Studying the Effects of Shoulder Dystocia and Neonate-Focused Delivery Maneuvers on Brachial Plexus Strain: A Computational Study.

The purpose of this computational study was to investigate the effects of neonate-focused clinical delivery maneuvers on brachial plexus (BP) during shoulder dystocia. During shoulder dystocia, the anterior shoulder of the neonate is obstructed behind the symphysis pubis of the maternal pelvis, postdelivery of the neonate's head. This is managed by a series of clinical delivery maneuvers. The goal of this study was to simulate these delivery maneuvers and study their effects on neonatal BP strain. Using madymo models of a maternal pelvis and a 90th-percentile neonate, various delivery maneuvers and positions were simulated including the lithotomy position alone of the maternal pelvis, delivery with the application of various suprapubic pressures (SPPs), neonate in an oblique position, and during posterior arm delivery maneuver. The resulting BP strain (%) along with the required maternal delivery force was reported in these independently simulated scenarios. The lithotomy position alone served as the baseline. Each of the successive maneuvers reported a decrease in the required delivery force and resulting neonatal BP strain. As the applied SPP force increased (three scenarios simulated), the required maternal delivery force and neonatal BP strain decreased. A further decrease in both delivery force and neonatal BP strain was observed in the oblique position, with the lowest delivery force and neonatal BP strain reported during the posterior arm delivery maneuver. Data obtained from the improved computational models in this study enhance our understanding of the effects of clinical maneuvers on neonatal BP strain during complicated birthing scenarios such as shoulder dystocia.

Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing.

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.

Development of a Finite Element Model of the Pediatric Thoracic and Lumbar Spine, Ribcage, and Pelvis With Orthotropic Region-Specific Vertebral Growth.

Finite element (FE) modeling of the spine has increasingly been applied in orthopedic precision-medicine approaches. Previously published FE models of the pediatric spine growth have made simplifications in the geometry of anatomical structures, material properties, and representation of vertebral growth. To address those limitations, a comprehensive FE model of a pediatric (10-year-old) osteo-ligamentous thoracic and lumbar spine (T1-L5 with intervertebral discs (IVDs) and ligaments), ribcage, and pelvis with age- and level-specific ligament properties and orthotropic region-specific vertebral growth was developed and validated. Range of motion (ROM) measures, namely, lateral bending, flexion-extension, and axial rotation, of the current 10 YO FE model were generally within reported ranges of scaled in vitro adult ROM data. Changes in T1-L5 spine height, as well as kyphosis (T2-T12) and lordosis (L1-L5), angles in the current FE model for two years of growth (from ages 10 to 12 years) were within ranges reported from corresponding pediatric clinical data. The use of such comprehensive pediatric FE models can provide clinically relevant insights into normative and pathological biomechanical responses of the spine, and also contribute to the development and optimization of clinical interventions for spine deformities.

Comparison of immunohistochemistry and gene expression profiling subtyping for diffuse large B-cell lymphoma in the phase III clinical trial of R-CHOP ± ibrutinib.

We assessed the concordance between immunohistochemistry (IHC) and gene expression profiling (GEP) for determining diffuse large B-cell lymphoma (DLBCL) cell of origin (COO) in the phase III PHOENIX trial of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with or without ibrutinib. Among 910 of 1114 screened patients with non-germinal centre B cell-like (non-GCB) DLBCL by IHC, the concordance with GEP for non-GCB calls was 82·7%, with 691 (75·9%) identified as activated B cell-like (ABC), and 62 (6·8%) as unclassified. Among 746 of 837 enrolled patients with verified non-GCB DLBCL by IHC, the concordance with GEP was 82·8%, with 567 (76·0%) identified as ABC and 51 (6·8%) unclassified; survival outcomes were similar regardless of COO or treatment, whereas among patients with ABC DLBCL aged <60 years, the overall and event-free survival were substantially better with ibrutinib versus placebo plus R-CHOP [hazard ratio (HR) 0·365, 95% confidence interval (CI) 0·147-0·909, P = 0·0305; HR 0·561, 95% CI 0·326-0·967, P = 0·0348, respectively]. IHC and GEP showed high concordance and consistent survival outcomes among tested patients, indicating centralised IHC may be used to enrich populations for response to ibrutinib plus R-CHOP.

