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Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. The pattern of lower motor neuron loss along the spinal cord follows the pattern of deposition of phosphorylated TDP-43 aggregates. The blood-spinal cord barrier (BSCB) restricts entry into the spinal cord parenchyma of blood components that can promote motor neuron degeneration, but in ALS there is evidence for barrier breakdown. Here we sought to quantify BSCB breakdown along the spinal cord axis, to determine whether BSCB breakdown displays the same patterning as motor neuron loss and TDP-43 proteinopathy. Cerebrospinal fluid hemoglobin was measured in living ALS patients (n = 87 control, n = 236 ALS) as a potential biomarker of BSCB and blood–brain barrier leakage. Cervical, thoracic, and lumbar post-mortem spinal cord tissue (n = 5 control, n = 13 ALS) were then immunolabelled and semi-automated imaging and analysis performed to quantify hemoglobin leakage, lower motor neuron loss, and phosphorylated TDP-43 inclusion load. Hemoglobin leakage was observed along the whole ALS spinal cord axis and was most severe in the dorsal gray and white matter in the thoracic spinal cord. In contrast, motor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the anterior gray matter of the cervical and lumbar cord. Our data show that leakage of the BSCB occurs during life, but at end-stage disease the regions with most severe BSCB damage are not those where TDP-43 accumulation is most abundant. This suggests BSCB leakage and TDP-43 pathology are independent pathologies in ALS.

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

ObjectiveThe primary aim of the study was to translate and evaluate the impact of a Physical Activity (PA) program on the physical function of older Aboriginal Elders on Noongar Boodjar (Country).MethodsA longitudinal design framed within an Indigenous methodology. Two groups, one metropolitan and one regional, of Aboriginal Elders, aged ≥45 years, participated in the Ironbark PA program. This comprised weekly strength and balance exercises followed by yarning circles. Physical function (primary outcome) and functional ability, cardiovascular risk factors (weight, waist circumference), falls efficacy and health-related quality of life were measured at baseline 6, 12 and 24 months. Data were analyzed using generalized linear mixed effects modeling.ResultsFifty-two Elders initially enrolled and of those, n = 23 (44.2%) Elders participated regularly for 24 months. There was a 6-month gap in program delivery due to the COVID-19 pandemic. Participants made significant improvement in physical function at 12 months compared to baseline: [short physical performance battery (SPPB) at baseline, 8.85 points (95% CI 8.10, 9.61); 12 months 10.28 (95% CI 9.44, 11.13), p = 0.001: gait speed at baseline 0.81 ms−1 (95% CI 0.60, 0.93); 12 months 1.14 (95% CI 1.01, 1.27), p < 0.001]. Some sustained improvement compared to baseline was still evident at 24 months after the 6-month gap in attendance [SPPB 9.60 (8.59, 10.60) p = 0.14, gait speed 1.11 (0.95, 1.26) p < 0.001]. Cardiovascular risk factors showed a non-significant improvement at 12 and 24 months compared to baseline. All participants reported that they enjoyed the program, found it culturally appropriate and would recommend it to others.ConclusionOlder Aboriginal people showed sustained improvements in physical function after engaging in a culturally appropriate PA program. Culturally appropriate PA programs provide safety, security and choice for older Aboriginal people to engage in evidence-based PA.

