Measurement properties of the Inclusion Body Myositis Functional Rating Scale.

OBJECTIVES: To evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS). METHODS: Data from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in IBM were used. Convergent validity was tested using Spearman correlation with other health outcomes. Discriminant (known groups) validity was assessed using standardised effect sizes (SES). Internal consistency was tested using Cronbach's alpha. Intrarater reliability in stable patients and equivalence of face-to-face and telephone administration were tested using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Responsiveness was assessed using a standardised response mean (SRM). An receiver operator characteristic (ROC) curve anchor-based approach was used to determine clinically meaningful IBMFRS change. RESULTS: Among the 150 patients, mean (SD) IBMFRS total score was 27.4 (4.6). Convergent validity was supported by medium to large correlations (rs modulus: 0.42-0.79) and discriminant validity by moderate to large group differences (SES=0.51-1.59). Internal consistency was adequate (overall Cronbach's alpha: 0.79). Test-retest reliability (ICCs=0.84-0.87) and reliability of telephone versus face-to-face administration (ICCs=0.93-0.95) were excellent, with Bland-Altman plots showing good agreement. Responsiveness in the worsened group defined by various external constructs was large at both 12 (SRM=-0.76 to -1.49) and 20 months (SRM=-1.12 to -1.57). In ROC curve analysis, a drop in two IBMFRS total score points was shown to represent a meaningful decline. CONCLUSIONS: When administered by trained raters, the IBMFRS is a reliable, valid and responsive tool that can be used to evaluate the impact of IBM and its treatment on physical function, with a 2-point reduction representing meaningful decline. TRIAL REGISTRATION NUMBER: NCT02753530.

Health-related quality of life following aortopexy for tracheomalacia: a cross-sectional study.

OBJECTIVES: The objective was to measure health-related quality of life (HRQoL) of children following treatment of all-cause tracheomalacia with aortopexy. METHODS: Children ≥5 years and parents of children <18 years who had undergone aortopexy completed the Paediatric Quality of Life Inventory (PedsQL4.0). Scores were compared to published norms. RESULTS: Completed questionnaires were received from 35 parents (65%) and 10 children (38%). Median age at aortopexy was 9.8 months (1 month-12.7 years) and median years of follow-up was 2.6 (4 months-6.9 years). Children who completed questionnaires had a median age of 8.4 (5.7-13.4) years. Parent and child-reported total PedsQL scores were 69.61 (SD : 19.74), and 63.15 (SD : 20.40) respectively. Half of parents and 80% of children reported scores suggesting poor HRQoL outcomes. Parent-reported total, physical and psycho-social scores were lower than those of healthy children and those with acute illness but comparable to children with chronic health conditions and cardiovascular disease. Similarly, children themselves reported comparable total scores to children with chronic illness but child-reported psycho-social scores were lower in the aortopexy group than any other group. There was no association between PedsQL scores and cause of malacia, age or time since aortopexy. The presence of complex congenital comorbidities had a significant (p < 0.05) impact on HRQoL scores. CONCLUSIONS: Following aortopexy children remain at risk of poor HRQoL, especially those with complex comorbidities. HRQoL reported by both parent and child provides important insight into the lives of children following this procedure. Further longitudinal and qualitative study are required to better understand this complex group.

An In-Depth Analysis of 1370 Consecutive Abdominoplasties: Fascial Plication Increases Risk of Venous Thromboembolism, and Scoring for Plication Improves the Caprini Risk Assessment Model.

