Preserving Endothelial Integrity in Human Saphenous Veins during Preparation for Coronary Bypass Surgery.

INTRODUCTION: While multiple factors influence coronary artery bypass graft (CABG) success rates, preserving saphenous vein endothelium during surgery may improve patency. Standard preparations include saphenous vein preparation in heparinized saline (saline) which can result in endothelial loss and damage. Here, we investigated the impact of preparing saphenous graft vessels in heparinized patient blood (blood) versus saline. METHODS: Saphenous vein tissues from a total of 23 patients undergoing CABG were split into 2 groups (1) saline and (2) heparinized patient blood. Excess tissue was fixed for analysis immediately following surgery. Level of endothelial coverage, oxidative stress marker 4-hydroxynonenal (4HNE), and oxidative stress protective marker nuclear factor erythroid 2-related factor 2 (NRF2) were evaluated. RESULTS: In saline patient veins, histological analysis revealed a limited luminal layer, suggesting a loss of endothelial cells (ECs). Immunofluorescent staining of EC markers vascular endothelial cadherin (VE-cadherin) and endothelial nitric oxide identified a significant improvement in EC coverage in the blood versus saline groups. Although both treatment groups expressed 4HNE to similar levels, EC blood samples expressed higher levels of NRF2. CONCLUSION: Our data indicate that use of heparinized patient blood helps preserve the endothelium and promotes vein graft health. This has the potential to improve long-term outcomes in patients.

Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives.

Gastrointestinal (GI) sequelae, such as vomiting, hyperacidity, dysphagia, dysmotility, and diarrhea, are nearly universal among patients with nephropathic cystinosis. These complications result from disease processes (e.g., kidney disease, cystine crystal accumulation in the GI tract) and side effects of treatments (e.g., cysteamine, immunosuppressive therapy). GI involvement can negatively impact patient well-being and jeopardize disease outcomes by compromising drug absorption and patient adherence to the strict treatment regimen required to manage cystinosis. Given improved life expectancy due to advances in kidney transplantation and the transformative impact of cystine-depleting therapy, nephrologists are increasingly focused on addressing extra-renal complications and quality of life in patients with cystinosis. However, there is a lack of clinical data and guidance to inform GI-related monitoring, interventions, and referrals by nephrologists. Various publications have examined the prevalence and pathophysiology of selected GI complications in cystinosis, but none have summarized the full picture or provided guidance based on the literature and expert experience. We aim to comprehensively review GI sequelae associated with cystinosis and its treatments and to discuss approaches for monitoring and managing these complications, including the involvement of gastroenterology and other disciplines.

Working Around: The Use of AngioVac and Micra Transcatheter Leadless Pacemaker Implantation in a Critically Ill Patient Receiving Extracorporeal Membrane Oxygenation.

The use of extracorporeal membrane oxygenation (ECMO) in critically ill patients has been on the rise in recent years. While ECMO has provided substantial benefit to patients who need cardiopulmonary support, its required use of large-bore catheters in major blood vessels often precludes the use of other transcatheter therapies. In this article, we demonstrate that two transcatheter procedures, AngioVac right-sided cardiac thrombus removal and Micra leadless pacemaker placement, both requiring large bore access, can both be safely and effectively implemented in patients who are dependent on ECMO to maintain cardiopulmonary function.

On-site construction of a point-of-care low-field MRI system in Africa.

PURPOSE: To describe the construction and testing of a portable point-of-care low-field MRI system on site in Africa. METHODS: All of the components to assemble a 50 mT Halbach magnet-based system, together with the necessary tools, were air-freighted from the Netherlands to Uganda. The construction steps included individual magnet sorting, filling of each ring of the magnet assembly, fine-tuning the inter-ring separations of the 23-ring magnet assembly, gradient coil construction, integration of gradient coils and magnet assembly, construction of the portable aluminum trolley and finally testing of the entire system with an open source MR spectrometer. RESULTS: With four instructors and six untrained personnel, the complete project from delivery to first image took approximately 11 days. CONCLUSIONS: An important step in translating scientific developments in the western world from high-income industrialized countries to low- and middle-income countries (LMICs) is to produce technology that can be assembled and ultimately constructed locally. Local assembly and construction are associated with skill development, low costs and jobs. Point-of-care systems have a large potential to increase the accessibility and sustainability of MRI in LMICs, and this work demonstrates that technology and knowledge transfer can be performed relatively seamlessly.

