New insights into morphological adaptation in common mole-rats (Cryptomys hottentotus hottentotus) along an aridity gradient.

Morphological adaptation is the change in the form of an organism that benefits the individual in its current habitat. Mole-rats (family Bathyergidae), despite being subterranean, are impacted by both local and broad-scale environmental conditions that occur above ground. Common mole-rats (Cryptomys hottentotus hottentotus) present an ideal mammalian model system for the study of morphological variation in response to ecology, as this species is found along an aridity gradient and thus can be sampled from geographically non-overlapping populations of the same species along an environmental longitudinal cline. Using the mass of five internal organs, ten skeletal measurements and 3D morphometric analyses of skulls, we assessed the morphology of wild non-breeding individuals from five common mole-rat populations in South Africa. We found that the body mass and mean relative mass of the spleen and kidneys in arid populations was larger, and individuals from arid regions possessed shorter legs and larger inter-shoulder widths compared to individuals from mesic regions. Additionally, arid populations demonstrated greater skull depth, and shape change of features such as angular processes of the lower jaw than mesic individuals, indicating that these distinct geographic populations show differences corresponding to the aridity gradient, potentially in response to environmental factors such as the variation in food sources found between different habitats, in addition to different soil compositions found in the different regions. Arid populations potentially require a stronger jaw and neck musculature associated with mastication to chew xeric-adapted plants and to dig through hard soil types, whereas mesic populations excavate through soft, looser soil and may make use of their front limbs to aid the movement of soils when digging. Aridity influences the morphology of this species and could indicate the impact of environmental changes on speciation and mammalian skull morphology.

Combining total synthesis and genetic engineering to probe dihydropyran formation in ambruticin biosynthesis.

The ambruticins are a family of potent antifungal polyketide derived natural products isolated from the myxobacterium Sorangium cellulosum. Their unusual structures include a trisubstituted cyclopropyl group and two oxygen heterocycles, a tetrahydropyran (THP) and dihydropyran (DHP). Herein we report a flexible modular approach for the total synthesis of ambruticins which is used to prepare ambruticins F and S as well as in the first total synthesis of 20,21-dihydroambruticin F. The flexible strategy unites 3 fragments via Julia-Kocienski olefinations and provides important standards for investigation of dihydropyran formation in ambruticin biosynthesis. Cultures of wild-type S. cellulosum So ce10 produce mainly ambruticin S and the VS series of metabolites. An efficient electroporation method enabled gene knockout experiments which revealed that the ΔambP-S mutant of S. cellulosum accumulated the bisTHP polyketide 20,21-dihydroambruticin F. In contrast, the ΔambN-S mutant gave ambruticin F with the 20,21-alkene as the major metabolite confirming that AmbP and AmbO (a Rieske enzyme and flavin-dependent monooxygenase respectively) are implicated in 20,21-alkene formation. The results of feeding studies to a Sorangium strain containing only ambP and ambO are in accord with formation of the 20,21-alkene occurring prior to generation of the C3 to C7 dihydroxylated tetrahydropyran in ambruticin biosynthesis.

Engineering Nitrogen-Doped Carbon Quantum Dots: Tailoring Optical and Chemical Properties through Selection of Nitrogen Precursors.

The process of N-doping is frequently employed to enhance the properties of carbon quantum dots. However, the precise requirements for nitrogen precursors in producing high-quality N-doped carbon quantum dots (NCQDs) remain undefined. This research systematically examines the influence of various nitrogen dopants on the morphology, optical features, and band structure of NCQDs. The dots are synthesized using an efficient, eco- friendly, and rapid continuous hydrothermal flow technique. This method offers unparalleled control over synthesis and doping, while also eliminating convention-related issues. Citric acid is used as the carbon source, and urea, trizma base, beta-alanine, L-arginine, and EDTA are used as nitrogen sources. Notably, urea and trizma produced NCQDs with excitation-independent fluorescence, high quantum yields (up to 40%), and uniform dots with narrow particle size distributions. Density functional theory (DFT) and time-dependent DFT modelling established that defects and substituents within the graphitic structure have a more significant impact on the NCQDs' electronic structure than nitrogen-containing functional groups. Importantly, for the first time, this work demonstrates that the conventional approach of modelling single-layer structures is insufficient, but two layers suffice for replicating experimental data. This study, therefore, provides essential guidance on the selection of nitrogen precursors for NCQD customization for diverse applications.