BACKGROUND: Venous thromboembolism (VTE) is the most dangerous complication of abdominoplasty. One relatively undefined risk factor is plication, which in theory increases VTE risk. OBJECTIVES: To assess the thromboembolic risk of plication. METHODS: A retrospective review of 1370 consecutive abdominoplasties by one surgeon was undertaken. Two groups were considered, plicated (n= 1089) and non-plicated (n = 281), and VTE rates were compared between these groups. RESULTS: There were 25/1089 cases of VTE (2.3%) in plicated patients and 1/281 case of VTE (0.36%) in non-plicated patients, which was statistically significant (Fisher's exact test, p=0.028) despite the non-plicated group being a higher risk population. Case-Control matching yielded 225 pairs which differed statistically only by the presence or absence of plication; there were 12/225(5.3%) VTE events in the plicated group and 0/225 in the non-plicated group (McNemar's test, p=0.0015). Logistic regression demonstrated increased VTE risk with increasing age (OR 1.08, p<0.001), BMI (OR 1.34, p=0.002), Caprini score (OR 2.17, p<0.001), and especially plication (OR 16.76, p=0.008). Adding two points for plication to Caprini scores offered better risk stratification at a level of 7, with an improved combination of sensitivity/specificity (0.31/0.98 vs 0.69/0.96) and a 27% improvement over the 2005 Caprini RAM in the area under a Receiver Operating Characteristic (ROC) curve (0.826 vs 0.651, Z-value -3.596, p = 0.003). CONCLUSIONS: Plication was shown to be a powerful risk factor for the development of VTE in abdominoplasty. Abdominal wall plication should be considered in risk assessment, and scoring for plication may improve the performance of the Caprini RAM.

Infection of Alfalfa Cotyledons by an Incompatible but Not a Compatible Species of Colletotrichum Induces Formation of Paramural Bodies and Secretion of EVs.

Hemibiotrophic fungi in the genus Colletotrichum employ a biotrophic phase invading host epidermal cells followed by a necrotrophic phase spreading through neighboring mesophyll and epidermal cells. We used serial block face scanning electron microscopy (SBF-SEM) to compare subcellular changes that occur in Medicago sativa (alfalfa) cotyledons during infection by Colletotrichum destructivum (compatible on M. sativa) and C. higginsianum (incompatible on M. sativa). Three-dimensional reconstruction of serial images revealed that alfalfa epidermal cells infected with C. destructivum undergo massive cytological changes during the first 60 hours following inoculation to accommodate extensive intracellular hyphal growth. Conversely, inoculation with the incompatible species C. higginsianum resulted in no successful penetration events and frequent formation of papilla-like structures and cytoplasmic aggregates beneath attempted fungal penetration sites. Further analysis of the incompatible interaction using focused ion beam-scanning electron microcopy (FIB-SEM) revealed formation of large multivesicular body-like structures that appeared spherical and were not visible in compatible interactions. These structures often fused with the host plasma membrane, giving rise to paramural bodies that appeared to be releasing extracellular vesicles (EVs). Isolation of EVs from the apoplastic space of alfalfa leaves at 60h post inoculation showed significantly more vesicles secreted from alfalfa infected with incompatible fungus compared to compatible fungus, which in turn was more than produced by non-infected plants. Thus, the increased frequency of paramural bodies during incompatible interactions correlated with an increase in EV quantity in apoplastic wash fluids. Together, these results suggest that EVs and paramural bodies contribute to immunity during pathogen attack in alfalfa.

Using Routinely Collected Electronic Healthcare Record Data to Investigate Fibrotic Multimorbidity in England.

