Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Worsening pulmonary outcomes during sex reassignment therapy in a transgender female with cystic fibrosis (CF) and asthma/allergic bronchopulmonary aspergillosis: a case report.

BACKGROUND: Cystic Fibrosis (CF) is a hereditary pulmonary and extra-pulmonary disease that occurs equally in men and women. However, a difference in morbidity and mortality rates between the sexes has been long documented. Similarly, a sex-disparity in disease severity has been reported in asthma as well. Studies done to date point to estrogen as a possible cause of this sex disparity in pulmonary outcomes in both conditions. CASE PRESENTATION: Here, we describe a case of a patient with CF and asthma/allergic bronchopulmonary aspergillosis (ABPA) undergoing sex reassignment therapy (male-to-female) and the negative impact it had on her lung function and frequency of pulmonary exacerbations in the context of increasing doses of exogenous estrogen. CONCLUSIONS: This case raises the possibility of a link between estrogen and worsening pulmonary outcomes and the need for further studies into transgender individuals with CF and/or asthma/ABPA as well as those undergoing high dose estrogen therapy for other indications.

The inframammary skin-sparing mastectomy technique.

Skin-sparing mastectomy and immediate implant-based breast reconstruction is technically a challenging procedures for women with large, ptotic breasts. This is usually performed using the Wise pattern incision resulting in an inverted T scar, which is associated with postoperative complications. The other challenge is obtaining adequate coverage of the prosthesis. We describe a technique that avoids the inverted T scar and provides a single horizontal scar with a double dermo-muscular layer coverage of the prosthesis.

Predictive significance of the European LeukemiaNet classification of genetic aberrations in patients with acute myeloid leukaemia undergoing allogeneic stem cell transplantation.

OBJECTIVES: The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (alloSCT). METHODS: We retrospectively analysed 274 patients transplanted at our centre between 2004 and 2014. RESULTS: The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT [overall P = 0.0064 for disease-free survival (DFS), overall P = 0.003 for relapse]. Patients with an intermediate-1 profile have a significantly elevated 5-yr relapse incidence as compared to favourable risk patients, that is 40% vs. 15%, [hazard ratio (HR) 2.58, P = 0.048]. An intermediate-1 risk profile is an independent predictor for relapse as determined by multivariate Cox regression analysis (HR 3.05, P = 0.023). In intermediate-1 patients, the presence of an FLT3 internal tandem duplication (FLT3-ITD) is associated with a significantly increased relapse incidence (P = 0.0323), and a lower DFS (P = 0.0465). FLT3-ITD is an independent predictor for overall survival, DFS and relapse incidence in the intermediate-1 subgroup. CONCLUSIONS: The ELN stratification of genetic risk predicts the outcome of patients with AML undergoing alloSCT. Patients with an intermediate-1 profile have a high risk for treatment failure due to relapse, which prompts the development of alternative treatment strategies.

Impact of early remission by induction therapy on allogeneic stem cell transplantation for acute myeloid leukemia with an intermediate-risk karyotype in first complete remission.

For patients with acute myeloid leukemia (AML) early achievement of remission during induction treatment is an important predictor for long-term outcome irrespective of the type of consolidation therapy employed. Here, we retrospectively examined the prognostic impact of early remission (ER) vs. delayed remission (DR) in a cohort of 132 AML patients with an intermediate-risk karyotype undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). In contrast to patients showing DR, patients achieving ER had a significantly higher 3-yr overall survival (OS) and disease-free survival (DFS) of 76% vs. 54% (P = 0.03) and 76% vs. 53% (P = 0.03). Likewise, 3 yr after alloSCT the cumulative incidence of relapse (CI-R) was significantly lower in the ER subgroup as compared to patients achieving DR, that is, 10% vs. 35% (P = 0.004), whereas non-relapse mortality (NRM) did not differ significantly. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, P = 0.002) and a higher CI-R (HR 3.55, P = 0.002). Taken together, these data may indicate that the rapid achievement of remission predicts a favorable outcome in patients with intermediate-risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be fully overcome by alloSCT.

Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long-term outcome.

For patients with refractory acute myeloid leukemia (AML), allogeneic stem cell transplantation (alloSCT) represents the only curative approach. We here analyzed the long-term outcome of 131 consecutive patients with active AML, which was either primary refractory or unresponsive to salvage chemotherapy, transplanted at our center between 1997 and 2013. After a median follow-up of 48 months for the surviving patients, disease-free survival (DFS) at 5 yr post alloSCT was 26% (94% CI: 17-35). Relapses, most of which occurred within the first 2 yr from transplant, were the predominant cause of treatment failure affecting 48% (95%CI: 40-58) of patients, whereas non-relapse mortality was 26% (95%CI: 20-36) at 5 yr and thereafter. A marrow blast count ≥20% before alloSCT was an independent prognosticator associated with an inferior DFS (HR: 1.58, P = 0.027), whereas the development of chronic graft-versus-host disease (cGvHD) predicted an improved DFS (HR 0.21, P < 0.001) and a decreased relapse incidence (HR: 0.18, P = 0.026), respectively. These results indicate that alloSCT represents a curative treatment option in a substantial proportion of patients with refractory AML. A pretransplant blast count <20% before alloSCT and the development of cGvHD are the most important predictors of long-term disease control.

Cytogenetic risk grouping by the monosomal karyotype classification is superior in predicting the outcome of acute myeloid leukemia undergoing allogeneic stem cell transplantation in complete remission.

We retrospectively analyzed the impact of cytogenetic abnormalities grouped according to the monosomal karyotype (MK) classification or the Southwest Oncology/Eastern Cooperative Oncology Group (SWOG/ECOG) definition in 263 patients with acute myeloid leukemia (AML) who underwent allogeneic stem cell transplantation (alloSCT) in complete remission (CR) at our center. Risk grouping using the MK criteria shows a highly significant difference in 5-yr overall survival (OS) ranging between 67%, for the most favorable, and 32%, for the poorest risk group (P = 0.001). Although similarly precise in predicting OS, the MK scheme better separates patients with respect to relapse incidence as compared to the SWOG/ECOG grouping (P = 0.0001 vs. P = 0.01). Notably, patients displaying non-MK abnormalities (MK-) had a 5-yr relapse incidence identical to those cytogenetically normal (CN), that is 24%. Multivariate analysis revealed that the MK classification is an independent prognosticator and superior in predicting OS (hazard ratios, HR 3.74, P = 0.01) and relapse incidence (HR 3.74, P = 0.005) as compared to the SWOG/ECOG criteria. Finally, subgroup analysis revealed that the prognostic capacity of the MK classification is highly significant in patients treated with standard myeloablative conditioning prior to alloSCT (P = 0.0011 for OS, P = 0.0007 for relapse). In contrast, the MK grouping failed to predict OS or relapse incidence in patients treated with reduced intensity conditioning. Taken together, these results indicate that the MK classification is superior in predicting the overall outcome of patients with AML undergoing alloSCT in CR. Furthermore, our data suggest that the genetic risk profile of MK- and CN patients is mostly overlapping in this setting.

Aeroacoustics of T-junction merging flow.

This paper reports a numerical study of the aeroacoustics of merging flow at T-junction. The primary focus is to elucidate the acoustic generation by the flow unsteadiness. The study is conducted by performing direct aeroacoustic simulation approach, which solves the unsteady compressible Navier-Stokes equations and the perfect gas equation of state simultaneously using the conservation element and solution element method. For practical flows, the Reynolds number based on duct width is usually quite high (>10(5)). In order to properly account for the effects of flow turbulence, a large eddy simulation methodology together with a wall modeling derived from the classical logarithm wall law is adopted. The numerical simulations are performed in two dimensions and the acoustic generation physics at different ratios of side-branch to main duct flow velocities VR (=0.5,0.67,1.0,2.0) are studied. Both the levels of unsteady interactions of merging flow structures and the efficiency of acoustic generation are observed to increase with VR. Based on Curle's analogy, the major acoustic source is found to be the fluctuating wall pressure induced by the flow unsteadiness occurred in the downstream branch. A scaling between the wall fluctuating force and the efficiency of the acoustic generation is also derived.