A Systematic Review of the Tensile Biomechanical Properties of the Neonatal Brachial Plexus.

Brachial plexus (BP) birth injury has a reported incidence of 1 to 4 per 1000 live births. During complicated deliveries, neonatal, maternal, and other birth-related factors can cause over-stretching or avulsion of the neonatal brachial plexus leading to injury. Understanding biomechanical responses of the neonate brachial plexus when subjected to stretch can offer insight into the injury outcomes while guiding the development of preventative maneuvers that can help reduce the occurrence of neonatal brachial plexus injuries. This review article aims to offer a comprehensive overview of existing literature reporting biomechanical responses of the brachial plexus, in both adults and neonates, when subjected to stretch. Despite the discrepancies in the reported biomechanical properties of the brachial plexus, available studies confirm the loading rate and loading direction dependency of the brachial plexus tissue. Future studies, possibly in vivo, that utilize clinically relevant neonatal large animal models can provide translational failure values of the biomechanical parameters for the neonatal brachial plexus when subjected to stretch.

An In Vitro Study to Investigate Biomechanical Responses of Peripheral Nerves in Hypoxic Neonatal Piglets.

Despite occurrence of neonatal hypoxia and peripheral nerve injuries in complicated birthing scenarios, the effect of hypoxia on the biomechanical responses of neonatal peripheral nerves is not studied. In this study, neonatal brachial plexus (BP) and tibial nerves, obtained from eight normal and eight hypoxic 3-5-day-old piglets, were tested in uniaxial tension until failure at a rate of 0.01 mm/s or 10 mm/s. Failure load, stress, and modulus of elasticity were reported to be significantly lower in hypoxic neonatal BP and tibial nerves than respective normal tissue at both 0.01 and 10 mm/s rates. Failure strain was significantly lower in the hypoxic neonatal BP nerves only at 10 mm/s rate when compared to normal BP nerve. This is the first available data that indicate weaker mechanical behavior of hypoxic neonatal peripheral nerves as compared to normal tissue and offer an understanding of the biomechanical responses of peripheral nerves of hypoxic neonatal piglets.

Using Virtual Reality in Biomedical Engineering Education.

This study explored virtual reality (VR) as an educational tool to offer immersive and experiential learning environments to biomedical engineering (BME) students. VR and traditional two-dimensional (2D) videos were created and used to teach required communication skills to BME students' while working with clinical partners in healthcare settings. The videos of interdisciplinary teams (engineering and nursing students) tackling medical device-related problems, similar to those commonly observed in healthcare settings, were shown to BME students. Student surveys indicated that, through VR videos, they felt more immersed in real-world clinical scenarios while learning about the clinical problems, each team-member's areas of expertise, their roles and responsibilities, and how an interdisciplinary team operated collectively to solve a problem in the presented settings. Students with a prior in-person immersion experience, in the presented settings, reported VR videos to serve as a possible alternative to in-person immersion and a useful tool for their preparedness for real-world clinical immersion. We concluded that VR holds promise as an educational tool to offer simulated clinical scenarios that are effective in training BME students for interprofessional collaborations.

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK.

Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR+ B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR+ ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCß) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR+ ALL. Consequently, in mouse xenograft models of pre-BCR+ ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ ALL and highlight the importance of ibrutinib effects on alternative kinase targets.

Efficacy of Clinical Simulation-Based Training in Biomedical Engineering Education.

