Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme.

CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2-74.2%) and 46.5% (95%CI 37.6-57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1-44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3-75.8) and 55.3% (95%CI 43.6-70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival.

Classification performance of sEMG and kinematic parameters for distinguishing between non-lame and induced lameness conditions in horses.

Despite its proven research applications, it remains unknown whether surface electromyography (sEMG) can be used clinically to discriminate non-lame from lame conditions in horses. This study compared the classification performance of sEMG absolute value (sEMGabs) and asymmetry (sEMGasym) parameters, alongside validated kinematic upper-body asymmetry parameters, for distinguishing non-lame from induced fore- (iFL) and hindlimb (iHL) lameness. Bilateral sEMG and 3D-kinematic data were collected from clinically non-lame horses (n = 8) during in-hand trot. iFL and iHL (2-3/5 AAEP) were induced on separate days using a modified horseshoe, with baseline data initially collected each day. sEMG signals were DC-offset removed, high-pass filtered (40 Hz), and full-wave rectified. Normalized, average rectified value (ARV) was calculated for each muscle and stride (sEMGabs), with the difference between right and left-side ARV representing sEMGasym. Asymmetry parameters (MinDiff, MaxDiff, Hip Hike) were calculated from poll, withers, and pelvis vertical displacement. Receiver-operating-characteristic (ROC) and area under the curve (AUC) analysis determined the accuracy of each parameter for distinguishing baseline from iFL or iHL. Both sEMG parameters performed better for detecting iHL (0.97 ≥ AUC ≥ 0.48) compared to iFL (0.77 ≥ AUC ≥ 0.49). sEMGabs performed better (0.97 ≥ AUC ≥ 0.49) than sEMGasym (0.76 ≥ AUC ≥ 0.48) for detecting both iFL and iHL. Like previous studies, MinDiff Poll and Pelvis asymmetry parameters (MinDiff, MaxDiff, Hip Hike) demonstrated excellent discrimination for iFL and iHL, respectively (AUC > 0.95). Findings support future development of multivariate lameness-detection approaches that combine kinematics and sEMG. This may provide a more comprehensive approach to diagnosis, treatment, and monitoring of equine lameness, by measuring the underlying functional cause(s) at a neuromuscular level.

Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL.

PURPOSE: We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant. METHODS: Data were collected for consecutive CYP (age 1-24 years) with Philadelphia chromosome-positive or Philadelphia chromosome-negative B-ALL who received Blina as first-line therapy. Blina was given as replacement for postremission intensive chemotherapy to patients with chemotherapy intolerance or resistance. Blina responders received further chemotherapy (Blin-CT) or first remission hematopoietic stem-cell transplant (Blin-HSCT) if indicated. Event-free survival (EFS) and overall survival (OS) of the Blin-CT group were compared with those of matched controls treated with standard chemotherapy in the UKALL 2003 trial. Events were defined as death, relapse, or secondary cancer. RESULTS: From February 2018 to February 2023, 105 patients were treated, of whom 85 were in the Blin-CT group and 20 were in the Blin-HSCT group. A majority of Blin-CT patients received Blina for chemotherapy intolerance (70 of 85, 82%), and the group had a higher-risk profile than unselected patients with B-ALL. Blina was well tolerated with only one patient having a grade 3/4-related toxicity event, and of the 60 patients who were minimal residual disease-positive pre-Blina, 58 of 60 (97%) responded. At a median follow-up of 22 months, the 2-year outcomes of the 80 matched Blin-CT group patients were similar to those of 192 controls (EFS, 95% [95% CI, 85 to 98] v 90% [95% CI, 65 to 93] and OS, 97% [95% CI, 86 to 99] v 94% [95% CI, 89 to 96]). Of the 20 in the HSCT group, three died because of transplant complications and two relapsed. CONCLUSION: Blina is safe and effective in first-line treatment of chemotherapy-intolerant CYP with ALL.

Electromyographic and Kinematic Comparison of the Leading and Trailing Fore- and Hindlimbs of Horses during Canter.