Describing the state of a research network: A mixed methods approach to network evaluation.

Diabetes Action Canada Strategy for Patient-Oriented Research (SPOR) Network in Chronic Disease was formed in 2016 and is funded primarily through the Canadian Institutes of Health Research (CIHR). We propose a novel mixed-methods approach to a network evaluation integrating the State of Network Evaluation framework and the Canadian Academy of Health Sciences (CAHS) preferred framework and indicators. We measure key network themes of connectivity, health and results, and impact and return on investment associated with health research networks. Our methods consist of a longitudinal cross-sectional network survey of members and social network analysis to examine Network Connectivity and assess the frequency of interactions, the topics discussed during them, and how networking effectively facilitates interactions and collaboration among members. Network Health will be evaluated through semistructured interviews, a membership survey inquiring about satisfaction and experience with the Network, and a review of documentary sources related to funding and infrastructure to evaluate Network Sustainability. Finally, we will examine Network Results and Impact using the CAHS preferred framework and indicators to measure returns on investment in health research across the five domains of the CAHS framework, which include: advancing knowledge, capacity building, informing decision making, health impact, and economic and social impact. Indicators will be assessed with various methods, including bibliometric analyses, review of relevant documentary sources (annual reports), member activities informing health and research policy, and Patient Partner involvement. The Network Evaluation will provide members and stakeholders with information for planning, improvements, and funding future Network endeavors.

Relapse recovery in relapsing-remitting multiple sclerosis: An analysis of the CombiRx dataset.

BACKGROUND: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery. OBJECTIVE: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS). METHODS: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to unconfirmed and confirmed relapse recovery. RESULTS: CombiRx included 1008 participants. We investigated 240 relapses. Median time to relapse recovery was 111 days. Most recovery events took place within 1 year of relapse onset: 202 of 240 (84%) individuals recovered during follow-up, 161 of 202 (80%) by 180 days, and 189 of 202 (94%) by 365 days. Relapse severity was the only factor associated with relapse recovery. CONCLUSION: Recovery from relapses takes place up to approximately 1 year after the event. Relapse severity, but no other patient factors, was associated with the speed of relapse recovery. Our findings inform clinical practice and trial design in RRMS.

Remission of severe myasthenia gravis after autologous stem cell transplantation.

OBJECTIVE: Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular junction disorder involving the acetylcholine receptors on the motor endplate. The safety and response to high-dose chemotherapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were assessed in a patient with severe refractory MG. METHODS: As part of a pilot study of HDIT/HCT for patients with treatment-resistant autoimmune neurological disorders, a patient with severe refractory MG underwent treatment. After mobilization of hematopoietic stem cells with rituximab, prednisone, and G-CSF, the patient had HDIT consisting of carmustine, etoposide, cytarabine, melphalan, and rabbit antithymocyte globulin, followed by autologous HCT. The effect of treatment on the autoantibody to the acetylcholine receptor (AChR) was assessed. RESULTS: The patient had been diagnosed with AChR antibody-positive MG 14 years before HDIT/HCT and had failed thymectomy, therapeutic plasma exchange, and multiple immunomodulatory agents. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was IVb before HDIT/HCT. She tolerated HDIT/HCT well and started to improve clinically within days of treatment. At both 1 and 2 years after HDIT/HCT, patients remained symptom-free. After HDIT/HCT, AChR-binding autoantibodies persisted, and the relative frequency of immune cell subtypes shifted. INTERPRETATION: HDIT/HCT induced a complete response of disease activity in a patient with severe refractory MG. This response may suggest that a cell-mediated etiology may be a significant contributing factor in refractory MG cases. A phase 2 clinical trial is warranted to establish if HDIT/HCT can be an effective therapy for severe refractory MG and to gain a further understanding of disease pathogenesis.