Background: Electronic healthcare records (EHRs) are used to document diagnoses, symptoms, tests, and prescriptions. Though not primarily collected for research purposes, owing to the size of the data as well as the depth of information collected, they have been used extensively to conduct epidemiological research. The Clinical Practice Research Datalink (CPRD) is an EHR database containing representative data of the UK population with regard to age, sex, race, and social deprivation measures. Fibrotic conditions are characterised by excessive scarring, contributing towards organ dysfunction and eventual organ failure. Fibrosis is associated with ageing as well as many other factors, it is hypothesised that fibrotic conditions are caused by the same underlying pathological mechanism. We calculated the prevalence of fibrotic conditions (as defined in a previous Delphi survey of clinicians) as well as the prevalence of fibrotic multimorbidity (the proportion of people with multiple fibrotic conditions). Methods: We included a random sample of 993,370 UK adults, alive, and enrolled at a UK general practice, providing data to the CPRD Aurum database as of 1st of January 2015. Individuals had to be eligible for linkage to hospital episode statistics (HES) and ONS death registration. We calculated the point prevalence of fibrotic conditions and multi-morbid fibrosis on the 1st of January 2015. Using death records of those who died in 2015, we investigated the prevalence of fibrosis associated death. We explored the most commonly co-occurring fibrotic conditions and determined the settings in which diagnoses were commonly made (primary care, secondary care or after death). Results: The point prevalence of any fibrotic condition was 21.46%. In total, 6.00% of people had fibrotic multimorbidity. Of the people who died in 2015, 34.82% had a recording of a fibrotic condition listed on their death certificate. Conclusion: The key finding was that fibrotic multimorbidity affects approximately 1 in 16 people.

Fibrotic conditions are scarring conditions which impact the way an organ functions and eventually lead to organ failure. We studied routinely collected health data from GPs, hospitals, and death certificates to estimate the percentage of UK adults who had fibrotic diseases. We found that 1 in 5 people had at least one fibrotic disease, and we also found that 1 in 16 people had more than one fibrotic disease.

Cytomegalovirus-induced peroxynitrite promotes virus entry and contributes to pathogenesis in a murine model of infection.

There are no licensed vaccines for human cytomegalovirus (HCMV), and current antiviral drugs that target viral proteins are toxic and prone to resistance. Targeting host pathways essential for virus replication provides an alternate strategy that may reduce opportunities for drug resistance to occur. Oxidative stress is triggered by numerous viruses including HCMV. Peroxynitrite is a reactive nitrogen species that is formed during oxidative stress. Herein, we identified that HCMV rapidly induces the generation of intracellular peroxynitrite upon infection in a manner partially dependent upon xanthine oxidase generation. Peroxynitrite promoted HCMV infection in both cell-free and cell-associated infection systems in multiple cell types. Inhibiting peroxynitrite within the first 24 hours of infection prevented HCMV replication and peroxynitrite promoted cell entry and pp65 translocation into the host cell nuclei. Furthermore, using the murine cytomegalovirus model, we demonstrated that antagonizing peroxynitrite significantly reduces cytomegalovirus replication and pathogenesis in vivo. Overall, our study highlights a proviral role for peroxynitrite in CMV infection and implies that RNS and/or the mechanisms that induce their production could be targeted as a novel strategy to inhibit HCMV infection. IMPORTANCE: Human cytomegalovirus (HCMV) causes significant disease in individuals with impaired or immature immune systems, such as transplant patients and after congenital infection. Antiviral drugs that target the virus directly are toxic and are susceptible to antiviral drug resistance due to virus mutations. An alternate strategy is to target processes within host cells that are required by the virus for replication. Herein, we show that HCMV infection triggers a highly reactive molecule, peroxynitrite, during the initial stages of infection. Peroxynitrite was required for the initial entry of the virus into the cell and promotes virus replication in multiple cell types, suggesting a broad pro-viral function. Importantly, targeting peroxynitrite dramatically inhibited cytomegalovirus replication in cells in the laboratory and in mice, suggesting that therapeutic targeting of this molecule and/or the cellular functions it regulates could represent a novel strategy to inhibit HCMV infection.

The Cannabis Gray Market: A Case for Cannabis Regulatory Science Research.

The cannabis gray market poses significant public health concerns and remains a major threat to consumer and/or potential consumer uptake of regulated cannabis markets in jurisdictions with legal state-sponsored cannabis programs. In this perspective, we provide an overview of the cannabis gray market, and describe an integrated epidemiological and regulatory science framework to study the gray market. Using tobacco regulatory science as a guide, we introduce example cannabis regulatory science research activities as a means to improve the field's understanding of the cannabis gray market. Cannabis regulatory science is a developing field that can improve our understanding of the cannabis regulatory ecosystem and provide regulatory officials and policymakers alike with much needed data to inform regulatory decision-making and improve the success and uptake of state-sponsored cannabis programs.