This study compared muscle activity and movement between the leading (Ld) and trailing (Tr) fore- (F) and hindlimbs (H) of horses cantering overground. Three-dimensional kinematic and surface electromyography (sEMG) data were collected from right triceps brachii, biceps femoris, middle gluteal, and splenius from 10 ridden horses during straight left- and right-lead canter. Statistical parametric mapping evaluated between-limb (LdF vs. TrF, LdH vs. TrH) differences in time- and amplitude-normalized sEMG and joint angle-time waveforms over the stride. Linear mixed models evaluated between-limb differences in discrete sEMG activation timings, average rectified values (ARV), and spatio-temporal kinematics. Significantly greater gluteal ARV and activity duration facilitated greater limb retraction, hip extension, and stifle flexion (p < 0.05) in the TrH during stance. Earlier splenius activation during the LdF movement cycle (p < 0.05), reflected bilateral activation during TrF/LdH diagonal stance, contributing to body pitching mechanisms in canter. Limb muscles were generally quiescent during swing, where significantly greater LdF/H protraction was observed through greater elbow and hip flexion (p < 0.05), respectively. Alterations in muscle activation facilitate different timing and movement cycles of the leading and trailing limbs, which justifies equal training on both canter leads to develop symmetry in muscular strength, enhance athletic performance, and mitigate overuse injury risks.

Towards an Evidence-Based Classification System for Para Dressage: Associations between Impairment and Performance Measures.

This study follows a previously defined framework to investigate the impact of impairment on performance in Para dressage athletes. Twenty-one elite Para dressage athletes (grades I to V) and eleven non-disabled dressage athletes (competing at Prix St. Georges or Grand Prix) participated. Data were collected in two phases: performing a two minute custom dressage test on a riding simulator while kinematic data were synchronously collected using inertial measurement units (2000 Hz) and optical motion capture (100 Hz), and clinically assessed using a battery of impairment assessment tools administered by qualified therapists. Impairment and performance measures were compared between Para and non-disabled athletes. Significant differences between athlete groups were found for all impairment measures and two performance measures: simulator trunk harmonics (p = 0.027) and athlete trunk dynamic symmetry (p < 0.001). Impairment assessments of sitting function and muscle tone could predict 19 to 35% of the impact of impairment on performance in Para athletes but not in non-disabled athletes. These findings provide the basis for a robust, scientific evidence base, which can be used to aid in the refinement of the current classification system for Para dressage, to ensure that it is in line with the International Paralympic Committee's mandate for evidence-based systems of classification.

Adaptations in equine axial movement and muscle activity occur during induced fore- and hindlimb lameness: A kinematic and electromyographic evaluation during in-hand trot.

BACKGROUND: The inter-relationship between equine thoracolumbar motion and muscle activation during normal locomotion and lameness is poorly understood. OBJECTIVE: To compare thoracolumbar and pelvic kinematics and longissimus dorsi (longissimus) activity of trotting horses between baseline and induced forelimb (iFL) and hindlimb (iHL) lameness. STUDY DESIGN: Controlled experimental cross-over study. METHODS: Three-dimensional kinematic data from the thoracolumbar vertebrae and pelvis, and bilateral surface electromyography (sEMG) data from longissimus at T14 and L1, were collected synchronously from clinically nonlame horses (n = 8) trotting overground during a baseline evaluation, and during iFL and iHL conditions (2-3/5 AAEP), induced on separate days using a lameness model (modified horseshoe). Motion asymmetry parameters, maximal thoracolumbar flexion/extension and lateral bending angles, and pelvis range of motion (ROM) were calculated from kinematic data. Normalised average rectified value (ARV) and muscle activation onset, offset and activity duration were calculated from sEMG signals. Mixed model analysis and statistical parametric mapping compared discrete and continuous variables between conditions (α = 0.05). RESULTS: Asymmetry parameters reflected the degree of iFL and iHL. Maximal thoracolumbar flexion and pelvis pitch ROM increased significantly following iFL and iHL. During iHL, peak lateral bending increased towards the nonlame side (NLS) and decreased towards the lame side (LS). Longissimus ARV significantly increased bilaterally at T14 and L1 for iHL, but only at LS L1 for iFL. Longissimus activation was significantly delayed on the NLS and precipitated on the LS during iHL, but these clear phasic shifts were not observed in iFL. MAIN LIMITATIONS: Findings should be confirmed in clinical cases. CONCLUSIONS: Distinctive, significant adaptations in thoracolumbar and pelvic motion and underlying longissimus activity occur during iFL and iHL and are detectable using combined motion capture and sEMG. For iFL, these adaptations occur primarily in a cranio-caudal direction, whereas for iHL, lateral bending and axial rotation are also involved.

