Citations

Objectives: Objectives: Previous analyses have characterized the incidence of lateral meniscus oblique radial tears (LMORT) commonly seen with ACL tears, and their impact on joint and meniscus stability in the presence of ACL deficiency. Purpose: To determine the clinically relevant kinematics associated with LMORT lesions untreated versus arthroscopic repair versus partial meniscectomy in combination with anterior cruciate ligament reconstruction (ACLR). Methods: Sixteen cadaver knees underwent robotic testing for anterior drawer (AD) and pivot shift (PS) simulations at multiple knee flexion angles in intact and ACL-deficient states, followed by sequential testing of arthroscopic ACL reconstruction (ACLR), creation of a LMORT 3 lesion, LMORT 3 repair, and partial meniscectomy (PM; n=8). The same testing sequence was performed for LMORT 4 lesions (n=8). Changes (Δ) from the intact state for anterior translation, internal rotation, and valgus displacements, as well as ultrasoundographic measurements of meniscal extrusion, were measured and comparatively analyzed. Results: ACLR restored kinematics in ACL-deficient knees to intact levels for all metrics tested. For AD, ACLR + LMORT3 tear and PM resulted in significantly greater anterior translation (0.8-2.1 mm differences) compared to ACL-intact at all angles ( P < 0.05) and compared to ACLR at 60 o and 90 o ( P < 0.014). For PS, ACLR + LMORT3 tear had significantly more anterior translation (1-1.4 mm differences) at 15 o than intact knees (P=0.041), and at 0 o and 15 o for PM ( P < 0.03). ACLR + LMORT4 tear and PM resulted in significantly greater anterior translation (0.9-2.3 mm differences) for AD ( P < 0.04) and PS testing ( P < 0.05) compared to intact and ACLR knees at all angles tested. ACLR+LMORT 3 repair and ACLR+LMORT4 repair restored kinematics to ACLR and intact levels at all angles tested. ACLR + LMORT3 tear ( P < 0.008) and both LMORT4 tear and PM ( P < 0.05) resulted in increased meniscal extrusion (1.8-11 mm differences) compared to intact and ACLR statuses at all tested angles for AD and PS while repairs restored meniscus stability to ACLR and intact levels. Conclusions: Untreated LMORT 3 and 4 tears increased anterior translation, pivot shift, and meniscus extrusion even after ACLR, while partial meniscectomy further exacerbated these detrimental effects. In contrast, arthroscopic side-to-side repair of LMORT lesions effectively restored measured knee kinematics. UPLOAD- https://planion-client-files.s3.amazonaws.com/AOSSM/blobs/6bf43418-abf1-49bd-b78b-cc0c501a2da0/1/AOSSM_Abstract_Images.docx UPLOAD- https://planion-client-files.s3.amazonaws.com/AOSSM/blobs/b0f0bf53-a166-4cec-bf73-176ea452b905/1/AOSSM_Abstract_CHART.docx

Mitochondria are a dynamic eukaryotic innovation that play diverse roles in biology and disease. The mitochondrial genome is remarkably conserved in all vertebrates, encoding the same 37-gene set and overall genomic structure, ranging from 16,596 base pairs (bp) in the teleost zebrafish (Danio rerio) to 16,569 bp in humans. Mitochondrial disorders are amongst the most prevalent inherited diseases, affecting roughly 1 in every 5000 individuals. Currently, few effective treatments exist for those with mitochondrial ailments, representing a major unmet patient need. Mitochondrial dysfunction is also a common component of a wide variety of other human illnesses, ranging from neurodegenerative disorders such as Huntington’s disease and Parkinson’s disease to autoimmune illnesses such as multiple sclerosis and rheumatoid arthritis. The electron transport chain (ETC) component of mitochondria is critical for mitochondrial biology and defects can lead to many mitochondrial disease symptoms. Here, we present a publicly available collection of genetic mutants created in highly conserved, nuclear-encoded mitochondrial genes in Danio rerio. The zebrafish system represents a potentially powerful new opportunity for the study of mitochondrial biology and disease due to the large number of orthologous genes shared with humans and the many advanced features of this model system, from genetics to imaging. This collection includes 15 mutant lines in 13 different genes created through locus-specific gene editing to induce frameshift or splice acceptor mutations, leading to predicted protein truncation during translation. Additionally, included are 11 lines created by the random insertion of the gene-breaking transposon (GBT) protein trap cassette. All these targeted mutant alleles truncate conserved domains of genes critical to the proper function of the ETC or genes that have been implicated in human mitochondrial disease. This collection is designed to accelerate the use of zebrafish to study many different aspects of mitochondrial function to widen our understanding of their role in biology and human disease.

