A Real-World Study of Nusinersen Effects in Adults with Spinal Muscular Atrophy Type 2 and 3.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive genetic disorder characterized by muscle weakness ultimately leading to pulmonary impairments that can be fatal. The recent approval of nusinersen, a disease-modifying therapy, substantially changed the prognosis for patients, particularly in children. However, real-world evidence about its long-term effectiveness in adults remains limited. This study aimed to document longitudinal data on motor function, pulmonary function and patient-reported outcome measures of Canadian adults with SMA type 2 and 3 treated with nusinersen. METHODS: Outcomes from 17 patients were collected at the Institut de réadaptation en déficience physique de Québec during routine clinical visits over 36 months post nusinersen treatment, using the Hammersmith Functional Motor Scale Expanded for SMA (HFMSE), Revised Upper Limb Module (RULM), 6-Minute Walk Test (6MWT), Children's Hospital of Philadelphia Adult Test of Neuromuscular Disorders (CHOP-ATEND), SMA functional rating scale (SMAFRS), pulmonary function testing and subjective changes reported by patients. RESULTS: After 36 months, 9 patients showed motor function improvement. Changes beyond the minimal clinically important difference were seen for four patients on the HFMSE, four patients on the RULM and five patients on the 6MWT. Pulmonary function remained stable for most subjects. Subjective positive changes were reported in 88% of patients and five patients showed improvement in the SMAFRS. CONCLUSION: This real-world study demonstrates the positive effects of nusinersen in adults with SMA types 2 and 3. Although stabilizing the patient's condition is considered therapeutic success, this study shows an improvement in motor function and subjective gains in several patients.

Predicting levels of prolonged grief disorder symptoms during the COVID-19 pandemic: An integrated approach of classical data exploration, predictive machine learning, and explainable AI.

BACKGROUND: Prior studies on Prolonged Grief Disorder (PGD) primarily employed classical approaches to link bereaved individuals' characteristics with PGD symptom levels. This study utilized machine learning to identify key factors influencing PGD symptoms during the COVID-19 pandemic. METHODS: We analyzed data from 479 participants through an online survey, employing classical data exploration, predictive machine learning, and SHapley Additive exPlanations (SHAP) to determine key factors influencing PGD symptoms measured with the Traumatic Grief Inventory - Self Report (TGI-SR) from 19 variables, comparing five predictive models. RESULTS: The classical approach identified eight variables associated with a possible PGD (TGI-SR score ≥ 59): unexpected causes of death, living alone, seeking professional support, taking anxiety and/or depression medications, using more grief services (telephone or online supports) and more confrontation-oriented coping strategies, and higher levels of depression and anxiety. Using machine learning techniques, the CatBoost algorithm provided the best predictive model of the TGI-SR score (r2 = 0.6479). The three variables influencing the most the level of PGD symptoms were anxiety, and levels of avoidance and confrontation coping strategies used. CONCLUSIONS: This pioneering approach within the field of grief research enabled us to leverage the extensive dataset collected during the pandemic, facilitating a deeper comprehension of the predominant factors influencing the grieving process for individuals who experienced loss during this period. LIMITATIONS: This study acknowledges self-selection bias, limited sample diversity, and suggests further research is needed to fully understand the predictors of PGD symptoms.

Natural History of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay: a 4-Year Longitudinal Study.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurologic disorder with generally well-known clinical manifestations. However, few studies assessed their progression rate using a longitudinal design. This study aimed to document the natural history of ARSACS over a 4-year period in terms of upper and lower limb functions, balance, walking capacity, performance in daily living activities, and disease severity. Forty participants were assessed on three occasions over 4 years. Participant performance was reported in raw data as well as in percentage from reference values to consider the normal aging process. Severe balance and walking capacity impairments were found, with a significant performance decrease over the 4 years. Balance reached a floor score of around 6 points on the Berg Balance Scale for participants aged >40 years, while other participants lost about 1.5 points per year. The mean loss in walking speed was 0.044 m/s per year and the mean decrease in the distance walked in 6 min was 20.8 m per year for the whole cohort. Pinch strength, balance, walking speed, and walking distance decreased over time even when reported in percentage from reference values. Major impairments and rapid progression rates were documented in the present study for upper limb coordination, pinch strength, balance, and walking capacity in the ARSACS population. A progression rate beyond the normal aging process was observed. These results provide fundamental insights regarding the disease prognosis that will help to better inform patients, develop specific rehabilitation programs, and improve trial readiness.