(1) Background: This work characterizes the sensitivity of magnetic resonance-based Relaxivity Contrast Imaging (RCI) to Amyotrophic Lateral Sclerosis (ALS)-induced changes in myofiber microstructure. Transverse Relaxivity at Tracer Equilibrium (TRATE), an RCI-based parameter, was evaluated in the lower extremities of ALS patients and healthy subjects. (2) Methods: In this IRB-approved study, 23 subjects (12 ALS patients and 11 healthy controls) were scanned at 3T (Philips, The Netherlands). RCI data were obtained during injection of a gadolinium-based contrast agent. TRATE, fat fraction and T2 measures, were compared in five muscle groups of the calf muscle, between ALS and control populations. TRATE was also evaluated longitudinally (baseline and 6 months) and was compared to clinical measures, namely ALS Functional Rating Scale (ALSFRS-R) and Hand-Held Dynamometry (HHD), in a subset of the ALS population. (3) Results: TRATE was significantly lower (p < 0.001) in ALS-affected muscle than in healthy muscle in all muscle groups. Fat fraction differences between ALS and healthy muscle were statistically significant for the tibialis anterior (p = 0.01), tibialis posterior (p = 0.004), and peroneus longus (p = 0.02) muscle groups but were not statistically significant for the medial (p = 0.07) and lateral gastrocnemius (p = 0.06) muscles. T2 differences between ALS and healthy muscle were statistically significant for the tibialis anterior (p = 0.004), peroneus longus (p = 0.004) and lateral gastrocnemius (p = 0.03) muscle groups but were not statistically significant for the tibialis posterior (p = 0.06) and medial gastrocnemius (p = 0.07) muscles. Longitudinally, TRATE, averaged over all patients, decreased by 28 ± 16% in the tibialis anterior, 47 ± 18% in the peroneus longus, 25 ± 19% in the tibialis posterior, 29 ± 14% in the medial gastrocnemius and 35 ± 18% in the lateral gastrocnemius muscles between two timepoints. ALSFRS-R scores were stable in two of four ALS patients. HHD scores decreased in three of four ALS patients. (4) Conclusion: RCI-based TRATE was shown to consistently differentiate ALS-affected muscle from healthy muscle and also provide a quantitative measure of longitudinal muscle degeneration.

Abstract Background This study is a systematic literature review of cost analyses conducted within implementation studies on behavioral health services. Cost analysis of implementing evidence-based practices (EBP) has become important within implementation science and is critical for bridging the research to practice gap to improve access to quality healthcare services. Costing studies in this area are rare but necessary since cost can be a barrier to implementation and sustainment of EBP. Methods We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology and applied the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Key search terms included: (1) economics, (2) implementation, (3) EBP, and (4) behavioral health. Terms were searched within article title and abstracts in: EconLit, SocINDEX, Medline, and PsychINFO. A total of 464 abstracts were screened independently by two authors and reduced to 37 articles using inclusion and exclusion criteria. After a full-text review, 18 articles were included. Results Findings were used to classify costs into direct implementation, direct services, and indirect implementation. While all studies included phases of implementation as part of their design, only five studies examined resources across multiple phases of an implementation framework. Most studies reported direct service costs associated with adopting a new practice, usually summarized as total EBP cost, cost per client, cost per clinician, and/or cost per agency. For studies with detailed analysis, there were eleven direct cost categories represented. For five studies that reported costs per child served, direct implementation costs varied from $886 to $9470 per child, while indirect implementation costs ranged from $897 to $3805 per child. Conclusions This is the first systematic literature review to examine costs of implementing EBP in behavioral healthcare settings. Since 2000, 18 studies were identified that included a cost analysis. Given a wide variation in the study designs and economic methods, comparison across studies was challenging, which is a major limitation in the field, as it becomes difficult to replicate studies or to estimate future costs to inform policy decisions related to budgeting. We recommend future economic implementation studies to consider standard economic costing methods capturing costs across implementation framework phases to support comparisons and replicability.

Abstract Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy.

Paget’s Disease of Bone (PDB) is a metabolic bone disease that is characterized by dysregulated osteoclast function leading to focal abnormalities of bone remodeling. It can lead to pain, fracture, and bone deformity. G protein-coupled receptor kinase 3 (GRK3) is an important negative regulator of G protein-coupled receptor (GPCR) signaling. GRK3 is known to regulate GPCR function in osteoblasts and preosteoblasts, but its regulatory function in osteoclasts is not well defined. Here, we report that Grk3 expression increases during osteoclast differentiation in both human and mouse primary cells and established cell lines. We also show that aged mice deficient in Grk3 develop bone lesions similar to those seen in human PDB and other Paget’s Disease mouse models. We show that a deficiency in Grk3 expression enhances osteoclastogenesis in vitro and proliferation of hematopoietic osteoclast precursors in vivo but does not affect the osteoclast-mediated bone resorption function or cellular senescence pathway. Notably, we also observe decreased Grk3 expression in peripheral blood mononuclear cells of patients with PDB compared with age- and gender-matched healthy controls. Our data suggest that GRK3 has relevance to the regulation of osteoclast differentiation and that it may have relevance to the pathogenesis of PDB and other metabolic bone diseases associated with osteoclast activation.

