Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).

A single-day polychemotherapy regimen with proteasome inhibitor combinations for relapsed/refractory myeloma in the era of novel therapies.

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics.

Regression-Based Machine Learning for Predicting Lifting Movement Pattern Change in People with Low Back Pain.

Machine learning (ML) algorithms are crucial within the realm of healthcare applications. However, a comprehensive assessment of the effectiveness of regression algorithms in predicting alterations in lifting movement patterns has not been conducted. This research represents a pilot investigation using regression-based machine learning techniques to forecast alterations in trunk, hip, and knee movements subsequent to a 12-week strength training for people who have low back pain (LBP). The system uses a feature extraction algorithm to calculate the range of motion in the sagittal plane for the knee, trunk, and hip and 12 different regression machine learning algorithms. The results show that Ensemble Tree with LSBoost demonstrated the utmost accuracy in prognosticating trunk movement. Meanwhile, the Ensemble Tree approach, specifically LSBoost, exhibited the highest predictive precision for hip movement. The Gaussian regression with the kernel chosen as exponential returned the highest prediction accuracy for knee movement. These regression models hold the potential to significantly enhance the precision of visualisation of the treatment output for individuals afflicted with LBP.

Do biomechanical foot-based interventions reduce patellofemoral joint loads in adults with and without patellofemoral pain or osteoarthritis? A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effects of biomechanical foot-based interventions (eg, footwear, insoles, taping and bracing on the foot) on patellofemoral loads during walking, running or walking and running combined in adults with and without patellofemoral pain or osteoarthritis. DESIGN: Systematic review with meta-analysis. DATA SOURCES: MEDLINE, CINAHL, SPORTdiscus, Embase and CENTRAL. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: English-language studies that assessed effects of biomechanical foot-based interventions on peak patellofemoral joint loads, quantified by patellofemoral joint pressure, reaction force or knee flexion moment during gait, in people with or without patellofemoral pain or osteoarthritis. RESULTS: We identified 22 footwear and 11 insole studies (participant n=578). Pooled analyses indicated low-certainty evidence that minimalist footwear leads to a small reduction in peak patellofemoral joint loads compared with conventional footwear during running only (standardised mean difference (SMD) (95% CI) = -0.40 (-0.68 to -0.11)). Low-certainty evidence indicated that medial support insoles do not alter patellofemoral joint loads during walking (SMD (95% CI) = -0.08 (-0.42 to 0.27)) or running (SMD (95% CI) = 0.11 (-0.17 to 0.39)). Very low-certainty evidence indicated rocker-soled shoes have no effect on patellofemoral joint loads during walking and running combined (SMD (95% CI) = 0.37) (-0.06 to 0.79)). CONCLUSION: Minimalist footwear may reduce peak patellofemoral joint loads slightly compared with conventional footwear during running only. Medial support insoles may not alter patellofemoral joint loads during walking or running and the evidence is very uncertain about the effect of rocker-soled shoes during walking and running combined. Clinicians aiming to reduce patellofemoral joint loads during running in people with patellofemoral pain or osteoarthritis may consider minimalist footwear.

Impaired Lumbar Extensor Force Control Is Associated with Increased Lifting Knee Velocity in People with Chronic Low-Back Pain.

The ability of the lumbar extensor muscles to accurately control static and dynamic forces is important during daily activities such as lifting. Lumbar extensor force control is impaired in low-back pain patients and may therefore explain the variances in lifting kinematics. Thirty-three chronic low-back pain participants were instructed to lift weight using a self-selected technique. Participants also performed an isometric lumbar extension task where they increased and decreased their lumbar extensor force output to match a variable target force within 20-50% lumbar extensor maximal voluntary contraction. Lifting trunk and lower limb range of motion and angular velocity variables derived from phase plane analysis in all planes were calculated. Lumbar extensor force control was analyzed by calculating the Root-Mean-Square Error (RMSE) between the participants' force and the target force during the increasing (RMSEA), decreasing (RMSED) force portions and for the overall force error (RMSET) of the test. The relationship between lifting kinematics and RMSE variables was analyzed using multiple linear regression. Knee angular velocity in the sagittal and coronal planes were positively associated with RMSEA (R2 = 0.10, ß = 0.35, p = 0.046 and R2 = 0.21, ß = 0.48, p = 0.004, respectively). Impaired lumbar extensor force control is associated with increased multiplanar knee movement velocity during lifting. The study findings suggest a potential relationship between lumbar and lower limb neuromuscular function in people with chronic low-back pain.

Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease.

BACKGROUND AIMS: The value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis. METHODS: Blood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD). RESULTS: Incomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003). CONCLUSIONS: High post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.

Survival in branching cellular populations.

We analyze evolutionary dynamics in a confluent, branching cellular population, such as in a growing duct, vasculature, or in a branching microbial colony. We focus on the coarse-grained features of the evolution and build a statistical model that captures the essential features of the dynamics. Using simulations and analytic approaches, we show that the survival probability of strains within the growing population is sensitive to the branching geometry: Branch bifurcations enhance survival probability due to an overall population growth (i.e., "inflation"), while branch termination and the small effective population size at the growing branch tips increase the probability of strain extinction. We show that the evolutionary dynamics may be captured on a wide range of branch geometries parameterized just by the branch diameter N0 and branching rate b. We find that the survival probability of neutral cell strains is largest at an "optimal" branching rate, which balances the effects of inflation and branch termination. We find that increasing the selective advantage s of the cell strain mitigates the inflationary effect by decreasing the average time at which the mutant cell fate is determined. For sufficiently large selective advantages, the survival probability of the advantageous mutant decreases monotonically with the branching rate.

Quadriceps muscle strength at 2 years following anterior cruciate ligament reconstruction is associated with tibiofemoral joint cartilage volume.

PURPOSE: Quadriceps strength deficits following anterior cruciate ligament reconstruction (ACLR) are linked to altered lower extremity biomechanics, tibiofemoral joint (TFJ) space narrowing and cartilage composition changes. It is unknown, however, if quadriceps strength is associated with cartilage volume in the early years following ACLR prior to the onset of posttraumatic osteoarthritis (OA) development. The purpose of this cross-sectional study was to examine the relationship between quadriceps muscle strength (peak and across the functional range of knee flexion) and cartilage volume at ~ 2 years following ACLR and determine the influence of concomitant meniscal pathology. METHODS: The involved limb of 51 ACLR participants (31 isolated ACLR; 20 combined meniscal pathology) aged 18-40 years were tested at 2.4 ± 0.4 years post-surgery. Isokinetic knee extension torque generated in 10° intervals between 60° and 10° knee flexion (i.e. 60°-50°, 50°-40°, 40°-30°, 30°-20°, 20°-10°) together with peak extension torque were measured. Tibial and patellar cartilage volumes were measured using magnetic resonance imaging (MRI). The relationships between peak and angle-specific knee extension torque and MRI-derived cartilage volumes were evaluated using multiple linear regression. RESULTS: In ACLR participants with and without meniscal pathology, higher knee extension torques at 60°-50° and 50°-40° knee flexion were negatively associated with medial tibial cartilage volume (p < 0.05). No significant associations were identified between peak concentric or angle-specific knee extension torques and patellar cartilage volume. CONCLUSION: Higher quadriceps strength at knee flexion angles of 60°-40° was associated with lower cartilage volume on the medial tibia ~ 2 years following ACLR with and without concomitant meniscal injury. Regaining quadriceps strength across important functional ranges of knee flexion after ACLR may reduce the likelihood of developing early TFJ cartilage degenerative changes. LEVEL OF EVIDENCE: III.

Machine Learning Derived Lifting Techniques and Pain Self-Efficacy in People with Chronic Low Back Pain.

