Citations

IntroductionVascularized bone allotransplantation may provide new options for reconstruction of segmental defects if problems of long‐term immune modulation can be solved. The current literature lacks an orthotopic large animal model, limited to bone and without the confounding effects of other tissue types, permitting a multifaceted evaluation before new methods are used clinically. The purpose of this study was to develop a large animal model for vascularized bone allotransplantation.Materials and methodsEight porcine hind limbs were dissected. Length, diameter, and location of all hindlimb vessels were measured and a single nutrient vessel supplying the tibial diaphysis identified enabling its use as a vascularized bone allotransplant. Four Yucatan minipigs were divided into two pairs with a major swine leukocyte antigen mismatch. A 3.5 cm tibial segment including its nutrient pedicle was raised simultaneously from each pig and transplanted into the matched defect of the other animal. Microarterial anastomosis of the pedicle and 3‐drug immunosuppression maintained VCA viability. Bone healing and limb function were followed for 16 weeks.ResultsA consistent tibia diaphyseal nutrient artery arose from the caudal tibial artery to enter bone a mean 2.8 mm distal to the tibial tubercle with a pedicle length of 6.6 ± 3.3 mm and diameter of 1.6 ± 0.2 mm. Using this pedicle, we reconstructed a 3.5 cm tibial defect with a vascularized bone allotransplant in four animals. Immediate weightbearing as well as progressive bone healing was demonstrated.ConclusionWe have developed a vascularized tibial bone allotranplantation large‐animal model suitable for future bone‐only allotranplantation research in mini‐pigs.

SummaryDue to the introduction of newer, more efficacious treatment options, there is a pressing need for policy makers and public health officials to develop or adapt national hepatitis C virus (HCV) control strategies to the changing epidemiological landscape. To do so, detailed, country‐specific data are needed to characterize the burden of chronic HCV infection. In this study of 17 countries, a literature review of published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates was conducted, and inputs were validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Hong Kong to 2.4% in Taiwan, while the largest viraemic populations were in Nigeria (2 597 000 cases) and Taiwan (569 000 cases). Diagnosis, treatment and liver transplant rates varied widely across the countries included in this analysis, as did the availability of reliable data. Addressing data gaps will be critical for the development of future strategies to manage and minimize the disease burden of hepatitis C.

SummaryFactors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV‐related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high‐treatment rate will contribute to a reduction in total cases and HCV‐related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV‐related morbidity and mortality.

SummaryThe hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets—“WHO Targets” (65% reduction in HCV‐related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.

Venous thromboembolism is recognized as a leading cause of maternal death in the United States. Thromboprophylaxis has been highlighted as a key preventive measure to reduce venous thromboembolism–related maternal deaths. However, the expanded use of thromboprophylaxis in obstetrics will have a major impact on the use and timing of neuraxial analgesia and anesthesia for women undergoing vaginal or cesarean delivery and other obstetric surgeries. Experts from the Society of Obstetric Anesthesia and Perinatology, the American Society of Regional Anesthesia, and hematology have collaborated to develop this comprehensive, pregnancy-specific consensus statement on neuraxial procedures in obstetric patients receiving thromboprophylaxis or higher dose anticoagulants. To date, none of the existing anesthesia societies’ recommendations have weighed the potential risks of neuraxial procedures in the presence of thromboprophylaxis, with the competing risks of general anesthesia with a potentially difficult airway, or maternal or fetal harm from avoidance or delayed neuraxial anesthesia. Furthermore, existing guidelines have not integrated the pharmacokinetics and pharmacodynamics of anticoagulants in the obstetric population. The goal of this consensus statement is to provide a practical guide of how to appropriately identify, prepare, and manage pregnant women receiving thromboprophylaxis or higher dose anticoagulants during the ante-, intra-, and postpartum periods. The tactics to facilitate multidisciplinary communication, evidence-based pharmacokinetic and spinal epidural hematoma data, and Decision Aids should help inform risk–benefit discussions with patients and facilitate shared decision making.

Fibrillary GN (FGN) is a rare primary glomerular disease. Histologic and histochemical features of FGN overlap with those of other glomerular diseases, and no unique histologic biomarkers for diagnosing FGN have been identified. We analyzed the proteomic content of glomeruli in patient biopsy specimens and detected DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) as the fourth most abundant protein in FGN glomeruli. Compared with amyloidosis glomeruli, FGN glomeruli exhibited a >6-fold overexpression of DNAJB9 protein. Sanger sequencing and protein sequence coverage maps showed that the DNAJB9 protein deposited in FGN glomeruli did not have any major sequence or structural alterations. Notably, we detected DNAJB9 in all patients with FGN but not in healthy glomeruli or in 19 types of non-FGN glomerular diseases. We also observed the codeposition of DNAJB9 and Ig- γ . Overall, these findings indicate that DNAJB9 is an FGN marker with 100% sensitivity and 100% specificity. The magnitude and specificity of DNAJB9 overabundance in FGN also suggests that this protein has a role in FGN pathogenesis. With this evidence, we propose that DNAJB9 is a strong biomarker for rapid diagnosis of FGN in renal biopsy specimens.