Attention: The blue spot reveals one of its secrets.

The locus coeruleus is the seat of a brain-wide neuromodulatory circuit. Using optogenetic and electrophysiological tools to selectively interrogate noradrenergic neurons in non-human primates, Ghosh and Maunsell show how locus coeruleus neurons contribute to a specific aspect of visual attention.

Global and regional seroprevalence, incidence, mortality of, and risk factors for scrub typhus: a systematic review and meta-analysis.

Background Scrub typhus is underdiagnosed and underreported but emerging as a global public health problem. We aimed to provide the first comprehensive review on the seroprevalence, incidence, mortality of and risk factors for scrub typhus. Methods We searched PubMed, Scopus, Web of Science, China National Knowledge Infrastructure and other databases. Trended incidence and median mortality were calculated and pooled seroprevalence and risk factors for scrub typhus were evaluated using the random-effects meta-analysis. Findings We included 663 articles from 29 countries/regions. The pooled seroprevalence was 10·73% (95%CI 9·47%-12·13%) among healthy individuals and 22·58% (95%CI: 20·55%-24·76%) among febrile patients. Mainland China reported the highest number of cases and South Korea and Thailand had the highest incidence rates. Median mortalities were 5·00% (range: 0·00%-56·00%) among hospital inpatients, 6·70% (range: 0·00%∼33·33%) among patients without specified admission status and 2·17% (range: 0·00%-22·22%) among outpatients. The significant risk factors included agricultural work, specific vegetation exposure, other outdoor activities, risky personal health habits, and proximity to rodents, livestock, or poultry. Conclusions Our comprehensive review elucidates the significant yet variable burden of scrub typhus across different regions, underscoring its emergence as a critical public health concern globally.

Identification of an endonuclease and N6-adenine methyltransferase from Ureaplasma parvum SV3F4 strain.

Here, we report a novel endonuclease and N6-adenine DNA methyltransferase (m6A methyltransferase) in the Ureaplasma parvum SV3F4 strain. Our previous study found that the SV3F4 strain carries 17 unique genes, which are not encoded in the two previously reported U. parvum serovar 3 strain, OMC-P162 and ATCC 700970. Of these 17 unique genes, UP3_c0261 and UP3_c0262, were originally annotated as encoding hypothetical proteins. Comparative genomics analyses more recently indicated they encode a Type II restriction endonuclease and an m6A methyltransferase, respectively. The UP3_c0261 and UP3_c0262 genes were individually expressed and purified in Escherichia coli. The UP3_c0261 recombinant protein showed endonuclease activity on the pT7Blue vector, recognizing and cleaving a GTNAC motif, resulting in a 5 base 5' extension. The UP3_c0261 protein digested a polymerase chain reaction (PCR) product harboring the GTNAC motif. The endonuclease UP3_c0261 was designated as UpaF4I. Treatment of the PCR product with the recombinant protein UP3_c0262 completely blocked the restriction enzyme activity of UpaF4I. Analysis of the treated PCR product harboring a modified nucleotide by UP3_c0262 with HPLC-MS/MS and MS/MS showed that UP3_c0262 was an m6A methyltransferase containing a methylated A residue in both DNA strands of the GTNAC motif. Whole genome methylation analysis of SV3F4 showed that 99.9 % of the GTNAC motif was m6A modified. These results suggest the UP3_c0261 and UP3_c0262 genes may act as a novel Type II restriction-modification system in the Ureaplasma SV3F4 strain.

Short-latency preference for faces in primate superior colliculus depends on visual cortex.

