A structural basis for antibody-mediated neutralization of Nipah virus reveals a site of vulnerability at the fusion glycoprotein apex.

Nipah virus (NiV) is a highly pathogenic paramyxovirus that causes frequent outbreaks of severe neurologic and respiratory disease in humans with high case fatality rates. The 2 glycoproteins displayed on the surface of the virus, NiV-G and NiV-F, mediate host-cell attachment and membrane fusion, respectively, and are targets of the host antibody response. Here, we provide a molecular basis for neutralization of NiV through antibody-mediated targeting of NiV-F. Structural characterization of a neutralizing antibody (nAb) in complex with trimeric prefusion NiV-F reveals an epitope at the membrane-distal domain III (DIII) of the molecule, a region that undergoes substantial refolding during host-cell entry. The epitope of this monoclonal antibody (mAb66) is primarily protein-specific and we observe that glycosylation at the periphery of the interface likely does not inhibit mAb66 binding to NiV-F. Further characterization reveals that a Hendra virus-F-specific nAb (mAb36) and many antibodies in an antihenipavirus-F polyclonal antibody mixture (pAb835) also target this region of the molecule. Integrated with previously reported paramyxovirus F-nAb structures, these data support a model whereby the membrane-distal region of the F protein is targeted by the antibody-mediated immune response across henipaviruses. Notably, our domain-specific sequence analysis reveals no evidence of selective pressure at this region of the molecule, suggestive that functional constraints prevent immune-driven sequence variation. Combined, our data reveal the membrane-distal region of NiV-F as a site of vulnerability on the NiV surface.

Restoration of the native humeral anatomy during stemless anatomic total shoulder arthroplasty: a radiographic comparison of intramedullary versus freehand resection.

BACKGROUND: During anatomic total shoulder arthroplasty (aTSA), the humeral head can be resected with or without the use of an intramedullary cutting guide, the former referred to as intramedullary (IM) resection and the latter referred to as freehand (FH) resection. Outcomes following aTSA are predicated upon the restoration of the native humeral anatomy, which can be more challenging with stemless implants. To date, no studies have determined which method of humeral head resection is superior in restoring native anatomy. Our purpose was to determine whether FH or IM resection was superior in restoring native anatomy during aTSA with stemless implants. METHODS: A review of all patients who underwent aTSA using the stemless Tornier Simpliciti Shoulder System at two academic institutions by two separate surgeons between January 2017 and June 2020 was performed. One surgeon at one institution performed stemless aTSA using the IM resection technique, while the second surgeon utilized the FH resection technique. Patients were excluded if they underwent surgery for an indication other than glenohumeral osteoarthritis, if they received a short-stem or standard-stem implant, or if they lacked adequate preoperative and postoperative Grashey radiographs. One hundred eleven patients across both institutions (51 IM, 60 FH) were included for the final radiographic assessment. The humeral head height (HH) and neck-shaft angle (NSA) were measured on preoperative and postoperative Grashey radiographs. The centers of rotation (CORs) were measured on postoperative Grashey radiographs. Patients were classified as having acceptable restoration of their native anatomy if the change (Δ) in COR or HH was ≤3 mm and ≤ 5 mm, respectively, or if the postoperative NSA was ≥130°. RESULTS: IM resection had the greatest acceptable restoration of COR (90.2% IM versus 70% FH, P = .009), HH (96.1% IM vs. 63.3% FH, P < .001), and NSA (96.1% IM vs. 78.3% FH, P = .006) relative to FH resection. The mean postoperative NSAs for the IM and FH cohorts were 134.4° (±2.1°) and 133.8° (±5.4°), respectively (P = .208). The mean ΔCORs for the IM and FH groups were 1.2 (±1.5) and 2.3 (±1.2) mm, respectively (P < .001). Finally, the mean ΔHHs for the IM and FH cohorts were 1.7 (±1.4) and 4.4 (±2.9) mm, respectively (P < .001). CONCLUSIONS: Restoration of the native humeral anatomy following stemless aTSA occurred at a significantly higher rate when using IM vs. FH resection.

Evolutionary Analyses of Base-Pairing Interactions in DNA and RNA Secondary Structures.

Pairs of nucleotides within functional nucleic acid secondary structures often display evidence of coevolution that is consistent with the maintenance of base-pairing. Here, we introduce a sequence evolution model, MESSI (Modeling the Evolution of Secondary Structure Interactions), that infers coevolution associated with base-paired sites in DNA or RNA sequence alignments. MESSI can estimate coevolution while accounting for an unknown secondary structure. MESSI can also use graphics processing unit parallelism to increase computational speed. We used MESSI to infer coevolution associated with GC, AU (AT in DNA), GU (GT in DNA) pairs in noncoding RNA alignments, and in single-stranded RNA and DNA virus alignments. Estimates of GU pair coevolution were found to be higher at base-paired sites in single-stranded RNA viruses and noncoding RNAs than estimates of GT pair coevolution in single-stranded DNA viruses. A potential biophysical explanation is that GT pairs do not stabilize DNA secondary structures to the same extent that GU pairs do in RNA. Additionally, MESSI estimates the degrees of coevolution at individual base-paired sites in an alignment. These estimates were computed for a SHAPE-MaP-determined HIV-1 NL4-3 RNA secondary structure. We found that estimates of coevolution were more strongly correlated with experimentally determined SHAPE-MaP pairing scores than three nonevolutionary measures of base-pairing covariation. To assist researchers in prioritizing substructures with potential functionality, MESSI automatically ranks substructures by degrees of coevolution at base-paired sites within them. Such a ranking was created for an HIV-1 subtype B alignment, revealing an excess of top-ranking substructures that have been previously identified as having structure-related functional importance, among several uncharacterized top-ranking substructures.

