AbstractThis paper presents a systematic experimental investigation into the impact of specimen preparation on the cyclic loading behavior of saturated sand, including the deformation pattern, ...pore-water pressure generation, stress-strain relationship, and cyclic shear strength. Moist tamping and dry deposition were used in the laboratory to prepare sand specimens with distinct fabrics for cyclic triaxial tests under a range of conditions. It is found that the soil fabric formed by dry deposition can lead to unique failure modes different from those of moist-tamped samples in certain situations. These failure modes are hybrid in nature, characterized by a contractive response in the form of limited flow followed by cyclic strain hardening in the form of either cyclic mobility or plastic-strain accumulation. The hybrid nature of the failure patterns makes defining failure for liquefaction-resistance evaluation crucial; the conventional failure criteria based on a certain level of strain or pore-water pressure do not appear to properly represent the failure mechanism involved and may lead to a substantial overestimation of liquefaction resistance. The experiments reveal that the method used to reconstitute specimens or the soil fabric they form plays a role that is far more complicated than previously thought. Depending on the combination of relative density, confining stress, and degree of stress reversal in cyclic loading, a change of reconstitution method can have a marked or little effect on the nature of the response in terms of deformation pattern and failure mechanism; nevertheless, the two reconstitution methods always give significantly different liquefaction-resistance values under otherwise similar testing conditions.
This paper reports findings from an experimental study that aimed to investigate the undrained behaviour of sand in non-symmetrical cyclic loading, and to clarify the role of initial static shear in ...liquefaction resistance. The testing programme, conducted on a standard sand under triaxial conditions, covers a broad range of initial states in terms of relative density, confining stress and initial shear stress ratio (α). Three distinct failure modes have been identified from the tests: flow-type failure, cyclic mobility and plastic strain accumulation. Of these, flow-type failure, characterised by abrupt runaway deformations without any prior warning, is the most critical, and pertains to sand in the loose state. The tests also demonstrate that the presence of initial static shear stress is beneficial to the liquefaction resistance of loose sand at low α levels, but it becomes detrimental at high α levels. In this connection the concept of threshold α is proposed, together with the use of a no-stress-reversal line for better characterisation of the effect of initial static shear. Furthermore, in the conceptual framework of critical state soil mechanics, a fairly good linear relationship has been established between the threshold α and the state parameter ψ that collectively accounts for the initial relative density and mean stress level. This relationship suggests that the threshold α decreases with increasing values of ψ, or with sand becoming looser than the critical state. It is further proposed that the concept of threshold α also applies to sand at high relative density, as long as the confining stress becomes sufficiently high. This proposal leads to a unified and consistent interpretation of the complicated static shear effect.
Background
Omacetaxine mepesuccinate (OME) has antileukemic effects against acute myeloid leukemia (AML) carrying an internal tandem duplication of Fms‐like tyrosine kinase 3 (FLT3‐ITD). A phase 2 ...clinical trial was conducted to evaluate a combination treatment of sorafenib and omacetaxine mepesuccinate (SOME).
Methods
Relapsed or refractory (R/R) or newly diagnosed patients were treated with sorafenib (200‐400 mg twice daily) and OME (2 mg daily) for 7 (first course) or 5 days (second course onward) every 21 days until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). The primary endpoint was composite complete remission, which was defined as complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were leukemia‐free survival (LFS) and overall survival (OS).
Results
Thirty‐nine R/R patients and 5 newly diagnosed patients were recruited. Among the R/R patients, 28 achieved CR or CRi. Two patients showed partial remission, and 9 patients did not respond. Among the 5 newly diagnosed patients, 4 achieved CR, and 1 achieved CRi. The median LFS and OS were 5.6 and 10.9 months, respectively. Prior Fms‐like tyrosine kinase 3 (FLT3) inhibitor exposure (P = .007), 2 or more inductions (P = .001), and coexisting IDH2 (P = .008) and RUNX1 mutations (P = .003) were associated with lower CR/CRi rates. HSCT consolidation and deep molecular responses (defined as an FLT3‐ITD variant allelic frequency VAF ≤ 0.1% or a nucleophosmin 1 NPM1 mutant VAF ≤ 0.01%) were associated with better OS and LFS. Prior FLT3 inhibitor exposure and 2 or more inductions were associated with inferior LFS.
Conclusions
SOME was safe and effective for R/R and newly diagnosed FLT3‐ITD AML.
A combination of an FLT3 inhibitor and omacetaxine is safe and effective for FLT3‐ITD acute myeloid leukemia. A deep molecular response can be achieved, and this confers survival benefits to patients with hitherto dismal outcomes.