This paper proposes an innovative methodology for finding how many lifting techniques people with chronic low back pain (CLBP) can demonstrate with camera data collected from 115 participants. The system employs a feature extraction algorithm to calculate the knee, trunk and hip range of motion in the sagittal plane, Ward's method, a combination of K-means and Ensemble clustering method for classification algorithm, and Bayesian neural network to validate the result of Ward's method and the combination of K-means and Ensemble clustering method. The classification results and effect size show that Ward clustering is the optimal method where precision and recall percentages of all clusters are above 90, and the overall accuracy of the Bayesian Neural Network is 97.9%. The statistical analysis reported a significant difference in the range of motion of the knee, hip and trunk between each cluster, F (9, 1136) = 195.67, p < 0.0001. The results of this study suggest that there are four different lifting techniques in people with CLBP. Additionally, the results show that even though the clusters demonstrated similar pain levels, one of the clusters, which uses the least amount of trunk and the most knee movement, demonstrates the lowest pain self-efficacy.

Effects of 12-Week Supervised Early Resistance Training (SEcReT) Versus Aerobic-Based Rehabilitation on Cognitive Recovery Following Cardiac Surgery via Median Sternotomy: A Pilot Randomised Controlled Trial.

AIMS: To investigate the effects of a 12-week early moderate-intensity resistance training program compared to aerobic-based rehabilitation on postoperative cognitive recovery following cardiac surgery via median sternotomy. METHODS: This was a multicentre, prospective, pragmatic, non-blinded, pilot randomised controlled trial (1:1 randomisation) of two parallel groups that compared a 12-week early moderate-intensity resistance training group to a control group, receiving aerobic-based rehabilitation. English-speaking adults (≥18 years) undergoing elective cardiac surgery via median sternotomy were randomised using sealed envelopes, with allocation revealed before surgery. The primary outcome was cognitive function, assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), at baseline, 14 weeks and 6 months postoperatively. RESULTS: The ADAS-cog score at 14 weeks was significantly better for the resistance training group (n=14, 7.2±1.4; 95% CI 4.3, 10.2, vs n=17, 9.2±1.3; 95% CI 6.6, 11.9, p=0.010). At 14 weeks postoperatively, 53% of the aerobic-based rehabilitation group (n=9/17) experienced cognitive decline by two points or more from baseline ADAS-cog score, compared to 0% of the resistance training group (n=0/14; p=0.001). CONCLUSION: Early resistance training appears to be safe and may improve cognitive recovery compared to standard, aerobic-based rehabilitation following cardiac surgery via median sternotomy, however as this was a pilot study, the sample size was small and further research is needed to determine a causal relationship.

Architectural anatomy of the quadriceps and the relationship with muscle strength: An observational study utilising real-time ultrasound in healthy adults.

Quadriceps atrophy and morphological change is a known phenomenon that can impact significantly on strength and functional performance in patients with acute or chronic presentations conditions. Real-time ultrasound (RTUS) imaging is a noninvasive valid and reliable method of quantifying quadriceps muscle anatomy and architecture. To date, there is a paucity of normative data on the architectural properties of superficial and deep components of the quadriceps muscle group to inform assessment and evaluation of intervention programs. The aims of this study were to (1) quantify the anatomical architectural properties of the quadriceps muscle group (rectus femoris, vastus intermedius, and vastus lateralis) using RTUS in healthy older adults and (2) to determine the relationship between RTUS muscle parameters and measures of quadriceps muscle strength. Thirty middle aged to older males and females (age range 55-79 years; mean age =59.9 ± 7.08 years) were recruited. Quadriceps muscle thickness, cross-sectional area, pennation angle, and echogenicity were measured using RTUS. Quadriceps strength was measured using hand-held dynamometry. For the RTUS-derived quadriceps morphological data, rectus femoris mean results; circumference 9.3 cm; CSA 4.6 cm2 ; thickness 1.5 cm; echogenicity 100.2 pixels. Vastus intermedius mean results; thickness 1.8 cm; echogenicity 99.1 pixels. Vastus lateralis thickness 1.9 cm; pennation angle 17.3°; fascicle length 7.0 cm. Quadriceps force was significantly correlated only with rectus femoris circumference (r = 0.48, p = 0.007), RF echogenicity (r = 0.38, p = 0.037), VI echogenicity (r = 0.43, p = 0.018), and VL fascicle length (r = 0.43, p = 0.019). Quadriceps force was best predicted by a three-variable model (adjusted R2  = 0.46, p < 0.001) which included rectus femoris echogenicity (B = 0.43, p = 0.005), vastus lateralis fascicle length (B = 0.33, p = 0.025) and rectus femoris circumference (B = 0.31, p = 0.041). Thus respectively, rectus femoris echogenicity explains 43%, vastus lateralis fascicle length explains 33% and rectus femoris circumference explains 31% of the variance of quadriceps force. The study findings suggest that RTUS measures were reliable and further research is warranted to establish whether these could be used as surrogate measures for quadriceps strength in adults to inform exercise and rehabilitation programs.