Background/Aims: Service users who have spent time in seclusion describe it as a negative experience, viewing it as punishment. Although occupational therapists work within these settings, there is limited research and documentation of interventions aimed at reducing occupational deprivation in seclusion. A service evaluation was conducted at a medium secure adult mental health unit to better understand the current practices of occupational therapists working in seclusion. Methods: A bespoke tool was developed to capture occupational therapy interventions within a 12-month timeline. Results: Data showed that there were 31 interventions provided across 300 days of seclusion for 16 patients. Therapy lasted between 5 and 45 minutes involving a range of adapted interventions and resources appropriate for positive risk taking. Conclusions: Despite creative and adaptive interventions identified, provision of occupational therapy appeared sporadic and restricted by a 5-day service. This illustrates the need for specialist training and guidelines to support an integrated and consistent approach. [ABSTRACT FROM AUTHOR]

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment. [ABSTRACT FROM AUTHOR]

We report the capture of 10 Symphurus plagiusa (Blackcheek Tonguefish) in 2022 and 2023 at the northern end of their range. These specimens are the first records from the tidal Hudson River, and we document other tonguefish specimens from New York waters from previous records. We establish the identification of juveniles based on caudal fin ray counts and discuss the benefits of community education networks in detecting and monitoring fish species. [ABSTRACT FROM AUTHOR]

Despite guidance to minimize restrictive practice within the UK, seclusion and long-term segregation are necessary to maintain the safety of patients and clinicians. There is little evidence to guide the work of occupational therapists with secluded patients. A literature search identified seven papers that met the study inclusion criteria. A deductive approach to thematic analysis was conducted using the 'Model of Human Occupation' as a theoretical framework to identify issues related to occupational need during a period of seclusion. Findings indicate ways in which occupational therapists could engage with patients in seclusion and suggest a need for future research. [ABSTRACT FROM AUTHOR]

Abstract Objective To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their utility as pharmacodynamic biomarkers for monitoring treatment effects. Methods De‐identified, longitudinal plasma, and cerebrospinal fluid (CSF) samples from PALS (n = 108; 85 with samples from ≥2 visits) and controls without neurological disease (n = 41) were obtained from the Northeast ALS Consortium (NEALS) Biofluid Repository. Seventeen of 108 PALS had familial ALS, of whom 10 had C9orf72 mutations. Additional healthy control CSF samples (n = 35) were obtained from multiple sources. We stratified PALS into fast‐ and slow‐progression subgroups using the ALS Functional Rating Scale‐Revised change rate. We compared cytokines/chemokines and neurofilament (NF) levels between PALS and controls, among progression subgroups, and in those with C9orf72 mutations. Results We found significant elevations of cytokines, including MCP‐1, IL‐18, and neurofilaments (NFs), indicators of neurodegeneration, in PALS versus controls. Among PALS, these cytokines and NFs were significantly higher in fast‐progression and C9orf72 mutation subgroups versus slow progressors. Analyte levels were generally stable over time, a key feature for monitoring treatment effects. We demonstrated that CSF/plasma neurofilament light chain (NFL) levels may predict disease progression, and stratification by NFL levels can enrich for more homogeneous patient groups. Interpretation Longitudinal stability of cytokines and NFs in PALS support their use for monitoring responses to immunomodulatory and neuroprotective treatments. NFs also have prognostic value for fast‐progression patients and may be used to select similar patient subsets in clinical trials.

Abstract Background Despite the large investments in donor-related health activities in areas of the globe prone to tension and conflict, few studies have examined in detail the role of these donor investments in human resources for health (HRH). Methods We used a mixed-methods research methodology comprising both quantitative and qualitative analyses to analyze the Enhanced Financial Reporting System of the Global Fund to Fight AIDS, Tuberculosis and Malaria budget and expenditure data from 2003 to 2017 for 13 countries in the Eastern Mediterranean Region (EMR). We analyzed additional detailed budgetary data over the period 2015–2017 for a sub-set of these countries. Two country-case studies were conducted in Afghanistan and Sudan for a more in-depth understanding of the HRH-related activities that occurred as a result of Global Fund grants. Results The results show that US$2.2 billion Global Fund dollars had been budgeted and US$1.6 billion were expended over the period 2003–2017 in 13 Eastern Mediterranean countries. The average expenditures for human resources for health (training and human resources) as a percentage of total expenditure are 28%. Additional detailed budgetary data analysis shows a more conservative investment in HRH with 13% of total budgets allocated to “direct” HRH activities such as salaries, training costs, and technical assistance. HRH-related activities supported by the Global Fund in Afghanistan and Sudan were similar, including pre-service and in-services training, hiring of program coordinators and staff, and top-ups for clinical staff. Conclusions HRH remains a key issue in strengthening the health systems of low- and middle-income countries. While this study suggests that Global Fund’s HRH investments in the EMR are not lagging behind the global average, there appears to be a need to further scale up these investments considering this region’s unique HRH challenges.