The need for biomedical engineering (BME) students to be trained in real-world healthcare settings, where most medical device industry emerges, is imperative. Clinical immersion helps accomplish this training goal. However, the growing student population in the field of BME and a shortage of clinical collaborators offer serious limitations to the clinical immersion experience. This paper describes the use of a clinical simulation-based training (SBT) tool in BME education as an alternative resource to the real-world clinical immersion experience. Through the inclusion of simulation labs in BME courses, we assessed their efficacy in need-finding and enhancing students' understanding of the current challenges of existing medical technology. We also explored the possibility of offering cross-disciplinary learning environments in these simulation labs, including engineers and students from other healthcare disciplines such as nursing. Simulation labs served as a helpful tool in the need-finding phase of the design process, and the immersed students reported higher adaptive and life-long learning outcomes. Students also reported the simulation lab immersion to be valuable to their future goals as engineers. Furthermore, the SBT labs offered repetitive training in a controlled learning environment, inclusion of an interdisciplinary setting, and feedback through student reflections. The inclusion of simulation lab immersion and SBT labs in the two BME courses served as an useful and alternative educational tool that helped train students to better understand the needs of the healthcare industry while working in interdisciplinary settings.

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study.

BACKGROUND: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. METHODS: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). FINDINGS: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). INTERPRETATION: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. FUNDING: Janssen Research & Development, LLC.

Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study.

BACKGROUND: Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. FINDINGS: Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. INTERPRETATION: In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. FUNDING: Janssen Research & Development.

Thoracic spine morphology of a pseudo-biped animal model (kangaroo) and comparisons with human and quadruped animals.

PURPOSE: Based on the structural anatomy, loading condition and range of motion (ROM), no quadruped animal has been shown to accurately mimic the structure and biomechanical function of the human spine. The objective of this study is to quantify the thoracic vertebrae geometry of the kangaroo, and compare with adult human, pig, sheep, and deer. METHODS: The thoracic vertebrae (T1-T12) from whole body CT scans of ten juvenile kangaroos (ages 11-14 months) were digitally reconstructed and geometric dimensions of the vertebral bodies, endplates, pedicles, spinal canal, processes, facets and intervertebral discs were recorded. Similar data available in the literature on the adult human, pig, sheep, and deer were compared to the kangaroo. A non-parametric trend analysis was performed. RESULTS: Thoracic vertebral dimensions of the juvenile kangaroo were found to be generally smaller than those of the adult human and quadruped animals. The most significant (p < 0.001) correlations (Rho) found between the human and kangaroo were in vertebrae and endplate dimensions (0.951 ≤ Rho ≤ 0.963), pedicles (0.851 ≤ Rho ≤ 0.951), and inter-facet heights (0.891 ≤ Rho ≤ 0.967). The deer displayed the least similar trends across vertebral levels. CONCLUSIONS: Similarities in thoracic spine vertebral geometry, particularly of the vertebrae, pedicles and facets may render the kangaroo a more clinically relevant human surrogate for testing spinal implants. The pseudo-biped kangaroo may also be a more suitable model for the human thoracic spine for simulating spine deformities, based on previously published similarities in biomechanical loading, posture and ROM.

Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma.

