Transcatheter Arterialization of Deep Veins in Chronic Limb-Threatening Ischemia.

BACKGROUND: Approximately 20% of patients with chronic limb-threatening ischemia have no revascularization options, leading to above-ankle amputation. Transcatheter arterialization of the deep veins is a percutaneous approach that creates an artery-to-vein connection for delivery of oxygenated blood by means of the venous system to the ischemic foot to prevent amputation. METHODS: We conducted a prospective, single-group, multicenter study to evaluate the effect of transcatheter arterialization of the deep veins in patients with nonhealing ulcers and no surgical or endovascular revascularization treatment options. The composite primary end point was amputation-free survival (defined as freedom from above-ankle amputation or death from any cause) at 6 months, as compared with a performance goal of 54%. Secondary end points included limb salvage, wound healing, and technical success of the procedure. RESULTS: We enrolled 105 patients who had chronic limb-threatening ischemia and were of a median age of 70 years (interquartile range, 38 to 89). Of the patients enrolled, 33 (31.4%) were women and 45 (42.8%) were Black, Hispanic, or Latino. Transcatheter arterialization of the deep veins was performed successfully in 104 patients (99.0%). At 6 months, 66.1% of the patients had amputation-free survival. According to Bayesian analysis, the posterior probability that amputation-free survival at 6 months exceeded a performance goal of 54% was 0.993, which exceeded the prespecified threshold of 0.977. Limb salvage (avoidance of above-ankle amputation) was attained in 67 patients (76.0% by Kaplan-Meier analysis). Wounds were completely healed in 16 of 63 patients (25%) and were in the process of healing in 32 of 63 patients (51%). No unanticipated device-related adverse events were reported. CONCLUSIONS: We found that transcatheter arterialization of the deep veins was safe and could be performed successfully in patients with chronic limb-threatening ischemia and no conventional surgical or endovascular revascularization treatment options. (Funded by LimFlow; PROMISE II study ClinicalTrials.gov number, NCT03970538.).

Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology.

BACKGROUND: Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN). METHODS: Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants (n: FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause. RESULTS: ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome-derived histidine metabolites. CONCLUSION: ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome-derived histidine metabolites are associated with OU.

MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

Determining Collision Cross Sections from Differential Ion Mobility Spectrometry.

The experimental determination of ion-neutral collision cross sections (CCSs) is generally confined to ion mobility spectrometry (IMS) technologies that operate under the so-called low-field limit or those that enable empirical calibration strategies (e.g., traveling wave IMS; TWIMS). Correlation of ion trajectories to CCS in other non-linear IMS techniques that employ dynamic electric fields, such as differential mobility spectrometry (DMS), has remained a challenge since its inception. Here, we describe how an ion's CCS can be measured from DMS experiments using a machine learning (ML)-based calibration. The differential mobility of 409 molecular cations (m/z: 86-683 Da and CCS 110-236 Å2) was measured in a N2 environment to train the ML framework. Several open-source ML routines were tested and trained using DMS-MS data in the form of the parent ion's m/z and the compensation voltage required for elution at specific separation voltages between 1500 and 4000 V. The best performing ML model, random forest regression, predicted CCSs with a mean absolute percent error of 2.6 ± 0.4% for analytes excluded from the training set (i.e., out-of-the-bag external validation). This accuracy approaches the inherent statistical error of ∼2.2% for the MobCal-MPI CCS calculations employed for training purposes and the <2% threshold for matching literature CCSs with those obtained on a TWIMS platform.

Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension.

RATIONALE: BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH. OBJECTIVES: To determine how an acquired deficiency of BMP9 signaling might contribute to PAH. METHODS: Plasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. MEASUREMENTS AND MAIN RESULTS: BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone. CONCLUSIONS: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.

Novel laser-based catheter for peripheral atherectomy: 6-month results from the Eximo Medical B-Laser™ IDE study.

