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Background:Hereditary transthyretin amyloidosis (hATTR) is a rare protein misfolding disorder that causes progressive and debilitating polyneuropathy. A randomized, controlled phase 3 trial (NEURO‐TTR; NCT01737398) demonstrated efficacy and safety of inotersen in patients with hATTR polyneuropathy (Benson 2018 NEJM).Aims:To provide an update on the long‐term efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of transthyretin protein production, in patients with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy.Methods:Patients who completed NEURO‐TTR were eligible to enroll in an ongoing open‐label extension (OLE) study (NCT02175004). We report an update on the long‐term efficacy and safety of inotersen in patients with hATTR polyneuropathy after 24 months in the OLE. Assessments included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7), Norfolk Quality of Life–Diabetic Neuropathy questionnaire total score (Norfolk QoL‐DN), Short Form 36 Health Survey version 2 (SF‐36v2) physical component summary (PCS), and safety monitoring.Results:Of 139 patients who completed NEURO‐TTR, 135 (97.1%) enrolled in the OLE. As of 5/31/2018, some patients were ongoing but had not yet completed 24 months in the OLE, and longest inotersen exposure in both studies was 5.2 years. Patients who switched from placebo to inotersen in the OLE demonstrated slowing of neurologic disease progression by mNIS+7 and Norfolk QoL‐DN as early as 6 months after starting inotersen (mean change from OLE baseline to month 6/year 2: 6.22/5.08 for mNIS+7 and 0.54/2.26 for Norfolk QoL‐DN). Patients who received inotersen for 39 months (15 months NEURO‐TTR + 24 months OLE) continued to show benefit (mean change from OLE baseline to year 2: 11.18 for mNIS+7 and 5.22 for Norfolk QoL‐DN). Patients who continued inotersen also showed stabilization of health‐related quality of life measured by SF‐36v2 PCS. No evidence of increased risk for grade 4 thrombocytopenia or severe renal events has been observed with increased exposure duration; no new safety concerns have been identified.Summary/Conclusion:In the OLE, inotersen improved, halted, or slowed progression of hATTR polyneuropathy, with greater stabilization observed in patients who initiated inotersen earlier.

Background. Kidneys from deceased donors with acute kidney injury (AKI) are more likely to be discarded because of concerns for poor outcomes after transplantation. The aim of this study was to determine the long-term outcomes of a large cohort of patients transplanted utilizing kidneys from deceased donors with AKI. Methods. All patients receiving a deceased donor kidney transplant during a recent 10-year period were included. Acute Kidney Injury Network (AKIN) criteria were used to classify the donors. Donor kidneys with >10% cortical necrosis or more than mild chronic changes were discarded. The primary outcome is the combined endpoint of death or graft loss. Results. The cohort included 1313 kidneys from 974 donors, AKIN stage 0 (no AKI) in 319 (24.3%), stage 1 in 370 (28.2%), stage 2 in 177 (13.5), and stage 3 in 447 (34.0%). Estimated 5-year graft survival (95% confidence interval) was 78.5% (72.5-84.5), 77.8% (72.8-82.1), 83.8% (76.8-88.9), and 84.6% (79.5-88.7) for AKIN donor stage 0 to 3, respectively (log-rank P = 0.10). After adjusting for baseline differences, the hazard ratio (95% confidence interval) for the combined endpoint for the AKIN stage 3 group (relative to AKIN 0 group) was 0.70 (0.45-1.10). Delayed graft function occurred in 44.6% and 75.4% of AKIN 2 and 3 groups, as compared to 33.9% and 33.5% in AKIN 0 and 1 ( P < 0.001). Conclusion. We conclude that transplanting selected kidneys from deceased donors with AKI with preimplantation biopsy showing <10% cortical necrosis and no more than mild chronic changes have excellent long-term graft survival.