CONTEXTO: O relacionamento entre a movimentação toracolombar e a ativação muscular durante a locomoção normal e quando há claudicação é pouco compreendido. OBJETIVOS: Comparar a cinemática toracolombar e pélvica e a atividade do músculo longissimus dorsi (longissimus) em cavalos ao trote entre o momento inicial (baseline) e claudicação induzida no membro torácico (iFL) e pélvico (iHL). DELINEAMENTO DO ESTUDO: Estudo experimental controlado cruzado. METODOLOGIA: Dados cinemáticos tridimensionais das vertebras toracolombar e pelve, e eletromiografia de superfície (sEMG) bilateral do longissimus na T14 e L1 foram coletados de forma síncrona de cavalos clinicamente não claudicantes (n = 8) trotando no momento inicial (baseline), e durante iFL e iHL (2-3/5 AAEP), induzidos separadamente em dias distintos utilizando um modelo de claudicação (ferradura modificada). Parâmetros de movimentação assimétrica, flexão/extensão máxima da toracolombar e ângulos de virada lateral, e amplitude de movimento da pelve (ROM) foram calculados a partir dos dados de cinemática. O valor médio normalizado retificado (ARV) e início da ativação muscular, e término e duração da atividade foram calculados utilizando sinais de sEMG. Análise de modelo misto e mapeamento paramétrico estatístico compararam variáveis discretas e contínuas entre condições (α=0.05). RESULTADOS: Parâmetros de assimetria refletiram o nível de iFL e iHL. A flexão toracolombar máxima e a ROM da pelve aumentaram significativamente com iFL e iHL. Durante iHL, o pico de flexão lateral aumentou em direção ao lado não-claudicante (NSL) e diminuiu em direção ao lado claudicante (LS). Longissimus ARV aumentou significativamente para ambos os lados na T14 e L1 para iHL, mas apenas no LS para iFL. A ativação do longissimus foi significativamente retardado no NLS e precipitado no LS durante iHL, mas essa mudança de fase clara não foi observada no iFL. PRINCIPAIS LIMITAÇÕES: Esses achados precisam ser confirmados em casos clínicos. CONCLUSÕES: Adaptações significantes e distintas na movimentação toracolombar e pélvica e atividade do músculo longissimus ocorre durante iFL e iHL e são detectadas utilizando captura de movimento e sEMG. Para iFL, essas adaptações ocorrem primariamente na direção cranio-caudal, enquanto que em iHL, movimento lateral e rotação axial também estão envolvidos.

Adaptations in equine appendicular muscle activity and movement occur during induced fore- and hindlimb lameness: An electromyographic and kinematic evaluation.

The relationship between lameness-related adaptations in equine appendicular motion and muscle activation is poorly understood and has not been studied objectively. The aim of this study was to compare muscle activity of selected fore- and hindlimb muscles, and movement of the joints they act on, between baseline and induced forelimb (iFL) and hindlimb (iHL) lameness. Three-dimensional kinematic data and surface electromyography (sEMG) data from the fore- (triceps brachii, latissimus dorsi) and hindlimbs (superficial gluteal, biceps femoris, semitendinosus) were bilaterally and synchronously collected from clinically non-lame horses (n = 8) trotting over-ground (baseline). Data collections were repeated during iFL and iHL conditions (2-3/5 AAEP), induced on separate days using a modified horseshoe. Motion asymmetry parameters and continuous joint and pro-retraction angles for each limb were calculated from kinematic data. Normalized average rectified value (ARV) and muscle activation onset, offset and activity duration were calculated from sEMG signals. Mixed model analysis and statistical parametric mapping, respectively, compared discrete and continuous variables between conditions (α= 0.05). Asymmetry parameters reflected the degree of iFL and iHL. Increased ARV occurred across muscles following iFL and iHL, except non-lame side forelimb muscles that significantly decreased following iFL. Significant, limb-specific changes in sEMG ARV, and activation timings reflected changes in joint angles and phasic shifts of the limb movement cycle following iFL and iHL. Muscular adaptations during iFL and iHL are detectable using sEMG and primarily involve increased bilateral activity and phasic activation shifts that reflect known compensatory movement patterns for reducing weightbearing on the lame limb. With further research and development, sEMG may provide a valuable diagnostic aid for quantifying the underlying neuromuscular adaptations to equine lameness, which are undetectable through human observation alone.

