Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.

Older, self-identifying gay men's conceptualisations of psychological well-being (PWB): A Canadian perspective.

Many older gay men experience diminished psychological well-being (PWB) due to unique circumstances including discrimination, living with HIV, and aging through the HIV/AIDS crisis. However, there remains ambiguity as to how older gay men define and understand PWB. Our team interviewed and analyzed the accounts of 26 older (50+) self-identifying English-speaking men living in southwestern British Columbia, Canada. We drew on tenets of constructivist grounded theory and intersectionality to account for unique contextual considerations and power relations. Semi-structured Zoom interviews were conducted from August-October 2022. Interview transcripts were compared to generate high-order conceptual findings underpinned by processes understood as central to PWB. Three PWB temporal processes highlighted interlocking social and contextual circumstances intersecting with power and maturation: (1) being emotionally balanced, (2) living gratitude (3) and fully embracing self-acceptance. Being emotionally balanced supported the affective and sustainable state of contentment, living gratitude drew from the wisdom of accrued experiences to cultivate a positive affective state inclusive to recognising social location privileges, whilst fully embracing self-acceptance redressed the harms of anti-gay discourses that men endured throughout their lives. The knowledge is relevant to service and resource development to deliver tailored PWB supports to older gay men.

Performance of the 2016 ACR-EULAR Myositis Response Criteria in adult dermatomyositis/polymyositis therapeutic trials and consensus profiles.

OBJECTIVE: The ACR-EULAR Myositis Response Criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength vs extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening. METHODS: Data from adult dermatomyositis/polymyositis patients in the rituximab (n = 147), etanercept (n = 14), and abatacept (n = 19) trials, and consensus patient profiles (n = 232) were evaluated. The Total Improvement Score (TIS), number of improving vs worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC. RESULTS: Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories. CONCLUSION: The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials.

Frequency and type of cancers in myotonic dystrophy: A retrospective cross-sectional study.

INTRODUCTION/AIMS: Myotonic dystrophies (DMs) are autosomal dominant diseases in which expression of a mutant expanded repeat mRNA leads to abnormal splicing of downstream effector genes thought to be responsible for their multisystem involvement. Cancer risk and cancer-related deaths are increased in DM patients relative to the general population. We aimed at determining the frequency and type of cancers in both DM1 and DM2 vs a non-DM muscular dystrophy cohort. METHODS: A retrospective, cross-sectional study was carried out on patients with genetically confirmed DM1, DM2, facioscapulohumeral muscular dystrophy (FSHD), and oculopharyngeal muscular dystrophy (OPMD) at our institutions from 2000 to 2020. RESULTS: One hundred eighty-five DM1, 67 DM2, 187 FSHD, and 109 OPMD patients were included. Relative to non-DM, DM patients had an increased cancer risk that was independent of age and sex. Specifically, an increased risk of sex-related (ovarian) and non-sex-related (non-melanoma skin, urological, and hematological) cancers was observed in DM1 and DM2, respectively. The length of CTG repeat expansion was not associated with cancer occurrence in the DM1 group. DISCUSSION: In addition to current consensus-based care recommendations, our findings prompt consideration of screening for skin, urological, and hematological cancers in DM2 patients, and screening of ovarian malignancies in DM1 female patients.

Neuromuscular Complications of COVID-19: Evidence from the Third Year of the Global Pandemic.

Accumulating evidence in the third year of the global pandemic suggests that coronavirus disease 2019 (COVID-19) can cause neuromuscular complications during or after the acute phase of infection. Direct viral infection and immune-mediated mechanisms have been hypothesized. Furthermore, in patients with underlying autoimmune neuromuscular diseases, COVID-19 infection may trigger a disease flare. COVID-19 vaccines appear to be safe and effective at preventing severe illness from COVID-19. Certain vaccines are associated with an increased risk of Guillain-Barré syndrome and possibly Bell's palsy, but the absolute incidence is low, and benefits likely outweigh the risks. Newer prophylactic therapies and treatments are also becoming available for patients who may not mount a sufficient response to vaccination or have contraindications. In this article, we discuss the current available evidence on neuromuscular complications of COVID-19 and clinical considerations regarding vaccination.

Mitochondrial DNA Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases.

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty-four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021;89:1240-1247.

Carbon conundrums: Do United States' current carbon market baselines represent an undesirable ecological threshold?

Relative frequency distribution of observed annual mortality expressed in aboveground (AG) carbon (C) (Mg CO2 e ha-1 year-1 ) summarized across supersections by forest type [Hardwood (HW) vs. Softwood (SW)] and site class (Low vs. High) based on approximately 130,000 remeasured USDA Forest Service Forest Inventory and Analysis plots across the US. Top panel summarizes conditions in plots that do and do not meet the California Air Resources Board standards based on total basal area, whereas bottom panel summarizes conditions in plots falling inside and outside of optimum relative density levels. The latter represents a biophysically-informed approach accounting for changes in tree (and carbon) packing over forest development.