Face processing is fundamental to primates and has been extensively studied in higher-order visual cortex. Here, we report that visual neurons in the midbrain superior colliculus (SC) of macaque monkeys display a preference for images of faces. This preference emerges within 40 ms of stimulus onset-well before "face patches" in visual cortex-and, at the population level, can be used to distinguish faces from other visual objects with accuracies of ∼80%. This short-latency face preference in SC depends on signals routed through early visual cortex because inactivating the lateral geniculate nucleus, the key relay from retina to cortex, virtually eliminates visual responses in SC, including face-related activity. These results reveal an unexpected circuit in the primate visual system for rapidly detecting faces in the periphery, complementing the higher-order areas needed for recognizing individual faces.

Iliac Accessory Rod Technique for Rod Fracture Prevention in Long Fusion Constructs: 2-Dimensional Operative Video.

Implant-related complications in surgery for adult spinal deformity (ASD) account for roughly $1 billion US health care expenditures over 5 years, with a majority due to primary rod fracture.1,2 Traditional two-rod constructs have demonstrated rod fracture rates of up to 40%, with a median time to fracture of 3 years.3 Current supplementary rod techniques for decreasing rod fractures inadequately address the issue of increased strain across the lumbosacral junction.4 Here, we describe a novel four-rod technique using "iliac accessory rods," designed to mitigate rod fractures by reinforcing osteotomy levels and dispersing biomechanical stress across the lumbosacral junction. Compared with other supplementary rod techniques for ASD, iliac accessory rods anchor to independent iliac bolts.5 The added fixation points across the lumbosacral junction (4 iliac bolts total) substantially offloads stress on primary rods, most of which fracture near the lumbosacral junction.3 Additionally, connecting these rods to primary rods rostrally via side-to-side connectors, above the osteotomy levels, ensures mobile osteotomy segments are reinforced. Presented is a 78-year-old woman with ASD and worsening lower back pain, radiculopathy, and bilateral leg weakness who failed nonoperative management. She underwent T9 to bi-iliac instrumented fusion with L1-S1 posterior column osteotomies, L4-S1 transforaminal lumbar interbody fusions, and bilateral iliac accessory rod fixation. Postoperatively, she recovered well and had improvement in her symptoms. Imaging revealed correction of spinal alignment. The patient consented to the procedure, and the participants and any identifiable individuals consented to publication of his/her image. Institutional Review Board approval was waived because of institutional exemption policy.

In Silico Drug Repurposing Uncovered the Antiviral Potential of the Antiparasitic Drug Oxibendazole Against the Chikungunya Virus.

Chikungunya virus (CHIKV) has been reported in over 120 countries and is the causative agent of Chikungunya fever. The debilitating nature of this disease, which can persist months to years after acute infection, drastically impacts the quality of life of patients. Yet, specific antivirals are lacking for the treatment of this disease, which makes the search for new drugs necessary. In this context, the nsP2 protease emerges as an attractive therapeutic target, and drug repurposing strategies have proven to be valuable. Therefore, we combined in silico and in vitro methods to identify known drugs as potential CHIKV nsP2 protease inhibitors with antiviral properties within DrugBank. Herein, we developed a hybrid virtual screening pipeline comprising pharmacophore- and target-based screening, drug-like, and pharmaceutical filtering steps. Six virtual hits were obtained, and two of them, capecitabine (CPB) and oxibendazole (OBZ), were evaluated against CHIKV replication in Vero cells. CPB did not present antiviral activity, whereas OBZ inhibited the replication of two different strains of CHIKV, namely, 181-25 (Asian genotype) and BRA/RJ/18 (clinical isolate from ECSA genotype). OBZ showed potent antiviral activity against the CHIKV BRA/RJ/18 (EC50 = 11.4 µM) with a high selectivity index (>44). Analogs of OBZ (albendazole, fenbendazole, and mebendazole) were also evaluated, but none exhibited anti-CHIKV activity, and further, their stereoelectronic features were analyzed. Additionally, we observed that OBZ acts mainly at post-entry steps. Hence, our results support further in vivo studies to investigate the antiviral potential of OBZ, which offers a new alternative to fight CHIKV infections.

Materials descriptors for advanced water dissociation catalysts in bipolar membranes.

