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Since an increasing number of rock engineering structures are constructed in the stratified rock mass, a comprehensive understanding of the mechanical properties of anisotropic rock is crucial for the stability evaluation of these structures. In this study, the combined influences of the dip angle of the bedding plane and intermediate principal stress on the strength and failure behavior of anisotropic rock are experimentally investigated. True triaxial compression tests on a sandstone possessing seven different bedding plane angles (i.e., 0°, 15°, 30°, 45°, 60°, 75°, and 90°) are conducted under six different intermediate principal stresses (i.e., 10 MPa, 60 MPa, 100 MPa, 130 MPa, 160 MPa, and 190 MPa). The effects of intermediate principal stress and bedding plane angle on the stress–strain curve, Young's modulus, strength, and failure mode of the rock are soundly examined and discussed. The results show that both intermediate principal stress and bedding plane angle have a large influence on the deformation properties of the rock. In addition, the peak strength exhibits a typical U-shaped variation with increasing bedding plane angle under low intermediate principal stress condition, and the U-shaped behavior gradually diminishes with the increase in intermediate principal stress. Multiple failure planes can be observed after the failure of the rock specimens, showing asymmetric V-shaped patterns. The failure angle of the tested rock is found to generally increase as the applied intermediate principal stress gradually increases. The results in the present study deepen our understanding of the strength and failure behavior of anisotropic rock under true triaxial loading conditions.HighlightsPeak strength shows a U-shaped variation with increasing bedding plane angle at small σ2.U-shaped behavior of rock strength diminishes with increasing intermediate principal stress.Multiple asymmetric V-shaped failure patterns are observed after the failure of the rock specimen.Failure angle exhibits an increasing trend as intermediate principal stress gradually increases.

In a randomized trial of bortezomib, cyclophosphamide, and dexamethasone as compared with the same therapy plus daratumumab, patients with light-chain amyloidosis who received daratumumab had a higher frequency of hematologic complete response than those who did not (53.3% vs. 18.1%). Deaths were most commonly due to cardiac failure.

In the first phase 3 study in relapsed/refractory AL amyloidosis (TOURMALINE-AL1 NCT01659658), 168 patients with relapsed/refractory AL amyloidosis after 1–2 prior lines were randomized to ixazomib (4 mg, days 1, 8, 15) plus dexamethasone (20 mg, days 1, 8, 15, 22; n = 85) or physician’s choice (dexamethasone ± melphalan, cyclophosphamide, thalidomide, or lenalidomide; n = 83) in 28-day cycles until progression or toxicity. Primary endpoints were hematologic response rate and 2-year vital organ deterioration or mortality rate. Only the first primary endpoint was formally tested at this interim analysis. Best hematologic response rate was 53% with ixazomib–dexamethasone vs 51% with physician’s choice (p = 0.76). Complete response rate was 26 vs 18% (p = 0.22). Median time to vital organ deterioration or mortality was 34.8 vs 26.1 months (hazard ratio 0.53; 95% CI, 0.32–0.87; p = 0.01). Median treatment duration was 11.7 vs 5.0 months. Adverse events of clinical importance included diarrhea (34 vs 30%), rash (33 vs 20%), cardiac arrhythmias (26 vs 15%), nausea (24 vs 14%). Despite not meeting the first primary endpoint, all time-to-event data favored ixazomib–dexamethasone. These results are clinically relevant to this relapsed/refractory patient population with no approved treatment options.