Unique characteristics of the type B aortic dissection patients with malperfusion in the Vascular Quality Initiative.

OBJECTIVE: Type B aortic dissection (TBAD) complicated by malperfusion carries high morbidity and mortality. The present study was undertaken to compare the characteristics of malperfusion and uncomplicated cohorts and to evaluate the long-term differences in survival using a granular, national registry. METHODS: Patients with TBAD entered into the thoracic endovascular aortic repair/complex endovascular aortic repair module of the Vascular Quality Initiative from 2010 to 2019 were included. The demographic, radiographic, operative, postoperative, in-hospital, and long-term reintervention data were compared between the malperfusion and uncomplicated TBAD groups using t tests and χ2 analysis, as appropriate. Overall survival was compared using Cox regression to generate survival curves. RESULTS: Of the 2820 included patients, 2267 had uncomplicated TBAD and 553 had malperfusion. The patients with malperfusion were younger (age, 55.8 vs 61.2 years; P < .001), were more often male (79.7% vs 68.1%; P < .001), had a higher preoperative creatinine (1.8 vs 1.1 mg/dL; P < .001), had more often presented with an American Society of Anesthesiologists class of 4 or 5 (81.9% vs 58.4%; P < .001), and had more often presented with urgent status (77.4% vs 32.8%; P < .001). In contrast, the uncomplicated TBAD group had had more medical comorbidities, including coronary artery disease and chronic obstructive pulmonary disease, and a larger aortic diameter (4.0 cm vs 4.9 cm; P < .001). The malperfusion group more frequently had proximal zones of disease in zones 0 to 2 (38.6% vs 31.5%; P = .002) and distal zones of disease in zones 9 and above (78.7% vs 46.2%; P < .001), with a greater number of aortic zones traversed (7.7 vs 5.1; P < .001) and a greater frequency of dissection extension into branch vessels (61.8% vs 23.1%; P < .001). Patients with malperfusion also exhibited greater case complexity, with a greater need for branch vessel stenting and longer procedure times. The overall incidence of postoperative complications was greater in the malperfusion group (39.4% vs 17.1%; P < .001) and included a greater rate of spinal cord ischemia (6.3% vs 2.2%; P < .001), acute kidney injury (10.4% vs 0.9%; P < .001), and in-hospital mortality (11.6% vs 5.6%; P < .001). In-hospital reintervention was also greater for the malperfusion patients (14.5% vs 7.4%; P < .001), although the incidence of long-term reinterventions was similar between the two groups (8.7% vs 9.7%; P = .548). A proximal zone of disease in zone 0 to 2 was associated with decreased survival. In contrast, a distal zone of disease in 9 and above, in-hospital reintervention, and long-term follow-up were associated with increased survival. Despite these differences, long-term survival did not differ between the malperfusion and uncomplicated groups (P = .320.) CONCLUSIONS: Patients presenting with TBAD and malperfusion represent a unique cohort. Despite the greater need for branch vessel stenting and in-hospital reintervention, they had similar long-term reintervention rates and survival compared with those with uncomplicated TBAD. These data lend insight with regard to the observed differences between uncomplicated and malperfusion TBAD.

Effects of dual antiplatelet therapy on graft patency after lower extremity bypass.