BACKGROUND: The B-Laser™ atherectomy system (Eximo Medical, Israel) is a 355 nm solid-state Nd:YAG short pulse laser for de-novo and restenotic infrainguinal PAD with enhanced affinity for atheroma and calcified plaque. METHODS: The study was a prospective, single-arm, multi-center, international, open-label study assessing the B-Laser™ in symptomatic (Rutherford 2 to 4) infrainguinal peripheral artery disease. Primary core lab efficacy was mean reduction in diameter stenosis >20% by the B-Laser™ catheter alone. Cardiovascular death, major amputation, target lesion revascularization, WIQ, ABI and Rutherford class were obtained at baseline and out to 6 months. Duplex ultrasound patency (PSVR <2.5), was evaluated by Core Lab. RESULTS: 97 (77 in USA) PAD subjects (51 male, mean 70.5 years [range 46-86]) with 107 lesions were treated with B-Laser™ (average length 5.4 cm [range 1-24], 29.0% infrapopliteal. 77.6% calcification [26.2% severe], 21.5% chronic total occlusions, 20.6% re-stenotic). Average reduction in residual stenosis post B-Laser™ alone was 33.6 ± 14.2%. Baseline and final stenosis (post laser and adjunctive therapy) were 85.7 ± 12.2% and 17.7 ± 11.0%, respectively. Duplex patency was 96.8% at 30-days and 85.6% at 6 months (95.7% 6-month patency with severe calcification), and did not differ between POBA vs. DCB sub-groups. ABI, Rutherford category and WIQ all improved. There was one MAE and three TLRs out of 101 lesions. No procedural distal embolization was noted and there were no major device-related dissections. CONCLUSIONS: Experience with the B-Laser™ atherectomy system in infrainguinal PAD procedures demonstrates a high level of safety and efficacy for denovo and restenotic infrainguinal arterial lesions.

Atherosclerotic cardiovascular disease in women with endometriosis: a systematic review of risk factors and prospects for early surveillance.

Endometriosis and atherosclerotic cardiovascular disease (ASCVD) share similar pathogenic mechanisms. Hence, this systematic review evaluates the association between endometriosis and lifetime ASCVD risk including co-prevalence with dyslipidaemia, atherosclerosis and non-invasive markers of endothelial dysfunction. The electronic databases Embase, PubMed, MEDLINE, Cochrane Register of Trials and ClinicalTrials.gov were systematically searched for relevant articles. Two prospective cohort studies demonstrated an increased lifetime ASCVD risk after controlling for demographic and lifestyle confounders in women with endometriosis, as measured by higher incidence of myocardial infarction (relative risk [RR] 1.52), angiography-confirmed angina (RR 1.91), or requiring coronary artery bypass graft surgery (RR 1.35). Among 10 studies that included 407 patients with surgically proven endometriosis and 557 controls, RR of developing hypercholesterolemia and hypertension were 1.25 and 1.14, respectively, while higher serum lipoprotein a and lower paraoxonase 1 levels were found in women with endometriosis that was negatively correlated with stage of disease (r = -0.74, P < 0.0001). Hence, currently available evidence suggests that women with endometriosis are at higher lifetime risk of developing ASCVD than women without endometriosis. However, robust causal evidence is still lacking and future studies are needed to determine whether women with endometriosis represent a high-risk population for lifelong ASCVD risk.

Multidisciplinary Care for Critical Limb Ischemia: Current Gaps and Opportunities for Improvement.

Critical limb ischemia (CLI), defined as ischemic rest pain or nonhealing ulceration due to arterial insufficiency, represents the most severe and limb-threatening manifestation of peripheral artery disease. A major challenge in the optimal treatment of CLI is that multiple specialties participate in the care of this complex patient population. As a result, the care of patients with CLI is often fragmented, and multidisciplinary societal guidelines have not focused specifically on the care of patients with CLI. Furthermore, multidisciplinary care has the potential to improve patient outcomes, as no single medical specialty addresses all the facets of care necessary to reduce cardiovascular and limb-related morbidity in this complex patient population. This review identifies current gaps in the multidisciplinary care of patients with CLI, with a goal toward increasing disease recognition and timely referral, defining important components of CLI treatment teams, establishing options for revascularization strategies, and identifying best practices for wound care post-revascularization.

Assessing Prognosis of Acute Coronary Syndrome in Recent Clinical Trials: A Systematic Review.

