Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease.

BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear. METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety. RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%). CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival. METHODS: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m2 on day 1 of cycle 1 and at 500 mg/m2 on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m2 per day orally on day 1-5, cyclophosphamide 150 mg/m2 per day orally on days 1-5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete. FINDINGS: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56-67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41-61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63-NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32-0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group. INTERPRETATION: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder. FUNDING: Cancer Research UK and Janssen.

Venetoclax ramp-up strategies for chronic lymphocytic leukaemia in the United Kingdom: a real world multicentre retrospective study.

This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high-risk cohorts. These observations require confirmation in larger studies.

Morphology of proximal and distal human semitendinosus compartments and the effects of distal tendon harvesting for anterior cruciate ligament reconstruction.

The human semitendinosus muscle is characterized by a tendinous inscription separating proximal and distal neuromuscular compartments. As each compartment is innervated by separate nerve branches, potential exists for independent operation and control of compartments. However, the morphology and function of each compartment have not been thoroughly examined in an adult human population. Further, the distal semitendinosus tendon is typically harvested for use in anterior cruciate ligament reconstruction surgery, which induces long-term morphological changes to the semitendinosus muscle-tendon unit. It remains unknown if muscle morphological alterations following anterior cruciate ligament reconstruction are uniform between proximal and distal semitendinosus compartments. Here, we performed magnetic resonance imaging on 10 individuals who had undergone anterior cruciate ligament reconstruction involving an ipsilateral distal semitendinosus tendon graft 14 ± 4 months prior, extracting morphological parameters of the whole semitendinosus muscle and each individual compartment from both the (non-injured) contralateral and surgical legs. In the contralateral leg, volume and length of the proximal compartment were smaller than the distal compartment. No between-compartment differences in volume or length were found for anterior cruciate ligament reconstructed legs, likely due to greater shortening of the distal compared to the proximal compartment after anterior cruciate ligament reconstruction. The maximal anatomical cross-sectional area of both compartments was substantially smaller on the anterior cruciate ligament reconstructed leg but did not differ between compartments on either leg. The absolute and relative between-leg differences in proximal compartment morphology on the anterior cruciate ligament reconstructed leg were strongly correlated with the corresponding between-leg differences in distal compartment morphological parameters. Specifically, greater between-leg morphological differences in one compartment were highly correlated with large between-leg differences in the other compartment, and vice versa for smaller differences. These relationships indicate that despite the heterogeneity in compartment length and volume, compartment atrophy is not independent or random. Further, the tendinous inscription endpoints were generally positioned at the same proximodistal level as the compartment maximal anatomical cross-sectional areas, providing a wide area over which the tendinous inscription could mechanically interact with compartments. Overall, results suggest the two human semitendinosus compartments are not mechanically independent.

Obinutuzumab as consolidation after chemo-immunotherapy: Results of the UK National Cancer Research Institute phase II/III GALACTIC trial.

The GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In chronic lymphocytic leukaemia (CLL) (GALACTIC) was a seamless phase II/III trial designed to test whether consolidation with obinutuzumab is safe and eradicates minimal residual disease (MRD) and, subsequently, whether this leads to prolonged progression-free survival (PFS) in patients with CLL who have recently responded to chemo-immunotherapy. Patients with a response 3-24 months after chemotherapy were assessed for MRD. MRD-positive patients were randomised to receive consolidation therapy with obinutuzumab or no consolidation. The trial closed after the phase II part due to slow recruitment. In all, 48 patients enrolled of whom 19 were MRD negative and were monitored. Of the 29 MRD-positive patients, 14 were randomised to receive consolidation and 15 to no consolidation. At 6 months after randomisation, 10 and 13 consolidated patients achieved MRD negativity by flow cytometry (sensitivity 10-4 ) in bone marrow and peripheral blood respectively. PFS was significantly better in consolidated patients compared to non-consolidated patients (p = 0.001). No difference was observed in PFS, overall survival or duration of MRD negativity when comparing the 10 MRD-negative patients after consolidation with the 19 MRD-negative patients in the monitoring group. Common adverse events in the consolidation arm were thrombocytopenia, infection, and cough. Only 1% of events were infusion-related reactions. This observation provides further evidence that consolidation to achieve MRD negativity improves outcomes in CLL and that obinutuzumab is well tolerated in patients with low levels of disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroconversion in hematology-oncology patients.