Upper Respiratory Tract Infection Trends in a Psychiatric Institute in Singapore.

OBJECTIVES: To compare the incidence of upper respiratory tract infection (URTI) between inpatients at the Institute of Mental Health in Singapore and the general population over 8 years to determine the effectiveness of our infection control strategies. METHODS: Data for cases of influenza and URTI at our institute between January 2012 and December 2019 were collected. National data were derived from weekly infectious disease bulletins that report daily averages of people attending polyclinics/surgeries with influenza and URTI. Interrupted time series analyses were used to determine the impact of infection prevention and control strategies on incidence. RESULTS: Over the 8 years, there were 1607 cases of URTI involving 182 clusters, equal to 3.16 cases per 10 000 patient-bed-days. 965 (60%) cases and 95 (52%) clusters occurred in long-stay wards, whereas 642 (40%) cases and 87 (48%) clusters occurred in acute wards. The median cluster size was 12 in the long-stay wards and 7 in the acute wards (p < 0.0001). The spikes in cases in June and December may be attributed to the increased staff and visitor mobility during school vacations in June and December. Strategies implemented during the study period did not significantly reduce the incidence of URTI. Previous strategies implemented in 2005 to meet accreditation standards are more likely to be contributors. CONCLUSION: Infection control strategies of our institute appear to be effective, because the incidence of URTI was lower in our institute than in the community. The similar incidence of URTI in acute and long-stay wards indicates that service-user turnover is not a contributor. Rather, staff and visitors are more likely to be the vector. The larger clusters in long-stay wards indicates a greater risk of transmission in such settings. Increased activity in our institute during school vacations may be associated with an increase in cases in June and December. It is difficult to determine if strategies implemented during the study period successfully reduce the incidence of URTI.

A modified EBMT risk score predicts the outcome of patients with acute myeloid leukemia receiving allogeneic stem cell transplants.

The systematic and standardized pretransplant risk assessment represents an important tool to predict the outcome of patients undergoing allogeneic stem cell transplantation (alloSCT). To investigate the capacity of a modified European group for blood and marrow transplantation (mEBMT) risk score to predict the outcome of patients with acute myeloid leukemia (AML) receiving allogeneic stem cell transplants, we retrospectively analyzed 214 patients transplanted at our center between 1995 and 2008. Overall survival (OS) of the whole cohort at 1, 3, and 5 yr was 62%, 48%, and 45%, whereas the cumulative incidence of relapse or non-relapse mortality (NRM) was 26%, 33%, and 33% or 19%, 21%, and 22%. In univariate analysis, a higher mEBMT risk score was associated with an inferior OS ranging from 69% for patients with a score of 0/1 to 26% for patients with a score of 5/6 at 5 yr (P < 0.0001) and steadily increasing hazard ratios for each additional score point. Likewise, a higher mEBMT risk score was associated with an increased incidence of relapse (P = 0.049). Importantly, the prognostic value of the mEBMT risk score in terms of OS and relapse was maintained in multivariate analysis. Taken together, this indicates that a mEBMT risk score may be used to predict the outcome of patients with AML following alloSCT.

Air dispersal of multidrug-resistant Acinetobacter baumannii: implications for nosocomial transmission during the COVID-19 pandemic.