Pulmonary Hypertension and Operative Risk in Mitral Valve and Coronary Surgery.

INTRODUCTION: Pulmonary hypertension (PHT) is a known risk factor for coronary artery bypass grafting (CABG), though less well understood for valve operations. We hypothesized PHT is associated with lower risk during mitral valve operations compared to CABG. METHODS: Patients undergoing isolated mitral valve or CABG operations (2011-2019) in a regional Society of Thoracic Surgeons (STS) database were stratified by pulmonary artery systolic pressure (PASP). The association of PASP by procedure type was assessed by hierarchical regression modeling, adjusting for STS predicted risk scores. RESULTS: Of the 2542 mitral and 11,059 CABG patients, the mitral population had higher mean STS risk of mortality (3.6% versus 2.4%, P < 0.0001) and median PASP (42 mmHg versus 32 mmHg, P < 0.0001). PASP was independently associated with operative mortality and major morbidity in both mitral and CABG patients. However, for mitral patients a 10-mmHg increase in PASP was associated with lower odds of morbidity (odds ratio: 1.06 versus 1.13), mortality (odds ratio: 1.11 versus 1.18) and intensive care unit time (4.3 versus 7.6 h) compared with CABG patients (interaction terms P < 0.0001). Among mitral patients, median PASP was higher in stenotic versus regurgitant disease (57 mmHg versus 40 mmHg, P < 0.0001). However, there was no differential association of PASP on morbidity or mortality (interaction terms P > 0.05). CONCLUSIONS: Although mitral surgery patients tend to have higher preoperative pulmonary artery pressures, PHT was associated with a lower risk for mitral outcomes compared with CABG. Further research on the management and optimization of patients with PHT perioperatively is needed to improve care for these patients.

Temporal Cluster Analysis of Deep Sternal Wound Infection in a Regional Quality Collaborative.

INTRODUCTION: Deep sternal wound infection (DSWI) is a rare complication associated with high mortality. Seasonal variability in surgical site infections has been demonstrated, however, these patterns have not been applied to DSWI. The purpose of this study was to assess temporal clustering of DSWIs. METHODS: All cardiac surgery patients who underwent sternotomy were queried from a regional Society of Thoracic Surgeons database from 17 centers from 2001 to 2019. All patients with the diagnosis of DSWI were then identified. Cluster analysis was performed at varying time intervals (monthly, quarterly, and yearly) at the hospital and regional level. DSWI rates were calculated by year and month, and compared using mixed-effects negative binomial regression. RESULTS: A total of 134,959 patients underwent a sternotomy for cardiac surgery, of whom 469 (0.35%) developed a DSWI. Rates of DSWI per hospital across all years ranged from 0.12% to 0.69%. Collaborative-level rates of DSWIs were the greatest in September (0.44%) and the lowest in January (0.30%). Temporal clustering was not seen across seasonal quarters (high rate in preceeding quarter was not associated with a high rate in the next quarter) (P = 0.39). There were yearly differences across all institutions in the DSWI rates. A downward trend in DSWI rates was seen from 2001 to 2019 (P < 0.001). A difference among hospitals in the cohort was observed (P < 0.001). CONCLUSIONS: DSWI are a rare event within our region. Unlike other surgical site infection, there does not appear to be a seasonal pattern associated with DSWI.

Tidal continuous cycling peritoneal dialysis in children.

About 10% of all home peritoneal dialysis regimens in children with chronic kidney disease stage 5 are reported to involve some form of a tidal peritoneal dialysis (TPD) prescription. Despite this, there remain several gaps in how pediatric nephrologists approach the use of TPD. This stems from a combination of factors such as the confusing technical terminology pertaining to TPD, seemingly conflicting data on the risks, benefits, and indications for TPD, and lastly, limited published guidelines on the practical aspects of how to write a TPD prescription, based on the indication, in children. Our educational review, using evidence-based data, attempts to bridge this gap and provide an easy-to-use guide on the key practical aspects of TPD in children.