AbstractBackground and AimEarly readmissions of spontaneous bacterial peritonitis (SBP) are often associated with poor outcomes. We compared characteristics and outcomes for index and 30‐day readmissions of SBP in the USA.MethodsWe analyzed the Nationwide Readmissions Database for 2018 to identify all adult (≥ 18 years) 30‐day readmissions of SBP in the USA. Hospitalization characteristics and outcomes for index and 30‐day readmissions of SBP were compared. Independent predictors of 30‐day readmissions were also identified.ResultsIn 2018, of the 5,797 index admissions for SBP, 30% (1726) were readmitted within 30 day. At the time of readmission, the most common admitting diagnosis was alcoholic cirrhosis of the liver with ascites (11.8%) followed by sepsis due to an unspecified organism (9.2%). SBP as an admitting diagnosis was identified for only 8.3% of these 30‐day readmissions. Compared with index admissions, 30‐day readmissions of SBP had a lower mean age (56.1 vs 58.6 years, P < 0.001) without a statistically significant difference for gender. Furthermore, 30‐day readmissions of SBP were associated with significantly higher odds of inpatient mortality (10% vs 4.9%, OR: 2.15, 95% CI: 1.66–2.79, P < 0.001), and mean total hospital charge ($85,031 vs $56,000, mean difference: 29,032, 95% CI: 12,867–45,197, P < 0.001) compared with index admissions. The presence of chronic pulmonary disease, liver failure, inpatient dialysis, and discharge against medical advice were identified as independent predictors for increased 30‐day readmissions of SBP.ConclusionThe 30‐day readmission rate of SBP was 30% and these readmissions were associated with higher odds of inpatient mortality compared with index admissions.

PURPOSE Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression–based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis. MATERIALS AND METHODS We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays. RESULTS In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen–derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners. CONCLUSION We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.

Background: Lateral meniscal oblique radial tears (LMORTs) affect joint and meniscal stability in anterior cruciate ligament (ACL)–deficient knees. Purpose: To determine the clinically relevant kinematics associated with the most common posterior horn LMORT lesion types, types 3 (LMORT3) and 4 (LMORT4), untreated versus arthroscopic repair versus partial meniscectomy in combination with ACL reconstruction (ACLR). Study: Controlled laboratory study. Methods: Sixteen cadaveric knees underwent robotic testing for anterior drawer and pivot-shift simulations at multiple knee flexion angles in ACL-intact and ACL-deficient states, followed by sequential testing of arthroscopic ACLR, LMORT3 lesion, LMORT3 repair, and partial meniscectomy (n = 8). The same testing sequence was performed for LMORT4 lesions (n = 8). Results: ACLR restored kinematics in ACL-deficient knees to intact levels for all metrics tested. For anterior drawer, ACLR + LMORT3 tear and partial meniscectomy resulted in significantly greater anterior translation compared with ACL-intact at all angles ( P < .05) and compared with ACLR at 60° and 90° ( P < .014). For pivot shift, compared with ACL-intact knees, ACLR + LMORT3 tear resulted in significantly more anterior translation at 15° ( P = .041); and for ACLR + partial meniscectomy, at both 0° and 15° ( P < .03). ACLR + LMORT4 tear and partial meniscectomy resulted in significantly greater anterior translation for anterior drawer ( P < .04) and pivot-shift testing ( P < .05) compared with intact and ACLR knees at all angles tested. ACLR + LMORT3 repair and ACLR + LMORT4 repair restored kinematics to ACLR and intact levels at all angles tested. ACLR + LMORT3 tear ( P < .008) and both LMORT4 tear and partial meniscectomy ( P < .05) resulted in increased meniscal extrusion compared with intact and ACLR statuses at all tested angles for anterior drawer and pivot shift, while repairs restored meniscal stability to ACLR and intact levels. Conclusion: Untreated LMORT tears increased anterior translation, pivot shift, and meniscal extrusion after ACLR, while partial meniscectomy further exacerbated these detrimental effects in this cadaveric model. In contrast, arthroscopic side-to-side repair of LMORT lesions effectively restored measured knee kinematics. Clinical Relevance: LMORT lesions are common with ACL tears and adversely affect joint stability and meniscal extrusion. This study highlights the importance of repair of LMORT 3 and 4 lesions at the time of ACLR.