There is no recent comprehensive overview of contemporary clinical trials assessing short and long-term outcomes in patients with acute coronary syndrome (ACS). This paper reviews factors from recent clinical trials that influenced prognosis in patients with ACS. Cochrane and PubMed databases were screened systematically for clinical trials published in the English literature reporting on ACS prognosis. Two authors independently screened titles, abstracts, and full text. Studies meeting inclusion criteria evaluated the impact of modern practice on prognosis. In vitro and animal models studies, conference abstracts, imaging studies, and review articles were excluded. Disagreement in inclusion criteria was resolved by consensus. A large study of 8,859 patients showed no difference in all-cause mortality between 31 days and 2 years in patients with ST segment elevation myocardial infarction (STEMI) compared to those with non-ST segment elevation myocardial infarction (NSTEMI) or stable ischemic heart disease (SIHD). Other studies showed a significant increase in all-cause mortality in patients with STEMI within the first 30 days, with NSTEMI patients exhibiting a higher mortality rate compared to those with SIHD during the 2-year follow-up period. Our review found that women have a poorer short-term prognosis compared to men. Additionally, reports from patients receiving comprehensive and coordinated care showed longer survival rates. In view of the improved prognosis demonstrated for patients suffering from ACS, assessing prognosis in patients represents a formidable task in modern practice. Our review highlights the need for further evidence-based studies evaluating long-term outcomes on diagnostic and treatment strategies.

The first transapical transcatheter aortic valve-in-valve implantation using the J-valve system into a failed biophysio aortic prosthesis in a patient with high risk of coronary obstruction.

We report the first successful valve-in-valve (ViV) implantation into a failed Edwards Biophysio surgical prosthesis (Edwards Lifesciences, Irvine, CA) and also the first use of the J-Valve system (Jie Cheng Medical Technologies, Suzhou, China) in a ViV configuration. A 77-year old male had symptomatic severe aortic stenosis secondary to failure of a 25 mm Biophysio bioprosthetic valve implanted 11 years previously, along with concomitant coronary artery bypass grafting. Transthoracic echocardiography (TTE) revealed calcified leaflets, a mean aortic gradient of 50 mm Hg, and an estimated valve area of 0.9 cm2 with no aortic insufficiency. The patient had low coronary ostial height with the right coronary artery arising only 8.5 mm from the valve annulus and the left main coronary artery arising only 9.4 mm from the valve annulus. Risk of coronary ostial obstruction was especially concerning in context of both the patient's extremely low coronary ostial height and the unique structure of the Biophysio valve. Under general anesthesia, transapical transcatheter aortic ViV implantation with a 25 mm J-Valve was performed in a hybrid operating room. The J-Valve prosthesis was deployed in the 25 mm Biophysio surgical valve without difficulty or complications. There were no intraoperative or postoperative complications. The patient was discharged home after 3 days. TTE at 1 year showed a mean aortic valve gradient of 14 mm Hg, and no aortic insufficiency. This case demonstrated that J-Valve implantation may be a new option for patients at high risk for coronary obstruction.

Impact of diabetes mellitus on procedural and one year clinical outcomes following treatment of severely calcified coronary lesions with the orbital atherectomy system: A subanalysis of the ORBIT II study.

OBJECTIVES: The goal of the study was to investigate the safety and efficacy of the coronary orbital atherectomy system to treat severe coronary artery calcification (CAC) prior to stent placement in diabetic and non-diabetic patients. BACKGROUND: The ORBIT II study reported the safety and efficacy of orbital atherectomy treatment in 443 patients with severe CAC. Percutaneous coronary intervention in diabetic patients is associated with an increased risk of major adverse cardiac events (MACE) compared with non-diabetics. The outcomes of diabetic patients who undergo orbital atherectomy are unknown. METHODS: Patients were sub-grouped as either diabetic (160/443, 36.1%) or non-diabetic (283/443, 63.9%). The MACE rate, defined as cardiac death, myocardial infarction (MI; CK-MB > 3X ULN), and target vessel revascularization, was examined at 30 days and 1 year after treatment. RESULTS: Procedural success was similar in the diabetic and non-diabetic groups (89.3 vs. 88.6%, P = 0.88). There was no significant difference in the 30-day and 1-year MACE rates between the diabetic and non-diabetic groups (30 day: 8.8 vs. 11.3%; P = 0.40; 1 year: 17.1 vs. 16.7%, P = 0.97). The individual components of cardiac death (3.9 vs. 2.9%, P = 0.58), MI (9.4 vs. 11.3%, P = 0.52), and target vessel revascularization (5.9 vs. 5.8%, P = 0.99) were also similar in both groups at 1 year. CONCLUSIONS: The rates of adverse clinical events in diabetic patients who underwent orbital atherectomy were low and similar to non-diabetic patients. This study suggests orbital atherectomy is a reasonable treatment strategy for diabetic patients with severe CAC.