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China at the end of 2019, the virus has spread rapidly across the globe leading to millions of infections and subsequent deaths. Although the virus infects those exposed indiscriminately, there are groups in society at an increased risk of severe infection, leading to increased morbidity. Patients suffering from hematological cancers, particularly leukemia, lymphoma, and myeloma, may be one such group and previous studies have suggested that they may be at a three to four times greater risk of severe COVID-19 after SARS-CoV-2 infection, leading to admissions to ICU, mechanical ventilation, and death compared to those without such malignancies. Serological testing for IgG seroconversion has been extensively studied in the immunocompetent, but fewer publications have characterized this process in large series of immunocompromised patients. This study described 20 patients with hematological cancers who tested positive for SARS-CoV-2 via PCR with 12 of the patients receiving further serological testing. We found that of the 12 patients screened for SARS-CoV-2 IgG antibodies, only 2 (16.6%) were able to generate an immune response to the infection. Yet despite this low seroconversion rate in this cohort, none of these patients died or became particularly unwell with COVID-19 or its related complications.

Thermal vesiculation during volcanic eruptions.

Terrestrial volcanic eruptions are the consequence of magmas ascending to the surface of the Earth. This ascent is driven by buoyancy forces, which are enhanced by bubble nucleation and growth (vesiculation) that reduce the density of magma. The development of vesicularity also greatly reduces the 'strength' of magma, a material parameter controlling fragmentation and thus the explosive potential of the liquid rock. The development of vesicularity in magmas has until now been viewed (both thermodynamically and kinetically) in terms of the pressure dependence of the solubility of water in the magma, and its role in driving gas saturation, exsolution and expansion during decompression. In contrast, the possible effects of the well documented negative temperature dependence of solubility of water in magma has largely been ignored. Recently, petrological constraints have demonstrated that considerable heating of magma may indeed be a common result of the latent heat of crystallization as well as viscous and frictional heating in areas of strain localization. Here we present field and experimental observations of magma vesiculation and fragmentation resulting from heating (rather than decompression). Textural analysis of volcanic ash from Santiaguito volcano in Guatemala reveals the presence of chemically heterogeneous filaments hosting micrometre-scale vesicles. The textures mirror those developed by disequilibrium melting induced via rapid heating during fault friction experiments, demonstrating that friction can generate sufficient heat to induce melting and vesiculation of hydrated silicic magma. Consideration of the experimentally determined temperature and pressure dependence of water solubility in magma reveals that, for many ascent paths, exsolution may be more efficiently achieved by heating than by decompression. We conclude that the thermal path experienced by magma during ascent strongly controls degassing, vesiculation, magma strength and the effusive-explosive transition in volcanic eruptions.

Determinants of last lap speed in paced and maximal 1500-m time trials.

PURPOSE: The present study identified the physiological and performance characteristics that are deterministic during a maximal 1500-m time trial and in paced 1500-m time trials, with an all-out last lap. METHODS: Thirty-two trained middle-distance runners (n = 21 male, VO2peak: 72.1 ± 3.2; n = 11, female, VO2peak: 61.2 ± 3.7 mL kg-1 min-1) completed a 1500-m time trial in the fastest time possible (1500FAST) as well as a 1500MOD and 1500SLOW trial whereby mean speed was reduced during the 0-1100 m by 5% and 10%, respectively. Anaerobic speed reserve (ASR), running economy (RE), the velocity corresponding with VO2peak (VVO2peak), maximal sprint speed (MSS) and maximal accumulated oxygen deficit (MAOD) were determined during additional testing. Carnosine content was quantified by proton magnetic resonance spectroscopy in the gastrocnemius and expressed as a Z-score to estimate muscle fibre typology. RESULTS: 1500FAST time was best explained by RE and VVO2peak in female runners (adjusted r2 = 0.80, P < 0.001), in addition to the 0-1100-m speed relative to VVO2peak in male runners (adjusted r2 = 0.72, P < 0.001). Runners with a higher gastrocnemius carnosine Z-score (i.e., higher estimated percentage of type II fibres) and greater MAOD, reduced their last lap time to a greater extent in the paced 1500-m trials. Neither ASR nor MSS was associated with last lap time in the paced trials. CONCLUSION: These findings suggest that VVO2 peak and RE are key determinants of 1500-m running performance with a sustained pace from the start, while a higher carnosine Z-score and MAOD are more important for last lap speed in tactical 1500-m races.

Association between hip muscle cross-sectional area and hip pain and function in individuals with mild-to-moderate hip osteoarthritis: a cross-sectional study.