Safety and outcomes of eculizumab for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice.

INTRODUCTION/AIMS: Safety and outcomes data on eculizumab for generalized myasthenia gravis (gMG) in clinical practice remain limited. Outcomes and concomitant medication use may differ in practice compared with clinical trials. We analyzed the clinical and safety outcomes of patients who received eculizumab at our institutions. METHODS: Patients with acetylcholine receptor antibody positive (AChR+) gMG, who received ≥1 dose of eculizumab and had ≥1 follow-up before December 10, 2021, were identified. Data were abstracted by chart review. Outcomes included MG Foundation of America Post Intervention Status (MGFA-PIS), Clinical Classification (MGFA-CC), MG-Activities of Daily Living (MG-ADL), concurrent immunomodulatory therapy use, and adverse events. RESULTS: Twelve patients were included. Mean age at eculizumab initiation was 57.4 y (range, 21-77). Eight had refractory MG. Four had history of thymoma and thymectomy. A mean of 3.2 (range, 2-5) immunomodulatory therapies were previously tried. Mean follow-up duration was 18 mo (range, 2-21.6). Clinical improvement occurred rapidly; MGFA-PIS was improved in 80%, and MGFA-CC improved in 83% at 1 mo. Mean MG-ADL decreased from 8.7 to 2.8 at 1 mo, and remained ≤3 .5 over 1.5 y. Mean daily prednisone dose decreased from 22.5 mg to 7.2 mg at 1.5 y. Five of 7 patients discontinued maintenance IVIG or PLEX. No patients had meningococcal infections and adverse events were mild. DISCUSSION: Clinical improvement occurred in most patients after eculizumab initiation, beginning as quickly as 1 mo. Steroids were tapered and maintenance IVIG and PLEX were discontinued in most. Eculizumab had a favorable safety profile even when combined with other immunosuppressants.

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.

Potential impacts of emerald ash borer and adaptation strategies on wildlife communities in black ash wetlands.

Black ash wetlands cover approximately 1.2 million ha of wetland forest in the western Great Lakes region, providing critical habitat for wildlife. The future of these wetlands is critically threatened by a variety of factors, including emerald ash borer (Agrilus planipennis; emerald ash borer [EAB]), which has been eliminating native populations of otherwise healthy ash throughout the Great Lakes region since it was discovered in 2002. To quantify the potential impacts of tree mortality from EAB on wildlife communities, we measured seasonal bird, mammal, and amphibian diversity in black ash wetlands using a dual approach: (1) documenting bird and amphibian species across 27 mature reference black ash wetlands in northern Minnesota, USA and (2) assessing how bird, mammal, and amphibian communities respond to experimental manipulations of black ash forests that emulate mortality and management strategies related to the potential impact of EAB. In total, 85 wildlife species were recorded for the entire study including 57 bird species, 5 amphibian species, and 23 mammal species. Results from the reference sites show that hydrologic regime, percentage of ash canopy cover, and understory cover were important habitat characteristics for bird and amphibian communities. Results from the experimental sites show there may be short-term increases in species richness for mammal and bird communities associated with changes in forest structure due to ash mortality; however, anticipated changes resulting from EAB-caused mortality, particularly the conversion of these sites to non-forested wetlands, will lead to significant shifts in bird and mammal community composition. Loss of ash may cause declines in forest-dependent species and increases in open-canopy and wetland-associated species. Additionally, whereas increased ponding extent and longer hydroperiods may be beneficial for some amphibian species, the loss of the forest canopy will result in an overall decrease in bird diversity and reduce forest connectivity for all species. Our results indicate the potential for significant large-scale impacts of black ash mortality on forest-associated wildlife. Management strategies that focus on establishing alternative trees species to maintain long-term forest cover and structural complexity in these wetlands will help to maintain and conserve wildlife diversity.

Removal of invasive Scotch broom increases its negative effects on soil chemistry and plant communities.