Patellar cartilage increase following ACL reconstruction with and without meniscal pathology: a two-year prospective MRI morphological study.

BACKGROUND: Anterior cruciate ligament reconstruction (ACLR) together with concomitant meniscal injury are risk factors for the development of tibiofemoral (TF) osteoarthritis (OA), but the potential effect on the patellofemoral (PF) joint is unclear. The aim of this study was to: (i) investigate change in patellar cartilage morphology in individuals 2.5 to 4.5 years after ACLR with or without concomitant meniscal pathology and in healthy controls, and (ii) examine the association between baseline patellar cartilage defects and patellar cartilage volume change. METHODS: Thirty two isolated ACLR participants, 25 ACLR participants with combined meniscal pathology and nine healthy controls underwent knee magnetic resonance imaging (MRI) with 2-year intervals (baseline = 2.5 years post-ACLR). Patellar cartilage volume and cartilage defects were assessed from MRI using validated methods. RESULTS: Both ACLR groups showed patellar cartilage volume increased over 2 years (p < 0.05), and isolated ACLR group had greater annual percentage cartilage volume increase compared with controls (mean difference 3.6, 95% confidence interval (CI) 1.0, 6.3%, p = 0.008) and combined ACLR group (mean difference 2.2, 95% CI 0.2, 4.2%, p = 0.028). Patellar cartilage defects regressed in the isolated ACLR group over 2 years (p = 0.02; Z = - 2.33; r = 0.3). Baseline patellar cartilage defect score was positively associated with annual percentage cartilage volume increase (Regression coefficient B = 0.014; 95% CI 0.001, 0.027; p = 0.03) in the pooled ACLR participants. CONCLUSIONS: Hypertrophic response was evident in the patellar cartilage of ACLR participants with and without meniscal pathology. Surprisingly, the increase in patellar cartilage volume was more pronounced in those with isolated ACLR. Although cartilage defects stabilised in the majority of ACLR participants, the severity of patellar cartilage defects at baseline influenced the magnitude of the cartilage hypertrophic response over the subsequent ~ 2 years.

Does Lymphocyte Count Impact Dosing of Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplantation?