BACKGROUND: To examine the associations between hip muscle cross-sectional area and hip pain and function in community-based individuals with mild-to-moderate hip osteoarthritis. METHODS: This study included 27 participants with mild-to-moderate hip osteoarthritis. Cross-sectional area of hip muscles, including psoas major, rectus femoris, gluteus maximus, gluteus medius and minimus, adductor longus and magnus, obturator internus, and obturator externus, were measured from magnetic resonance images. Hip pain and function were evaluated using the Hip Disability and Osteoarthritis Outcome Score (HOOS) categorised into 5 subscales: pain, symptoms, activity of daily living, sport and recreation function, and hip-related quality of life (for each subscale 0 representing extreme problems and 100 representing no problems). RESULTS: Mean age of the 27 participants was 63.2 (SD 7.6) years and 66.7% (n = 18) were female. After adjusting for age and gender, greater cross-sectional area of adductor longus and magnus was associated with a higher HOOS score in quality of life (regression coefficient 1.4, 95% confidence interval (CI) 0.2-2.7, p = 0.02), activity of daily living (regression coefficient 1.3, 95% CI 0.1-2.6, p = 0.04) and sport and recreation function (regression coefficient 1.6, 95% CI 0.1-3.0, p = 0.04). There was a trend towards an association between greater cross-sectional area of psoas major and a higher quality of life score (regression coefficient 3.6, 95% CI - 0.5 to 7.7, p = 0.08). The cross-sectional area of hip muscles was not significantly associated with HOOS pain or symptom score. CONCLUSION: Greater cross-sectional area of hip adductors was associated with better function and quality of life in individuals with mild-to-moderate hip osteoarthritis. Greater cross-sectional area of hip flexors might be associated with better quality of life. These findings, while need to be confirmed in longitudinal studies, suggest that targeting the hip adductor and flexor muscles may improve function and quality of life in those with mild-to-moderate hip osteoarthritis.

CUDC-907 blocks multiple pro-survival signals and abrogates microenvironment protection in CLL.

CUDC-907, a dual PI3K/HDAC inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL) remain elusive. We show that CLL cells are sensitive to CUDC-907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC-907 inhibited PI3K/AKT and HDAC activity, as expected, but also suppressed RAF/MEK/ERK and STAT3 signalling and reduced the expression of anti-apoptotic BCL-2 family proteins BCL-2, BCL-xL, and MCL-1. Moreover, CUDC-907 downregulated cytokines BAFF and APRIL and their receptors BAFFR, TACI, and BCMA, thus blocking BAFF-induced NF-κB signalling. T cell chemokines CCL3/4/17/22 and phosphorylation of CXCR4 were also reduced by CUDC-907. These data indicated that CUDC-907 abrogates different protective signals and suggested that it might sensitize CLL cells to other drugs. Indeed, combinations of low concentrations of CUDC-907 with inhibitors of BCL2, BTK, or the NF-κB pathway showed a potent synergistic effect. Our data indicate that, apart from its known functions, CUDC-907 blocks multiple pro-survival pathways to overcome microenvironment protection in CLL cells. This provides a rationale to evaluate the clinical relevance of CUDC-907 in combination therapies with other targeted inhibitors.

Kinetics of T-cell subset reconstitution following treatment with bendamustine and rituximab for low-grade lymphoproliferative disease: a population-based analysis.

Delayed lymphocyte and T-cell immune reconstitution following bendamustine-rituximab (BR) for indolent non-Hodgkin lymphoma (iNHL) has been described, but no information is available for chronic lymphocytic leukaemia (CLL). We present a population-based retrospective analysis of immune reconstitution and risk of infection following BR. Outcomes included timing/correlates of CD4+ recovery and risk of ≥grade 3 infections. Consecutively treated patients (1 April 2014 to 31 January 2017) were included (n = 295),with a median age of 65 years (range 33-92); 57% were 1st line treatments. Median cumulative bendamustine dose was 1080 mg/m2 (range 140-1440 mg/m2 ). CD4/CD8/CD19/NK subsets were available for 148 patients. Median follow-up was 24 months. Median times to lymphocyte count (ALC) recovery (≥1 × 109 /l) and CD4+ recovery (≥0·2 × 109 /l) were 26 and 24 months, respectively. Bendamustine total dose >1080 mg/m2 (hazard ratio [HR] 0·4; 95% confidence interval [CI]: 0·2-0·8), end-of-treatment ALC ≤0·4 × 109 /l (HR 0·53; 95% CI: 0·3-0·9) and CD4+ <0·1 × 109 /l 1-year post-BR (HR 0·03; 95% CI: 0·008-0·15) were covariables for delayed CD4+ recovery. ALC-recovery ≥1 × 109 /l was an unreliable predictor of CD4+ recovery (negative predictive vale 74%, positive predictive value 86%, likelihood ratio 3·3). CD4+ lymphopenia >3 years was a significant risk factor for ≥grade 3 infections (Odds ratio 3·4; 95% CI: 1·4-6·9). CD4+ recovery after BR is unexpectedly delayed and late recovery is associated with risk of serious infections. Monitoring CD4+ following BR could identify patients at high risk of delayed infections.

Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study.

We performed an observational study on the efficacy of ben-damustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion.

Microstructural changes in the median and ulnar nerve in people with and without diabetic neuropathy in their hands: A cross-sectional diffusion MRI study.

PURPOSE: Diffusion weighted imaging (DWI) has revealed microstructural changes in lower limb nerves in people with diabetic neuropathy. Microstructural changes in upper limb nerves using DWI in people with diabetes have not yet been explored. METHODS: This cross-sectional study aimed to quantify and compare the microstructure of the median and ulnar nerve in people without diabetes (n = 10), people with diabetes without distal symmetrical polyneuropathy (DSPN; n = 10), people with DSPN in the lower limbs only (DSPN FEET ONLY; n = 12), and people with DSPN in the upper and lower limbs (DSPN HANDS & FEET; n = 9). DSPN diagnosis included electrodiagnosis and corneal confocal microscopy. Tensor metrics, such as fractional anisotropy, radial diffusivity and axial diffusivity, and constrained spherical deconvolution metrics, such as dispersion and complexity, were calculated. Linear mixed-models were used to quantify DWI metrics from multiple models in median and ulnar nerves across the groups, and to evaluate potential differences in metrics at the wrist and elbow based on the principle of a distal-to-proximal disease progression. RESULTS: Tensor metrics revealed microstructural abnormalities in the median and ulnar nerve in people with DSPN HANDS & FEET, and also already in DSPN FEET ONLY. There were significant negative correlations between electrodiagnostic parameters and tensor metrics. A distal-to-proximal pattern was more pronounced in the median nerve. Non-tensor metrics showed early microstructural changes in people with diabetes without DSPN. CONCLUSION: Compared to people without diabetes, microstructural changes in upper limb nerves can be identified in people with diabetes with and without DSPN, even before symptoms occur.

Damage amplification during repetitive seismic waves in mechanically loaded rocks.

Cycles of stress build-up and release are inherent to tectonically active planets. Such stress oscillations impart strain and damage, prompting mechanically loaded rocks and materials to fail. Here, we investigate, under uniaxial conditions, damage accumulation and weakening caused by time-dependent creep (at 60, 65, and 70% of the rocks' expected failure stress) and repeating stress oscillations (of ± 2.5, 5.0 or 7.5% of the creep load), simulating earthquakes at a shaking frequency of ~ 1.3 Hz in volcanic rocks. The results show that stress oscillations impart more damage than constant loads, occasionally prompting sample failure. The magnitudes of the creep stresses and stress oscillations correlate with the mechanical responses of our porphyritic andesites, implicating progressive microcracking as the cause of permanent inelastic strain. Microstructural investigation reveals longer fractures and higher fracture density in the post-experimental rock. We deconvolve the inelastic strain signal caused by creep deformation to quantify the amount of damage imparted by each individual oscillation event, showing that the magnitude of strain is generally largest with the first few oscillations; in instances where pre-existing damage and/or the oscillations' amplitude favour the coalescence of micro-cracks towards system scale failure, the strain signal recorded shows a sharp increase as the number of oscillations increases, regardless of the creep condition. We conclude that repetitive stress oscillations during earthquakes can amplify the amount of damage in otherwise mechanically loaded materials, thus accentuating their weakening, a process that may affect natural or engineered structures. We specifically discuss volcanic scenarios without wholesale failure, where stress oscillations may generate damage, which could, for example, alter pore fluid pathways, modify stress distribution and affect future vulnerability to rupture and associated hazards.

Hamstring harvest results in significantly reduced knee muscular protection during side-step cutting two years after anterior cruciate ligament reconstruction.