AIM: To describe the nosocomial transmission of Air, multidrug-resistant, Acinetobacter baumannii, nosocomial, COVID-19 Acinetobacter baumannii (MRAB) in an open-cubicle neurology ward with low ceiling height, where MRAB isolates collected from air, commonly shared items, non-reachable high-level surfaces and patients were analysed epidemiologically and genetically by whole-genome sequencing. This is the first study to understand the genetic relatedness of air, environmental and clinical isolates of MRAB in the outbreak setting. FINDINGS: Of 11 highly care-dependent patients with 363 MRAB colonization days during COVID-19 pandemic, 10 (90.9%) and nine (81.8%) had cutaneous and gastrointestinal colonization, respectively. Of 160 environmental and air samples, 31 (19.4%) were MRAB-positive. The proportion of MRAB-contaminated commonly shared items was significantly lower in cohort than in non-cohort patient care (0/10, 0% vs 12/18, 66.7%; P<0.001). Air dispersal of MRAB was consistently detected during but not before diaper change in the cohort cubicle by 25-min air sampling (4/4,100% vs 0/4, 0%; P=0.029). The settle plate method revealed MRAB in two samples during diaper change. The proportion of MRAB-contaminated exhaust air grills was significantly higher when the cohort cubicle was occupied by six MRAB patients than when fewer than six patients were cared for in the cubicle (5/9, 55.6% vs 0/18, 0%; P=0.002). The proportion of MRAB-contaminated non-reachable high-level surfaces was also significantly higher when there were three or more MRAB patients in the cohort cubicle (8/31, 25.8% vs 0/24, 0%; P=0.016). Whole-genome sequencing revealed clonality of air, environment, and patients' isolates, suggestive of air dispersal of MRAB. CONCLUSIONS: Our findings support the view that patient cohorting in enclosed cubicles with partitions and a closed door is preferred if single rooms are not available.

A modified EBMT risk score and the hematopoietic cell transplantation-specific comorbidity index for pre-transplant risk assessment in adult acute lymphoblastic leukemia.

BACKGROUND: Disease stage is the most important prognostic parameter in allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia, but other factors such as donor/host histocompatibility and gender combination, recipient age, performance status and comorbidities need to be considered. Several scoring systems are available to predict outcome in HCT recipients; however, their prognostic relevance in acute lymphoblastic leukemia is not well defined. DESIGN AND METHODS: In the present study we evaluated a modified EBMT risk score (mEBMT) and the HCT-specific comorbidity index (HCT-CI) in 151 adult acute lymphoblastic leukemia patients who received allogeneic HCT from 1995 until 2007 at our center. RESULTS: Disease status was first complete remission (CR1) (47%), CR>1 (21%) or no CR (32%). Overall survival (OS) at one, two and five years was 62%, 51% and 40% and non-relapse mortality (NRM) was 21%, 24% and 32%. Median mEBMT was 3 (0-6). Higher mEBMT was associated with inferior OS (hazard ratio per score unit (HR): 1.50, P<0.001), higher NRM (HR: 1.36, P=0.042) and higher relapse mortality (HR: 1.68, P<0.001). Disease stage was the predominant prognostic factor in this score. Comorbidities were present in 71% of patients with mild hepatic disease (29%), moderate pulmonary disease (28%) and infections (23%) being the most common. Median HCT-CI was 1 (0-9). In univariate analysis a trend for inferior OS (HR: 1.08, P=0.20) and higher NRM (HR: 1.14, P=0.11) with increasing HCT-CI was observed but the level of significance was not reached. In additional analyses we found that reduced Karnofsky Performance Status (KPS) was associated with inferior OS (HR: 1.34, P=0.023) and higher relapse mortality (HR: 1.71, P=0.001) when analyzed univariately. However, KPS was associated with disease stage and significance was lost in multivariate analysis. CONCLUSIONS: The mEBMT was prognostic in our patient cohort with predominant influence of disease stage, whereas a trend but no significant prognostic value was observed for the HCT-CI.

On sound propagation from a slanted side branch into an infinitely long rectangular duct.