The voltage penalty driving water dissociation (WD) at high current density is a major obstacle in the commercialization of bipolar membrane (BPM) technology for energy devices. Here we show that three materials descriptors, that is, electrical conductivity, microscopic surface area and (nominal) surface-hydroxyl coverage, effectively control the kinetics of WD in BPMs. Using these descriptors and optimizing mass loading, we design new earth-abundant WD catalysts based on nanoparticle SnO2 synthesized at low temperature with high conductivity and hydroxyl coverage. These catalysts exhibit exceptional performance in a BPM electrolyser with low WD overvoltage (ηwd) of 100 ± 20 mV at 1.0 A cm-2. The new catalyst works equivalently well with hydrocarbon proton-exchange layers as it does with fluorocarbon-based Nafion, thus providing pathways to commercializing advanced BPMs for a broad array of electrolysis, fuel-cell and electrodialysis applications.

Force Field X: A computational microscope to study genetic variation and organic crystals using theory and experiment.

Force Field X (FFX) is an open-source software package for atomic resolution modeling of genetic variants and organic crystals that leverages advanced potential energy functions and experimental data. FFX currently consists of nine modular packages with novel algorithms that include global optimization via a many-body expansion, acid-base chemistry using polarizable constant-pH molecular dynamics, estimation of free energy differences, generalized Kirkwood implicit solvent models, and many more. Applications of FFX focus on the use and development of a crystal structure prediction pipeline, biomolecular structure refinement against experimental datasets, and estimation of the thermodynamic effects of genetic variants on both proteins and nucleic acids. The use of Parallel Java and OpenMM combines to offer shared memory, message passing, and graphics processing unit parallelization for high performance simulations. Overall, the FFX platform serves as a computational microscope to study systems ranging from organic crystals to solvated biomolecular systems.

A(H2N2) and A(H3N2) influenza pandemics elicited durable cross-reactive and protective antibodies against avian N2 neuraminidases.

Human cases of avian influenza virus (AIV) infections are associated with an age-specific disease burden. As the influenza virus N2 neuraminidase (NA) gene was introduced from avian sources during the 1957 pandemic, we investigate the reactivity of N2 antibodies against A(H9N2) AIVs. Serosurvey of healthy individuals reveal the highest rates of AIV N2 antibodies in individuals aged ≥65 years. Exposure to the 1968 pandemic N2, but not recent N2, protected against A(H9N2) AIV challenge in female mice. In some older adults, infection with contemporary A(H3N2) virus could recall cross-reactive AIV NA antibodies, showing discernable human- or avian-NA type reactivity. Individuals born before 1957 have higher anti-AIV N2 titers compared to those born between 1957 and 1968. The anti-AIV N2 antibodies titers correlate with antibody titers to the 1957 N2, suggesting that exposure to the A(H2N2) virus contribute to this reactivity. These findings underscore the critical role of neuraminidase immunity in zoonotic and pandemic influenza risk assessment.

Following a strict renal protection protocol in cloacal malformations: A descriptive analysis.