Food insecurity is associated with prediabetes and dietary differences in U.S. adults aged 20-39.

Food insecurity has been linked with lifestyle and metabolic health differences in varying populations. We sought to assess how food insecurity may have been associated with prediabetes and dietary differences in a relatively young subset of U.S. adults. We examined data from the United States National Health and Nutrition Examination Survey (2003-2014) participants aged 20-39 with complete data regarding food insecurity and metabolic laboratory assessment. We also assessed macronutrient intake and Supplemental Nutrition Assistance Program (SNAP) usage. All logistic regression models controlled for age, sex, and household income. Among 3684 included participants, food insecurity had 19.12% (95% confidence interval [95%CI]: 16.16, 22.08) prevalence. Food-insecure participants had prediabetes/diabetes prevalence of 37.36% (95%CI: 30.47, 44.25) and higher odds of having prediabetes/diabetes (adjusted odds ratio [aOR] = 1.36, 95%CI: 1.00, 1.85). Food-insecure adults has significantly different macronutrient intake: higher carbohydrates (p = 0.02), less protein (p = 0.01), and less total fat (p = 0.04) consumption. Food-insecure adults who used SNAP (compared to food-insecure adults who did not use SNAP) had higher odds of having metabolic syndrome (ATP-III MetS) (aOR = 2.56, 95%CI: 1.27, 5.22). We found that food insecurity was relatively prevalent in this subset of younger U.S. adults. We showed that food-insecure participants had increased prevalence and odds of prediabetes. These associations were also correlated with dietary differences.

Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,5-a]pyrimidines as potent and selective ALK2 inhibitors.

The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties.

ORBIT II sub-analysis: Impact of impaired renal function following treatment of severely calcified coronary lesions with the Orbital Atherectomy System.

OBJECTIVES: To investigate the safety and efficacy of the coronary Orbital Atherectomy System (OAS) to prepare severely calcified lesions for stent deployment in patients grouped by renal function. BACKGROUND: Percutaneous coronary intervention (PCI) of severely calcified lesions is associated with increased rates of major adverse cardiac events (MACE), including death, myocardial infarction (MI), and target vessel revascularization (TVR) compared with PCI of non-calcified vessels. Patients with chronic kidney disease (CKD) are at increased risk for MACE after PCI. The impact of CKD on coronary orbital atherectomy treatment has not been well characterized. METHODS: ORBIT II was a prospective, multicenter trial in the U.S., which enrolled 443 patients with severely calcified coronary lesions. The MACE rate was defined as a composite of cardiac death, MI, and target vessel revascularization. RESULTS: Of the 441 patients enrolled with known estimated glomerular filtration rate (eGFR) values at baseline, 333 (75.5%) patients had eGFR < 90 ml/min/1.73 m2 and 108 patients had eGFR ≥ 90 ml/min/1.73 m2 . The mean eGFR at baseline in the eGFR < 90 ml/min/1.73 m2 and eGFR ≥ 90 ml/min/1.73 m2 groups was 65.0 ± 0.9 ml/min/1.73 m2 and 109.1 ± 2.0 ml/min/1.73 m2 , respectively. Freedom from MACE was lower in the eGFR < 90 ml/min/1.73 m2 group at 30 days (87.4% vs. 96.3%, P = 0.02) and 1-year (80.6% vs. 90.7%, P = 0.02). CONCLUSIONS: Patients with renal impairment had a higher MACE rate through one year follow-up due to a higher rate of periprocedural MI. Interestingly, the rates of cardiac death and revascularization through 1-year were similar in patients with eGFR < 90 ml/min/1.73 m2 and eGFR ≥ 90 ml/min/1.73 m2 . Future studies are needed to identify the ideal revascularization strategy for patients with renal impairment and severely calcified coronary lesions. © 2016 Wiley Periodicals, Inc.