Left Ventricular Diastolic Dysfunction and Pulmonary Hypertension: Outcomes in SAVR.

BACKGROUND: Severe pulmonary hypertension (PH) and left ventricular diastolic dysfunction (LVDD) are independently associated with poor outcomes in cardiac surgery. We evaluated the relationship of several measures of LVDD, PH, and hemodynamic subtypes of PH including precapillary pulmonary hypertension(pcPH) and isolated post-capillary pulmonary hypertension(ipcPH) and combined pre and post capillary pulmonary hypertension(cpcPH) capillary PH to postoperative outcomes in a cohort of patients who underwent elective isolated-AVR. METHODS: We evaluated (n = 206) patients in our local STS database who underwent elective isolated-AVR between 2014 and 2018, with transthoracic echocardiogram (n = 177) or right heart catheterization (n = 183) within 1 year of operation (or both, n = 161). The primary outcome was a composite end point of death, prolonged ventilation, ICU readmission, and hospital stay >14 days. RESULTS: Severe PH was associated with worse outcomes (moderate: OR, 1.1, p = 0.09; severe: OR, 1.28, p = 0.01), but degree of LVDD was not associated with worse outcomes. Across hemodynamic subtypes of PH, odds of composite outcome were similar (p = 0.89), however, patients with cpcPH had more postoperative complications (67 vs. 36%, p = 0.06) and patients with ipcPH had greater all-cause mortality at 1 (8 vs. 1%, p = 0.03) and 3 years (27 vs. 4%, p = 0.008). CONCLUSION: Severe PH conferred modestly greater risk of adverse events, and both LVDD grade and the combination of severe PH and LVDD were not associated with worse outcomes. However, hemodynamic stratification of PH revealed higher postoperative complications and worse long-term outcomes for those with cpcPH and ipcPH. Preoperative stratification of PH by hemodynamic subtype in valve replacement surgery may improve our risk stratification in this heterogenous condition. Further evaluation of the significance of LVDD and PH in other cardiac operations is warranted.

Biomechanical Performance of Biodegradable Screw Fixation in Mandibular Distraction Osteogenesis.

Internal distraction devices are commonly used in congenital micrognathia. The eventual need for device and screw removal can be challenging, requiring extensive dissection and disturbance of bone regenerate. Bioabsorbable poly-L-lactide (PLLA) screws, compared to traditional titanium screws, simplify device removal. Previous in vivo studies have found that the maximal compressive force generated by mandibular distraction is 69.4N. We hypothesized that PLLA screws could support these compressive/distraction forces. Ten mandibles were obtained from 5 canine cadavers. Paired mandibles from the same cadaver were each fixated to a mandibular distractor with eight screws (either titanium or PLLA). Devices were each set to 15 and 30 mm of distraction distance. Compression force of 80 N was then generated parallel to the axis of the distraction device. Distractor displacement was measured to detect any mechanical failure during this pre-set load. Finally, if no failure was observed at 80 N, a load-to-failure compression test was done in the PLLA group to determine the mechanical failure point. All distractors in both the titanium and PLLA screw groups withstood 80 N of compression without failure. When the load-to-failure test was performed in the PLLA group, the average device failure point was 172.8 N (range 148-196 N). Review of high-frame-rate video demonstrated that all failures occurred due to the PLLA screws breaking or falling out. Bioabsorbable PLLA screws can withstand compressive forces more than double that of the maximal in vivo forces needed during mandibular distraction. These screws may be an acceptable alternative for the fixation of internal mandibular distractors.

Predictive Capability of Metabolic Panels for Postoperative Atrial Fibrillation in Cardiac Surgery Patients.