Toward a Better Understanding of Walking Speed in Ataxia of Charlevoix-Saguenay: a Factor Exploratory Study.

Mobility limitations, including a decrease in walking speed, are major issues for people with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Improving our understanding of factors influencing walking speed in ARSACS may inform the development of future interventions for gait rehabilitation and contribute to better clinical practices. The objective of the study was to identify the factors influencing the self-selected walking speed in adults with ARSACS. The dependent variable of this cross-sectional study was the self-selected speed and the factors (independent variables) were age, sex, balance, balance confidence, knee flexion and extension cocontraction indexes, lower limb coordination, passive range of motion of ankle dorsiflexion, knee and hip extension, and global spasticity. Multiple regression models were used to assess the relationships between walking speed and each factor individually. Six factors were significantly associated with walking speed and thus included in regression models. The models explained between 42.4 and 66.5% of the total variance of the self-selected walking speed. The factors that most influence self-selected walking speed are balance and lower limb coordination. In order of importance, the other factors that also significantly influence self-selected walking speed are ankle dorsiflexion range of motion, lower limb spasticity, knee extension range of motion, and confidence in balance. Balance and lower limb coordination should be targeted in rehabilitation interventions to maintain walking ability and functional independence as long as possible. The six factors identified should also be included in future studies to deepen our understanding of walking speed.

Characterization of muscle strength and mobility in oculopharyngeal muscular dystrophy.

INTRODUCTION/AIMS: Muscle weakness, and its association with mobility limitations, has received little study in oculopharyngeal muscular dystrophy (OPMD) using quantitative and standardized assessments. The objectives of this study were to (1) document upper and lower limb muscle strength, upper limb functions, fatigue, and mobility capacities; (2) compare them with reference values and across participant age groups; and (3) explore associations between muscle strength, fatigue, and mobility capacities among adults with OPMD. METHODS: Thirty-four participants were included in this cross-sectional study. The following variables were assessed: quantitative maximal isometric muscle strength, grip and pinch strength, fatigue, walking speed, walking endurance, sit-to-stand, and stair ascent and descent capacities. RESULTS: Muscle strength was lower for older than younger participants for five muscle groups (P < .05). Walking endurance, sit-to-stand, stairs (ascent and descent), and strength of hip flexion, grip, and pinch were below 80% of reference values in participants ≥56 y old (55.3%-78.2%). Moderate to strong correlations were found between muscle strength and mobility capacities (ρ = 0.42-0.80, P < .05), and between fatigue and either muscle strength or mobility capacities (ρ = 0.42-0.75, P < .05). DISCUSSION: This study highlights the impact of OPMD on strength, endurance, and functional capacity, among others, with patients being well below reference values even before the age of 65 y. In addition to helping health professionals to offer better clinical guidance, these results will improve clinical trial readiness. The next steps will be to assess the metrological properties of outcome measures and continue to document the disease progression rate.

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.

The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This review will summarize and discuss recent progress in NR biology and drug development derived from integrating various approaches, including biophysical techniques, structural studies, and translational investigation. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling. SIGNIFICANCE STATEMENT: Nuclear receptors (NRs) are ligand-regulated transcription factors that are critical regulators of myriad physiological processes. NRs serve as receptors for an array of drugs, and in this review, we provide an update on recent research into the roles of these drug targets.

Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1.