Abstract Purpose Management reasoning is a critical yet understudied phenomenon in clinical practice and medical education. The authors sought to empirically identify key features of management reasoning and construct a model describing the management reasoning process. Method In November 2020, 4 investigators each reviewed 10 video clips of simulated outpatient physician–patient encounters and used a coding form to document key features and insights related to management reasoning. The team used a constant comparative approach to distill 120 pages of raw observations into an 18-page list of management tasks, processes, and insights. The team then had a series of discussions to iteratively refine these findings into a parsimonious model of management reasoning. Results The investigators empirically identified 12 distinct features of management reasoning: contrasting and selection among multiple solutions; prioritization of patient, clinician, and system preferences and constraints; communication and shared decision making; ongoing monitoring and adjustment of the management plan; dynamic interplay among people, systems, and competing priorities; illness-specific knowledge; process knowledge; management scripts; clinician roles as patient teacher and salesperson; clinician–patient relationship; prognostication; and organization of the clinical encounter (sequencing and time management). Management scripts seemed to play a prominent and critical role. The model of management reasoning comprised 4 steps: instantiation of a management script, identifying (multiple) options and beginning to teach the patient, shared decision making, and ongoing monitoring and adjustment. This model also conceives 2 overarching features: that management reasoning is personalized to the patient and that it occurs between individuals rather than exclusively within the clinician’s mind. Conclusions Management scripts constitute a key feature of management reasoning, along with teaching patients about viable options, shared decision making, ongoing monitoring and adjustment, and personalization. Management reasoning seems to be constructed and negotiated between individuals rather than exclusively within the clinician.

Purpose An essential yet oft-neglected step in cost evaluations is the selection of resources (ingredients) to include in cost estimates. The ingredients that most influence the cost of physician continuous professional development (CPD) are unknown, as are the relative costs of instructional modalities. This study’s purpose was to estimate the costs of cost ingredients and instructional modalities in physician CPD. Method The authors conducted a systematic review in April 2020, searching MEDLINE, Embase, PsycInfo, and the Cochrane Library for comparative cost evaluations of CPD for practicing physicians. Two reviewers, working independently, screened articles for inclusion and extracted information on costs (converted to 2021 U.S. dollars) for each intervention overall, each ingredient, and each modality. Results Of 3,338 eligible studies, 62 were included, enumerating costs for 86 discrete training interventions or instructional modalities. The most frequently reported ingredients were faculty time (25 of 86 interventions), materials (24), administrator/staff time (23), and travel (20). Ingredient costs varied widely, ranging from a per-physician median of $4 for postage (10 interventions) to $525 for learner time (13); equipment (9) and faculty time were also relatively expensive (median > $170). Among instructional modalities (≤ 11 interventions per modality), audit and feedback performed by physician learners, computer-based modules, computer-based virtual patients, in-person lectures, and experiences with real patients were relatively expensive (median > $1,000 per physician). Mailed paper materials, video clips, and audit and feedback performed by others were relatively inexpensive (median ≤ $62 per physician). Details regarding ingredient selection (10 of 62 studies), quantitation (10), and pricing (26) were reported infrequently. Conclusions Some ingredients, including time, are more important (i.e., contribute more to total costs) than others and should be prioritized in cost evaluations. Data on the relative costs of instructional modalities are insightful but limited. The methods and reporting of cost valuations merit improvement.

Background and objectives C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, & measurements To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

ObjectivePatients with myelin oligodendrocyte glycoprotein antibody (MOG‐IgG)‐associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro‐axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON‐independent retinal atrophy can be detected in MOGAD.MethodsEighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high‐definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified.ResultsAt baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD‐ON) compared with MOGAD eyes without a history of ON (MOGAD‐NON) and HCs (p < 0.001). MOGAD‐NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow‐up up to 3 years), MOGAD‐ON with ON within the last 6–12 months before baseline exhibited greater pRNFL thinning than MOGAD‐ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort.InterpretationOur study suggests the absence of attack‐independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD. ANN NEUROL 2022;92:476–485

Abstract Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4–69.3; P = 1.3 × 10−7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.