OBJECTIVE: Current guidelines recommend single-agent antiplatelet therapy for patients with symptomatic peripheral artery disease and consideration of dual antiplatelet therapy (DAPT) after surgical revascularization. The objective of this study was both to explore prescribing patterns of single antiplatelet therapy vs DAPT after lower extremity bypass surgery and to investigate the effects of antiplatelet therapy on bypass graft patency. METHODS: A retrospective analysis of prospectively collected nonemergent infrainguinal lower extremity bypass operations entered in the national Vascular Quality Initiative (2003-2018) with captured long-term follow-up was performed. Patients discharged on aspirin monotherapy or DAPT were identified. Linear regression investigated temporal trends in antiplatelet use. Multivariable Cox regression investigated predictors of primary, primary assisted, and secondary patency. RESULTS: Of the 13,020 patients investigated, 52.2% were discharged on aspirin monotherapy and 47.8% on DAPT. The proportion of patients discharged on DAPT increased from 10.6% in 2003 to 60.6% in 2018 (P < .001). The DAPT cohort was younger, had higher rates of medical (hypertension, diabetes, congestive heart failure, chronic obstructive pulmonary disease) and atherosclerotic (coronary artery disease, prior coronary artery bypass graft or percutaneous coronary intervention, prior lower extremity intervention) comorbidities, and had higher risk bypass procedures (more distal targets, prior inflow bypass procedure, prosthetic conduit use). Multivariable Cox regression analysis did not show any difference between the DAPT and aspirin cohorts in primary patency (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.88-1.10; P = .78), primary assisted patency (HR, 0.93; 95% CI, 0.80-1.07; P = .30), or secondary patency (HR, 0.88; 95% CI, 0.74-1.06; P = .18). On subgroup analysis based on bypass conduit, DAPT was found to have a protective effect on patency only in the prosthetic bypass cohort (primary patency: HR, 0.81 [95% CI, 0.66-1.00; P = .05]; primary assisted patency: HR, 0.74 [95% CI, 0.58-0.94; P = .01]; and secondary patency: HR, 0.60 [95% CI, 0.44-0.82; P < .001]). No patency differences were observed on adjusted subgroup analysis for the other bypass conduits. CONCLUSIONS: A significant and increasing proportion of patients are discharged on DAPT after lower extremity bypass revascularization. These patients represent a higher risk cohort with more medical comorbidities and higher risk bypass features. After controlling for these differences, DAPT therapy had no beneficial effect on overall bypass graft patency or major adverse limb events. However, on subgroup analysis, DAPT was associated with improved bypass graft patency in patients receiving prosthetic bypass conduits. Further study is warranted to investigate optimal duration of DAPT therapy and its possible bleeding complications in prosthetic bypass patients.

Difference between kwashiorkor and marasmus: Comparative meta-analysis of pathogenic characteristics and implications for treatment.

Kwashiorkor and marasmus are two clinical syndromes observed in severe acute malnutrition. In this review, we highlighted the differences between these two syndromes by reviewing the data comparing kwashiorkor and marasmus in literature, combined with recent microbiological findings and meta-analysis. Depletion of antioxidants, vitamins and minerals were more severe in kwashiorkor than marasmus. This was consistent with the severe and uncontrolled oxidative stress associated with the depletion of gut anaerobes and the relative proliferation of aerotolerant gut pathogens. This relative proliferation and invasion of gut microbes belonging to the aerotolerant Proteobacteria phylum and pathogens suggested a specific microbial process critical in the pathogenesis of kwashiorkor. Liver mitochondrial and peroxisomal dysfunction could be secondary to toxic microbial compounds produced in the gut such as ethanol, lipopolysaccharides and endotoxins produced by Proteobacteria, particularly Klebsiella pneumoniae, and aflatoxin produced by Aspergillus species. The gut-liver axis alteration is characterized by oedema and a fatty and enlarged liver and was associated with a dramatic depletion of methionine and glutathione, an excessive level of free circulating iron and frequent lethal bacteraemia by enteric pathogens. This was consistent with the fact that antibiotics improved survival only in children with kwashiorkor but not marasmus. The specific pathogenic characteristics of kwashiorkor identified in this review open new avenues to develop more targeted and effective treatments for both marasmus and/or kwashiorkor. Urgent correction of plasma glutathione depletion, alongside supply of specific essential amino acids, particularly methionine and cysteine, early detection of pathogens and an antibiotic more efficient than amoxicillin in supressing gut Proteobacteria including K. pneumoniae, and probiotics to restore the human gut anaerobic mature microbiota could save many more children with kwashiorkor.

Long-read amplicon denoising.

Long-read next-generation amplicon sequencing shows promise for studying complete genes or genomes from complex and diverse populations. Current long-read sequencing technologies have challenging error profiles, hindering data processing and incorporation into downstream analyses. Here we consider the problem of how to reconstruct, free of sequencing error, the true sequence variants and their associated frequencies from PacBio reads. Called 'amplicon denoising', this problem has been extensively studied for short-read sequencing technologies, but current solutions do not always successfully generalize to long reads with high indel error rates. We introduce two methods: one that runs nearly instantly and is very accurate for medium length reads and high template coverage, and another, slower method that is more robust when reads are very long or coverage is lower. On two Mock Virus Community datasets with ground truth, each sequenced on a different PacBio instrument, and on a number of simulated datasets, we compare our two approaches to each other and to existing algorithms. We outperform all tested methods in accuracy, with competitive run times even for our slower method, successfully discriminating templates that differ by a just single nucleotide. Julia implementations of Fast Amplicon Denoising (FAD) and Robust Amplicon Denoising (RAD), and a webserver interface, are freely available.

The use of intravascular ultrasound in the treatment of type B aortic dissection with thoracic endovascular aneurysm repair is associated with improved long-term survival.