The purpose of this study was to determine the effect of donor muscle morphology following tendon harvest in anterior cruciate ligament (ACL) reconstruction on muscular support of the tibiofemoral joint during sidestep cutting. Magnetic resonance imaging (MRI) was used to measure peak cross-sectional area (CSA) and volume of the semitendinosus (ST) and gracilis (GR) muscles and tendons (bilaterally) in 18 individuals following ACL reconstruction. Participants performed sidestep cutting tasks in a biomechanics laboratory during which lower-limb electromyography, ground reaction loads, whole-body motions were recorded. An EMG driven neuro-musculoskeletal model was subsequently used to determine force from 34 musculotendinous units of the lower limb and the contribution of the ST and GR to muscular support of the tibiofemoral joint based on a normal muscle-tendon model (Standard model). Then, differences in peak CSA and volume between the ipsilateral/contralateral ST and GR were used to adjust their muscle-tendon parameters in the model followed by a recalibration to determine muscle force for 34 musculotendinous units (Adjusted model). The combined contribution of the donor muscles to muscular support about the medial and lateral compartments were reduced by 52% and 42%, respectively, in the adjusted compared to standard model. While the semimembranosus (SM) increased its contribution to muscular stabilisation about the medial and lateral compartment by 23% and 30%, respectively. This computer simulation study demonstrated the muscles harvested for ACL reconstruction reduced their support of the tibiofemoral joint during sidestep cutting, while the SM may have the potential to partially offset these reductions. This suggests donor muscle impairment could be a factor that contributes to ipsilateral re-injury rates to the ACL following return to sport.

Match Running Performance in Australian Football Is Related to Muscle Fiber Typology.

PURPOSE: To examine the association between muscle fiber typology and match running performance in professional Australian football (AF) athletes. METHODS: An observational time-motion analysis was performed on 23 professional AF athletes during 224 games throughout the 2020 competitive season. Athletes were categorized by position as hybrid, small, or tall. Athlete running performance was measured using Global Navigation Satellite System devices. Mean total match running performance and maximal mean intensity values were calculated for moving mean durations between 1 and 10 minutes for speed (in meters per minute), high-speed-running distance (HSR, >4.17 m·s-1), and acceleration (in meters per second squared), while intercept and slopes were calculated using power law. Carnosine content was quantified by proton magnetic resonance spectroscopy in the gastrocnemius and soleus and expressed as a carnosine aggregate z score (CAZ score) to estimate muscle fiber typology. Mixed linear models were used to determine the association between CAZ score and running performance. RESULTS: The mean (range) CAZ score was -0.60 (-1.89 to 1.25), indicating that most athletes possessed a greater estimated proportion of type I muscle fibers. A greater estimated proportion of type I fibers (ie, lower CAZ score) was associated with a larger accumulation of HSR (>4.17 m·s-1) and an increased ability to maintain HSR as the peak period duration increased. CONCLUSION: AF athletes with a greater estimated proportion of type I muscle fibers were associated with a greater capacity to accumulate distance running at high speeds, as well as a greater capacity to maintain higher output of HSR running during peak periods as duration increases.

Reducing oral steroid intolerability and drug costs for acute wheezers: A retrospective evaluation of a clinical management algorithm in a Pediatric Emergency Department.

PROJECT AIM: To retrospectively evaluate a clinical management algorithm for acute wheezers in a UK Pediatric Emergency Department (PED). OVERVIEW AND RATIONALE: Acute wheezing attacks are a leading cause of PED attendances and inpatient admissions. Prednisolone, a routine treatment, is intolerable in almost one-third of children, requiring repeated dosing, which may prolong length of stay (LOS). To address this problem, we: (1) developed an acute management algorithm (concise, single-sided flow-chart, instructing immediate management); (2) modified the OCS regime from prednisolone (1 mg/kg, 3-day course) to dexamethasone (600 then 300 mcg/kg); (3) and disseminated guidance regionally. Written information-handouts, e-mails, and posters-were followed-up with verbal reinforcement. We implemented the algorithm in 2017 and revised it further in 2018. EVALUATION: In 2019, we retrospectively collected data on 100 acute wheeze attendances (those requiring OCS, aged 2-14), between October and December in 2016, 2017, and 2018 (n = 300), and assessed outcomes. RESULTS: Over a 48-month period, we reduced OCS intolerability by 67.2% and OCS drug costs by 85.8% (saving £41,470.14), while not significantly influencing the other outcomes. CONCLUSIONS: Reduced intolerability and substantial cost savings can be achieved by implementing a structured acute pediatric wheeze algorithm and modifying the OCS to single-dose dexamethasone (300 mcg/kg).

Defining the prognosis of early stage chronic lymphocytic leukaemia patients.

Approximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n = 1154) with a median follow-up of 8 years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP-70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP-70 expression and FISH were also prognostic variables; combinations of these markers increased prognostic power in concordant cases. Multivariate analysis revealed that only LDT, IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.