An exploration of stakeholder perceptions to inform the development of an evidence-based classification system in para dressage.

In dressage, horse-rider combinations must demonstrate harmony whilst performing a test of gaits and movements, scored by judge(s) using predetermined criteria. The para dressage governing body is working towards compliance with the International Paralympic Committee's mandate for evidence-based classification, which requires a comprehensive understanding of key performance determinants. This study aimed to explore stakeholder perceptions surrounding the key determinants of, and impact of impairment on, para dressage performance. Semi-structured interviews with 30 para dressage stakeholders (athletes, classifiers, judges, coach) were analysed using the Framework method. Themes relating to the equine and human athlete were associated with overall dressage performance and discussed within the context of impairment and horse-rider partnership. Key performance determinants were summarised as the athlete's ability to maintain dynamic postural control for absorbing the horse's movement and coordinating leg, hand, and seat aids, which directly influence the horse's quality and accuracy of movements during dressage. Thus, muscular coordination, joint mobility that influences rider posture, and personality traits that influence the horse-rider partnership were considered performance determinants. These themes will inform the development of an evidence-based classification system, through the establishment of standardised, sport-specific performance measures for assessing the relationship between impairment and activity limitation in para dressage.

Rider Skill Affects Time and Frequency Domain Postural Variables When Performing Shoulder-in.

In equestrian sports the novice rider learns first to follow the movements of the horse's back and then how to influence the horse's performance. One of the rider's challenges is to overcome inherent horse and/or rider asymmetry patterns when riding in straight lines, mirroring the movements on the left, and right sides when turning. This study compares the performance of novice and advanced riders when riding in sitting trot on straight lines and when riding shoulder-in to the left and right sides. Eight novice and eight advanced horse-rider combinations performed sitting trot in a straight line, shoulder-in left and shoulder-in right while wearing a full body set of inertial sensors. An experienced dressage judge indicated when the movements were being performed correctly and assigned scores on a scale of 0-10 for the quality of performance. Kinematic data from the inertial sensors were analyzed in time and frequency domain. Comparisons were made between trotting on the straight, shoulder-in left, and shoulder-in right. Advanced riders received higher dressage scores on all three movements, but significantly (P < .05) lower scores were found for shoulder-in right across the two groups. When riding shoulder-in, advanced riders had greater hip extension (advanced = -5.8 ± 17.7; novice = 7.8 ± 8.9 degrees) and external rotation (advanced = -32.4 ± 15.5; novice = -10.8 ± 13.2 degrees) in the outside leg compared with novices (P < .05), which reflects an important cue in achieving the required body rotation in the horse. Lower scores for shoulder-in right may be linked to significant (P < .05) changes in harmonics of trunk to pelvis rotation.

Characteristics of the Flight Arc in Horses Jumping Three Different Types of Fences in Olympic Competition.

Show jumping horses must execute fences of varying height and width, but the effect of this on jumping kinematics during the airborne phase have not been described. The aim of this study was to describe differences within- and between-horses in CM trajectory, trunk orientation and average trunk angular velocity in a group of elite horses executing three fences: vertical fence (1.60 m), spread fence (1.50 × 1.80 m), water jump (4.5 m) during an Olympic competition. Two-dimensional kinematic data (60 Hz) were collected from video cameras set perpendicular to each fence. After manual digitization, linear and angular variables related to the position and rotation of the CM and trunk were calculated. Linear fixed effects models evaluated within-group differences between fences and kinematic variables. Repeated measures correlation (rmcorr) evaluated within-horse associations between kinematic variables and fence type. Compared with the water jump, CM vertical velocity, CM peak height, and average trunk angular velocity were significantly higher (P < .05) and CM horizontal velocity was significantly lower (P < .05) for the vertical and spread fences. Peak CM height coincided approximately with the middle of the spread fence, toward the take-off for the water jump and landing for the vertical fence. The trunk was significantly more inclined at take-off for the vertical fence and significantly less inclined for the water jump at landing. Rmcorr analysis revealed that individual horses generally employ similar jumping techniques for each fence type. Findings provide original insight into the mechanical requirements for elite horses jumping different fence types.