BACKGROUND: It has been demonstrated that several inhibitors of histone deacetylase (HDAC) can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models. The authors sought to determine the maximum tolerated dose, pharmacokinetics/pharmacodynamics, safety, and toxicity of the HDAC inhibitor abexinostat (PCI-24781) when administered with doxorubicin to patients with metastatic sarcomas. METHODS: Participants were enrolled in a standard, phase 1, 3 + 3, dose-escalation study design. Abexinostat was administered on days 1 through 5 with 75 mg/m(2) of doxorubicin administered on day 4 of every 21-day cycle until patients developed disease progression or drug intolerance or reached a cumulative lifetime doxorubicin dose of 450 mg/m(2). Granulocyte-colony-stimulating factor (G-CSF) support was provided at physician discretion on arm A and was provided to all participants in arm B. From 3 to 6 participants initially received abexinostat 30 mg/m(2) twice daily, and subsequent cohorts were administered doses of 15 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily. All patients without progressive disease after receiving a cumulative lifetime doxorubicin dose of 450 mg/m(2) were given the option to continue with abexinostat as a single agent until they developed disease progression. RESULTS: In total, 22 participants (10 who had previously experienced tumor growth after doxorubicin therapy) were enrolled (6 in arm A, 14 in arm B), 20 were evaluable for dose-limiting toxicity (DLT), and 17 were evaluable for radiologic response. In arm A, participants received abexinostat 15 mg/m(2) or 30 mg/m(2) twice daily. DLTs of grade 3 and 4 neutropenia were observed in 2 of 3 participants who received abexinostat 30 mg/m(2) twice daily. Neither of those patients received G-CSF prophylaxis. In arm B, participants received abexinostat at doses of 30 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily, all with mandated G-CSF support. Two DLTs were observed at the 60 mg/m(2) twice-daily dose (grade 3 infection, grade 4 thrombocytopenia). The pharmacokinetics of abexinostat were not affected by doxorubicin. HDAC activity, as measured by histone acetylation in peripheral blood mononuclear cells, was maximally inhibited at the abexinostat 30 mg/m(2) twice-daily dose. Of the 17 participants who were evaluable for radiologic response, 1 patient had a partial response, 9 patients had stable disease, and 7 patients had progressive disease as their best response; and 8 patients completed ≥ 5 cycles. Three of those participants had stable disease as their most recent disease status when the current report was written. Four participants who continued on monotherapy remained in stable disease for a median of 9.8 weeks after completing doxorubicin. The most common toxicities were fatigue, thrombocytopenia, and anemia. No study-related deaths were observed. CONCLUSIONS: The maximum tolerated dose for abexinostat was 45 mg/m(2) twice daily administered on days 1 through 5 when patients received doxorubicin 75 mg/m(2) on day 4 of a 3-week cycle and G-CSF support was mandated. Toxicities were manageable, and tumor responses were observed. Additional studies are needed to further define the specific contributions of HDAC inhibition in patients who receive doxorubicin for the treatment of metastatic sarcoma.

Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study.

BACKGROUND: Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma. METHODS: In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750. FINDINGS: From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose. INTERPRETATION: Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial. FUNDING: Janssen.

A comprehensive review of thoracic deformity parameters in scoliosis.

PURPOSE: The combined spine and rib cage deformity in scoliosis is best described as a thoracic deformity, and recent advances in imaging have enabled better definition of three-dimensional (3D) deformity of the thorax in scoliosis. However, a comprehensive report that summarizes the published thorax deformity quantification parameter studies is lacking in the orthopaedic literature. METHODS: An extensive literature review on the quantification of thorax deformity was performed, and a total of 25 thorax deformity parameters were compiled into eight independent categories based on their similarities of deformity assessment. RESULTS: This review serves as the first comprehensive summary of radiographic and CT-based thorax deformity quantification measures. CONCLUSIONS: Future work on the complex relationships between spine and ribcage deformity and the relationship with pulmonary function could help improve clinical interventions for scoliosis treatment.

Direct Linear Transformation for the Measurement of In-Situ Peripheral Nerve Strain During Stretching.

Peripheral nerves undergo physiological and non-physiological stretch during development, normal joint movement, injury, and more recently while undergoing surgical repair. Understanding the biomechanical response of peripheral nerves to stretch is critical to the understanding of their response to different loading conditions and thus, to optimizing treatment strategies and surgical interventions. This protocol describes in detail the calibration process of the stereo-imaging camera system via direct linear transformation and the tracking of the three-dimensional in-situ tissue displacement of peripheral nerves during stretch, obtained from three-dimensional coordinates of the video files captured by the calibrated stereo-imaging camera system. From the obtained three-dimensional coordinates, the nerve length, change in the nerve length, and percent strain with respect to time can be calculated for a stretched peripheral nerve. Using a stereo-imaging camera system provides a non-invasive method for capturing three-dimensional displacements of peripheral nerves when stretched. Direct linear transformation enables three-dimensional reconstructions of peripheral nerve length during stretch to measure strain. Currently, no methodology exists to study the in-situ strain of stretched peripheral nerves using a stereo-imaging camera system calibrated via direct linear transformation. Capturing the in-situ strain of peripheral nerves when stretched can not only aid clinicians in understanding underlying injury mechanisms of nerve damage when overstretched but also help optimize treatment strategies that rely on stretch-induced interventions. The methodology described in the paper has the potential to enhance our understanding of peripheral nerve biomechanics in response to stretch to improve patient outcomes in the field of nerve injury management and rehabilitation.