Anti-thymocyte globulin (ATG) is used to reduce the incidence and severity of graft-versus-host disease (GVHD) with hematopoietic cell transplantation, yet optimum dosing has yet to be determined. We have previously demonstrated that 2.5 mg/kg ATG in conditioning can reduce the incidence of GVHD in unrelated donor transplants. Recent literature has suggested that ATG dosing based on absolute lymphocyte count (ALC) could lead to more optimum exposure of the drug. We sought to determine if ALC at the time of transplant could impact clinical outcomes. We conducted a retrospective single-center study analyzing all consecutive patients at The Ottawa Hospital who received a matched unrelated donor stem cell transplant with ATG between 2009 and 2014. Patients received rabbit ATG (thymoglobulin) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1. Univariate and multivariate analyses were used to determine if any patient- or transplant-related factors, including weight, ALC, and total ATG dose given, impacted GVHD, relapse, or mortality. In total, 111 patients met inclusion, with a median age of 50 years (range, 19 to 70). The most common diagnoses were acute myelogenous leukemia (43%), Myelodysplasia/myeloproliferative neoplasms (13%), and lymphoma (12%). The median weight at time of conditioning was 80.3 kg (range, 45 to 216). The median ALC on the first day of ATG administration was 0.1 × 109/L (range, 0 to 190). The median total dose of ATG received was 201 mg (range, 112 to 540 mg). The incidence of acute and chronic GVHD was 35.1% and 21.6%, respectively. In the multivariate model, the actual dose of ATG given to patients was not associated with GVHD (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.99 to 1.25; P = .07), relapse (HR, 1.13; 95% CI, 0.98 to 1.30; P = .1), or mortality (HR, 1.09; 95% CI, 0.92 to 1.28; P = .32). Similarly, the pretransplant ALC was not associated with GVHD (HR, 1; P = .82), relapse (HR, 1; P = .90), or mortality (HR, 1; P = .39). If patients had received ALC-based dosing according to previously published work (Admiraal et al., Lancet Haematol 2017), the mean total dose of ATG received would have been 1205 mg, more than 5 times the mean dose that was actually given based on weight. With GVHD outcomes being similar to that published by Admiraal et al. and ALC not independently associated with outcomes in our study, further studies are still needed to compare standard weight-based dosing to ALC-based dosing of ATG in matched unrelated donor stem cell transplant.

Presalvage International Staging System Stage and Other Important Outcome Associations in CD34+-Selected Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Despite ongoing therapeutic advances, multiple myeloma (MM) remains largely incurable, and outcomes in patients who develop resistance to immunomodulatory drugs or proteasome inhibitors remain grim. Allogeneic hematopoietic cell transplantation (alloHCT) is an alternative option that may offer potential for cure. Although rates of transplantation-related morbidity and mortality have decreased in recent years, weighing this approach's potential benefits against nontransplantation therapies demands a thoroughly informed pre-alloHCT assessment. Here we assess the impact of pre-alloHCT variables on important clinical outcomes in a large cohort of relapsed refractory MM (RRMM) CD34+-selected alloHCT recipients. We included all patients with MM who underwent CD34+-selected alloHCT at our center between June 2010 and December 2015. Patients were conditioned with busulfan (0.8 mg/kg × 10), melphalan (70 mg/m2 × 2), and fludarabine (25 mg/m2 × 5), followed by infusion of a CD34+-selected peripheral blood stem cell graft, without post-alloHCT graft-versus-host disease (GVHD) prophylaxis. The 73-patient cohort had a median age of 55 years (range, 37 to 66 years). Overall survival (OS) and progression-free survival (PFS) rates were 70% and 53%, respectively, at 1 year (95% confidence interval [CI], 58% to 79% and 41% to 64%) and 50% and 30%, respectively, at 3 years (95% CI, 38% to 62% and 19% to 41%). The cumulative incidence of relapse was 25% at 1 year (95% CI, 15% to 35%) and 47% at 3 years (95% CI, 35% to 58%). Nonrelapse mortality at 1 year was 22% (95% CI, 13% to 32%). The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 7% at 100 days (95% CI, 3% to 14%), and that of any chronic GVHD (cGVHD) was 8% at 1 year (95% CI, 3% to 16%). International Staging System (ISS) stage II-III assessed before salvage therapy was associated with poorer 3-year OS (30% versus 54%; P = .037) and 3-year PFS (9% versus 33%; P = .013), and increased 3-year relapse incidence (72% versus 39%; P = .004). Older age and GVHD before 6 months (aGVHD grade II-IV or cGVHD of any grade) were also associated with poorer OS, and a greater number of pre-alloHCT lines of therapy was also associated with increased relapse incidence. Our findings reinforce that CD34+-selected alloHCT can achieve prolonged disease control and long-term survival in high- risk, heavily treated refractory MM populations. We also identified numerous pre-alloHCT variables associated with OS, PFS, and relapse. Amongst these, presalvage ISS stage II-III was consistently associated with poorer survival and relapse outcomes. Given the lack of established alternate therapies for patients with RRMM, we advocate the identification of adverse pre-alloHCT variables to inform alloHCT decision making rather than to exclude patient cohorts from this potentially curative treatment option.