Recovery of ecosystem properties following removal of invasive plants likely varies with characteristics of the plant and the relative soil quality at a given site. These factors may influence the occurrence of soil legacies and secondary invasions, hindering the effectiveness of restoration strategies. We assessed the potential for ecosystem recovery following removal of N-fixing Scotch broom for 4 years at two sites that contrasted strongly in soil quality in western Washington and Oregon, USA. Comparisons were made among plots, where Scotch broom was never present (uninvaded), retained, or removed. Scotch broom removal increased PAR and soil temperature but had limited effects on soil moisture. Concentrations of soil Ca, Mg, K, and P were significantly lower with Scotch broom removal, with the effect being most pronounced at the low-quality site. NMS ordinations indicated that the treatments differed in vegetation composition, with limited recovery following broom removal. Non-native and native species varied inversely in their abundance responses, where non-native species abundance was greatest in the removal treatment, intermediate in the retained treatment, and lowest in the uninvaded treatment, indicating occurrence of a secondary invasion following removal. As with the soil response, effects were more pronounced at the low-quality site. Our findings indicate that Scotch broom removal exacerbates negative effects on soil chemistry and plant communities, with little evidence of recovery over our study period. These findings highlight the importance of controlling Scotch broom invasions immediately after the species establishes, especially on low-quality sites that are more susceptible to Scotch broom invasion.

Neuromuscular complications of coronavirus disease-19.

PURPOSE OF REVIEW: Since its outbreak in Wuhan, China in late 2019, coronavirus disease-19 (COVID-19) has become a global pandemic. The number of affected cases and deaths continues to rise. Primarily a respiratory illness, COVID-19 is now known to affect various organ systems including peripheral nerve and skeletal muscle. The purpose of this review is to discuss the scope of neuromuscular manifestations and complications of COVID-19. RECENT FINDINGS: Several neuromuscular conditions, including Guillain-Barré syndrome, rhabdomyolysis, and myositis, have been reported in patients infected with COVID-19, but even with a temporal association, a causal relationship remains unproven. Direct invasion of neurons or myocytes by the virus, and immune-mediated injury have been speculated but not consistently demonstrated. In addition to potentially causing the above conditions, COVID-19 can trigger exacerbations of preexisting neuromuscular conditions such as myasthenia gravis, and severe infections can lead to critical illness myopathy/polyneuropathy. SUMMARY: COVID-19 appears to be potentially associated with a wide range of neuromuscular manifestations and complications. Further studies are needed to examine these possible associations, understand the pathogenesis, and develop preventive and treatment strategies.

Retrospective analysis of safety and outcomes of rituximab for myasthenia gravis in patients ≥65 years old.

INTRODUCTION/AIMS: Optimal management of myasthenia gravis (MG) in individuals ≥65 y old is unknown and patient factors may limit therapeutic choices. Safety and efficacy of rituximab in older patients with MG has not been well-studied. METHODS: This retrospective study examined 40 patients (14 patients ≥65 y old) treated with rituximab for MG. The primary efficacy outcome was the proportion of patients reaching "Improved" or better on Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) at 12 mo, compared between younger and older patients. RESULTS: Ninety-two percent of patients ≥65 y old achieved MGFA PIS Improved or better at 12 mo compared to 69% of those <65 y old (P = .11). Median prednisone dose for the cohort decreased in the year following rituximab initiation (20 mg [interquartile range, 10-35] to 10 mg [0-13], P = .01). Non-refractory MG was predictive of favorable outcome, whereas age was not. Serious adverse events (SAEs) were similar between older and younger patients (21.4% vs. 30.8%, P = .715). No patients ≥65 y old required discontinuation of rituximab due to SAE. One death occurred in a patient <65 y old due to systemic inflammatory response syndrome. DISCUSSION: At 12 mo following initiation of rituximab for MG, patients ≥65 y old experienced similarly high rates of improvement in their myasthenic symptoms as younger patients, without an increased risk of experiencing SAEs. Rituximab should be considered in the treatment paradigm in older patients and in non-refractory MG patients of any age.

Forest density intensifies the importance of snowpack to growth in water-limited pine forests.

Warming climate and resulting declines in seasonal snowpack have been associated with drought stress and tree mortality in seasonally snow-covered watersheds worldwide. Meanwhile, increasing forest density has further exacerbated drought stress due to intensified tree-tree competition. Using a uniquely detailed data set of population-level forest growth (n = 2,495 sampled trees), we examined how inter-annual variability in growth relates to snow volume across a range of forest densities (e.g., competitive environments) in sites spanning a broad aridity gradient across the United States. Forest growth was positively related to snowpack in water-limited forests located at low latitude, and this relationship was intensified by forest density. However, forest growth was negatively related to snowpack in a higher latitude more energy-limited forest, and this relationship did not interact with forest density. Future reductions in snowpack may have contrasting consequences, as growth may respond positively in energy-limited forests and negatively in water-limited forests; however, these declines may be mitigated by reducing stand density through forest thinning.

Assessing the ecological impacts of biomass harvesting along a disturbance severity gradient.