Abstract The RNA binding protein (RBP) RBM45 forms nuclear and cytoplasmic inclusions in neurons and glia in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), and Alzheimer’s disease (AD). The normal functions of RBM45 are poorly understood, as are the mechanisms by which it forms inclusions in disease. To better understand the normal and pathological functions of RBM45, we evaluated whether the protein functions via association with several membraneless organelles and whether such an association could promote the formation of nuclear RBM45 inclusions. Under basal conditions, RBM45 is diffusely distributed throughout the nucleus and does not localize to membraneless organelles, including nuclear speckles, Cajal bodies, or nuclear gems. During cellular stress, however, nuclear RBM45 undergoes a reversible, RNA-binding dependent incorporation into nuclear stress bodies (NSBs). Chronic stress leads to the persistent association of RBM45 with NSBs and the irreversible accumulation of nuclear RBM45 inclusions. We also quantified the cell type- and disease-specific patterns of RBM45 pathology in ALS, FTLD-TDP, and AD. RBM45 nuclear and cytoplasmic inclusions are found in both neurons and glia in ALS, FTLD-TDP, and AD but are absent in non-neurologic disease controls. Across neurodegenerative diseases, RBM45 nuclear inclusion pathology occurs more frequently than cytoplasmic RBM45 inclusion pathology and exhibits cell type-specific variation. Collectively, our results define new stress-associated functions of RBM45, a mechanism for nuclear RBM45 inclusion formation, a role for NSBs in the pathogenesis of ALS, FTLD-TDP, and AD, and further underscore the importance of protein self-association to both the normal and pathological functions of RBPs in these diseases.

Abstract The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both upper and lower motor neuron loss, as well as altered proteomic and metabolomic signatures in the CSF. The role of the BCSFB and the CP in ALS is unknown. Here we describe a transcriptomic and ultrastructural analysis of BCSFB and CP alterations in human postmortem tissues from ALS and non-neurologic disease controls. ALS-CP exhibited widespread disruptions in tight junctional components of the CP epithelial layer and vascular integrity. In addition, we detected loss of pericytes around ALS blood vessels, accompanied by activation of platelet aggregation markers vWF and Fibrinogen, reminiscent of vascular injury. To investigate the immune component of ALS-CP, we conducted a comprehensive analysis of cytokines and chemokine panels in CP lysates and found a significant down-regulation of M-CSF and V-CAM1 in ALS, as well as up-regulation of VEGF-A protein. This phenotype was accompanied by an infiltration of MERTK positive macrophages into the parenchyma of the ALS-CP when compared to controls. Taken together, we demonstrate widespread structural and functional disruptions of the BCSFB in human ALS increasing our understanding of the disease pathology and identifying potential new targets for ALS therapeutic development.

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.

ABSTRACTColombia provides a unique setting to understand the complicated interaction between health systems, health insurance, migrant populations, and COVID-19 due to its system of Universal Health Coverage and its hosting of the second-largest population of displaced persons globally, including approximately 1.8 million Venezuelan migrants. We surveyed 8,130 Venezuelan migrants and Colombian nationals across 60 municipalities using a telephone survey during the first wave of the pandemic (September through November 2020). Using self-reported enrollment in one of the several Colombian health insurance schemes, we analyzed the access to and disparities in the use of health-care services for both Colombians and Venezuelan migrants by insurance status, including access to formal health services, virtual visits, and COVID-19 testing for both groups. We found that compared with 3.6% of Colombians, 73.6% of Venezuelan telephone survey respondents remain uninsured, despite existing policies that allow legally present migrants to enroll in national health insurance schemes. Enrolling migrants in either the subsidized or contributory regime increases their access to health-care services, and equality between Colombians and Venezuelans within the same insurance schemes can be achieved for some services. Colombia’s experience integrating Venezuelan migrants into their current health system through various insurance schemes during the first wave of their COVID-19 pandemic shows that access and equality can be achieved, although there continue to be challenges.