Surface texture heterogeneity in maculated bird eggshells.

Many of the world's 10 000 bird species lay coloured or patterned eggs. The large diversity of eggshell patterning among birds, achieved through pigment, has been attributed to a few selective agents such as crypsis, thermoregulation, egg recognition, mate signalling, egg strength and protecting the embryo from UV. Pigmentation may influence the texture of eggshells, which in turn may be important for dealing with water and microbes. We measured surface roughness (Sa, nm), surface skewness (Ssk) and surface kurtosis (Sku), which describe different aspects of surface texture, across 204 bird species with maculated (patterned) eggs and 166 species with immaculate (non-patterned) eggs. Using phylogenetically controlled analyses, we tested whether maculated eggshells have different surface topography between the foreground colour and background colour, and between the background colour of maculated eggshells and the surface of immaculate eggshells. Secondly, we determined to what extent variation in eggshell pigmentation of the foreground and background colour is determined by phylogenetic relatedness, and whether certain life-history traits are important predictors of eggshell surface structure. We show that the surface of maculated eggs consists of a rougher foreground pigment compared to the background pigment across 71% of the 204 bird species (54 families) investigated. Species that lay immaculate eggs showed no difference in surface roughness, kurtosis or skewness compared to background pigment of maculated eggs. The difference in eggshell surface roughness between foreground and background pigmentation was greater among species that occupied dense habitats, such as forests with closed canopies, compared to those that nest in open and semi-open habitats (e.g. cities, deserts, grasslands, open shrubland and seashores). Among maculated eggs, foreground texture was correlated with habitat, parental care, diet, nest location, avian group and nest type, while background texture was correlated with clutch size, annual temperature, development mode and annual precipitation. Surface roughness among immaculate eggs was greatest for herbivores, and species that have larger clutch sizes. Together, this suggests that multiple life-history traits have influenced the evolution of eggshell surface textures in modern birds.

Threshold definitions for significant change on the timed 25-foot walk and nine-hole peg test in primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: The timed 25-foot walk (T25FW) and nine-hole peg test (NHPT) exhibit random variability in the short term. A threshold of ≥20% change from baseline has been used to indicate true disability change, but other threshold definitions may be better suited to exclude false and include true change events. The aim of this study was to use patient-level original trial data to investigate the short-term variation in T25FW and NHPT, and to compare its extent with disability change at 12-month follow-up in people with primary progressive multiple sclerosis (PPMS). METHODS: We used original patient-level data from PROMISE, a large PPMS trial. In this trial, three separate T25FW and NHPT measurements were performed 1 week apart during screening. We used these repeated measures to describe the extent of short-term variation. We used binary logistic regression models to investigate the association between screening characteristics and unacceptable short-term variation. RESULTS: The traditional 20% threshold excluded a reasonable number of false change events, while also yielding a large number of change events at follow-up. Increasing index values on the T25FW and NHPT were associated with higher short-term variation. CONCLUSIONS: The traditional ≥20% change threshold for the T25FW and NHPT represents a reasonable compromise between reducing the number of false change events and achieving the largest number of change events in people with PPMS. Our analyses inform the design of clinical trials in PPMS.

Eggshell composition and surface properties of avian brood-parasitic species compared with non-parasitic species.