OBJECTIVE: Intravascular ultrasound (IVUS) examination is an integral technique used for treating type B aortic dissection (TBAD) because it verifies true lumen access. The purpose of this study was to evaluate the use of IVUS, to determine factors associated with IVUS use, and to investigate the potential survival benefit associated with IVUS in the treatment of TBAD. METHODS: A retrospective review of TEVARs performed for TBAD in the national Vascular Quality Initiative was performed from January 2010 to August 2018. Data collected included demographics, intraoperative and postoperative variables, and long-term mortality. Multivariable logistic regression evaluated variables associated with IVUS the use and mortality, and Cox regression was performed for adjusted survival analysis. RESULTS: In this study of 2686 patients, the average age was 60.4 years, 69.3% were male, and IVUS examination was used in 74.6% of cases. IVUS patients were younger (60.0 years vs 61.7 years; P = .004), more often male (72.1% vs 61.3%; P < .001), exhibited less coronary disease, but had higher preoperative creatinine (1.27 ± 0.89 mg/dL vs 1.14 ± 0.68 mg/dL; P < .001) and were more often treated in the acute setting (55.2% vs 49.7%; P = .03). Interestingly, there were no differences in contrast use (117.4 ± 77.6 mL vs 123.0 ± 81.90.1 mL; P = .11) or fluoroscopy time (20.3 ± 16.5 minutes vs 19.0 ± 22.1 minutes; P = .10). However, IVUS cases had a greater number of devices implanted (1.84 vs 1.65; P < .001), higher rates of Zone 0 to 2 proximal seal (43.9% vs 30.7%; P < .001), higher rates of distal seal zones beyond the diaphragm (53.9% vs 37.4%; P = .001), and larger proximal and distal graft diameters, with no differences in postoperative renal function. IVUS patients notably also had higher rates of follow-up imaging (61.3% vs 54.8%; P = .003), larger maximum aortic diameters at follow-up, and more reinterventions over time. The number of aortic devices (odds ratio [OR] 1.56; 95% confidence interval [CI], 1.24-1.97; P < .001), malperfusion indication (OR, 1.68; 95% CI, 1.17-2.42; P = .005) and distal seal zone beyond the diaphragm (OR, 1.64; 95% CI, 1.30-2.07; P < .001) were independently associated with IVUS use, whereas female gender showed a trend towards less IVUS use (OR, 0.79; 95% CI, 0.62-1.01; P = .063). Even after controlling for age, preoperative comorbidities, and postoperative complications like spinal cord ischemia, IVUS was associated with a 61% decrease in the odds of mortality (OR, 0.39; 95% CI, 0.20-0.78; P = .008), with a clear survival advantage shown in adjusted survival curves. CONCLUSIONS: IVUS examination was used in the majority of TBAD, although not universally. IVUS examination was used more often in acute TBAD and more complex aortic repairs, and was independently associated with improved long-term survival. Further study is needed to understand these patterns.

The evolution of open abdominal aortic aneurysm repair at a tertiary care center.

BACKGROUND: The characteristics of and indications for open abdominal aortic aneurysm (AAA) repair have evolved over time. We evaluated these trends through the experience at a tertiary care academic center. METHODS: A retrospective review was conducted for patients undergoing open AAA repair (inclusive of type IV thoracoabdominal aortic aneurysms) from 2005 to 2018 at an academic institution. Trends over time were evaluated using the Spearman test; Cox regression was used to determine predictors of mortality and to generate adjusted survival curves. RESULTS: There were 628 patients (71.5% male; 88.2% white) with a mean age of 70.5 ± 9.4 years who underwent open AAA repair with a mean aneurysm diameter of 6.2 ± 1.5 cm. The median length of stay was 10 days, and the median intensive care unit length of stay was 3 days. Urgent repair was undertaken in 21.1%; 22.3% were type IV thoracoabdominal aortic aneurysm repairs, and 9.9% were performed for explantation. Our series favored a retroperitoneal approach in the majority of cases (82.5%). The proximal clamp sites were supraceliac (46.1%), suprarenal (29.1%), and infrarenal (24.8%), with approximately a third requiring renal artery reimplantation. The average cross-clamp time was 25.5 ± 14.9 minutes; the mean renal ischemia time for supraceliac and suprarenal clamp sites was 28.4 ± 12.3 minutes and 23.5 ± 12.7 minutes, respectively. Postoperative renal dysfunction occurred in 19.6% of the overall cohort, with 6.2% requiring hemodialysis. Of those requiring postoperative hemodialysis, the majority (75%) received an urgent repair. The in-hospital mortality was 2.3% for elective cases vs 20.9% for urgent repair, and 29.8% of patients were discharged to rehabilitation, with an overall 30-day readmission rate of 7.9%. Over time, there were trends of increased aneurysm repair complexity, with decreasing infrarenal clamp sites, increasing supraceliac clamp sites, increasing proportion of explantations, and increasing need for bifurcated grafts. The acuity of aneurysm repair likewise changed, with the proportion of urgent repairs increasing over time, largely attributable to the rise in explantations. Clamp site influenced the frequency of perioperative complications. Urgent repairs and age at operation were associated with mortality, whereas mortality was not associated with need for explantation and clamp location. CONCLUSIONS: Aneurysm repair reflected increasing complexity over time, with the need for explantation among urgent repairs significantly on the rise. Urgency and clamp location independently predicted long-term mortality, even after adjustment for age. These findings underscore the changing landscape of open AAA repair in the current era.