Predicting radiographic outcomes of vertebral body tethering in adolescent idiopathic scoliosis patients using machine learning.

Anterior Vertebral Body Tethering (AVBT) is a growing alternative treatment for adolescent idiopathic scoliosis (AIS), offering an option besides spinal fusion. While AVBT aims to correct spinal deformity through growth correction, its outcomes have been mixed. To improve surgical outcomes, this study aimed to develop a machine learning-based tool to predict short- and midterm spinal curve correction in AIS patients who underwent AVBT surgery, using the most predictive clinical, radiographic, and surgical parameters. After institutional review board approval and based on inclusion criteria, 91 AIS patients who underwent AVBT surgery were selected from the Shriners Hospitals for Children, Philadelphia. For all patients, longitudinal standing (PA or AP, and lateral) and side bending spinal Radiographs were retrospectively obtained at six visits: preop and first standing, one year, two years, five years postop, and at the most recent follow-up. Demographic, radiographic, and surgical features associated with curve correction were collected. The sequential backward feature selection method was used to eliminate correlated features and to provide a rank-ordered list of the most predictive features of the AVBT correction. A Gradient Boosting Regressor (GBR) model was trained and tested using the selected features to predict the final correction of the curve in AIS patients. Eleven most predictive features were identified. The GBR model predicted the final Cobb angle with an average error of 6.3 ± 5.6 degrees. The model also provided a prediction interval, where 84% of the actual values were within the 90% prediction interval. A list of the most predictive features for AVBT curve correction was provided. The GBR model, trained on these features, predicted the final curve magnitude with a clinically acceptable margin of error. This model can be used as a clinical tool to plan AVBT surgical parameters and improve outcomes.

The Efficacy of Body-Weight Supported Treadmill Training and Neurotrophin-Releasing Scaffold in Minimizing Bone Loss Following Spinal Cord Injury.

Spinal cord injury (SCI) can lead to significant bone loss below the level of the lesion increasing the risk of fracture and increased morbidity. Body-weight-supported treadmill training (BWSTT) and transplantation strategies using neurotrophins have been shown to improve motor function after SCI. While rehabilitation training including BWSTT has also been effective in reducing bone loss post-SCI, the effects of transplantation therapies in bone restoration are not fully understood. Furthermore, the effects of a combinational treatment strategy on bone post-SCI also remain unknown. The aim of this study was to determine the effect of a combination therapy including transplantation of scaffold-releasing neurotrophins and BWSTT on the forelimb and hindlimb bones of a T9-T10 contused SCI animals. Humerus and tibia bones were harvested for Micro-CT scanning and a three-point bending test from four animal groups, namely injury, BWSTT (injury with BWSTT), scaffold (injury with scaffold-releasing neurotrophins), and combinational (injury treated with scaffold-releasing neurotrophins and BWSTT). BWSTT and combinational groups reported higher biomechanical properties in the tibial bone (below injury level) and lower biomechanical properties in the humerus bone (above injury level) when compared to the injury and scaffold groups. Studied structural parameters, including the cortical thickness and bone volume/tissue volume (BV/TV) were also higher in the tibia and lower in the humerus bones of BWSTT and combinational groups when compared to the injury and scaffold groups. While no significant differences were observed, this study is the first to report the effects of a combinational treatment strategy on bone loss in contused SCI animals and can help guide future interventions.

The effect of age and bracing on vehicle occupant responses during sled-simulated evasive swerving.