The eggs of avian obligate brood-parasitic species have multiple adaptations to deceive hosts and optimize development in host nests. While the structure and composition of the eggshell in all birds is essential for embryo growth and protection from external threats, parasitic eggs may face specific challenges such as high microbial loads, rapid laying and ejection by the host parents. We set out to assess whether eggshells of avian brood-parasitic species have either (i) specialized structural properties, to meet the demands of a brood-parasitic strategy or (ii) similar structural properties to eggs of their hosts, due to the similar nest environment. We measured the surface topography (roughness), wettability (how well surfaces repel water) and calcium content of eggshells of a phylogenetically and geographically diverse range of brood-parasitic species (representing four of the seven independent lineages of avian brood-parasitic species), their hosts and close relatives of the parasites. These components of the eggshell structure have been demonstrated previously to influence such factors as the risk of microbial infection and overall shell strength. Within a phylogenetically controlled framework, we found no overall significant differences in eggshell roughness, wettability and calcium content between (i) parasitic and non-parasitic species, or (ii) parasitic species and their hosts. Both the wettability and calcium content of the eggs from brood-parasitic species were not more similar to those of their hosts' eggs than expected by chance. By contrast, the mean surface roughness of the eggs of brood-parasitic species was more similar to that of their hosts' eggs than expected by chance, suggesting brood-parasitic species may have evolved to lay eggs that match the host nest environment for this trait. The lack of significant overall differences between parasitic and non-parasitic species, including hosts, in the traits we measured, suggests that phylogenetic signal, as well as general adaptations to the nest environment and for embryo development, outweigh any influence of a parasitic lifestyle on these eggshell properties.

Association of age and inflammatory disease activity in the pivotal natalizumab clinical trials in relapsing-remitting multiple sclerosis.

BACKGROUND: Focal inflammatory disease activity in relapsing-remitting multiple sclerosis (RRMS) diminishes with increasing age. Here we use patient-level data from randomised controlled trials (RCTs) of natalizumab treatment in RRMS to investigate the association of age and inflammatory disease activity. METHODS: We used patient-level data from the AFFIRM (natalizumab vs placebo in relapsing-remitting MS, NCT00027300) and SENTINEL (natalizumab plus interferon beta vs interferon beta in relapsing remitting MS, NCT00030966) RCTs. We determined the proportion of participants developing new T2 lesions, contrast-enhancing lesions (CELs) and relapses over 2 years of follow-up as a function of age, and investigated the association of age with time to first relapse using time-to-event analyses. RESULTS: At baseline, there were no differences between age groups in T2 lesion volume and number of relapses in the year before inclusion. In SENTINEL, older participants had a significantly lower number of CELs. During both trials, the number of new CELs and the proportion of participants developing new CELs were significantly lower in older age groups. The number of new T2 lesions and the proportion of participants with any radiological disease activity during follow-up were also lower in older age groups, especially in the control arms. CONCLUSIONS: Older age is associated with a lower prevalence and degree of focal inflammatory disease activity in treated and untreated RRMS. Our findings inform the design of RCTs, and suggest that patient age should be taken into consideration when deciding on immunomodulatory treatment in RRMS.

Etiologies of Poor Weight Gain and Ultimate Diagnosis in Children Admitted for Growth Faltering.

BACKGROUND AND OBJECTIVES: Growth faltering (GF) (previously failure to thrive) is a common reason for hospital admission, but there is little data on whether diagnoses made during initial admission remain accurate in follow-up. We sought to characterize infants admitted for isolated GF and identify diagnoses at discharge and ultimate diagnoses determined over 2 years of follow-up, to determine how diagnoses changed. We also sought to identify patient factors on admission associated with ultimate diagnosis. METHODS: We conducted a retrospective study of children aged 2 weeks to 2 years with index admissions for GF from 2013 to 2017. We reviewed clinical data and documentation to determine discharge and ultimate diagnosis, and identify factors associated with ultimate diagnosis. RESULTS: Of 497 patients, 292 (59%) had insufficient intake, 103 (20%) had organic disease including 36 genetic disorders, 52 (11%) had mechanical feeding difficulties, and 50 (10%) had mixed or unknown diagnoses 2 years after admission. Over 90% of cases of insufficient intake were diagnosed during admission. Sixty-five percent of organic diseases, and only 39% of genetic disorders, were diagnosed during admission. Patient factors associated with genetic disorders included previous NICU stay, low birth weight, dysphagia, hypotonia, and dysmorphisms. CONCLUSIONS: Insufficient intake remains the most common diagnosis, and this diagnosis was accurately made during admission. Organic disease, especially genetic disease, was often not diagnosed during admission. Better tools are needed to identify patients with organic disease. We identified patient factors on admission associated with ultimate diagnosis, which could be used to prioritize evaluation and expedite follow-up.