Length of Stay after Thoracic Endovascular Aortic Repair Depends on Indication and Acuity.

BACKGROUND: Length of stay (LOS) is a commonly used metric to optimize value in medical care. Although pathways have been developed for some procedures in vascular surgery to reduce LOS, they do not yet exist for thoracic endovascular aortic repair (TEVAR). The purpose of this study is to identify and define the risk factors for prolonged LOS in patients undergoing TEVAR to facilitate pathway development. METHODS: We included TEVAR patients in the National Surgical Quality Improvement Program database from 2005 to 2015. Prolonged LOS was defined as LOS > 75th percentile of the overall cohort (11 days). Because initial analysis revealed the distinct clinical differences between dissection and aneurysm patients, further analysis was stratified by aortic pathology. Student's t-test and Chi-square tests were used to compare demographic and perioperative variables between dissection and aneurysm patients, respectively. Multivariable logistic regression was used to evaluate the predictors for prolonged LOS. RESULTS: A total of 3,021 patients underwent TEVAR, with 858 patients (28.4%) undergoing TEVAR for dissection and 2,163 (71.6%) undergoing TEVAR for aneurysm. An initial analysis with logistic regression identified dissection indication (odds ratio [OR], 2.87; 95% confidence interval [CI], 1.1-7.3) as an independent predictor of prolonged LOS. Further analysis for prolonged LOS was subsequently performed separating dissection and aneurysm patients. Aneurysm patients were older (71.2 ± 11.7 vs. 63.1 ± 13.6 years, P < 0.001), more often Caucasian (76.8% vs. 61.8%, P < 0.001), and had more medical comorbidities (chronic obstructive pulmonary disease, cardiac history, diabetes, peripheral vascular disease, transient ischemic attack [TIA], P < 0.001). In contrast, dissection patients had higher American Society of Anesthesiology (ASA) classification score (58.5% had >3 ASA vs. 45.5%, P < 0.001), longer hospitalizations (10.2 ± 9.3 vs. 8.5 ± 10.4 days, P < 0.001), were more likely to have been transferred from another hospital or emergency room (58.4% vs. 48.3%, P < 0.001), and were more often emergent (32.4% vs. 15.4%, P < 0.001). In dissection patients, ASA classification score (OR, 1.49; 95% CI, 1.1-2.1) and dialysis (OR, 1.98; 95% CI, 1.0-3.9) were independent predictors for prolonged LOS. In aneurysm patients, dependent functional status (OR, 2.03; 95% CI, 1.4-2.8), diabetes (OR, 1.75; 95% CI, 1.1-2.8), cardiac history (OR, 1.37; 95% CI, 1.0-1.9), emergency status (OR, 1.98; 95% CI, 1.4-2.8), and dialysis (OR, 2.08; 95% CI, 1.2-3.7) predicted prolonged LOS. Postoperative complications including stroke/TIA; failure to wean from ventilator, sepsis, and pneumonia; and need for reoperation similarly increased LOS in both dissection and aneurysm patients. CONCLUSIONS: Dissection and aneurysm patients undergoing TEVAR are comprised of different patient populations, with dissection patients more often enduring prolonged hospitalizations. In contrast, TEVAR performed for nonemergent aneurysm repair had the shortest LOS. These data support the development of separate pathways defined by indication and acuity for patients undergoing TEVAR.

A Generative Angular Model of Protein Structure Evolution.

Recently described stochastic models of protein evolution have demonstrated that the inclusion of structural information in addition to amino acid sequences leads to a more reliable estimation of evolutionary parameters. We present a generative, evolutionary model of protein structure and sequence that is valid on a local length scale. The model concerns the local dependencies between sequence and structure evolution in a pair of homologous proteins. The evolutionary trajectory between the two structures in the protein pair is treated as a random walk in dihedral angle space, which is modeled using a novel angular diffusion process on the two-dimensional torus. Coupling sequence and structure evolution in our model allows for modeling both "smooth" conformational changes and "catastrophic" conformational jumps, conditioned on the amino acid changes. The model has interpretable parameters and is comparatively more realistic than previous stochastic models, providing new insights into the relationship between sequence and structure evolution. For example, using the trained model we were able to identify an apparent sequence-structure evolutionary motif present in a large number of homologous protein pairs. The generative nature of our model enables us to evaluate its validity and its ability to simulate aspects of protein evolution conditioned on an amino acid sequence, a related amino acid sequence, a related structure or any combination thereof.

Characterization and outcomes of reinterventions in Food and Drug Administration-approved versus trial endovascular aneurysm repair devices.