INTRODUCTION: Postoperative atrial fibrillation (POAF) occurs in up to 65% of cardiac surgery patients and is associated with an increased risk for stroke and mortality. Electrolyte disturbances in sodium (Na+), potassium (K+), total calcium (Ca2+), chloride (Cl-), and magnesium (Mg2+) are predisposing factors for POAF, but these imbalances are yet to be used to predict POAF. The purpose of this study is to determine whether the development of POAF can be predicted by blood plasma ionic composition. METHODS: Metabolic panels of patients with no prior history of atrial fibrillation who did (n = 763) and did not develop POAF (n = 2144) after cardiac surgery were obtained from the Carilion Clinic electronic medical record system. We initially evaluated serum Na+, K+, Ca2+, Cl-, and Mg2+ in the two groups using descriptive statistics via scatter and spaghetti plots and then with predictive modeling via logistic regression and random forest models. RESULTS: Neither scatter nor spaghetti plots of electrolyte data revealed a significant difference between those who did and did not develop POAF. Two logistic regression models and two random forest models with POAF status as the outcome were generated using the first observation for each electrolyte and the coefficient of the linear regression, which was obtained from a linear fit of the scatter plot. The random forest model using the first observation had a sensitivity of only 12.2%, but all four models had specificities more than 97%. CONCLUSIONS: Neither of the two logistic regression nor two random forest models were able to effectively predict the development of POAF from plasma ionic concentrations, but the random forest models effectively classified patients who would not develop POAF.

Evaluation of cytokine response to extracorporeal membrane oxygenation.

RATIONALE: Increased cytokine response is common in patients receiving extracorporeal life support and is often a poor prognostic indicator. There is interest in using adjunctive cytokine adsorption technologies to reduce inflammatory burden, However, it is debated whether extracorporeal membrane oxygenation (ECMO) itself provides therapeutic benefit beyond gas exchange. Thus, we sought to characterize the inflammatory profile of ECMO in the first 72-96 h of and quantify its effect on cytokine levels in a case series of patients undergoing ECMO. METHODS: Eight patients initiating ECMO were studied. Of these, we measured cytokines pre- and post-oxygenator over 96 h. Comparisons of cytokine levels were made across the oxygenator and over time. RESULTS: The average age of patients was 64.3 years with 62% being male. Centrally cannulated patients had higher IL-6 levels (820.43 vs. 6907.53 pg/ml, p < 0.03), whereas peripherally cannulated patients had higher IL-12p70 levels (7.73 vs. 2.59 pg/ml, p < 0.05). Cytokine levels on day one included IL-12p70 (4.17 ± 2.56), IL-6 (4971.23 ± 8569.88), TNF (undetected), IL-8 (346.68 ± 670.18), IL-1B (undetected), and IL-10 (72.27 ± 87.9). Cytokine levels increased over 96 h; however, no significant differences were appreciated despite blood product transfusion. On day 3, IL-12p70 levels were significantly lower post-oxygenator (p < 0.05). CONCLUSION: The inflammatory profile of ECMO does not change significantly over the early course of illness when accounting for transfusion. However, the decrease in IL-12p70 specifically at day 3 of ECMO may indicate adsorption of specific inflammatory markers by the oxygenator although the clinical significance of this is still unknown. Further investigation of the oxygenator on cytokine response is warranted.

Contemporary prevalence and outcomes of rheumatic mitral valve surgery.

OBJECTIVE: Rheumatic mitral valve disease is often viewed as a historic disease in North America with limited contemporary data. We hypothesized that rheumatic pathology remains common and has worse short-term outcomes and higher resource utilization compared to other mitral valve pathologies. METHOD: All patients undergoing mitral valve repair or replacement (2011-2019) were extracted from a regional Society of Thoracic Surgeons database. Resource utilization metrics included inflation-adjusted hospital costs. Patients were stratified by mitral valve pathology for univariate analysis. RESULT: Out of the 6625 mitral valve procedures, 835 (12.6%) were from rheumatic disease, a proportion that incrementally increased over time (+0.39% per year, p = .032). Among 19 hospitals, there was high variability in number of rheumatic mitral operations (median: 22, interquartile range [IQR]: 5-80) and rate of rheumatic repairs (median: 3%, IQR: 0%-6%). Rheumatic patients were younger (62 vs. 65, p < .0001), more often female (75% vs. 43%, p < .001) and with greater burden of heart failure, multi-valve disease, and lung disease, but less coronary disease. There were no differences in operative mortality (5.2% vs. 5.0%, p = .85) or major morbidity (22.2% vs. 21.8%, p = .83). However, resource utilization was higher for rheumatic patients, including more frequent transfusions (43% vs. 39%, p = .012), longer ICU (73 vs. 64 h, p < .0001) and postoperative length of stay (8 vs. 7 days, p < .0001). CONCLUSIONS: Rheumatic mitral disease accounts for a meaningful (12%) and rising percentage of mitral valve operations in the region, with high variability among hospitals. Rheumatic mitral surgery yielded similar short-term outcomes compared to nonrheumatic pathology, but required greater resource utilization.