Longitudinal Changes in Cognitive Test Scores in Patients With Relapsing-Remitting Multiple Sclerosis: An Analysis of the DECIDE Dataset.

BACKGROUND AND OBJECTIVES: Cognitive impairment is a common and impactful symptom of relapsing-remitting multiple sclerosis (RRMS). Cognitive outcome measures are often used in cross-sectional studies, but their performance as longitudinal outcome measures in clinical trials is not widely researched. In this study, we used data from a large clinical trial to describe change on the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) over up to 144 weeks of follow-up. METHODS: We used the data set from DECIDE (clinicaltrials.gov identifier NCT01064401), a large randomized controlled RRMS trial to describe change on the SDMT and PASAT over 144 weeks of follow-up. We compared change on these cognitive outcomes with change on the timed 25-foot walk (T25FW), a well-established physical outcome measure. We investigated several definitions for clinically meaningful change: any change, 4-point change, 8-point change, and 20% change for the SDMT, any change, 4-point change, and 20% change for the PASAT, and 20% change for the T25FW. RESULTS: DECIDE included 1,814 trial participants. SDMT and PASAT scores steadily improved throughout follow-up: the SDMT from a mean 48.2 (SD, 16.1) points at baseline to 52.6 (SD 15.2) at 144 weeks and the PASAT from 47.0 (SD 11.3) at baseline to 50.0 (SD 10.8) at 144 weeks. This improvement in scores is most likely due to a practice effect. Throughout the trial, participants were more likely to experience improvement than worsening of their SDMT and PASAT performance, whereas the number of worsening events on the T25FW steadily increased. Changing the definition of clinically meaningful change for the SDMT and PASAT or using a 6-month confirmation changed the overall number of worsening or improvement events but did not affect the overall behavior of these measures. DISCUSSION: Our findings suggest that the SDMT and PASAT scores do not accurately reflect the steady cognitive decline that people with RRMS experience. Both outcomes show postbaseline increases in scores, which complicates the interpretation of these outcome measures in clinical trials. More research into the size of these changes is needed before recommending a general threshold for clinically meaningful longitudinal change.

A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer.

BACKGROUND: Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. METHODS: We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. RESULTS: A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. CONCLUSIONS: Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.

Closed displaced femur fractures in children with nonambulatory cerebral palsy.

Femoral fractures in children withcerebral palsy (CP) represent a frequent medical problem, and treatment represents a challenge. The purpose of this study was to review the closed displaced femoral fractures in our population of nonambulatory children with CP to compare the results of nonoperative and operative treatment modalities to improve the care of these children. From 2006 to 2020, children with nonambulatory CP were selected with inclusion criteria of displaced femoral fracture and were divided into nonoperative and operative groups. Forty-four children met the inclusion criteria. The nonoperative group included 23 children and the operative group included 21 children. Mechanism of injury was unknown in 48% of the fractures. Fourteen (25%) fractures occurred after a femoral plate fixation during a reconstructive hip surgery, and 38 (86%) children had osteopenia. Our results reveal a high prevalence of osteopenia, low-energy trauma, malunion in nonoperative treatment, and peri-implant fractures. Suspicion of child abuse should be considered when the fracture has an unclear mechanism of the injury. Removal of proximal femoral implants may be considered to prevent peri-implant fractures. Femoral fractures should preferably be treated nonoperatively. Operative treatment should be considered for diaphyseal fractures in children capable of standing transfers, larger children, children with more severe spasticity or movement disorder or those who have suffered a high-energy fracture. Due to the high prevalence of proximal fractures in the presence of hardware, operative treatment is usually required for these fractures. In contrast, distal fractures are adequately managed nonoperatively.

The microstructure and mechanical properties of microwave-heated lunar simulants at different input powers under vacuum.

