Citations

AbstractObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel‐based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

AbstractThe purpose of this study was to determine patient-reported outcomes, hardware removal rates, as well as conversion to arthroplasty at mid-term follow-up following high tibial osteotomy (HTO) with a modern polyetheretherketone (PEEK) system. All PEEK system-based HTOs performed at a single institution between January 2010 and January 2016 with a minimum of 2 years follow-up were reviewed. Rates of postoperative complications, hardware removal and conversion to arthroplasty were calculated. Patient-reported outcomes including visual analog pain scale (VAS), Tegner activity scale, Lysholm, Knee Injury and Osteoarthritis Outcome Score (KOOS), and 36-Item Short Form Survey (SF-36) were obtained. Forty-seven HTOs in 43 patients (mean age: 37.6 ± 10.8 years; 30 M, 13 F) were followed for a mean of 6.0 ± 1.5 years. A total of four postoperative complications occurred in three patients, resulting in an overall complication rate of 6.4%. Hardware removal occurred in three patients at a mean of 0.73 ± 0.53 years after surgery, with overall survival free of hardware removal of 96% (95% confidence interval [CI]: 85–99) at 1 year, 94% (95% CI: 82–98) at 2 years, and 94% (95% CI: 82–98) at 8 years. Conversion to arthroplasty occurred in three patients at a mean of 3.2 ± 1.0 years after surgery, with mean survival of 100% (95% CI: 94–100) at 1 year, 100% (95% CI: 94–100) at 2 years, and 93% (95% CI: 81–98) at 8 years. VAS at rest improved, from 3.1 ± 2.5 preoperatively to 1.1 ± 1.6 postoperatively (p < 0.001). Patients remained active, with a mean Tegner activity scale of 4.4 ± 1.4 at final follow-up and satisfactory Lysholm, KOOS, and SF-36 scores. At mid-term follow-up, medial opening-wedge HTO using a modern PEEK-based system was found to be safe, efficacious, and durable, with satisfactory outcome scores and a low rate of conversion to arthroplasty. PEEK-based implants were found to have low hardware removal rates of 6% at 5 years, which compares favorably to historic metal fixation. This is a Level III study.

Abstract A variety of options exist for management of patients with developmental dysplasia of the hip (DDH). Most studies to date have focused on clinical outcomes; however, there are currently no data on comparative cost of these techniques. The purpose of this study was to evaluate in-hospital costs between patients managed with periacetabular osteotomy, hip arthroscopy or a combination for DDH. One hundred and nine patients were included: 35 PAO + HA, 32 PAO and 42 HA. There were no significant differences in the demographic parameters. Operative times were significantly different between groups with a mean of 52 min for PAO, 100 min for HA and 155 min for PAO + HA, (P &lt; 0.001). Total direct medical costs were calculated and adjusted to nationally representative unit costs in 2017 inflation-adjusted dollars. Total in-hospital costs were significantly different between each of the three treatment groups. PAO + HA was the most expensive with a median of $21 852, followed by PAO with a median of $15 124, followed by HA with a median of $11 582 (P &lt; 0.001). There was a significant difference between outpatient median costs of $11 385 compared with $24 320 for inpatients (P &lt; 0.001). Procedures with greater complexity were more expensive. However, a change from outpatient to inpatient status with HA moved that group from the least expensive to similar to PAO and PAO + HA. These data provide an important complement to clinical outcomes reports as surgeons and policymakers aim to provide optimal value.

AbstractFebrile infection‐related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL‐1 receptor antagonist that blocks biologic activity of IL‐1β) are recommended.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

The COVID-19, due to SARS-CoV-2, has uncovered many real-world issues when it comes to healthcare management and has led to a widespread mortality. Observations thus far from the reports of COVID-19 have indicated that certain risk groups for example, those with pre-existing cardiovascular (CV) disease, hypertension, diabetes, chronic kidney disease and tobacco use are prone to disease development and specifically development of severe disease and possible fatality. It is increasingly evident that many CV conditions occur frequently. These include myopericarditis, acute coronary syndromes, thrombosis, arrhythmias, hypertension and heart failure. Many professional organisations and societies related to cardiology have produced guidelines or recommendations on most of the above-mentioned aspects. Given these rapid developments, the aims of this review manuscript were to summarise and integrate recent publications with newly developed guidelines and with the first-hand experience of frontline physicians and to yield a pragmatic insight and approach to CV complications of COVID-19. We emphasise on a strategic tier-based approach for initial assessment and management of COVID-19, and then delve into focused areas within CV domains, and additionally highlighting the role of point-of-care ultrasound especially lung ultrasound, echocardiography and electrocardiography, in the management of these patients. We hope this paper will serve as a useful tool in the CV management of COVID-19 for clinicians practicing in both developing and developed countries.

Background: Meniscus root tears are increasingly being recognized. Meniscal extrusion has previously been associated with medial root tears; however, the relationship between secondary meniscal restraints, such as the meniscotibial (MT) ligament, extrusion, and root tears has yet to be formally evaluated. Purpose: To better understand the association between MT ligament competence, medial meniscal extrusion, and medial meniscus posterior root tears (MMPRTs) as well as to determine the progression of meniscal extrusion over time. Study Design: Case series; Level of evidence, 4. Methods: Serial magnetic resonance imaging (MRI) scans were reviewed for patients who showed evidence of medial meniscal extrusion and MMPRTs on at least 1 of ≥2 available MRI scans. All patients were symptomatic at the time of diagnosis. All MRI scans were analyzed independently by 2 board-certified musculoskeletal radiologists. MT ligament disruption, medial meniscal extrusion, and MMPRTs were recorded for each MRI scan. The time between MRI scans, presence of insufficiency fractures, and Outerbridge classification for the medial femur and tibia were also evaluated. Results: Overall, 27 knees in 26 patients were included in this study, with a total of 63 MRI scans analyzed (21 knees with 2 MRI scans, 3 with 3 MRI scans, and 3 with 4 MRI scans). All patients demonstrated clear medial meniscal extrusion and MT ligament disruption before the subsequent development of MMPRTs ( P < .001). Mean extrusion at the time of initial MRI was 3.3 ± 1.1 mm and increased significantly to 5.5 ± 1.8 mm at the time of first imaging with an identified MMPRT ( P < .001). The mean time between initial MRI and the first identification of an MMPRT on later MRI was 1.7 ± 1.6 years. Conclusion: In a sample of 27 symptomatic knees with serial MRI scans both before and after an MMPRT diagnosis, all patients demonstrated MT ligament disruption and associated meniscal extrusion before the development of subsequent medial meniscus root tears. These findings suggest that MT ligament disruption and medial meniscal extrusion represent early and predisposing events contributing to MMPRTs. Therefore, this provides a possible explanation of why meniscal extrusion is not corrected with medial meniscus root repair.

Abstract Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28BR25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b C211T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.