OBJECTIVE: Published rates of reintervention after endovascular aneurysm repair (EVAR) range from 10% to 30%. We evaluated a single university center's experience with reinterventions in the context of Food and Drug Administration (FDA)-approved and trial devices. METHODS: Retrospective data collection was performed for patients who underwent infrarenal EVAR and required reintervention from 2000 to 2016. Trial devices included those used in FDA feasibility and pivotal trials. Time-to-event analysis was performed using Cox regression. Predictors of mortality and explantation were evaluated using logistic regression; survival analysis was performed using Kaplan-Meier methods. RESULTS: From 2000 to 2016, there were 1835 EVARs performed, and 137 patients (116 men; mean age, 72.2 ± 10.0 years) underwent reintervention with a mean aneurysm size of 5.9 ± 1.2 cm. The median follow-up was 5 years with an overall survival of 70.1%. The overall reintervention rate was 7.5%. FDA-approved devices had a reintervention rate of 6.4%, whereas trial devices had a rate of 14.4% (P < .001). For all devices, the most common cause of reintervention was type II endoleak (52.5%), followed by type I endoleak (18.2%), type III endoleak (9.5%), limb kink (7.3%), iliac occlusive disease (5.8%), endotension (1.5%), and other. The overall mean time to first reintervention was 2.3 ± 2.5 years, and univariate Cox regression identified male gender (hazard ratio, 1.91; 95% confidence interval [CI], 1.17-3.10; P = .010) and age at the time of EVAR (hazard ratio, 1.03; 95% CI, 1.01-1.05; P = .006) as risk factors for time to first reintervention. Among patients requiring reintervention, the mean number of reinterventions for trial devices was significantly greater than that for FDA-approved devices (2.18 vs 1.65; P = .01). Trial devices requiring reintervention had a nearly threefold higher odds for the need for more than two reinterventions (odds ratio, 2.88; 95% CI, 1.12-7.37; P = .034). Trial device, cause of reintervention, and type of reintervention were not predictive of the need for explantation or mortality, but the number of reinterventions was significantly associated with the need for explantation (odds ratio, 1.86; 95% CI, 1.17-2.96; P = .012). EVAR device and the need for explantation did not have an impact on mortality. CONCLUSIONS: Despite the rigorous nature of patient enrollment in clinical trials and the development of newer iterations of investigational devices, patients undergoing EVAR with trial devices are more likely to undergo a greater number of reinterventions than with FDA-approved devices. Although mortality and the need for explantation were not significantly associated with trial devices, the finding of a greater number of reinterventions highlights the need to properly inform patients willing to partake in investigational device trials.

Change in quality of malnutrition surveys between 1986 and 2015.

BACKGROUND: Representative surveys collecting weight, height and MUAC are used to estimate the prevalence of acute malnutrition. The results are then used to assess the scale of malnutrition in a population and type of nutritional intervention required. There have been changes in methodology over recent decades; the objective of this study was to determine if these have resulted in higher quality surveys. METHODS: In order to examine the change in reliability of such surveys we have analysed the statistical distributions of the derived anthropometric parameters from 1843 surveys conducted by 19 agencies between 1986 and 2015. RESULTS: With the introduction of standardised guidelines and software by 2003 and their more general application from 2007 the mean standard deviation, kurtosis and skewness of the parameters used to assess nutritional status have each moved to now approximate the distribution of the WHO standards when the exclusion of outliers from analysis is based upon SMART flagging procedure. Where WHO flags, that only exclude data incompatible with life, are used the quality of anthropometric surveys has improved and the results now approach those seen with SMART flags and the WHO standards distribution. Agencies vary in their uptake and adherence to standard guidelines. Those agencies that fully implement the guidelines achieve the most consistently reliable results. CONCLUSIONS: Standard methods should be universally used to produce reliable data and tests of data quality and SMART type flagging procedures should be applied and reported to ensure that the data are credible and therefore inform appropriate intervention. Use of SMART guidelines has coincided with reliable anthropometric data since 2007.

Severely malnourished children with a low weight-for-height have similar mortality to those with a low mid-upper-arm-circumference: II. Systematic literature review and meta-analysis.

BACKGROUND: The WHO recommended criteria for diagnosis of sever acute malnutrition (SAM) are weight-for-height/length Z-score (WHZ) of <- 3Z of the WHO2006 standards, a mid-upper-arm circumference (MUAC) of < 115 mm, nutritional oedema or any combination of these parameters. A move to eliminate WHZ as a diagnostic criterion has been made on the assertion that children with a low WHZ are healthy, that MUAC is a "superior" prognostic indicator of mortality and that adding WHZ to the assessment does not improve the prediction of death. Our objective was to examine the literature comparing the risk of death of SAM children admitted by WHZ or MUAC criteria. METHODS: We conducted a systematic search for reports which examined the relationship of WHZ and MUAC to mortality for children less than 60 months. The WHZ, MUAC, outcome and programmatic variables were abstracted from the reports and examined. Individual study's case fatality rates were compared by chi-squared analysis and random effects meta-analyses for combined data. RESULTS: Twenty-one datasets were reviewed. All the patient studies had an ascertainment bias. Most were inadequate because they had insufficient deaths, used obsolete standards, combined oedematous and non-oedematous subjects, did not report the proportion of children with both deficits or the deaths occurred remotely after anthropometry. The meta-analyses showed that the mortality risks for children who have SAM by MUAC < 115 mm only and those with SAM by WHZ < -3Z only are not different. CONCLUSIONS: As the diagnostic criteria identify different children, this analysis does not support the abandonment of WHZ as an important independent diagnostic criterion for the diagnosis of SAM. Failure to identify such children will result in their being denied treatment and unnecessary deaths from SAM.