Muscle stem cells, the engine of muscle repair, are affected in myotonic dystrophy type 1 (DM1); however, the underlying molecular mechanism and the impact on the disease severity are still elusive. Here, we show using patients' samples that muscle stem cells/myoblasts exhibit signs of cellular senescence in vitro and in situ. Single cell RNAseq uncovers a subset of senescent myoblasts expressing high levels of genes related to the senescence-associated secretory phenotype (SASP). We show that the levels of interleukin-6, a prominent SASP cytokine, in the serum of DM1 patients correlate with muscle weakness and functional capacity limitations. Drug screening revealed that the senolytic BCL-XL inhibitor (A1155463) can specifically remove senescent DM1 myoblasts by inducing their apoptosis. Clearance of senescent cells reduced the expression of SASP, which rescued the proliferation and differentiation capacity of DM1 myoblasts in vitro and enhanced their engraftment following transplantation in vivo. Altogether, this study identifies the pathogenic mechanism associated with muscle stem cell defects in DM1 and opens a therapeutic avenue that targets these defective cells to restore myogenesis.

Functional responses of male and female European green crabs suggest potential sex-specific impacts of invasion.

Predicting the impacts of predatory invasive species is important for prioritising conservation interventions. Functional response experiments, which examine consumption by predators in relation to prey density, are a useful way to assess the potential strength of novel predator-prey relationships. However, such experiments are often conducted without consideration of sex or only with males to reduce invasion risk. Here, we compared the functional responses of male and female European green crabs (Carcinus maenas), a global invader, feeding on varnish clams (Nuttallia obscurata) to test whether the two sexes have similar potential for impact. We also examined potential correlates of predation behaviour by measuring sex-specific movement and prey choice. Both sexes displayed a Type II hyperbolic functional response, which can destabilise prey populations at low prey densities. However, males and females exhibited some differences in foraging behaviour. Female green crabs had slightly lower attack rates, which were not linked to sex differences in movement, and slightly longer handling times, which were not linked to sex differences in prey choice. These small, non-significant differences nevertheless translated into significantly greater functional response ratios, which are used to predict the ecological impact of invasive species, for males than females. There was no difference in the proportion of clams consumed between males and females with similar crusher claw heights, but females have smaller crusher claws on average, hence they consumed a smaller proportion of clams. Repeated surveys of four populations of European green crabs established in British Columbia, Canada, showed that sex ratio is highly variable. Taken together, these results and population-level modelling suggest that trying to evaluate the potential impact of European green crabs on clam populations by sampling only males could result in overestimation, even in populations that have male-biased sex-ratios. Consumer sex might generally be an important feature to consider when using functional response experiments to forecast the impact of new invasive species, especially those with marked sexual dimorphism that affect foraging.

Baseline dynamics of Symbiodiniaceae genera and photochemical efficiency in corals from reefs with different thermal histories.

Ocean warming and marine heatwaves induced by climate change are impacting coral reefs globally, leading to coral bleaching and mortality. Yet, coral resistance and resilience to warming are not uniform across reef sites and corals can show inter- and intraspecific variability. To understand changes in coral health and to elucidate mechanisms of coral thermal tolerance, baseline data on the dynamics of coral holobiont performance under non-stressed conditions are needed. We monitored the seasonal dynamics of algal symbionts (family Symbiodiniaceae) hosted by corals from a chronically warmed and thermally variable reef compared to a thermally stable reef in southern Taiwan over 15 months. We assessed the genera and photochemical efficiency of Symbiodiniaceae in three coral species: Acropora nana, Pocillopora acuta, and Porites lutea. Both Durusdinium and Cladocopium were present in all coral species at both reef sites across all seasons, but general trends in their detection (based on qPCR cycle) varied between sites and among species. Photochemical efficiency (i.e., maximum quantum yield; Fv/Fm) was relatively similar between reef sites but differed consistently among species; no clear evidence of seasonal trends in Fv/Fm was found. Quantifying natural Symbiodiniaceae dynamics can help facilitate a more comprehensive interpretation of thermal tolerance response as well as plasticity potential of the coral holobiont.

Do classical and computerized cognitive tests have equal intrarater reliability in myotonic dystrophy type 1?