The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. ...Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.
ObjectiveLoneliness is a significant and independent risk factor for depression in later life. Particularly in Asian culture, older people may find it less stigmatising to express loneliness than ...depression. This study aimed to adapt a simple loneliness screen for use in older Chinese, and to ascertain its relevance in detecting depressive symptoms as a community screening tool.Design, setting and participantsThis cross-sectional study was conducted among 1653 older adults aged 60 years or above living in the community in Hong Kong. This was a convenient sample recruited from four local non-governmental organisations providing community eldercare or mental healthcare services. All data was collected by trained social workers through face-to-face interviews.MeasuresLoneliness was measured using an adapted Chinese version of UCLA 3-item Loneliness Scale, depression symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and social support with emotional and instrumental support proxies (number of people who can offer help). Basic demographics including age, gender, education and living arrangement were also recorded.ResultsThe average loneliness score was 3.9±3.0, and it had a moderate correlation with depressive symptoms (r=0.41, p<0.01). A loneliness score of 3 can distinguish those without depression from those with mild or more significant depressive symptoms, defined as a PHQ-9 score of ≥5 (sensitivity 76%, specificity 62%, area under the curve=0.73±0.01). Loneliness explained 18% unique variance of depressive symptoms, adding to age, living arrangement and emotional support as significant predictors.ConclusionA 3-item loneliness scale can reasonably identify older Chinese who are experiencing depressive symptoms as a quick community screening tool. Its wider use may facilitate early detection of depression, especially in cultures with strong mental health stigma.Trial registration numberClinicalTrials.gov NCT03593889
Landslide risks arising from boulder falls and debris flows are commonly mitigated using rigid and flexible barriers. Debris-barrier interaction is a complicated process, so current design methods ...rely on the use of the pseudo-static force approach. In addition to physical testing, numerical simulations can be used to provide insight into the impact mechanism. This paper presents the applications of numerical models to simulate rigid and flexible barriers subjected to rockfall and debris-flow impacts, respectively. For rigid barriers, rock-filled gabions, a recycled glass cullet, cellular glass aggregates, and ethylene-vinyl acetate (EVA) foam were assessed for their performance as cushioning materials. From the results, empirical equations were established for predicting the boulder impact forces and penetration into the cushion layer. Amongst the materials considered in this study, rock-filled gabions appear to be the most promising for use in practice. For flexible barriers, finite-element models, calibrated using documented case histories, were developed to simulate the debris-barrier interaction. The models were used to investigate the barriers' behavior under debris impacts from both force and energy perspectives. From the results, the hydrodynamic pressure coefficient was found to be lower than the current recommended value whilst only a small amount of debris energy was transferred to the barrier.
Infection risk assessment is very useful in understanding the transmission dynamics of infectious diseases and in predicting the risk of these diseases to the public. Quantitative infection risk ...assessment can provide quantitative analysis of disease transmission and the effectiveness of infection control measures. The Wells–Riley model has been extensively used for quantitative infection risk assessment of respiratory infectious diseases in indoor premises. Some newer studies have also proposed the use of dose‐response models for such purpose. This study reviews and compares these two approaches to infection risk assessment of respiratory infectious diseases. The Wells–Riley model allows quick assessment and does not require interspecies extrapolation of infectivity. Dose‐response models can consider other disease transmission routes in addition to airborne route and can calculate the infectious source strength of an outbreak in terms of the quantity of the pathogen rather than a hypothetical unit. Spatial distribution of airborne pathogens is one of the most important factors in infection risk assessment of respiratory disease. Respiratory deposition of aerosol induces heterogeneous infectivity of intake pathogens and randomness on the intake dose, which are not being well accounted for in current risk models. Some suggestions for further development of the risk assessment models are proposed.
Practical Implications
This review article summarizes the strengths and limitations of the Wells–Riley and the dose‐response models for risk assessment of respiratory diseases. Even with many efforts by various investigators to develop and modify the risk assessment models, some limitations still persist. This review serves as a reference for further development of infection risk assessment models of respiratory diseases. The Wells–Riley model and dose‐response model offer specific advantages. Risk assessors can select the approach that is suitable to their particular conditions to perform risk assessment.
Summary
Background
The number of patients infected with Aspergillus rose dramatically in recent years. However, studies on the clinical spectrum and antifungal susceptibilities of non‐classical ...(non‐fumigatus, non‐flavus, non‐niger and non‐terreus) pathogenic Aspergillus species are very limited.