A retrospective comparison of albumin versus mannitol priming fluid with relation to postoperative atrial fibrillation.

BACKGROUND AND AIM OF THE STUDY: Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery which can result in increased mortality and increased healthcare costs. During Hurricane Maria (2017), a nationwide shortage of mannitol occurred, and our institution switched to the utilization of albumin as a priming fluid solution. We observed decreased rates of POAF during that time and began alternating albumin and mannitol priming fluid solutions. We hypothesized this observation may be from altered perinexal conduction from albumin utilization. METHODS: A retrospective chart review of all patients from January 2020 through December 2020 who underwent cardiac surgery was performed, to determine if albumin was associated with reduced POAF rates. Two hundred and thirteen patients were identified and 4 were excluded. Two hundred and nine patients (110 albumin priming fluid and 99 mannitol priming fluid) were included in our final analysis. RESULTS: Analysis was performed for all patients with POAF and in patients with new-onset AF (without a history of prior AF) after surgery. POAF rates showed no statistically significant difference between cohorts. For all patients, POAF occurred in 43% of the albumin subgroup and 47% of the mannitol subgroup (p = .53) and for patients with new-onset AF, POAF occurred in 35% of the albumin subgroup versus 42% of the mannitol subgroup (p = .36). Logistic regression revealed that age, ejection fraction and cardiopulmonary bypass time was associated with POAF, in our cohort. CONCLUSIONS: The use of albumin compared to mannitol as priming fluid solutions was not associated with statistically significant reductions in POAF rate, in our population.

To Anticoagulate or Not? That Is the Question. Management of High-Risk Patients with Mechanical Mitral and Double Valves: A Case Series.

The Achilles heel of mechanical valves appears to be the need for anticoagulation. Several different types of mechanical valves have come and gone. The success or lack thereof of these valves depended on their various designs. We compared the two most promising mechanical valves of different eras and the need for anticoagulation through a case review. Both the Medtronic-Hall tilting disc valve and the bileaflet On-X valve were compared and contrasted in terms of durability and management of anticoagulation in high-risk patient populations. We present two cases of challenging anticoagulation management: a patient who underwent a mitral valve replacement with a Medtronic-Hall tilting disc valve who was off anticoagulation for close to six years, and a patient who underwent On-X mitral and aortic valve replacements and suffered a subsequent intracranial bleed requiring surgical intervention. We explore the ethical dilemmas associated with these patients and the risk of restarting anticoagulation for each.

First Molecular Phylogenetic Analysis of the Lagothrix Taxon Living in Southern Peru and Northern Bolivia: Lagothrix lagothricha tschudii (Atelidae, Primates), a New Subspecies.