Introduction: Alexander disease is a rare neurodegenerative disease caused by variants in the glial fibrillary acidic protein gene (GFAP). This disorder can develop as an infantile, juvenile or adult-onset form and is characterized by several clinical features, including macrocephaly, seizures, ataxia, and bulbar/pseudobulbar signs. While the majority of these patients have the more progressive infantile form which causes severe leukodystrophy and early death; the less common adult form is more variable (ie, onset age, symptoms), with bulbar dysfunction as the primary feature. Case Report: In our investigation, we describe a patient with progressive neuromuscular issues including dyspnea, dysphagia, dysarthria and progressive ataxia with palatal tremor. Conclusions: Through genetic testing, we determined that our patient has a novel variant in GFAP typical of Alexander disease.

Background and Purpose— Few data exist on the long-term outcomes of patients with spontaneous echo contrast (SEC), left atrial/left atrial appendage (LA/LAA) thrombus, and complex aortic plaque (CAP), in patients with atrial fibrillation receiving oral anticoagulation. We explored the relationship between these 3 echocardiographic findings and clinical outcomes, and the comparative efficacy and safety of apixaban and warfarin for each finding. Methods— Patients from the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) with SEC, LA/LAA thrombus, or CAP diagnosed by either transthoracic or transesophageal echocardiography were compared with patients with none of these findings on transesophageal echocardiography. Results— A total of 1251 patients were included: 217 had SEC, 127 had LA/LAA thrombus, 241 had CAP, and 746 had none. The rates of stroke/systemic embolism were not significantly different among patients with and without these echocardiographic findings (hazard ratio, 0.96; 95% confidence interval, 0.25–3.60 for SEC; hazard ratio, 1.27; 95% confidence interval, 0.23–6.86 for LA/LAA thrombus; hazard ratio, 2.21; 95% confidence interval, 0.71–6.85 for CAP). Rates of ischemic stroke, myocardial infarction, cardiovascular death, and all-cause death were also not different between patients with and without these findings. For patients with either SEC or CAP, there was no evidence of a differential effect of apixaban over warfarin. For patients with LA/LAA thrombus, there was also no significant interaction, with the exception of all-cause death and any bleeding where there was a greater benefit of apixaban compared with warfarin among patients with no LA/LAA thrombus. Conclusions— In anticoagulated patients with atrial fibrillation and risk factors for stroke, echocardiographic findings do not seem to add to the risk of thromboembolic events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.

We have ascertained two families affected with familial amyotrophic lateral sclerosis (ALS) in which they both carry a hexanucleotide repeat expansion in the C9orf72 gene, specifically in individuals who also presented with frontotemporal dementia (FTD) or behavioral variant FTD (bvFTD). While some reports attribute this phenotypic heterogeneity to the C9orf72 expansion alone, we screened for additional genetic variation in known ALS‐FTD genes that may also contribute to or modify the phenotypes. We performed genetic testing consisting of C9orf72 hexanucleotide expansion, ATXN2 polyglutamine (polyQ) expansion, and targeted next generation sequencing using the ONDRISeq, a gene panel consisting of 80 genes known to be associated with neurodegenerative diseases such as ALS, FTD, Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment. In addition to the C9orf72 expansion, we observed an ATXN2 polyQ intermediate length expansion, and OPTN p.Met468Arg in patients who exhibited ALS and FTD or bvFTD. We conclude that the C9orf72 expansion likely explains much of the ALS‐FTD phenotype; however, inheritance of these additional variants likely modifies the disease course and may provide further evidence for biologically relevant oligogenic inheritance in ALS.

Background: Nonvascularized bone grafting (NVBG) and vascularized bone grafts (VBGs) have been used to treat scaphoid nonunions. A comparison of a single institution’ s experience using structural iliac crest bone graft (ICBG), 1,2-intercompartmental supraretinacular artery (1,2-ICSRA), and medial femoral condyle (MFC) grafts to treat scaphoid nonunions was undertaken. Methods: Thirty-one patients underwent ICBG, 33 patients underwent 1,2-ICSRA, and 45 patients underwent MFC grafting. Mean time to follow-up was 16 months (range, 2-153). Twenty-three percent used tobacco products. Mean age was 24 years (range, 11-66), with 86% male patients. Outcomes included union rate, time to healing, range of motion, complications, and reoperations. Results: Union rates and mean time to union were 71% and 19 weeks for the ICBG group, 79% and 26 weeks for the 1,2-ICSRA group, and 89% and 16 weeks for the MFC group, respectively. Failure of union was associated with tobacco use but not with age, gender, time from injury to surgery, or type of fixation. There was no significant difference between the groups regarding range of motion or strength. Conclusions: These findings demonstrate the need for careful patient selection. In patients with the most complicated scaphoid nonunions (avascular necrosis, carpal collapse, and previous surgeries), the MFC group had the highest union rate and fastest time to union. Patients with risk factors for failure should be counseled on the outcomes and possible need for salvage fusion surgery.