Background Cardiac amyloidosis (CA) is an under‐recognized cause of heart failure. Left atrial (LA) myopathy contributes to a worse prognosis in heart failure and is a feature of transthyretin (ATTR) and light‐chain (AL) CA. LA mechanical dispersion (LA‐MD) is a novel marker of intra‐atrial dyssynchrony implicated in LA myopathy and the future development of atrial fibrillation (AF). Aims This study aimed to determine the characteristics and prognostic value of LA myopathy in ATTR and AL cardiomyopathy through a comprehensive LA echocardiographic evaluation. Methods ATTR (n = 86) and AL (n = 86) CA patients were compared with hypertensive heart disease (HHT) patients (n = 58). Transthoracic echocardiographic measurements including LA strain and LA‐MD were obtained with patient follow‐up for mortality. Results ATTR and AL patients had a median follow‐up of 66 months, with 26 mortality events. Left ventricular (LV) mass, diastolic function (average‐e′ and E/e′), LV global longitudinal strain, and LA volume and function (LA function index and strain) were more impaired in ATTR versus AL; these echocardiographic parameters were more impaired in both amyloid groups compared to HHT patients (P < 0.05). LA‐MD was increased in ATTR versus AL [median 72.2 (inter‐quartile range 55–88.9) vs. 54 (43.5–64.2), respectively, P < 0.001]. Multivariable logistic regression adjusted for age, presence of AF, LV mass, global and basal strain, and E/e′ demonstrated that LA‐MD was an independent determinant of ATTR CA (P = 0.014). On multivariable analysis, LA reservoir strain was independently associated with the presence of heart failure in the CA group (P < 0.001). LA minimum volume (cut‐off ≥18 mL/m2) was a determinant of mortality in AL CA [Cox proportional hazard ratio (HR) 1.042 (1.003–1.082), P = 0.034 and Kaplan–Meier analysis, P = 0.016]. Conclusion Characterizing LA myopathy has significant diagnostic and prognostic utility in CA. ATTR patients have increased atrial dyssynchrony, which may have implications for AF development. LA reservoir strain was associated with heart failure in CA, whilst LA minimum volume was a predictor of mortality in AL CA.

For analogue granular materials simulated using DEM, contact networks are often drawn by joining the centroids of contacting particles. Although a limited amount of research has been done to characterise the temporal aspects of such contact networks at a micro-scale, many simple questions regarding the duration of contacts in evolving granular systems remain unanswered. This paper addresses this gap in the existing knowledge by using the open-source code LAMMPS to run and analyse nine (3D) triaxial simulations of 20,164 polydisperse spherical particles. Contacts which exist for a long duration are preferentially oriented in the direction of the major principal stress while the fabric anisotropy for contacts with a given duration increases with duration. Regardless of simulation conditions, there is a linear relationship between the percentage of contacts present for a given duration and contact duration, despite the non-linear overall behaviour of the material. The forces transmitted by contacts increase, on average, with increasing duration. The total number of unique contacts which appear during triaxial compression increases linearly after 10 % axial strain, although the number of contacts, both total and subdivided into strong and weak force subnetworks, remains quite stable. The majority of contacts in these evolving granular systems, even those participating in strong force chains, are formed and lost repeatedly.

A 68-year-old woman with known metastatic renal cell carcinoma presented with an acutely swollen right leg. In between the two sessions of palliative radiotherapy to the right hip, she also had right hip modified Harrington procedure for tumour resection with hip replacement. Initial clinical evaluation raised the suspicion of right leg deep vein thrombosis (DVT). However, DVT was excluded and further investigations revealed stenosis of the right external and common iliac veins, likely secondary to radiotherapy.

Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits is a form of monoclonal gammopathy of renal significance that can rarely co-occur with thrombotic microangiopathy (TMA). We report a rare case in a patient who presented with nephrotic syndrome, in whom the renal biopsy showed TMA and underlying granular electron-dense deposits predominantly along the subendothelial aspect of the glomerular basement membrane and mesangium. Immunofluorescence performed on proteinase-digested formalin-fixed, paraffin-embedded sections showed IgG3 kappa light chain restriction. Further clinical, radiologic and haematologic investigations showed no evidence of any underlying neoplastic B-cell or plasma cell clone. Following multidisciplinary team input, the patient was treated with bortezomib and plasma exchange, allowing long-term clinical stabilisation.