AbstractIntroductionAutonomic modulation has been used as a therapy to control recurrent ventricular arrhythmia (VA). This study was to explore stellate ganglion block (SGB) effect on cardiac electrophysiologic properties and evaluate the long‐term outcome of cardiac sympathetic denervation (CSD) for patients with recurrent VA and structural heart disease (SHD).Materials and MethodsPatients who had recurrent VA due to SHD were enrolled prospectively. Electrophysiologic study and ventricular tachycardia (VT) induction were performed before and after left and right SGB. VA burden and long‐term outcomes were assessed for a separate patient group who underwent left or bilateral CSD for drug‐refractory VA due to SHD.ResultsElectrophysiologic study of nine patients showed that baseline mean (SD) corrected sinus node recovery time (cSNRT) increased from 320.4 (73.3) ms to 402.9 (114.2) ms after left and 482.4 (95.7) ms after bilateral SGB (P = .03). SGB did not significantly change P‐R, QRS, and Q‐T intervals and ventricular effective refractory period, nor did the inducibility of VA. Nineteen patients underwent left (n = 14) or bilateral (n = 5) CSD. CSD reduced VA burden and appropriate ICD therapies from a median (interquartile range) of 2.5 (0.4‐11.6) episodes weekly to 0.1 (0.0‐2.4) episodes weekly at 6‐month follow‐up (P = .002). Three‐year freedom from orthotopic heart transplant (OHT) and death was 52.6%. New York Heart Association functional class III/IV and VT rate less than 160 beats per minute were predictors of recurrent VA, OHT, and death.ConclusionSGB increased cSNRT without changing heart rate. CSD was more beneficial for patients with mild‐to‐moderate heart failure and faster VA.

AbstractBackgroundStudies have suggested transplantation using older donor livers results in similar short‐term outcomes as younger donor livers; however, little data exist on long‐term patient/graft outcomes of the octogenarian liver recipient.MethodsRetrospective data were collected from 2 centers, (Valencia, Spain and Rochester, MN, USA) of all recipients of octogenarian donor liver allografts from 2000 to 2011 with follow‐up to 2016. The aim was to compare long‐term patient/graft survival as well as metabolic outcomes of the recipient with the octogenarian liver vs younger than 60 years donor.Results78 recipients of older liver allografts were compared to 78 matched controls. No difference in 10‐year patient mortality was demonstrated (P = 0.074). Octogenarian livers were associated with 3‐fold higher likelihood of graft failure (P = 0.002) but no increase in the risk of post‐LT cardiovascular disease (P = 0.60), hypertension (P = 0.33), vascular complications (P = 0.53), or malignancy (P = 0.14). In multivariate analysis, elder livers remained a significant factor associated with rejection (P = 0.034) with a trend not reaching statistical significance for graft failure (P = 0.052).ConclusionsFor appropriately selected recipients, receiving an octogenarian liver does not clearly influence patient survival but does impact early graft survival with a notable increase in early posttransplant rejection rates and re‐transplantation. Over 1.5 decades, older allografts have not adversely affected metabolic outcomes.