BACKGROUND: In children with cloacal malformations, renal dysfunction is a constant concern, with reported incidence as high as 50%. Multiple factors exist that may impair renal function. Our institution follows a strict renal protection protocol in this population. Incidence of renal dysfunction in these patients is unknown. OBJECTIVE: We aimed to evaluate incidence of renal dysfunction while implementing this protocol in a cohort of children with cloacal malformation. STUDY DESIGN: We reviewed a prospectively collected database of children with cloacal malformations managed at a single institution since implementation of a renal protection protocol. This involves regular laboratory evaluation, appropriate selection of total urogenital mobilization or urogenital separation, proactive imaging in patients with signs of impending renal dysfunction or urinary retention, and early catheterization teaching and implementation if necessary. Glomerular filtration rate (GFR) was calculated with the Schwartz formula and CKD grades assigned per standard definitions. Renal dysfunction was defined as CKD grade 3b or higher, need for renal replacement therapy (RRT) or transplantation. Descriptive statistics were computed. RESULTS: A total of 105 children were managed under this protocol with a median follow-up of 4.2 years [IQR: 2.0-5.9]. Six children (5.7%) had renal dysfunction at most recent follow-up; of these children, only three (2.9%) progressed from normal renal function at initial evaluation to renal dysfunction (Table). No child with normal presenting renal function thus far has progressed to require dialysis or transplantation. DISCUSSION: Previous literature estimated rates of renal dysfunction in cloaca patients as high as 50%; in contrast, we demonstrate a rate of progression to renal dysfunction of 2.9% in girls following a strict renal protection protocol. Most children who developed renal dysfunction had dysfunctional kidneys on presentation. This suggests that preservation of renal function may be possible in early childhood with a strict, multi-disciplinary renal protection protocol. CONCLUSION: In our cohort of patients with cloacal malformations following a strict renal protection protocol, incidence of progressive renal dysfunction is low at 2.9%. Most who go on to renal dysfunction present with impaired renal function.

Characterisation of phenotypic patterns in equine exercise-associated myopathies.

BACKGROUND: Equine exercise-associated myopathies are prevalent, clinically heterogeneous, generally idiopathic disorders characterised by episodes of myofibre damage that occur in association with exercise. Episodes are intermittent and vary within and between affected horses and across breeds. The aetiopathogenesis is often unclear; there might be multiple causes. Poor phenotypic characterisation hinders genetic and other disease analyses. OBJECTIVES: The aim of this study was to characterise phenotypic patterns across exercise-associated myopathies in horses. STUDY DESIGN: Historical cross-sectional study, with subsequent masked case-control validation study. METHODS: Historical clinical and histological features from muscle samples (n = 109) were used for k-means clustering and validated using principal components analysis and hierarchical clustering. For further validation, a blinded histological study (69 horses) was conducted comparing two phenotypic groups with selected controls and horses with histopathological features characterised by myofibrillar disruption. RESULTS: We identified two distinct broad phenotypes: a non-classic exercise-associated myopathy syndrome (EAMS) subtype was associated with practitioner-described signs of apparent muscle pain (p < 0.001), reluctance to move (10.85, p = 0.001), abnormal gait (p < 0.001), ataxia (p = 0.001) and paresis (p = 0.001); while a non-specific classic RER subtype was not uniquely associated with any particular variables. No histological differences were identified between subtypes in the validation study, and no identifying histopathological features for other equine myopathies identified in either subtype. MAIN LIMITATIONS: Lack of an independent validation population; small sample size of smaller identified subtypes; lack of positive control myofibrillar myopathy cases; case descriptions derived from multiple independent and unblinded practitioners. CONCLUSIONS: This is the first study using computational clustering methods to identify phenotypic patterns in equine exercise-associated myopathies, and suggests that differences in patterns of presenting clinical signs support multiple disease subtypes, with EAMS a novel subtype not previously described. Routine muscle histopathology was not helpful in sub-categorising the phenotypes in our population.

