period (P = .13) despite the ongoing changes in the educational environment. CONCLUSIONS: Despite the increasing importance placed on vascular surgery education by national vascular societies, publications on vascular surgery education have remained sparse among all journals. Also, the vascular surgery educational content has not changed during the past 10 years, with a primary focus on curriculum and simulation training. Further promotion of vascular surgery educational research is required to increase the quality, volume, and diversity of education publications.

A framework for perioperative care for lower extremity vascular bypasses: A Consensus Statement by the Enhanced Recovery after Surgery (ERAS®) Society and Society for Vascular Surgery.

The Society for Vascular Surgery and the Enhanced Recovery After Surgery (ERAS) Society formally collaborated and elected an international, multi-disciplinary panel of experts to review the literature and provide evidence-based suggestions for coordinated perioperative care for patients undergoing infrainguinal bypass surgery for peripheral artery disease. Structured around the ERAS core elements, 26 suggestions were made and organized into preadmission, preoperative, intraoperative, and postoperative sections.

Factors associated with successful median arcuate ligament release in an international, multi-institutional cohort.

OBJECTIVE: Prior research on median arcuate ligament syndrome has been limited to institutional case series, making the optimal approach to median arcuate ligament release (MALR) and resulting outcomes unclear. In the present study, we compared the outcomes of different approaches to MALR and determined the predictors of long-term treatment failure. METHODS: The Vascular Low Frequency Disease Consortium is an international, multi-institutional research consortium. Data on open, laparoscopic, and robotic MALR performed from 2000 to 2020 were gathered. The primary outcome was treatment failure, defined as no improvement in median arcuate ligament syndrome symptoms after MALR or symptom recurrence between MALR and the last clinical follow-up. RESULTS: For 516 patients treated at 24 institutions, open, laparoscopic, and robotic MALR had been performed in 227 (44.0%), 235 (45.5%), and 54 (10.5%) patients, respectively. Perioperative complications (ileus, cardiac, and wound complications; readmissions; unplanned procedures) occurred in 19.2% (open, 30.0%; laparoscopic, 8.9%; robotic, 18.5%; P < .001). The median follow-up was 1.59 years (interquartile range, 0.38-4.35 years). For the 488 patients with follow-up data available, 287 (58.8%) had had full relief, 119 (24.4%) had had partial relief, and 82 (16.8%) had derived no benefit from MALR. The 1- and 3-year freedom from treatment failure for the overall cohort was 63.8% (95% confidence interval [CI], 59.0%-68.3%) and 51.9% (95% CI, 46.1%-57.3%), respectively. The factors associated with an increased hazard of treatment failure on multivariable analysis included robotic MALR (hazard ratio [HR], 1.73; 95% CI, 1.16-2.59; P = .007), a history of gastroparesis (HR, 1.83; 95% CI, 1.09-3.09; P = .023), abdominal cancer (HR, 10.3; 95% CI, 3.06-34.6; P < .001), dysphagia and/or odynophagia (HR, 2.44; 95% CI, 1.27-4.69; P = .008), no relief from a celiac plexus block (HR, 2.18; 95% CI, 1.00-4.72; P = .049), and an increasing number of preoperative pain locations (HR, 1.12 per location; 95% CI, 1.00-1.25; P = .042). The factors associated with a lower hazard included increasing age (HR, 0.99 per increasing year; 95% CI, 0.98-1.0; P = .012) and an increasing number of preoperative diagnostic gastrointestinal studies (HR, 0.84 per study; 95% CI, 0.74-0.96; P = .012) Open and laparoscopic MALR resulted in similar long-term freedom from treatment failure. No radiographic parameters were associated with differences in treatment failure. CONCLUSIONS: No difference was found in long-term failure after open vs laparoscopic MALR; however, open release was associated with higher perioperative morbidity. These results support the use of a preoperative celiac plexus block to aid in patient selection. Operative candidates for MALR should be counseled regarding the factors associated with treatment failure and the relatively high overall rate of treatment failure.

Soft tissue tumor imaging in adults: European Society of Musculoskeletal Radiology-Guidelines 2023-overview, and primary local imaging: how and where?

OBJECTIVES: Early, accurate diagnosis is crucial for the prognosis of patients with soft tissue sarcomas. To this end, standardization of imaging algorithms, technical requirements, and reporting is therefore a prerequisite. Since the first European Society of Musculoskeletal Radiology (ESSR) consensus in 2015, technical achievements, further insights into specific entities, and the revised WHO-classification (2020) and AJCC staging system (2017) made an update necessary. The guidelines are intended to support radiologists in their decision-making and contribute to interdisciplinary tumor board discussions. MATERIALS AND METHODS: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements were scored online by level of agreement (0 to 10) during two iterative rounds. Either "group consensus," "group agreement," or "lack of agreement" was achieved. RESULTS: Eight sections were defined that finally contained 145 statements with comments. Overall, group consensus was reached in 95.9%, and group agreement in 4.1%. This communication contains the first part consisting of the imaging algorithm for suspected soft tissue tumors, methods for local imaging, and the role of tumor centers. CONCLUSION: Ultrasound represents the initial triage imaging modality for accessible and small tumors. MRI is the modality of choice for the characterization and local staging of most soft tissue tumors. CT is indicated in special situations. In suspicious or likely malignant tumors, a specialist tumor center should be contacted for referral or teleradiologic second opinion. This should be done before performing a biopsy, without exception. CLINICAL RELEVANCE: The updated ESSR soft tissue tumor imaging guidelines aim to provide best practice expert consensus for standardized imaging, to support radiologists in their decision-making, and to improve examination comparability both in individual patients and in future studies on individualized strategies. KEY POINTS: • Ultrasound remains the best initial triage imaging modality for accessible and small suspected soft tissue tumors. • MRI is the modality of choice for the characterization and local staging of soft tissue tumors in most cases; CT is indicated in special situations. Suspicious or likely malignant tumors should undergo biopsy. • In patients with large, indeterminate or suspicious tumors, a tumor reference center should be contacted for referral or teleradiologic second opinion; this must be done before a biopsy.