Myotonic dystrophy type 1 (DM1) is a multisystemic inherited neuromuscular disease leading to central nervous system symptoms, including cognitive impairments, among multiple other symptoms. However, information is presently lacking regarding the psychometric properties of neuropsychological tests and promising computerized cognitive tests, such as the Cambridge Neuropsychological Test Automated Battery (CANTABⓇ). This type of information is critical to improve clinical trial readiness and provide knowledge of DM1 natural history. The aims of the present study were (1) to document the intrarater reliability of classic paper-pencil tests assessing visuospatial working memory, cognitive flexibility, attention, episodic memory and apathy, and (2) to compare these findings with their equivalent computerized automated tests from the CANTABⓇ. Thirty participants were seen twice at four-week intervals. Results showed that the Stroop Color and Word Test (ICC = 0.741-0.869) and the Ruff 2 & 7 (ICC = 0.703-0.871) appear to be reliable paper-and-pencil tests in the DM1 population. For the CANTABⓇ, a similar observation was made for the Multitasking test (ICC = 0.588-0.792). Further studies should explore the applicability and concurrent validity of the CANTAB® and classic neuropsychological assessments in additional cohorts of DM1 patients.

Abundance modulates the ecosystem functional contributions of two sympatric Caribbean sea cucumbers.

In highly diverse systems such as coral reefs, many species appear to fulfil similar ecological roles, suggesting that they might be ecologically equivalent. However, even if species provide similar functions, the magnitude of those roles could modulate their impact within ecosystems. Here, we compare the functional contributions of two common, co-occurring Caribbean sea cucumber species, Holothuria mexicana and Actynopyga agassizii, in terms of ammonium provisioning and sediment processing on Bahamian patch reefs. We quantified these functions through empirical measures of ammonium excretion, and in situ observations of sediment processing coupled with fecal pellet collections. On a per-individual level, H. mexicana excreted approximately 23% more ammonium and processed approximately 53% more sediment per hour than A. agassizii. However, when we combined these species-specific functional rates to species abundances to produce reef-wide estimates, we found that A. agassizii contributed more than H. mexicana to sediment processing at 57% of reefs (1.9 times more per unit area across all surveyed reefs), and more to ammonium excretion at 83% of reefs (5.6 times more ammonium per unit area across all surveyed reefs), owing to its higher abundance. We conclude that sea cucumber species can differ in the rates at which they deliver per capita ecosystem functions but their ecological impacts at the population level depend on their abundance at a given location.

Induction of antigen-specific tolerance by hepatic AAV immunotherapy regardless of T cell epitope usage or mouse strain background.

In vivo induction of antigen (Ag)-specific regulatory T cells (Treg) is considered the holy grail of therapeutic strategies for restoring tolerance in autoimmunity. Unfortunately, in the autoimmune disease multiple sclerosis, an effective and durable therapy targeting the diverse repertoire of emerging Ags without compromising the patient's natural immunity has remained elusive. To address this deficiency, we have developed an Ag-specific adeno-associated virus (AAV) immunotherapy that will restore tolerance in a Treg-dependent manner. Using multiple strains of mice with different genetic and immunological backgrounds, we demonstrate that a liver directed AAV vector expressing a single transgene can prevent experimental autoimmune encephalomyelitis from developing and effectively mitigate pre-existing or established disease that was induced by one or more auto-reactive myelin oligodendrocyte glycoprotein-derived peptides. Overall, the results suggests that AAV can efficiently restore Ag-specific immune tolerance to an immunogenic protein that is neither restricted by the major histocompatibility complex haplotype, nor by the specific antigenic epitope(s) presented. These findings may pave the way for developing a comprehensive Ag-specific immunotherapy that does not require prior knowledge of the specific immunogenic epitopes and that may prove to be universally applicable to all MS patients, and adaptable for other autoimmune diseases.

French-Canadian validation of the Traumatic Grief Inventory-Self Report (TGI-SR).

The Traumatic Grief Inventory Self-Report (TGI-SR), which aims to assess both Persistent Complex Bereavement Disorder and Prolonged Grief Disorder, has been validated in several languages. This study sought to validate the French-Canadian version. We conducted an online survey exploring the impact of the COVID-19 pandemic on grief. With data from 728 participants, the scale demonstrated high internal consistency, correlated significantly with three other scales known to measure similar concepts, and distinguished between groups known to be different. This study supports the use of the TGI-SR French-Canadian version by clinicians and researchers to assess complications of grief.