Severely malnourished children with a low weight-for-height have a higher mortality than those with a low mid-upper-arm-circumference: III. Effect of case-load on malnutrition related mortality- policy implications.

BACKGROUND: Severe acute malnutrition (SAM) is diagnosed when the weight-for-height Z-score (WHZ) is <-3Z of the WHO2006 standards, or a mid-upper-arm circumference (MUAC) of < 115 mm or there is nutritional oedema. Although there has been a move to eliminate WHZ as a diagnostic criterion we have shown that children with a low WHZ have at least as high a mortality risk as those with a low MUAC. Here we take the estimated case fatality rates and published case-loads to estimate the proportion of total SAM related deaths occurring in children that would be excluded from treatment with a MUAC-only policy. METHODS: The effect of varying case-load and mortality rates on the proportion of all deaths that would occur in admitted children was examined. We used the same calculations to estimate the proportion of all SAM-related deaths that would be excluded with a MUAC-only policy in 48 countries with very different relative case loads for SAM by only MUAC, only WHZ and children with both deficits. The case fatality rates (CFR) are taken from simulations, empirical data and the literature. RESULTS: The relative number of cases of SAM by MUAC alone, WHZ alone and those with both criteria have a dominant effect on the proportion of all SAM-related deaths that would occur in children excluded from treatment by a MUAC-only program. Many countries, particularly in the Sahel, West Africa and South East Asia would fail to identify the majority of SAM-related deaths if a MUAC only program were to be implemented. Globally, the estimated minimum number of deaths that would occur among children excluded from treatment in our analyses is 300,000 annually. CONCLUSIONS: The number, proportion or attributable fraction of children excluded from treatment with any change of current policy are the correct indicators to guide policy change. CRFs alone should not be used to guide policy in choosing whether or not to drop WHZ as a diagnostic for SAM. All the criteria for diagnosis of malnutrition need to be retained. It is critical that methods are found to identify those children with a low WHZ, but not a low MUAC, in the community so that they will not remain undetected.

Severely malnourished children with a low weight-for-height have a higher mortality than those with a low mid-upper-arm-circumference: I. Empirical data demonstrates Simpson's paradox.

BACKGROUND: According to WHO childhood severe acute malnutrition (SAM) is diagnosed when the weight-for-height Z-score (WHZ) is <-3Z of the WHO2006 standards, the mid-upper-arm circumference (MUAC) is < 115 mm, there is nutritional oedema or any combination of these parameters. Recently there has been a move to eliminate WHZ as a diagnostic criterion on the assertion that children meeting the WHZ criterion are healthy, that MUAC is universally a superior prognostic indicator of mortality and that adding WHZ to the assessment does not improve the prediction; these assertions have lead to a controversy concerning the role of WHZ in the diagnosis of SAM. METHODS: We examined the mortality experience of 76,887 6-60 month old severely malnourished children admitted for treatment to in-patient, out-patient or supplementary feeding facilities in 18 African countries, of whom 3588 died. They were divided into 7 different diagnostic categories for analysis of mortality rates by comparison of case fatality rates, relative risk of death and meta-analysis of the difference between children admitted using MUAC and WHZ criteria. RESULTS: The mortality rate was higher in those children fulfilling the WHO2006 WHZ criterion than the MUAC criterion. This was the case for younger as well as older children and in all regions except for marasmic children in East Africa. Those fulfilling both criteria had a higher mortality. Nutritional oedema increased the risk of death. Having oedema and a low WHZ dramatically increased the mortality rate whereas addition of the MUAC criterion to either oedema-alone or oedema plus a low WHZ did not further increase the mortality rate. The data were subject to extreme confounding giving Simpson's paradox, which reversed the apparent mortality rates when children fulfilling both WHZ and MUAC criteria were included in the estimation of the risk of death of those fulfilling either the WHZ or MUAC criteria alone. CONCLUSIONS: Children with a low WHZ, but a MUAC above the SAM cut-off point are at high risk of death. Simpson's paradox due to confounding from oedema and mathematical coupling may make previous statistical analyses which failed to distinguish the diagnostic groups an unreliable guide to policy. WHZ needs to be retained as an independent criterion for diagnosis of SAM and methods found to identify those children with a low WHZ, but not a low MUAC, in the community.

Functionally conserved architecture of hepatitis C virus RNA genomes.

Hepatitis C virus (HCV) infects over 170 million people worldwide and is a leading cause of liver disease and cancer. The virus has a 9,650-nt, single-stranded, messenger-sense RNA genome that is infectious as an independent entity. The RNA genome has evolved in response to complex selection pressures, including the need to maintain structures that facilitate replication and to avoid clearance by cell-intrinsic immune processes. Here we used high-throughput, single-nucleotide resolution information to generate and functionally test data-driven structural models for three diverse HCV RNA genomes. We identified, de novo, multiple regions of conserved RNA structure, including all previously characterized cis-acting regulatory elements and also multiple novel structures required for optimal viral fitness. Well-defined RNA structures in the central regions of HCV genomes appear to facilitate persistent infection by masking the genome from RNase L and double-stranded RNA-induced innate immune sensors. This work shows how structure-first comparative analysis of entire genomes of a pathogenic RNA virus enables comprehensive and concise identification of regulatory elements and emphasizes the extensive interrelationships among RNA genome structure, viral biology, and innate immune responses.