We sequenced mitochondrial COI and COII genes (1,377 base pairs) of 166 woolly monkeys (Lagothrix) to determine the phylogenetic relationships of tschudii in reference to the other taxa within the genus Lagothrix, to provide the first genetic diversity level estimates for tschudii, and to reconstruct the historical demographic evolution of this taxon. The sample set included, for the first time, 10 individuals of the elusive tschudii taxon sensu Groves from southern Peru and northern Bolivia. Our phylogenetic analyses showed that these 10 exemplars formed a statistically significant and differentiated (molecularly and morphologically) monophyletic clade relative to other traditional subspecies of Lagothrix lagothricha. Therefore, tschudii should be recognized as a fifth subspecies: Lagothrix lagothricha tschudii. The temporal divergence of the ancestors of tschudii and L. l. cana was estimated to have occurred around 1.8 million years ago (MYA). Additionally, mitochondrial diversification within tschudii started no later than 0.96 MYA (Bayesian Inference) or 0.88 MYA (Median Joining -Network), respectively. In contrast to the phylogenetic trees, the FSTstatistic and the gene flow estimates showed L. l. lugens to be the least differentiated taxon of L. lagothricha from L. l. tschudii. Based on genetic distances, L. l. tschudii had the smallest average genetic distance from the other subspecies of L. lagothricha.It was also the taxon within L. lagothricha that had the smallest genetic distance from L. flavicauda. It should be related to L. l. tschudii as the first original taxon in L. lagothricha. Furthermore, the Andean mountains were extremely important in the original diversification of the Lagothrix genus and in the original diversification of L. lagothricha. Although L. l. tschudii has the smallest geographical range of all the taxa of L. lagothricha, its genetic diversity is even higher than in other taxa with wider geographical ranges, such as L. l. lagothricha and L. l. cana. L. l. tschudii showed a very slight demographic increase during the Pleistocene with a decrease of females in the last 10,000 Y, similar to that found for L. l. lugens in a previous study.

Phylogeography of the Mantled Howler Monkey (Alouatta palliata; Atelidae, Primates) across Its Geographical Range by Means of Mitochondrial Genetic Analyses and New Insights about the Phylogeny of Alouatta.

We analyzed 156 specimens of diverse howler monkey taxa (Alouatta; Atelidae, Primates) for different mitochondrial genes (5,567 base pairs), with special emphasis on A. palliata and related taxa. Our results showed no relevant differences among individuals of different putative taxa, A. p. palliata, A. p. aequatorialis, A. coibensis coibensis, and A. c. trabeata. We found no spatial differences in genetic structure of A. p. palliata throughout Costa Rica, Nicaragua, and Honduras. A. p. mexicana (genetic distance: 1.6-2.1%) was the most differentiated taxon within A. palliata. Therefore, we postulate the existence of only 2 clearly defined subspecies within A. palliata (A. p. palliata and A. p. mexicana). A. palliata and A. pigra (traditionally considered a subspecies of A. palliata) are 2 clearly differentiated species as was demonstrated by Cortés-Ortiz and colleagues in 2003, with a temporal split between the 2 species around 3.6-3.7 million years ago (MYA). Our results with the Median Joining Network procedure showed that the ancestors of the cis-Andean Alouatta gave rise to the ancestors of the trans-Andean Alouatta around 6.0-6.9 MYA. As Cortés-Ortiz et al. showed, A. sara and A. macconnelli are differentiable species from A. seniculus, although the first 2 taxa were traditionally considered subspecies of A. seniculus. Our findings agree with the possibility that the ancestor of A. sara gave rise to the ancestor of A. pigra in northern South America. In turn, the ancestor of A. pigra originated the ancestor of A. palliata. Two of our results strongly support the hypothesis that the South American A. palliata (the putative A. p. aequatorialis) was the original population of this species; it has high genetic diversity and no evidence of population expansion. The Central America A. palliata is the derived population. It has low genetic diversity and there is clear evidence of population expansion. However, A. palliata and A. pigra probably migrated into Central America by 2 different routes: the Isthmus of Panama (A. palliata) and Caribbean island arch (A. pigra). Finally, the red howler monkeys from the island of Trinidad in the Caribbean Sea were not A. macconnelli (= A. s. stramineus) as Groves maintained in his influential 2001 publication on primate taxonomy. This taxon is more related to A. s. seniculus, although it formed a monophyletic clade. Future molecular and karyotypic studies will show if the Trinidad red howler monkeys should be considered as an extension of the Venezuelan taxon, A. arctoidea, as a subspecies of A. seniculus(A. s. seniculus), or, in the case of extensive chromosomal rearrangements, even a new species.

Progression of Liver Fibrosis and Modern Combination Antiretroviral Therapy Regimens in HIV-Hepatitis C-Coinfected Persons.