A global biological conservation horizon scan of issues for 2023.

We present the results of our 14th horizon scan of issues we expect to influence biological conservation in the future. From an initial set of 102 topics, our global panel of 30 scientists and practitioners identified 15 issues we consider most urgent for societies worldwide to address. Issues are novel within biological conservation or represent a substantial positive or negative step change at global or regional scales. Issues such as submerged artificial light fisheries and accelerating upper ocean currents could have profound negative impacts on marine or coastal ecosystems. We also identified potentially positive technological advances, including energy production and storage, improved fertilisation methods, and expansion of biodegradable materials. If effectively managed, these technologies could realise future benefits for biological diversity.

Using Risk Scores to Estimate Lower Extremity Fragility Fracture Risk among Individuals with Chronic Spinal Cord Injury: A Preliminary Model.

Objectives: To develop SCI-FX, a risk score to estimate 5-year lower extremity fragility fracture risk among patients living with chronic spinal cord injury (cSCI). Methods: Adults with traumatic cSCI (n = 90) participated in a 2-year prospective longitudinal cohort study describing bone mineral density (BMD) change and fracture incidence conducted at the Lyndhurst Centre (University Health Network), University of Waterloo, and Physical Disability Rehabilitation Institute of Québec City. Prior publication and clinical intuition were used to identify fragility fracture risk factors including prior fragility fracture, years post-injury, motor complete injury (AIS A/B), benzodiazepine use, opioid use, and parental osteoporosis. We conducted bivariate analyses to identify variables associated with fracture. Multiple logistic regressions were performed using fragility fracture incidence as the dependent variable and all variables from the univariate analyses with a highly liberal p value at 0.2. Using the odds ratios (ORs) from the multiple logistic regression model, a point system for fragility fracture risk score was developed, and the odds of fracture for each point was estimated. Results: All initial variables, with the exception of benzodiazepine exposure, were included in the final model. Conclusion: We identified a simple preliminary model for clinicians to estimate 5-year fracture risk among patients with cSCI based on their total score.

The Progression of Interstitial Fibrosis and Tubular Atrophy at 6 Months Is an Independent Predictor of Poor Graft Outcomes in Kidney Transplant Recipients.

Interstitial fibrosis and tubular atrophy (IFTA) found on 1-y surveillance biopsies has been associated with poor graft outcomes. However, its progression over time and relationship to outcomes are less well defined. Methods: We studied implantation and 6-mo surveillance biopsies and examined the association between the progression of IFTA (ΔIFTA) and a composite of censored graft loss or doubling of serum creatinine in 248 adult kidney recipients. Results: The percentage of patients with ΔIFTA of 1 or ≥2 was 35% and 22%, respectively. Positive ΔIFTA was a risk factor for the composite endpoint (hazard ratio, 1.36; 95% confidence interval, 1.03-1.79). This estimate was robust to adjustment for recipient and donor baseline characteristics, baseline IFTA, tacrolimus levels, and rejection status. ΔIFTA was associated with decreased estimated glomerular filtration rate at 3 and 5 y. IFTA+i was a predictor in the cohort; however, IFTA progression was not limited to those with a mononuclear cell interstitial inflammation (Banff "i") score above zero. Notably, donor age was a predictor of IFTA at 6 mo, but not of ΔIFTA, whereas rejection, donor diabetes, and recipient smoking status were. Conclusions: Progression of IFTA at 6 mo can predict outcomes. ΔIFTA was not related to donor age but may be linked to other risk factors influencing decision-making for donor versus recipient selection.