Muscle Function and Kinematics during Submaximal Equine Jumping: What Can Objective Outcomes Tell Us about Athletic Performance Indicators?

Selection and training practices for jumping horses have not yet been validated using objective performance analyses. This study aimed to quantify the differences and relationships between movement and muscle activation strategies in horses with varying jump technique to identify objective jumping performance indicators. Surface electromyography (sEMG) and three-dimensional kinematic data were collected from horses executing a submaximal jump. Kinematic variables were calculated based on equestrian-derived performance indicators relating to impulsion, engagement and joint articulation. Horses were grouped using an objective performance indicator-center of mass (CM) elevation during jump suspension (ZCM). Between-group differences in kinematic variables and muscle activation timings, calculated from sEMG data, were analyzed using one-way ANOVA. Statistical parametric mapping (SPM) evaluated between-group differences in time and amplitude-normalized sEMG waveforms. Relationships between movement and muscle activation were evaluated using Pearson correlation coefficients. Horses with the greatest ZCM displayed significantly (p < 0.05) shorter gluteal contractions at take-off, which were significantly correlated (p < 0.05) with a faster approach and more rapid hindlimb shortening and CM vertical displacement and velocity, as well as shorter hindlimb stance duration at take-off. Findings provide objective support for prioritizing equestrian-derived performance indicators related to the generation of engagement, impulsion and hindlimb muscle power when selecting or training jumping horses.

Characterizing EBV-associated lymphoproliferative diseases and the role of myeloid-derived suppressor cells.

Chronic active Epstein-Barr virus (CAEBV) typically presents as persistent infectious mononucleosis-like disease and/or hemophagocytic lymphohistocytosis (HLH), reflecting ectopic Epstein-Barr virus (EBV) infection and lymphoproliferation of T and/or NK cells. Clinical behavior ranges from indolent, stable disease through to rapidly progressive, life-threatening disease. Although it is thought the chronicity and/or progression reflect an escape from immune control, very little is known about the phenotype and function of the infected cells vs coresident noninfected population, nor about the mechanisms that could underpin their evasion of host immune surveillance. To investigate these questions, we developed a multicolor flow cytometry technique combining phenotypic and functional marker staining with in situ hybridization for the EBV-encoded RNAs (EBERs) expressed in every infected cell. This allows the identification, phenotyping, and functional comparison of infected (EBERPOS) and noninfected (EBERNEG) lymphocyte subset(s) in patients' blood samples ex vivo. We have characterized CAEBV and HLH cases with monoclonal populations of discrete EBV-activated T-cell subsets, in some cases accompanied by EBV-activated NK-cell subsets, with longitudinal data on the infected cells' progression despite standard steroid-based therapy. Given that cytotoxic CD8+ T cells with relevant EBV antigen specificity were detectable in the blood of the best studied patient, we searched for means whereby host surveillance might be impaired. This revealed a unique feature in almost every patient with CAEBV studied: the presence of large numbers of myeloid-derived suppressor cells that exhibited robust inhibition of T-cell growth. We suggest that their influence is likely to explain the host's failure to contain EBV-positive T/NK-cell proliferation.

Biomechanical and wearability testing of novel legwear for variably limiting extension of the metacarpophalangeal joint of horses.