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Long-acting muscarinic antagonist/long-acting ß2-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). METHODS: This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD ( NCT01085045 ). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 µg or 36/9.6 µg), GP MDI 36 µg BID, FF MDI 7.2 and 9.6 µg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 µg BID or tiotropium DPI 18 µg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 7 relative to baseline FEV1. Secondary endpoints included pharmacokinetics and safety. RESULTS: GFF MDI 72/9.6 µg or 36/9.6 µg led to statistically significant improvements in FEV1 AUC0-12 after 7 days' treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 µg was non-inferior to GFF MDI 72/9.6 µg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. CONCLUSIONS: GFF MDI 72/9.6 µg and 36/9.6 µg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01085045 . Registered 9 March 2010.

Treating Peripheral Artery Disease in the Wake of Rising Costs and Protracted Length of Stay.

BACKGROUND: There has been growing scrutiny in the treatment of patients with peripheral artery disease due to the utilization of resources to manage this complex patient population. The purpose of this study was to determine the factors associated with prolonged length of stay (LOS > 7 days) following lower extremity bypass using data from the Vascular Quality Initiative as well as to define the additional costs incurred due to prolonged LOS in our health system. METHODS: Summary statistics were performed of patients undergoing lower extremity bypass from 2010 to 2015. Student's t-tests and χ2 tests were performed to compare those with and without prolonged LOS. Multivariable logistic regression was then performed to determine the independent predictors for increased LOS. We then compared our institutional LOS with that of representative institutions from the University Health System Consortium and evaluated the impact of prolonged LOS on limb salvage and survival. RESULTS: This study included 334 patients with a mean age of 66.4 ± 12.4 years, 64.7% males, 58.5% of white race, 11.1% on dialysis, 80.5% smokers, and 53.6% with diabetes. The mean LOS was 15.7 ± 12.2 days. Prolonged LOS was associated with transfer (15.4% vs. 2.3%, P = 0.001), diabetes (58.3% vs. 40.2%, P = 0.004), critical limb ischemia (71.3% vs. 49.4%, P < 0.001), preoperative need for ambulatory assistance (44.5% vs. 16.1%, P < 0.001), prior ipsilateral bypass (6.9% vs. 1.1%, P = 0.042), urgent surgery (39.7% vs. 9.8%, P < 0.001), tibial or distal target vessel (52.7% vs. 28.0%, P < 0.001), use of vein (65.4% vs. 46.3%, P = 0.002), return to operating room (42.6% vs. 1.2%, P < 0.001), ambulatory assistance (65.0% vs. 34.1%, P < 0.001) as well as discharge anticoagulant (22.8% vs. 9.8%, P = 0.010). Multivariable logistic regression identified urgency (odds ratio [OR] = 5.09, 95% confidence interval [CI] 2.16-12.02, P < 0.001), critical limb ischemia (OR = 3.12, 95% CI 1.65-5.90, P < 0.001), return to OR (OR = 40.30, 95% CI 5.36-303.20, P < 0.001), use of vein (OR = 2.19, 95% CI 1.18-4.07, P = 0.013), and the need for anticoagulation at discharge (OR = 2.56, 95% CI 1.03-6.33, P = 0.043) as independent predictors of LOS > 7 days. Prolonged hospital stays accounted for an additional $40,561.64 in total cost and $26,028 in direct costs incurred. Despite these increased costs, limb salvage and overall survival were not adversely impacted in the prolonged LOS group in follow-up. CONCLUSIONS: Lower extremity bypass is associated with a longer than expected LOS in our health system, much of which can be attributed to return to the OR for minor amputations and wound issues. This led to added total and direct costs, where the majority of this increase was attributable to prolonged LOS. Limb salvage and overall survival were preserved, however, in this subset of patients in follow-up. These findings suggest that lower extremity bypass patients are a resource-intensive population of patients, but that these costs are worthwhile in the setting of preserved limb salvage and overall survival.

Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension™ Delivery Technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD.

BACKGROUND: This study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: This randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 µg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 µg, once daily [QD]) in patients with moderate-to-severe COPD. Patients were randomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on Days 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (≥10 % improvement in mean FEV1) and the proportion of patients achieving ≥12 % improvement in FEV1 on Day 1; and pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed. RESULTS: GP MDI 18, 9, 4.6, and 2.4 µg demonstrated statistically significant and clinically relevant increases in FEV1 AUC0-12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120). GP MDI 18 µg was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose trough FEV1 on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings. CONCLUSIONS: These efficacy and safety results support GP MDI 18 µg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01566773 . Registered 27 March 2012.