BACKGROUND: Liver diseases progress faster in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected persons than HIV-monoinfected persons. The aim of this study was to compare rates of liver fibrosis progression (measured by the aspartate-to-platelet ratio index [APRI]) among HIV-HCV-coinfected users of modern protease inhibitor (PI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens with a backbone of tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC). METHODS: Data from a Canadian multicenter cohort study were analyzed, including 315 HCV polymerase chain reaction-positive persons who initiated antiretroviral therapy with a PI or NNRTI and a backbone containing either TDF/FTC or ABC/3TC. Multivariate linear regression analyses with generalized estimating equations were performed after propensity score matching to balance covariates across classes of anchor agent. RESULTS: A backbone of TDF/FTC was received by 67% of PI users and 69% of NNRTI users. Both PI and NNRTI use was associated with increases in APRI over time when paired with a backbone of ABC/3TC: 16% per 5 years (95% confidence interval [CI], 4%, 29%) and 11% per 5 years (95% CI, 2%, 20%), respectively. With TDF/FTC use, no clear association was found among PI users (8% per 5 years, 95% CI, -3%, 19%) or NNRTI users (3% per 5 years, 95% CI, -7%, 12%). CONCLUSIONS: Liver fibrosis progression was more influenced by the backbone than by the class of anchor agent in HIV-HCV-coinfected persons. Only ABC/3TC-containing regimens were associated with an increase of APRI score over time, regardless of the class of anchor agent used.

How Generalizable Are the Results From Trials of Direct Antiviral Agents to People Coinfected With HIV/HCV in the Real World?

BACKGROUND: Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have been described as revolutionary. However, it remains uncertain how effective these drugs will be for individuals coinfected with human immunodeficiency virus (HIV)-HCV. Bridging this gap between efficacy and effectiveness requires a focus on the generalizability of clinical trials. METHODS: Generalizability of DAA trials was assessed by applying the eligibility criteria from 5 efficacy trials: NCT01479868, PHOTON-1 (NCT01667731), TURQUOISE-I (NCT01939197), ION-4 (NCT02073656), and ALLY-2 (NCT02032888) that evaluated simeprevir; sofosbuvir; ombitasvir, paritaprevir/ritonavir/dasabuvir; sofosbuvir/ledipasvir; and daclatasvir/sofosbuvir, respectively, to the Canadian Coinfection Cohort, representing approximately 23% of the total coinfected population in care in Canada. RESULTS: Of 874 active participants, 70% had chronic HCV, of whom 410, 26, 94, and 11 had genotypes 1, 2, 3, and 4, respectively. After applying trial eligibility criteria, only 5.9% (24/410) would have been eligible for enrollment in the simeprevir trial, 9.8% (52/530) in PHOTON-1, 6.3% (26/410) in TURQUOISE-I, and 8.1% (34/421) in ION-4. The ALLY-2 study was more inclusive; 43% (233/541) of the cohort would have been eligible. The most exclusive eligibility criteria across all trials with the exception of ALLY-2 were restriction to specific antiretroviral therapies (63%-79%) and active illicit drug use (53%-55%). CONCLUSIONS: DAA trial results may have limited generalizability, since the majority of coinfected individuals were not eligible to participate. Exclusions appeared to be related to improving treatment outcomes by not including those at higher risk of poor adherence and reinfection--individuals for whom real-world data are urgently needed.

A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family.

Mutations in the PIGN gene involved in the glycosylphoshatidylinositol (GPI) anchor biosynthesis pathway cause Multiple Congenital Anomalies-Hypotonia-Seizures syndrome 1 (MCAHS1). The syndrome manifests developmental delay, hypotonia, and epilepsy, combined with multiple congenital anomalies. We report on the identification of a homozygous novel c.755A>T (p.D252V) deleterious mutation in a patient with Israeli-Arab origin with MCAHS1. The mutated PIGN caused a significant decrease of the overall GPI-anchored proteins and CD24 expression. Our results, strongly support previously published data, that partial depletion of GPI-anchored proteins is sufficient to cause severe phenotypic expression.