Metabolic risk factors in nondiabetic adolescents with glomerular hyperfiltration.

BACKGROUND: In adults, glomerular hyperfiltration is associated with abnormalities related to metabolic syndrome (MetS). We investigated if glomerular hyperfiltration was associated with metabolic abnormalities in US adolescents without diabetes. METHODS: We analyzed data from the National Health and Nutrition Examination Survey, a nationally representative sample of US adolescents ages 12-17 years. Estimated glomerular filtration rate (eGFR) was determined using the bedside Schwartz equation; adolescents with hyperfiltration (eGFR >120 mL/min/1.73 m 2 ) were compared to those with normal eGFR (90-120 mL/min/1.73 m 2 ). We calculated mean levels of factors related to MetS, insulin resistance and diabetes risk, adjusting for age, race/ethnicity, sex, socioeconomic status, and BMI z -score. RESULTS: Overall, 11.8% of US adolescents had hyperfiltration [95% confidence interval (CI) 10.6-13.0]. Hyperfiltration prevalence varied by race (20.2% in Hispanics versus 9.8% non-Hispanic whites and 7.4% non-Hispanic blacks; P< 0.001). Compared to those with normal eGFR, adolescents with hyperfiltration had higher adjusted mean levels of triglyceride (83 versus 77 mg/dL; P = 0.05), fasting insulin (15.1 versus 12.9; P< 0.001) and homeostatic model assessment of insulin resistance (3.52 versus 3.01; P = 0.001). These differences persisted after adjusting for BMI z- score. Adolescents with hyperfiltration had increased odds for hypertriglyceridemia [odds ratio 1.58 (95% CI 1.11-2.23)]. These relationships varied by racial/ethnic group. CONCLUSIONS: Glomerular hyperfiltration is associated with hypertriglyceridemia and increased insulin resistance independent of BMI z- score in a nationally representative sample of US adolescents. Hispanic adolescents are more likely to have hyperfiltration than other racial/ethnic groups. These findings could have significance in evaluations of renal function and MetS in adolescents to identify related risks and target interventions.

Gender differences in acute and 30-day outcomes after orbital atherectomy treatment of de novo, severely calcified coronary lesions.

OBJECTIVES: The aim of this analysis is to evaluate potential differences according to gender in terms of acute and 30-day clinical outcomes in patients enrolled in the ORBIT II trial with de novo, severely calcified coronary lesions treated with orbital atherectomy to facilitate stent delivery. BACKGROUND: Previous studies have shown an increased risk of safety events in females compared to males undergoing percutaneous coronary intervention. METHODS: ORBIT II, a prospective, nonrandomized, multicenter, single arm study conducted in the US evaluated the safety and efficacy of the coronary OAS to facilitate stent placement in de novo, severely calcified coronary lesions in 443 subjects (286 males and 157 females). The rate of major adverse cardiac events (MACE) defined as a composite of myocardial infarction, target vessel revascularization, and cardiac death was evaluated in-hospital and 30-days postprocedure. For this analysis, the ORBIT II safety and efficacy results were stratified by gender. RESULTS: At baseline, females were significantly older than males and had a lower mean estimated glomerular filtration rate. Males had a higher rate of previous coronary artery bypass grafting and history of smoking. The rates of successful stent delivery and <50% residual stenosis were similar in males and females. In-hospital and 30-day MACE rates did not differ by gender. CONCLUSIONS: Despite females being older, having smaller arteries, and more renal dysfunction, preparation of severely calcified coronary lesions with orbital atherectomy to facilitate stent deployment results in similar rates of in-hospital and 30-day MACE, irrespective of gender.

Two-year outcomes after treatment of severely calcified coronary lesions with the orbital atherectomy system and the impact of stent types: Insight from the ORBIT II trial.