Disturbance is a central driver of forest development and ecosystem processes with variable effects within and across ecosystems. Despite the high levels of variation in disturbance severity often observed in forests following natural and anthropogenic disturbance, studies quantifying disturbance impacts often rely on categorical classifications, thus limiting opportunities to examine potential gradients in ecosystem response to a given disturbance or management regime. Given the potential increases in disturbance severity associated with global change, as well as shifts in management regimes related to procurement of biofuel feedstocks, there is an increasing need to quantitatively describe disturbance severity and associated responses of forest development, soil processes, and structural conditions. This study took advantage of two replicated large-scale studies of forest biomass harvesting in Populus tremuloides and Pinus bansksiana forests, respectively, to develop and test the utility of a continuous, quantitative, disturbance severity index (DSI) for describing postharvest response of plant communities and nutrient pools to different levels of biomass removal and legacy retention (i.e., live trees and coarse woody material). There was a high degree of variability in DSI within categorical treatments associated with different levels of legacy retention and regression models using DSI as a predictor explained a portion of the variation (>50%) for many of the ecosystem- and community-level responses to biomass harvesting examined. Nutrient losses associated with biomass harvesting were positively related to disturbance severity, particularly in P. tremuloides forests, with postharvest nutrient availability generally declining along the gradient of impacts. Consistent with expectations from ecological theory, species richness and diversity of woody plant communities were greatest at intermediate disturbance severities and regeneration densities of dominant trees species were most abundant at highest levels of disturbance. Although categorical benchmarks will continue to be the primary way through which management guidelines are conveyed to practitioners, evaluation of their effectiveness at sustaining ecosystem functioning should be through continuous analyses, such as the DSI approach used in this study, to allow for the more precise identification of thresholds that ensure a range of desirable outcomes exist across managed landscapes.

Retention forestry influences understory diversity and functional identity.

In recent decades, a paradigm shift in forest management and associated policies has led to greater emphasis on harvest practices that retain mature, overstory trees in forest stands that would otherwise be clear-cut. While it is often assumed that the maintenance of compositional and structural complexity, such as that achieved through retention forestry approaches, will also mitigate negative impacts to functional diversity, empirical evidence of this relationship is sparse. We examined the effects of an aggregated retention system on taxonomic and functional diversity in a regenerating aspen-dominated forest. Sampling was conducted along transects arranged to capture the transition from harvested (regenerating) forest to mature, unharvested forest (both intact forest stands and 0.1 ha retention aggregates). We then assessed the magnitude and distance of edge effects on multiple indices of taxonomic and functional diversity as well as functional identity. Twelve years after harvest, the distance and magnitude of edge effects on functional and taxonomic diversity did not differ between the two unharvested patch sizes (intact vs. aggregate); however, intact forest exhibited greater resistance to edge effects and greater depth of edge influence into harvested areas for some traits compared to aggregates. Analyses relying on functional traits were generally applicable across sites within a highly variable forest type, and our results demonstrate the promise of using functional traits to assess management impacts on plant diversity across a landscape. Aggregates maintained some functional attributes associated with interior forest and influenced adjacent regeneration. However, trends in some traits (i.e., shade tolerance and seed mass), particularly in the seedling layer, suggest aggregates of this size provide primarily edge habitat.

Highly differentiated cytotoxic T cells in inclusion body myositis.

Inclusion body myositis is a late onset treatment-refractory autoimmune disease of skeletal muscle associated with a blood autoantibody (anti-cN1A), an HLA autoimmune haplotype, and muscle pathology characterized by cytotoxic CD8+ T cell destruction of myofibres. Here, we report on translational studies of inclusion body myositis patient muscle compared with a diverse set of other muscle disease samples. Using available microarray data on 411 muscle samples from patients with inclusion body myositis (n = 40), other muscle diseases (n = 265), and without neuromuscular disease (normal, n = 106), we identified a signature of T-cell cytotoxicity in inclusion body myositis muscle coupled with a signature of highly differentiated CD8 T-cell effector memory and terminally differentiated effector cells. Further, we examined killer cell lectin-like receptor G1 (KLRG1) as a marker of this population of cells, demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity across 28 870 human tissue samples, and identified the presence of KLRG1 on pathogenic inclusion body myositis muscle invading T cells and an increase in KLRG1 expressing T cells in inclusion body myositis blood. We examined inclusion body myositis muscle T-cell proliferation by Ki67 immunohistochemistry demonstrating that diseased muscle-invading T cells are minimally or non-proliferative, in accordance with known properties of highly differentiated or terminally differentiated T cells. We found low expression of KLRG1 on infection-protective human lymphoid tissue central memory T cells and autoimmune-protective human blood regulatory T cells. Targeting highly differentiated cytotoxic T cells could be a favourable approach to treatment of inclusion body myositis.