Prognostic Factors for Postrelapse Survival after ex Vivo CD34+-Selected (T Cell-Depleted) Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma.

Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graft-versus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before alloHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early (<6 months; 28%), early (6 to 24 months; 50%), or late (>24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P = .002). Older age, relapse with EMD,

Unrelated Donor Transplant Recipients Given Thymoglobuline Have Superior GRFS When Compared to Matched Related Donor Recipients Undergoing Transplantation without ATG.

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors (URDs) and mismatched related donors (MMRDs) typically have a higher incidence of acute and chronic graft-versus-host disease (GVHD) compared with matched related donors (MRDs). Anti-T-cell globulins (ATGs) are often used to reduce GVHD in these recipients. We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol, in which ATG (Thymoglobuline 4.5 mg/kg) was administered to recipients of URD and MMRD (n = 147) but not MRD (n = 64) transplant. For all patients, incidence of acute GVHD grades 2 to 4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% (95% confidence interval, 55.8% to 71.5%), relapse-free survival was 55.3% (47.4% to 64.6%), and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2% to 40.8%). There were no differences between recipients of MRDs and other donors in relapse, nonrelapse mortality, and overall and relapse-free survival. However, compared with MRD, recipients from URDs and MMRDs had reduced moderate to severe chronic GVHD (10.4% versus 30.1%, P= .002), less chronic GVHD requiring systemic therapy (19.4% versus 38.9%, P = .006), and superior 2-year GRFS (35.5% versus 20.0%, P = .003). In this retrospective review of nonrandomized transplant groups, outcomes of HSCT performed using an URD with ATG during conditioning were superior to transplant from an MRD without ATG. The addition of Thymoglobuline to conditioning in HSCT from MRD should be further examined in prospective trials.

Visual displays for cyber network defense.

Five computer network Defence displays (one Alphanumeric and four graphical displays: Radial Traffic Analyser, Bar Graph, Cube, and Treemap) were evaluated. Two experiments were conducted using different methodological procedures. Participants responded to questions that were structured to approximate various ways in which analysts might need to consider network traffic. Numerous significant effects were obtained and a fairly clear rank ordering of performance for the four graphical displays was obtained across experiments (from best to worst): Bar Graph, Cube, Radial Traffic Analyser, and Treemap. The results are interpreted from the perspective of ecological interface design: the quality of performance is directly related to the quality of semantic mapping between work domain, display, and human constraints. Factors that may have contributed to the poor performance for the Radial Traffic Analyser and Treemap displays are discussed. General implications for display and interface design are provided. Practitioner summary: Proposed displays for computer network Defence are evaluated; the results are interpreted from the perspective of ecological interface design. The associated design principles are applicable to all analogical graphical displays. Abbreviation: CND: cyber network defence; CSE: cognitive systems engineering; EID: ecological interface design; ICMP: internet control message protocol; IP: internet protocol; RTA: radial traffic analyzer; TCP: transmission control protocol; UDP: user datagram protocol.

Muscular Coordination of Single-Leg Hop Landing in Uninjured and Anterior Cruciate Ligament-Reconstructed Individuals.