Background: Some prior reports of total knee arthroplasty after high tibial osteotomy have shown high rates of aseptic loosening. As such, the goal of this study was to analyze the outcomes of contemporary total knee arthroplasty after high tibial osteotomy, with particular emphasis on survivorship free from aseptic loosening, any revision, and any reoperation; complications; radiographic results; and clinical outcomes. Methods: We retrospectively reviewed 207 patients who underwent 231 total knee arthroplasties using cemented prostheses after high tibial osteotomy from 2000 to 2012 through our total joint registry: 87% were after a closing-wedge osteotomy and 13% were after an opening-wedge osteotomy. The mean follow-up from total knee arthroplasty was 8 years. At the time of the total knee arthroplasty, the mean age was 64 years and the mean body mass index was 31 kg/m 2 . The majority of total knee arthroplasties had a posterior-stabilized design (93%), and 4% had a varus-valgus constraint design. Tibial stems were utilized in 8% of cases. Bivariate and multivariate Cox regression analyses were utilized to analyze risk factors for poorer survival. Results: At 10 years, survivorship free from aseptic loosening was 97%, survivorship free from any revision was 90%, and survivorship free from any reoperation was 85%. Fifteen patients (15 total knee arthroplasties [6%]) underwent aseptic revision, most commonly for instability (3%), aseptic loosening (2%), and periprosthetic fracture (1%). On bivariate analysis, patient age of <60 years was a significant risk factor for poorer revision-free survival (hazard ratio, 2.9; p = 0.02); on multivariate analysis, younger age was the only significant risk factor for revision (p = 0.04). There were 14 complications (6%), the most common being a manipulation under anesthesia in 9 cases (4%). No unrevised total knee arthroplasties had definitive radiographic evidence of loosening. Knee Society scores improved from a mean preoperative score of 59 points to a mean postoperative score of 93 points (p < 0.001). Conclusions: Contemporary total knee arthroplasty with a cemented prosthesis after high tibial osteotomy demonstrated excellent long-term durability, with 10-year survivorship free from aseptic loosening of 97%. There was reliable improvement in clinical outcomes, but perfect knee balance was sometimes challenging, as reflected by a 4% prevalence of manipulation under anesthesia and a 3% prevalence of revision for instability. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Human herpesviruses 6 (HHV-6) A and B cause encephalitis in patients with hematologic malignancies, especially those undergoing allogeneic hematopoietic stem cell transplantation. In this cohort of 10 patients, persistent neurologic deficits associated with moderate to severe bilateral hippocampal atrophy were characteristic long-term findings, despite prolonged antiviral treatment.

AimsThere is little literature about total knee arthroplasty (TKA) after distal femoral osteotomy (DFO). Consequently, the purpose of this study was to analyze the outcomes of TKA after DFO, with particular emphasis on: survivorship free from aseptic loosening, revision, or any re-operation; complications; radiological results; and clinical outcome.Patients and MethodsWe retrospectively reviewed 29 patients (17 women, 12 men) from our total joint registry who had undergone 31 cemented TKAs after a DFO between 2000 and 2012. Their mean age at TKA was 51 years (22 to 76) and their mean body mass index 32 kg/m2(20 to 45). The mean time between DFO and TKA was ten years (2 to 20). The mean follow-up from TKA was ten years (2 to 16). The prostheses were posterior-stabilized in 77%, varus-valgus constraint (VVC) in 13%, and cruciate-retaining in 10%. While no patient had metaphyseal fixation (e.g. cones or sleeves), 16% needed a femoral stem.ResultsThe ten-year survivorship was 95% with aseptic loosening as the endpoint, 88% with revision for any reason as the endpoint, and 81% with re-operation for any reason as the endpoint. Three TKAs were revised for instability (n = 2) and aseptic tibial loosening (n = 1). No femoral component was revised for aseptic loosening. Patients under the age of 50 years were at greater risk of revision for any reason (hazard ratio 7; p = 0.03). There were two additional re-operations (6%) and four complications (13%), including three manipulations under anaesthetic (MUA; 10%). The Knee Society scores improved from a mean of 50 preoperatively (32 to 68) to a mean of 93 postoperatively (76 to 100; p < 0.001).ConclusionA cemented posterior-stabilized TKA has an 88% ten-year survivorship with revision for any reason as the endpoint. No femoral component was revised for aseptic loosening. Patients under the age of 50 years have a greater risk of revision. The clinical outcome was significantly improved but balancing the knee was challenging in 13% of TKAs requiring VVC. Overall, 10% of TKAs needed an MUA, and 6% of TKAs were revised for instability. Cite this article: Bone Joint J 2019;101-B:660–666.