OBJECTIVE: To evaluate the ability of novel legwear designed to limit extension of the metacarpophalangeal joint (MCPJ) to redirect loading forces from the flexor apparatus during walk, trot, and canter on a treadmill and during unrestrained and restrained activity in a stall. ANIMALS: 6 adult horses without musculoskeletal disease. PROCEDURES: Legwear-derived force data were recorded under 4 conditions: inactive state (unlimited legwear extension) and 3 active (restrictive) states (mild, 30° extension; moderate, 20° extension; or maximum, 10° extension). Associations between peak legwear loads and torques among legwear states and treadmill gaits and stall activities were assessed. The hair coat and skin of the forelimbs were examined for any legwear-induced adverse effects after testing. RESULTS: During the treadmill exercises, moderate restriction of legwear extension resulted in significantly higher peak load and torque than mild restriction, and faster speeds (canter vs walk or trot and trot vs walk) yielded significantly higher peak load and torque. During in-stall activity, maximum restriction of legwear extension yielded significantly higher peak load and torque than moderate restriction. Unrestrained in-stall activity resulted in significantly higher peak load and torque than restrained activity. The legwear caused minimal adverse effects on the hair coat and skin of the forelimbs. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that the legwear variably reduced peak loads on the flexor apparatus. Extension of the MCPJ may be incrementally adjusted through the legwear such that return to activity may be controlled, and controlled return to activity is crucial for rehabilitating flexor apparatus injuries.

Kinematic and kinetic analyses of the gait of horses wearing novel legwear for variably limiting extension of the metacarpophalangeal joint.

OBJECTIVE: To investigate the effects of novel legwear designed to limit metacarpophalangeal joint (MCPJ) extension and redirect loading forces from the flexor apparatus through analyses of 2-D kinematic and kinetic data. ANIMALS: 6 adult horses without musculoskeletal disease. PROCEDURES: Horses were subjected to 4 treatments: control (no legwear), inactive legwear (unlimited legwear extension), and active legwear with mild (30°) and moderate (20°) legwear extension limitation. Two-dimensional kinematic data were collected for the right forelimb (FL) during walk and trot and from leading and trailing FLs during canter on a treadmill. Ground reaction force (GRF) data were collected from FLs during overground walk and trot. Peak MCPJ angle and angular velocity were calculated from kinematic data, and peak force and average loading rate were calculated from vertical GRF data during the stance phase of the gait. Interactions between gait and treatment were determined via ANOVA. RESULTS: Interactions between gait and treatment for peak MCPJ angle were significant. Significant reductions in MCPJ angle were noted between the control treatment and legwear with moderate extension limitation for trot and canter (leading and trailing FL) and between inactive legwear and legwear with moderate extension limitation for trot and leading FL during canter. Interactions among peak MCPJ angular velocity, peak vertical GRF, and average loading rate of the vertical GRF showed nonsignificance. CONCLUSIONS AND CLINICAL RELEVANCE: Significant reductions in MCPJ extension without significant alterations to peak vertical GRF suggested the legwear's ability to redistribute internal forces. Findings suggested that the legwear may be beneficial for horses rehabilitating from flexor apparatus injuries.

BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK-cell lymphoma.

Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell malignancies, such as extranodal NK-/T-cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have a poor prognosis. The rare nature of such cancers and nonmalignant T/NK lymphoproliferative disorders, such as chronic active EBV (CAEBV), has limited our understanding of the pathogenesis of these diseases. Here, we characterize a panel of ENKTL- and CAEBV-derived cell lines that had been established from human tumors to be used as preclinical models of these diseases. These cell lines were interleukin-2 dependent and found to carry EBV in a latency II gene-expression pattern. All cell lines demonstrated resistance to cell death induction by DNA damage-inducing agents, the current standard of care for patients with these malignancies. This resistance was not correlated with the function of the multidrug efflux pump, P-glycoprotein. However, apoptotic cell death could be consistently induced following treatment with A-1331852, a BH3-mimetic drug that specifically inhibits the prosurvival protein BCL-XL. A-1331852-induced apoptosis was most efficacious when prosurvival MCL-1 was additionally targeted, either by BH3-mimetics or genetic deletion. Xenograft models established from the ENKTL cell line SNK6 provided evidence that A-1331852 treatment could be therapeutically beneficial in vivo. The data here suggest that therapeutic targeting of BCL-XL would be effective for patients with EBV-driven T/NK proliferative diseases, however, MCL-1 could be a potential resistance factor.