OBJECTIVE: Bracing can reduce adult occupants' out-of-position postures, but it is unclear if this finding can be extended to child occupants. We investigated the effect of bracing, and age on the motion of vehicle occupants of different ages during sled-simulated pre-crash maneuvers. METHODS: Forty seatbelt restrained subjects (9-40 y.o.) experienced sled simulated evasive swerving maneuvers during a brace condition, where subjects actively brace before the maneuver onset, and an unbraced condition. A 3D motion capture system, electromyography (EMG), and seatbelt load cells captured head and trunk kinematics, muscle activation, and seat belt reaction forces, respectively. The effects of age and bracing on peak lateral head and trunk displacement were examined with Mixed Effects Model (p ≤ 0.05). RESULTS: In the braced condition, all subjects had reduced normalized peak head (0.09 ± 0.05) and trunk (0.11 ± 0.05) displacements compared to the unbraced condition (Head: 0.14 ± 0.06, Trunk: 0.17 ± 0.07) (p < 0.05). For the into-the-belt direction in the unbraced condition, children showed the smallest peak head and trunk displacement of all age groups (p < 0.01) while teens had the greatest peak head and trunk displacement compared to all other age groups (p < 0.02). Similar trends were found in the out-of-the-belt direction in the unbraced condition (p < 0.01). In the unbraced condition, all occupants showed greater shoulder seat belt reaction loads than the braced condition (unbraced 1.6-2.7 N/kg, braced 1.0-1.4 N/kg). Children also showed greater neck muscle activation (50-64% MVIC) compared to other muscles and older occupants regardless of the bracing condition or direction of motion. CONCLUSION: Bracing reduced out-of-position postures across all ages. In the unbraced condition, children move less than teens and adults due to greater activation in the neck muscles. In the unbraced condition, teens showed the greatest motion, potentially due to their developing neuromotor control transitioning to a more mature stage. Across all age groups in the unbraced condition, occupants relied more heavily on the seat belt to maintain their position rather than their muscles to brace, suggesting the importance of good seatbelt-torso interaction in unbraced occupants.

Type V collagen exhibits distinct regulatory activities in TMJ articular disc versus condylar cartilage during postnatal growth and remodeling.

Understanding matrix molecular activities that regulate the postnatal growth and remodeling of the temporomandibular joint (TMJ) articular disc and condylar cartilage will enable the development of effective regenerative strategies targeting TMJ disorders. This study elucidated the distinct roles of type V collagen (collagen V) in regulating these two units. Studying the TMJ of young adult Col5a1+/- mice, we found that loss of collagen V resulted in substantial changes in the proliferation, clustering and density of progenitors in condylar cartilage, but did not have a major impact on disc cells that are more fibroblast-like. Although loss of collagen V led to thickened collagen fibrils with increased heterogeneity in the disc, there were no significant changes in local micromodulus, except for a reduction at the posterior end of the inferior side. Following the induction of aberrant occlusal loading by the unilateral anterior crossbite (UAC) procedure, both wild-type (WT) and Col5a1+/- condylar cartilage exhibited salient remodeling, and Col5a1+/- condyle developed more pronounced degeneration and tissue hypertrophy at the posterior end than the WT. In contrast, neither UAC nor collagen V deficiency induced marked changes in the morphology or biomechanical properties of the disc. Together, our findings highlight the distinct roles of collagen V in regulating these two units during postnatal growth and remodeling, emphasizing its more crucial role in condylar cartilage due to its impact on the highly mechanosensitive progenitors. These results provide the foundation for using collagen V to improve the regeneration of TMJ and the care of patients with TMJ disorders. STATEMENT OF SIGNIFICANCE: Successful regeneration of the temporomandibular joint (TMJ) articular disc and condylar cartilage remains a significant challenge due to the limited understanding of matrix molecular activities that regulate the formation and remodeling of these tissues. This study demonstrates that collagen V plays distinct and critical roles in these processes. In condylar cartilage, collagen V is essential for regulating progenitor cell fate and maintaining matrix integrity. In the disc, collagen V also regulates fibril structure and local micromechanics, but has a limited impact on cell phenotype or its remodeling response. Our findings establish collagen V as a key component in maintaining the integrity of these two units, with a more crucial role in condylar cartilage due to its impact on progenitor cell activities.