OBJECTIVES: We report 2-year outcomes of the Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions (ORBIT II) trial, with emphasis on the impact of stent type. BACKGROUND: The ORBIT II trial demonstrated the safety and efficacy of the Diamondback 360° Coronary Orbital Atherectomy System (OAS; Cardiovascular Systems, Inc., St. Paul, MN) in the treatment of de novo, severely calcified coronary lesions. METHODS: ORBIT II was a single-arm trial that enrolled 443 subjects with severely calcified lesions at 49 US sites. All patients were intended to be treated with OAS before stent implantation. The primary safety endpoint was 30-day major adverse cardiac events (MACE: Cardiac death, myocardial infarction, or target vessel revascularization). For the purpose of this study, we divided patients into three groups according to the type of stent implanted (i.e., bare metal stent [BMS], first-generation drug-eluting stent [DES], or second-generation DES). The 2-year MACE rate and its components were compared between groups. RESULTS: In the ORBIT II study cohort, 2-year rates of MACE, cardiac death, and target vessel revascularization were 19.4%, 4.3%, and 8.1%, respectively. Two year data were available in 419 of 443 patients (94.6%) with median follow up time of 25.1 months. Stent-type data were available in 435 of the 443 patients (98.2%). Six patients received stents of more than one type and were excluded from the stent type comparisons. Among the 429 patients included in the stent comparison analyses, 43 patients (10.0%) received BMS, 74 (17.2%) received first-generation DES, and 312 (72.7%) received second-generation DES. The 1 and 2-year target lesion revascularization rates were lower among patients receiving first-generation (1.4% and 6.3%) and second-generation (3.9% and 5.0%) DES compared to patients receiving BMS (15.3% and 15.3%), respectively (1 year: P = 0.007; 2 year: P = 0.047). Higher diameter stenosis and the use of BMS were independently associated with the occurrence of MACE and TVR at 2 years. CONCLUSIONS: OAS remained safe and effective for patients with de novo, severely calcified lesions at 2 years in the ORBIT II study. Adverse ischemic events were significantly higher with BMS compared with DES. © 2016 Wiley Periodicals, Inc.

Factors influencing Recombinase polymerase amplification (RPA) assay outcomes at point of care.

Recombinase Polymerase Amplification (RPA) can be used to detect pathogen-specific DNA or RNA in under 20 min without the need for complex instrumentation. These properties enable its potential use in resource limited settings. However, there are concerns that deviations from the manufacturer's protocol and/or storage conditions could influence its performance in low resource settings. RPA amplification relies upon viscous crowding agents for optimal nucleic acid amplification, and thus an interval mixing step after 3-6 min of incubation is recommended to distribute amplicons and improve performance. In this study we used a HIV-1 RPA assay to evaluate the effects of this mixing step on assay performance. A lack of mixing led to a longer time to amplification and inferior detection signal, compromising the sensitivity of the assay. However lowering the assay volume from 50 µL to 5 µL showed similar sensitivity with or without mixing. We present the first peer-reviewed study that assesses long term stability of RPA reagents without a cold chain. Reagents stored at -20 °C, and 25 °C for up to 12 weeks were able to detect 10 HIV-1 DNA copies. Reagents stored at 45 °C for up to 3 weeks were able to detect 10 HIV-1 DNA copies, with reduced sensitivity only after >3 weeks at 45 °C. Together our results show that reducing reaction volumes bypassed the need for the mixing step and that RPA reagents were stable even when stored for 3 weeks at very high temperatures.

Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings.

In recent years, an increasing amount of literature is emerging on candidate urine and blood-based biomarkers associated with incidence and severity of preeclampsia (PE) in pregnant women. While enthusiasm on the usefulness of several of these markers in predicting PE is evolving, essentially all work so far has focused on the needs of high-resource settings and high-income countries, resulting primarily in multi-parameter laboratory assays based on proteomic and metabolomics analysis techniques. These highly complex methods, however, require laboratory capabilities that are rarely available or affordable in low-resource settings (LRS). The importance of quantifying maternal and perinatal risks and identifying which pregnancies can be safely prolonged is also much greater in LRS, where intensive care facilities that can rapidly respond to PE-related health threats for women and infants are limited. For these reasons, simple, low cost, sensitive, and specific point-of-care (POC) tests are needed that can be performed by antenatal health care providers in LRS and that can facilitate decisions about detection and management of PE. Our study aims to provide a comprehensive systematic review of current and emerging blood and urine biomarkers for PE, not only on the basis of their clinical performance, but also of their suitability to be used in LRS-compatible test formats, such as lateral flow and other variants of POC rapid assays.