This study compared lower-limb muscle function, defined as the contributions of muscles to center-of-mass support and braking, during a single-leg hopping task in anterior cruciate ligament-reconstructed (ACLR) individuals and uninjured controls. In total, 65 ACLR individuals and 32 controls underwent a standardized anticipated single-leg forward hop. Kinematics and ground reaction force data were input into musculoskeletal models to calculate muscle forces and to quantify muscle function by decomposing the vertical (support) and fore-aft (braking) ground reaction force components into contributions by individual lower-limb muscles. Four major muscles, the vasti, soleus, gluteus medius, and gluteus maximus, were primarily involved in support and braking in both ACLR and uninjured groups. However, although the ACLR group demonstrated lower peak forces for these muscles (all Ps < .001, except gluteus maximus, P = .767), magnitude differences in these muscles' contributions to support and braking were not significant. ACLR individuals demonstrated higher erector spinae (P = .012) and hamstrings forces (P = .085) to maintain a straighter, stiffer landing posture with more forward lumbar flexion. This altered landing posture may have enabled the ACLR group to achieve similar muscle function to controls, despite muscle force deficits. Our findings may benefit rehabilitation and the development of interventions to enable faster and safer return to sport.

Improving Walking Ability in People With Neurologic Conditions: A Theoretical Framework for Biomechanics-Driven Exercise Prescription.

The purpose of this paper is to discuss how knowledge of the biomechanics of walking can be used to inform the prescription of resistance exercises for people with mobility limitations. Muscle weakness is a key physical impairment that limits walking in commonly occurring neurologic conditions such as cerebral palsy, traumatic brain injury, and stroke. Few randomized trials to date have shown conclusively that strength training improves walking in people living with these conditions. This appears to be because (1) the most important muscle groups for forward propulsion when walking have not been targeted for strengthening, and (2) strength training protocols have focused on slow and heavy resistance exercises, which do not improve the fast muscle contractions required for walking. We propose a theoretical framework to improve exercise prescription by integrating the biomechanics of walking with the principles of strength training outlined by the American College of Sports Medicine to prescribe exercises that are specific to improving the task of walking. The high angular velocities that occur in the lower limb joints during walking indicate that resistance exercises targeting power generation would be most appropriate. Therefore, we propose the prescription of plyometric and ballistic resistance exercise, applied using the American College of Sports Medicine guidelines for task specificity, once people with neurologic conditions are ambulating, to improve walking outcomes. This new theoretical framework for resistance training ensures that exercise prescription matches how the muscles work during walking.

Tibiofemoral joint structural change from 2.5 to 4.5 years following ACL reconstruction with and without combined meniscal pathology.

BACKGROUND: People who have had anterior cruciate ligament reconstruction (ACLR) are at a high risk of developing tibiofemoral joint (TFJ) osteoarthritis (OA), with concomitant meniscal injury elevating this risk. This study aimed to investigate OA-related morphological change over 2 years in the TFJ among individuals who have undergone ACLR with or without concomitant meniscal pathology and in healthy controls. A secondary aim was to examine associations of baseline TFJ cartilage defects and bone marrow lesions (BML) scores with tibial cartilage volume change in ACLR groups. METHODS: Fifty seven ACLR participants aged 18-40 years (32 isolated ACLR, 25 combined meniscal pathology) underwent knee magnetic resonance imaging (MRI) 2.5 and 4.5 years post-surgery. Nine healthy controls underwent knee MRI at the ~ 2-year intervals. Tibial cartilage volume, TFJ cartilage defects and BMLs were assessed from MRI. RESULTS: For both ACLR groups, medial and lateral tibial cartilage volume increased over 2 years (P <  0.05). Isolated ACLR group had greater annual percentage increase in lateral tibial cartilage volume compared with controls and with the combined group (P = 0.03). Cartilage defects remained unchanged across groups. Both ACLR groups showed more lateral tibia BML regression compared with controls (P = 0.04). Baseline cartilage defects score was positively associated with cartilage volume increase at lateral tibia (P = 0.002) while baseline BMLs score was inversely related to medial tibia cartilage volume increase (P = 0.001) in the pooled ACLR group. CONCLUSIONS: Tibial cartilage hypertrophy was apparent in ACLR knees from 2.5 to 4.5 years post-surgery and was partly dependent upon meniscal status together with the nature and location of the underlying pathology at baseline. Magnitude and direction of change in joint pathologies (i.e., cartilage defects, BMLs) were less predictable and either remained stable or improved over follow-up.