Abstract Aims The prognosis of light-chain (AL) amyloidosis, a plasma cell dyscrasia, is largely determined by the presence of cardiac involvement. Conventional staging is achieved using cardiac biomarkers (high-sensitivity troponin, N-terminal pro-beta natriuretic peptide) and free light-chain difference (Mayo staging). We sought to evaluate the role of echocardiographic parameters as prognostic markers in AL amyloidosis and examine their utility compared with conventional staging. Methods and results Seventy-five consecutive patients with AL amyloidosis reviewed at a referral amyloid clinic who underwent comprehensive echocardiographic assessment were retrospectively identified. The evaluated echocardiographic parameters included left ventricular (LV) ejection fraction, mass, diastolic function parameters, global longitudinal strain (GLS), and left atrial (LA) volume. Mortality was assessed through a review of clinical records. During a median follow-up of 51 months, 29/75 (39%) patients died. Patients who died had a larger LA volume (47 ± 12 vs. 35 ± 10 mL/m2, P < 0.001) and a higher E/e′ (18 ± 10 vs. 14 ± 6, P = 0.026). Univariate clinical and echocardiographic predictors of survival included LA volume, E/e′, e′, LVGLS, and Mayo stage (at significance of P < 0.1). Left atrial volume and LVGLS were significant determinants of mortality when examined using clinical cut-offs, although E/e′ was not. A composite echocardiographic risk score comprising LA volume and LVGLS provided similar prognostic performance to Mayo stage [area under the curve (AUC) 0.75, 95% confidence interval (CI) 0.64–0.85 vs. AUC 0.75, 95% CI 0.65–0.858, P = 0.91]. Conclusion Left atrial volume and LVGLS were independent predictors of mortality in AL amyloidosis. A composite echocardiographic score combining LA volume and LVGLS has similar prognostic power to Mayo stage for all-cause mortality. Graphical Abstract Graphical Abstract An echocardiographic risk score was derived using a cohort of 74 patients with light-chain amyloidosis from a single centre. A composite score using left atrial volume and global longitudinal strain, stratified patients into three distinct risk groups. Patients were allocated one point for left atrial dilatation (indexed left atrial volume >42 mL/m2) and reduced left ventricular global longitudinal strain (>−12%). Prognostic power in predicting all-cause mortality was similar to the existing Mayo staging system [area under the curve (AUC) 0.75, 95% confidence interval (CI) 0.64–0.85 vs. AUC 0.75, 95% CI 0.65–0.858, P = 0.91].

ObjectivesHereditary Transthyretin amyloidosis (ATTRv) is characterised by progressive sensorimotor and autonomic neuropathy, and cardiac failure. We aim to describe the spectrum of ATTRv neuropathy in Australia.MethodsA retrospective analysis of ATTRv patients attending Australian Amyloidosis Network clinics between 2007–2022 was performed. TTR variants, clinical features and treatments were evaluated.Results161 individuals were identified (62% NSW/ACT, 20% QLD, 12% VIC/TAS, 4% WA, 2% SA). Average age was 59.4 years (range 21.5–91.4). 53% were male. 37% were presymptomatic (average age 52.7 years, range 21.5–71.0). 24 genetic variants were identified, including Thr60Ala (31%), Val30Met (23%), Val122Ile (12%), Ala97Ser (6%), Glu89Gln (5%).The diagnosis rate has increased from 2 p.a in 2011–13 to 5 p.a in 2015–17, and 12 p.a in 2020–22. The average time to diagnosis was 3.8 years (range 1–15). 13 asymptomatic individuals developed symptomatic disease over an average 2.3 years (range 0–8).40% had neuropathic-predominant disease, 32% cardiac, 25% mixed cardiac and neuropathic, and 3% had other organ-predominant disease. Of the 130 living individuals 45% had a PND score of 0, 22% PND1,10% PND2, and 9% PND3a or above. Similarly, 53% of individuals had a FAP0, 31% FAP1, 15% FAP2 and 1% FAP3.Of individuals with PND0–2, only 22% were on highly efficacious treatments, all via clinical trial or compassionate access scheme.ConclusionsOur study is the first to demonstrate the spectrum of ATTRv in Australia. Affordable TTR genotyping and access to highly efficacious novel therapies remain substantial unmet needs in this population.