A rehabilitation program to increase balance and mobility in ataxia of Charlevoix-Saguenay: An exploratory study.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by balance impairment and mobility limitations, which both increase the risk of falling. The objective of this study was to explore the effects of a rehabilitation program aimed at increasing trunk and lower limb motor control on balance and walking abilities, and accomplishment of activities of daily living. In this exploratory study, a group-supervised rehabilitation program was performed three times a week for 8 weeks (two sessions at a rehabilitation gym and one pool session). Outcome measures included the Ottawa Sitting Scale, Berg Balance Scale, modified Activities-specific Balance Confidence Scale, 30-Second Chair Stand Test, 10-Meter Walk Test, Barthel Index, and Scale for the Assessment and Rating of Ataxia. Significant improvements in balance, trunk control, maximal and self-selected walking speed difference, ataxia severity and accomplishment of specific activities of daily living were noted for the whole group at the end of the program. At the individual level, all participants improved beyond the standard error of measurement in at least two outcome measures. Also, most participants reported many perceived improvements related to balance, posture and functional mobility. This study provides encouraging results on the effects of a rehabilitation program for ambulatory people with ARSACS. Group intervention could have a positive impact on their daily lives and improve the health care service offered to this population. Future studies with larger sample sizes including control groups and other forms of ataxia are necessary to validate our results to generalize them.

Effects of sediment on spore performance as a potential constraint on kelp distribution.

Kelp habitats contribute to marine productivity and diversity, making understanding the constraints on their distribution important. In the Gulf of St. Lawrence, Alaria esculenta occupies a subset of Saccharina latissima's range. Since tolerance to sedimentation by early life stages was suggested to cause this contrasting distribution, we tested the influence of sediment levels on spore attachment and development. For both species, the proportion of attached spores that developed decreased with increasing sediment. However, spore attachment and gametophyte density increased with sediment concentration but only for Saccharina. At the maximum sediment level examined, spore attachment and gametophyte densities of the two species were similar, contrary to the idea that sediment effects on early life stages explain differences in adult distribution. Further investigation, particularly with higher sediment loads, is required to confirm this conclusion. As turbidity is increasing globally, understanding the mechanisms underpinning changes in seaweed distribution will facilitate appropriate local-scale management.

A global horizon scan of issues impacting marine and coastal biodiversity conservation.

The biodiversity of marine and coastal habitats is experiencing unprecedented change. While there are well-known drivers of these changes, such as overexploitation, climate change and pollution, there are also relatively unknown emerging issues that are poorly understood or recognized that have potentially positive or negative impacts on marine and coastal ecosystems. In this inaugural Marine and Coastal Horizon Scan, we brought together 30 scientists, policymakers and practitioners with transdisciplinary expertise in marine and coastal systems to identify new issues that are likely to have a significant impact on the functioning and conservation of marine and coastal biodiversity over the next 5-10 years. Based on a modified Delphi voting process, the final 15 issues presented were distilled from a list of 75 submitted by participants at the start of the process. These issues are grouped into three categories: ecosystem impacts, for example the impact of wildfires and the effect of poleward migration on equatorial biodiversity; resource exploitation, including an increase in the trade of fish swim bladders and increased exploitation of marine collagens; and new technologies, such as soft robotics and new biodegradable products. Our early identification of these issues and their potential impacts on marine and coastal biodiversity will support scientists, conservationists, resource managers and policymakers to address the challenges facing marine ecosystems.

Participation and Functional Independence in Adults With Recessive Spastic Ataxia of Charlevoix-Saguenay.

Background. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a progressive disorder where upper and lower extremities motor performances may bring participation restriction. Purpose. To document participation in adults with ARSAC and explore associations with motor performances. Method. Twenty-eight participants took part in the study. Participation was assessed using the LIFE-H. Motor performance was assessed using several outcomes including the SARA, LEMOCOT, Berg Balance Scale, 10-Meter Walk Test, and Finger-to-nose Test. Findings. Participation was significantly lower in the wheelchair user subgroup. Also, for 29 activities out of 77, at least 15% of participants reported severely disrupted participation. Participation was correlated with upper and lower limbs coordination, walking ability, balance, disease severity, and fine dexterity (Spearman r = .41-0.85, p < .03). Implications. Results showed significant participation restrictions and suggest that interventions aiming to improve or compensate upper and lower limbs functions could help to decrease disease burden.