Objectives
We examined the clinical spectrum and antifungal susceptibilities of 34 non‐duplicated, non‐classical Aspergillus isolates collected from Hong Kong, Shenzhen and Shanghai.
Methods
The Aspergillus isolates were identified by internal transcribed spacer, partial BenA and partial CaM sequencing and phylogenetic analyses. Susceptibility testing against eight antifungals was performed following the European Committee for Antimicrobial Susceptibility Testing's methodology.
Results
The 34 Aspergillus isolates were identified as 14 different rare/cryptic species of four sections (Flavi n = 8, Nidulantes n = 8, Nigri n = 17 and Restricti n = 1). Except for one patient whose clinical history could not be retrieved, 72.7% of the remaining patients had underlying conditions predisposing them to Aspergillus infections. The most common diseases were pulmonary infections (n = 15), followed by skin/nail infections (n = 6), chronic otitis externa and/or media (n = 5), wound infections (n = 2) and mastoiditis/radionecrosis (n = 1), while three were colonisations. Five patients succumbed due to the infections during the admission, and another two died 5 years later because of chronic pulmonary aspergillosis. Antifungal susceptibility testing showed that they possessed different susceptibility profiles compared to the classical Aspergillus species. The majority of isolates characterised were sensitive or wild‐type to amphotericin B. The minimum effective concentrations for all the three echinocandins were also low.
Conclusion
Susceptibility testing should be performed for infections due to these rare/cryptic Aspergillus species to guide proper patient management.
The existence of initial shear stress can have a significant effect on the cyclic strength or liquefaction potential of sand. This effect is not yet fully understood because of a lack of convergence ...and consistency in the existing data and interpretations, leading to great uncertainty in quantifying the effect for practical applications. This paper presents new experimental results on a silica sand to validate the concept known as threshold α, below which the cyclic strength of sand increases with α and above which the cyclic strength decreases with α (with α representing the sustained shear stress level). On the basis of a series of monotonic loading tests on the same sand, and in the framework of critical state soil mechanics, it is further confirmed that threshold α can be well related to a state parameter in the void ratio-mean effective stress plane and thereby a unified and consistent interpretation can be established. A new platform is proposed on which the relationship between cyclic strength and state parameter is represented by a linear line, and this line will rotate clockwise as α increases. This platform provides an effective analytical tool for the study of the effect of sustained shear stress on the cyclic strength of sand. Moreover, the study also shows that the cyclic loading path is well linked with the monotonic loading path under different sustained shear stress levels, and this correspondence sheds light on the mechanisms underlying a variety of experimental observations.
Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)–negative, antibody to hepatitis B core antigen (anti‐HBc)–positive patients after allogeneic hematopoietic stem cell ...transplantation (HSCT) has not been prospectively studied. HBsAg‐negative, anti‐HBc–positive patients with undetectable HBV DNA undergoing allogeneic HSCT were prospectively monitored every 4 weeks. The primary endpoint was HBV reactivation, defined as detectable HBV DNA (≥10 IU/mL). Secondary endpoints included overall survival, HBsAg positivity, and changes in liver biochemistry and antibody to HBsAg levels. Among 297 allogeneic HSCT recipients, 85 (28.7%) were HBsAg‐negative, anti‐HBc–positive, of whom 62 were recruited and monitored for a median of 48 (4‐104) weeks. The 2‐year cumulative HBV DNA detectability rate was 40.8%, occurring at a median of 44 (8‐100) weeks. Multivariate analysis showed that age ≥50 years (P = 0.004, hazard ratio = 8.2) and chronic graft‐versus‐host disease (P = 0.010, hazard ratio = 5.3) were significantly associated with HBV reactivation. Other clinical parameters, including baseline antibody to HBsAg status, serial changes in antibody to HBsAg levels, and donor serology, were not associated with HBV reactivation. Patients <50 years old and without chronic graft‐versus‐host disease, compared with the remaining patient cohort, had a significantly lower 2‐year cumulative HBV reactivation rate (5.6% versus 65.0%, P = 0.004). Entecavir successfully suppressed HBV DNA to undetectable levels, with no cases developing biochemical hepatitis. Conclusion: HBsAg‐negative, anti‐HBc–positive patients had a high rate of HBV reactivation after allogeneic HSCT, with determinants of HBV reactivation including age ≥50 years and chronic graft‐versus‐host disease; treatment strategies based on these parameters may prevent HBV reactivation and subsequent complications. (ClinicalTrials.gov identifier NCT01481649.) (Hepatology 2017;65:1451‐1461).
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