Abstract Background The aetiology of Crohn’s disease [CD] involves immune dysregulation in a genetically susceptible individual. Genome-wide association studies [GWAS] have identified 200 loci associated with CD, ulcerative colitis, or both, most of which fall within non-coding DNA regions. Long non-coding RNAs [lncRNAs] regulate gene expression by diverse mechanisms and have been associated with disease activity in inflammatory bowel disease. However, disease-associated lncRNAs have not been characterised in pathogenic immune cell populations. Methods Terminal ileal samples were obtained from 22 CD patients and 13 controls. RNA from lamina propria CD4+ T cells was sequenced and long intergenic non-coding RNAs [lincRNAs] were detected. Overall expression patterns, differential expression [DE], and pathway and gene enrichment analyses were performed. Knockdown of novel lincRNAs XLOC_000261 and XLOC_000014 was performed. Expression of Th1 or Th17-associated transcription factors, T-bet and RORγt, respectively, was assessed by flow cytometry. Results A total of 6402 lincRNAs were expressed, 960 of which were novel. Unsupervised clustering and principal component analysis showed that the lincRNA expression discriminated patients from controls. A total of 1792 lincRNAs were DE, and 295 [79 novel; 216 known] mapped to 267 of 5727 DE protein-coding genes. The novel lincRNAs were enriched in inflammatory and Notch signalling pathways [p &lt;0.05]. Furthermore, DE lincRNAs in CD patients were more frequently found in DNA regions with known inflammatory bowel disease [IBD]-associated loci. The novel lincRNA XLOC_000261 negatively regulated RORγt expression in Th17 cells. Conclusions We describe a novel set of DE lincRNAs in CD-associated CD4+ cells and demonstrate that novel lincRNA XLOC_000261 appears to negatively regulate RORγt protein expression in Th17 cells.

Background: During rehabilitation throwing programs, baseball players are commonly asked to throw at reduced levels of effort (ie, 50% effort, 75% effort, etc) to moderate stress to healing tissues. It is currently unknown how changes in players’ perceived exertion compares with changes in actual exertion during structured long-toss programs. Purpose: To determine whether decreased effort correlates with decreased throwing metrics, whether metrics decrease proportionally with reductions in perceived effort, and to quantify intrathrower variability. Study Design: Descriptive laboratory study. Methods: Sixty male high school and collegiate baseball pitchers participated in a structured throwing program. A motusBASEBALL sleeve was worn by all players, which measured elbow varus torque, arm velocity, arm slot, and shoulder rotation. Ball velocity was measured with a radar gun. Each pitcher threw 5 throws a distance of 120 ft with 3 efforts: maximum effort, 75% effort, and 50% effort. Throwing metrics were compared among the 3 levels of effort to see if each 25% decrease resulted in proportional decreases in elbow varus torque and ball velocity. Intrathrower variability was determined for each throwing metric at each degree of effort. Results: All throwing metrics decreased as players decreased their perceived effort ( P < .001). However, these observed decreases were much smaller in magnitude than the decreases in perceived effort. During the 75% effort throws, elbow varus torque was only reduced to 93% of maximum and velocity dropped to 86% of maximum. Similarly, for the 50% effort throws, elbow varus torque remained 87% of max effort torque, while velocity remained 78% of max. Intrathrower reliability was considered excellent for most metrics (intraclass correlation coefficient, >0.75). Conclusion: For every 25% decrease in perceived effort, elbow varus torque only decreased 7% and velocity only decreased 11%. Thus, when players throw at what they perceive to be reduced effort, their actual throwing metrics do not decrease at the same rate as their perceived exertion. Clinical Relevance: Measured effort decreased with decreasing perceived effort, but these were not proportional. This has significant implications for physical therapists, physicians, trainers, coaches, and athletes to understand and monitor elbow stress during the rehabilitation process.

Background Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. Methods Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or discontinued the study. Adult patients with episodic migraine enrolled in the open-label treatment phase initially received 70 mg erenumab monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events, electrocardiograms, laboratory assessments, and vital signs. Results Of 383 patients enrolled in the open-label treatment phase, at data cutoff 235 (61.3%) remained in the study, all received 140 mg for ≥1 year. Median (Q1, Q3) exposure (70 or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. The most frequent adverse events (≥4.0/100 patient-years) were reported as viral upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious adverse event rates were 4.2/100 patient-years. There was no increase in cardiovascular events over time. Conclusions In this long-term study of a CGRP-receptor antibody, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. Trial registration ClinicalTrials.gov NCT01952574