A scoping review of determinants of performance in dressage.

As a first step in achieving an evidence-based classification system for the sport of Para Dressage, there is a clear need to define elite dressage performance. Previous studies have attempted to quantify performance with able-bodied riders using scientific methods; however, definitive measures have yet to be established for the horse and/or the rider. This may be, in part, due to the variety of movements and gaits that are found within a dressage test and also due to the complexity of the horse-rider partnership. The aim of this review is therefore to identify objective measurements of horse performance in dressage and the functional abilities of the rider that may influence them to achieve higher scores. Five databases (SportDiscuss, CINAHL, MEDLINE, EMBASE, VetMed) were systematically searched from 1980 to May 2018. Studies were included if they fulfilled the following criteria: (1) English language; (2) employ objective, quantitative outcome measures for describing equine and human performance in dressage; (3) describe objective measures of superior horse performance using between-subject comparisons and/or relating outcome measures to competitive scoring methods; (4) describe demands of dressage using objective physiological and/or biomechanical measures from human athletes and/or how these demands are translated into superior performance. In total, 773 articles were identified. Title and abstract screening resulted in 155 articles that met the eligibility criteria, 97 were excluded during the full screening of articles, leaving 58 included articles (14 horse, 44 rider) involving 311 equine and 584 able-bodied human participants. Mean ± sd (%) quality scores were 63.5 ± 15.3 and 72.7 ± 14.7 for the equine and human articles respectively. Significant objective measures of horse performance (n = 12 articles) were grouped into themes and separated by gait/movement. A range of temporal variables that indicated superior performance were found in all gaits/movements. For the rider, n = 5 articles reported variables that identified significant differences in skill level, which included the postural position and ROM of the rider's pelvis, trunk, knee and head. The timing of rider pelvic and trunk motion in relation to the movement of the horse emerged as an important indicator of rider influence. As temporal variables in the horse are consistently linked to superior performance it could be surmised that better overall dressage performance requires minimal disruption from the rider whilst the horse maintains a specific gait/movement. Achieving the gait/movement in the first place depends upon the intrinsic characteristics of the horse, the level of training achieved and the ability of the rider to apply the correct aid. The information from this model will be used to develop an empirical study to test the relative strength of association between impairment and performance in able-bodied and Para Dressage riders.

IgG4-related pancreatitis: an uncommon cause of hyperglycaemia.

Hyperglycaemia is one of the most common metabolic disturbances encountered in clinical practice, with an important differential diagnosis. We report a case of a 72-year-old woman referred to diabetes services with rapidly increasing blood glucose and weight loss despite oral hypoglycaemic therapy. She reported mild upper abdominal discomfort and liver function tests were deranged, prompting further investigation. Abdominal imaging demonstrated a diffusely enlarged pancreas and subsequent investigations noted a markedly raised serum IgG4. She was diagnosed with IgG4-related pancreatitis and swiftly responded to steroid therapy. Secondary causes of diabetes should be considered in people with atypical presentation such as weight loss or rapid progression to insulin use. While IgG4-related disease is rare, its varied clinical presentation as a result of its multiorgan involvement requires a high index of suspicion. This case highlights the importance of a detailed diagnostic work-up and describes an unusual clinical presentation of this increasingly recognised multisystem disease.

Rare case of chorea-hyperglycaemia-basal ganglia (C-H-BG) syndrome.

An 83-year-old woman presented with acute-onset haemichorea and haemiballism particularly affecting the left side of the body. She was known to have type 2 diabetes, which was poorly controlled with sitagliptin. She was hyperglycaemic but not ketotic or acidotic. After she was started on insulin and good glycaemic control was achieved, her abnormal movements dramatically improved. MRI of the brain showed a T1-weighted hyperintense lesion on the right basal ganglia, which is typical of chorea-hyperglycaemia-basal ganglia syndrome. Other causes of chorea, for example, Huntington's disease, Sydenham chorea, Wilson's disease, malignancy, systemic lupus erythematosus, haemorrhage/infarction, thyroid dysfunction, drug-induced chorea and antiphospholipid syndrome, were excluded or deemed less likely given her rapid response to achieving near euglycaemia.