To achieve a sustainable human presence on the Moon, it is critical to develop technologies utilising the local resources (a.k.a. in-situ resource utilisation or ISRU) for construction and resource extraction. In this study, we investigate the viability of microwave heating of two lunar soil simulants (JSC-1A and OPRH3N) under vacuum conditions, to simulate a lunar surface environment compared to previous studies performed at atmospheric pressure. All simulants are thermally treated in a bespoke 2.45 GHz microwave apparatus using three input powers: 1000 W, 600 W and 250 W. The microstructures and mechanical properties of the microwaved samples are analysed to identify their potential applications. Our key findings are: (i) higher input powers generate materials in shorter fabrication times with higher mechanical strengths and higher yields despite the same total energy input; (ii) the microstructures of the microwaved samples under vacuum are very different from those under atmospheric conditions due to the widespread vesicles/bubbles; and (iii) different heating rates caused by different input powers can be utilised for specific ISRU purposes: higher input powers for extra-terrestrial construction and lower input powers for resource extraction. Findings from this study have significant implications for developing a microwave-heating payload for lunar ISRU demonstration missions.

Diabetic Retinopathy and Dementia Association, Beyond Diabetes Severity.

PURPOSE: To investigate whether associations between diabetic retinopathy (DR) and dementia and Alzheimer's disease (AD) remain significant after controlling for several measures of diabetes severity. DESIGN: Retrospective cohort study. METHODS: Adult Changes in Thought (ACT) is a prospective cohort study of adults aged ≥65 years, randomly selected and recruited from the membership rolls of Kaiser Permanente Washington, who are dementia free at enrollment and followed biennially until incident dementia. The ACT participants were included in this study if they had type 2 diabetes mellitus at enrollment or developed it during follow-up, and data were collected through September, 2018 (3516 person-years of follow-up). Diabetes was defined by ≥ 2 diabetes medication fills in 1 year. Diagnosis of DR was based on International Classification of Diseases Ninth and Tenth Revision codes. Estimates of microalbuminuria, long-term glycemia, and renal function from longitudinal laboratory records were used as indicators of diabetes severity. Alzheimer's disease and dementia were diagnosed using research criteria at expert consensus meetings. RESULTS: A total of 536 participants (median baseline age 75 [interquartile range 71-80], 54% women) met inclusion criteria. Significant associations between DR >5 years duration with dementia (hazard ratio 1.81 [95% CI 1.23, 2.65]) and AD (1.80 [1.15, 2.82]) were not altered by adjustment for estimates of microalbuminuria, long-term glycemia, and renal function (dementia: 1.69 [1.14, 2.50]; AD: 1.73 [1.10, 2.74]). CONCLUSIONS: Among people with type 2 diabetes, DR itself appears to be an important biomarker of dementia risk in addition to glycemia and renal complications.

The nine hole peg test as an outcome measure in progressive MS trials.

BACKGROUND: The nine-hole peg test (NHPT) is the outcome measure with the least change in secondary and primary progressive MS (SPMS and PPMS) trials. The Standard NHPT is defined as the average of four measurements, two in each hand. Little is known about the performance of alternative NHPT scoring methods as longitudinal outcome measures in progressive MS. Non-ambulatory people with progressive MS are now generally excluded from clinical trials, and there is little information on longitudinal NHPT change in this patient group. In this investigation, we used patient-level data from two large randomized controlled trials in progressive MS to explore alternative NHPT scoring methods and NHPT change in non-ambulatory people with progressive MS. METHODS: We used patient-level data from the ASCEND (SPMS, n = 889) and PROMISE (PPMS, n = 943) clinical trials to compare significant change on the Standard NHPT with the alternatives dominant hand (DH), non-dominant hand (NDH), and either hand (EH) NHPT in ambulatory and non-ambulatory trial participants. RESULTS: The Standard NHPT changed slowly and showed few worsening events, as did the DH and NDH alternatives. Using the EH NHPT resulted in a substantial increase of worsening events. Non-ambulatory trial participants with PPMS experienced more NHPT worsening than ambulatory participants, especially when using the EH NHPT. CONCLUSION: Using the EH NHPT yielded substantially more worsening events in people with progressive MS. Clinical trials in non-ambulatory people may be possible with the NHPT as the primary outcome measure. More research into the precision of these measures in this patient group is necessary.