The transmission of sound from a slanted side branch into an infinitely long rectangular duct is studied numerically using the method of finite element with absorptive domain exit boundaries. The sound transmission coefficients associated with various acoustic modes are investigated in details. The results show that the plane wave assumption is only valid at very low frequency. It is also found that the intensities of the higher modes are stronger than that of the plane wave once they are excited. Besides, a critical side-branch slant angle is found over which a significant change of sound propagation mode takes place. This affects substantially the energy distribution between various acoustic modes inside the main duct. A simplified model is proposed to explain the phenomenon and the relationship of this critical angle with the width ratio between the side branch and the main duct is established.

Multi-Product Microalgae Biorefineries: From Concept Towards Reality.

Although microalgae are a promising biobased feedstock, industrial scale production is still far off. To enhance the economic viability of large-scale microalgae processes, all biomass components need to be valorized, requiring a multi-product biorefinery. However, this concept is still too expensive. Typically, downstream processing of industrial biotechnological bulk products accounts for 20-40% of the total production costs, while for a microalgae multi-product biorefinery the costs are substantially higher (50-60%). These costs are high due to the lack of appropriate and mild technologies to access the different product fractions such as proteins, carbohydrates, and lipids. To reduce the costs, simplified processes need to be developed for the main unit operations including harvesting, cell disruption, extraction, and possibly fractionation.

Inducible expression of double-stranded RNA directs specific genetic interference in Drosophila.

BACKGROUND: The introduction of double-stranded RNA (dsRNA) can selectively interfere with gene expression in a wide variety of organisms, providing an ideal approach for functional genomics. Although this method has been used in Drosophila, it has been limited to studies of embryonic gene function. Only inefficient effects have been seen at later stages of development. RESULTS: When expressed under the control of a heat-inducible promoter, dsRNA interfered efficiently and specifically with gene expression during larval and prepupal development in Drosophila. Expression of dsRNA corresponding to the EcR ecdysone receptor gene generated defects in larval molting and metamorphosis, resulting in animals that failed to pupariate or prepupae that died with defects in larval tissue cell death and adult leg formation. In contrast, expression of dsRNA corresponding to the coding region of the betaFTZ-F1 orphan nuclear receptor had no effect on puparium formation, but led to an arrest of prepupal development, generating more severe lethal phenotypes than those seen with a weak betaFTZ-F1 loss-of-function allele. Animals that expressed either EcR or betaFTZ-F1 dsRNA showed defects in the expression of corresponding target genes, indicating that the observed developmental defects are caused by disruption of the genetic cascades that control the onset of metamorphosis. CONCLUSIONS: These results confirm and extend our understanding of EcR and betaFTZ-F1 function. They also demonstrate that dsRNA expression can inactivate Drosophila gene function at later stages of development, providing a new tool for functional genomic studies in Drosophila.

Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors.

HIV-1-infected long-term nonprogressors are a heterogeneous group of individuals with regard to immunologic and virologic markers of HIV-1 disease. CC chemokine receptor 5 (CCR5) has recently been identified as an important coreceptor for HIV-1 entry into CD4+ T cells. A mutant allele of CCR5 confers a high degree of resistance to HIV-1 infection in homozygous individuals and partial protection against HIV disease progression in heterozygotes. The frequency of CCR5 heterozygotes is increased among HIV-1- infected long-term nonprogressors compared with progressors; however, the host defense mechanisms responsible for nonprogression in CCR5 heterozygotes are unknown. We hypothesized that nonprogressors who were heterozygous for the mutant CCR5 gene might define a subgroup of nonprogressors with higher CD4+ T cell counts and lower viral load compared with CCR5 wild-type nonprogressors. However, in a cohort of 33 HIV-1-infected long-term nonprogressors, those who were heterozygous for the mutant CCR5 gene were indistinguishable from CCR5 wild-type nonprogressors with regard to all measured immunologic and virologic parameters. Although epidemiologic data support a role for the mutant CCR5 allele in the determination of the state of long-term nonprogression in some HIV-1- infected individuals, it is not the only determinant. Furthermore, long-term nonprogressors with the wild-type CCR5 genotype are indistinguishable from heterozygotes from an immunologic and virologic standpoint.