CONTEXTE: Les myopathies induites à l'exercice demeurent fréquentes, hétérogènes cliniquement et représentent des désordres idiopathiques caractérisés par des épisodes de dommages myofibrillaires en lien avec l'exercice. Les épisodes sont intermittents et varient à la fois chez le même cheval, entre chevaux et entre les différentes races. L'étiopathogénie demeure obscure et pourrait être multifactorielle. La pauvre caractérisation phénotypique des myopathies ne simplifie pas les analyses génétiques ni celles d'autres maladies. OBJECTIFS: Le but de cette étude est de caractériser les patrons phénotypiques en lien avec les myopathies induites à l'exercice chez le cheval. TYPE D'ÉTUDE: Étude transversale historique et étude subséquente de validation de cas témoins aveugle. MÉTHODES: Les facteurs clés cliniques et histologiques provenant d'échantillons de muscles (n = 109) ont été utilisés pour l'algorithme de K­moyennes et validés par le biais d'analyse des composantes principales et de classification hiérarchique. Pour validation additionnelle, une étude histologique à l'aveugle (69 chevaux) a été faite comparant les deux groupes phénotypiques avec des contrôles sélectionnés et des chevaux avec éléments histopathologiques caractérisés par de la discontinuité myofibrillaire. RÉSULTATS: Deux phénotypes distincts ont été identifiés: un premier sous­type de syndrome de myopathie induite à l'exercice non­classique (EAMS) associé à de la douleur musculaire telle que décrite par le praticien suivant le cheval (χ2 (df=1,n=109) = 19.33, p < 0.001), difficulté à se déplacer (χ2 (df=1,n=109) = 10.85, p = 0.001), démarche anormale (χ2 (df=1,n=109) = 34.61, p < 0.001), ataxie (χ2 (df=1,n=109) = 10.88, p = 0.001) et parésie (χ2 (df=1,n=109) = 10.88, p = 0.001); alors qu'un sous­type RER classique non­spécifique n'était associé à aucune variable en particulier. Aucune différente histologique n'a été identifié entre les sous­types dans l'étude de validation et aucune caractéristique histopathologique d'autres myopathies équines n'a été identifiées dans les différents sous­types. LIMITES PRINCIPALES: Aucune population indépendante pour validation; petite taille d'échantillon pour les sous­types peu nombreux identifiés; aucun cas contrôles positifs de myopathie fibrillaire; description des cas provenant de multiples praticiens indépendants et non­aveugles. CONCLUSION: Cette étude est la première utilisant des méthodes de regroupement informatique pour identifier des patrons phénotypiques de myopathies équines induites à l'exercice et suggère que des différences existent dans les patrons de signes cliniques en faveur de multiples sous­types de maladie, incluant EAMS qui représente un nouveau sous­type non décrit jusqu'à maintenant. L'histopathologie musculaire de routine n'a pas permis de sous­catégoriser les phénotypes dans cette population.

Belantamab mafodotin concentration-QTc relationships in patients with relapsed or refractory multiple myeloma from the DREAMM-1 and -2 studies.

AIMS: To evaluate relationships between plasma concentrations of belantamab mafodotin, total monoclonal antibody, and its payload and changes in electrocardiogram (ECG) parameters in patients with relapsed or refractory multiple myeloma from the DREAMM-1 and DREAMM-2 studies. METHODS: Hysteresis plots and linear regression analyses of pharmacokinetic (PK) analyte (belantamab mafodotin, total monoclonal antibody, and cytotoxic cysteine-maleimidocaproyl monomethyl auristatin F payload) concentrations vs. time-matched ECG parameters (absolute/change from baseline in QT interval corrected for RR interval [QTc/ΔQTc] and QT interval corrected for heart rate by Fridericia's formula [QTcF/ΔQTcF]) were performed. Concentrations of PK analyte required for a 10-ms increase in QTc in DREAMM-2 were calculated via simulation, as was the probability of ΔQTc/ΔQTcF exceeding 10 ms for the expected Cmax of PK analyte concentrations associated with the doses (2.5 and 3.4 mg/kg) administered in DREAMM-2. RESULTS: Time-matched PK and ECG data from 290 patients (DREAMM-1, n = 73; DREAMM-2, n = 217) were analysed. Hysteresis plots did not clearly indicate any concentration-related prolongation in QTc or QTcF; regression analyses indicated a very small rate of increase in ΔQTc and ΔQTcF with increasing concentrations of PK analytes. Calculated concentrations of PK analyte required for a 10-ms prolongation in QTc were higher than the maximum analyte concentrations observed following treatment with belantamab mafodotin in DREAMM-2; the probability that each dose would prolong ΔQTc and ΔQTcF by >10 ms was 0 and <0.25%, respectively. CONCLUSION: This study of belantamab mafodotin and its payload did not provide evidence of QT prolongation in patients with relapsed or refractory multiple myeloma at clinically relevant doses.