Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia.

PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients. EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL. CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.     

Infection with IBV DMV/1639 at a Young Age Leads to Increased Incidence of Cystic Oviduct Formation Associated with False Layer Syndrome

Infectious bronchitis virus (IBV) is an avian coronavirus that causes respiratory disease but can affect the reproductive tract of laying-type chickens. If infection occurs in pullets, false layer syndrome, which is characterized by the development of large, fluid-filled cystic oviducts, can occur. Recently, IBV strain DMV/1639 has been detected in parts of Canada and the U.S., where false layer syndrome has occurred, though it is not clear if IBV is the sole cause or if age at infection is an influencing variable. Our study investigates the role and timing of IBV infection on the development of false layer syndrome, using the IBV types DMV/1639 and Massachusetts (Mass). Six groups of 120 SPF chickens were challenged at either three, seven, or fourteen days of age, using either DMV/1639 or Mass IBV. Cystic oviducts were seen in all the challenged groups, and the pullets challenged at 14 days of age had fewer cystic oviducts than pullets challenged at 3 or 7 days of age. The highest percentage of severe histology lesion scores were seen in the 3-day challenge groups. The data collected in this experiment confirm that IBV DMV/1639 causes cystic oviducts and indicate that age at infection plays a role in the pathogenesis of false layer syndrome.     

Efficacy of routine follow-up in patients with recurrent uterine cancer

OBJECTIVE: To evaluate the efficacy of routine follow-up in patients with recurrent uterine cancer. METHODS: In a single institution study, a total of 2637 patients were treated curatively for uterine cancer from 1990 to 2006. A total of 438 patients experienced disease recurrence. Data for detailed analysis were available from 280 of the 438 patients. Prior to the diagnosis of recurrence, all patients had regular follow-up and were investigated through internal examination, vaginal vault cytology and imaging. Overall survival (OS) was the main study endpoint and was calculated from recurrence diagnosis to death or date censored. RESULTS: Clinical and histopathological features as well as patterns of recurrence were similar in symptomatic and asymptomatic patients. Eighty-one patients (28.9%) were diagnosed with asymptomatic recurrence while 199 patients (71.1%) presented with symptomatic recurrence. The overall survival probability at 5 years was 41.0% and 28.9% respectively for asymptomatic and symptomatic patients (log-rank p=0.013). Those patients with stage 1 or 2 tumors of endometrioid type were found to have an overall survival probability at 5 years of 38.0% and 25.7% respectively for asymptomatic and symptomatic recurrence (log-rank p=0.05). The absence of symptoms did not impact on the outcome of patients with stage 3 tumors or tumors of non-endometrioid type. CONCLUSIONS: While patients at low/intermediate risk of recurrence may benefit from intensive follow-up including internal examinations, routine vaginal vault cytology and imaging, high-risk patients might gain more from an alternate follow-up strategy with emphasis on imaging in conjunction with symptom education.     

Neonatal and 5-year outcomes after birth at 30-34 weeks of gestation

OBJECTIVE: To evaluate the rates of in-hospital death, neonatal complications, and 5-year outcomes of infants born at 30-34 weeks of gestation. METHODS: In nine regions of France, all 2,020 stillbirths and live births at 30, 31, and 32 weeks in 1997 and all 457 births at 33 and 34 weeks in April and October 1997 were recorded. Survivors were evaluated at 5 years of age. RESULTS: Increasing gestational age from 30 to 34 weeks was associated with progressive decreases in in-hospital mortality (from 8.1% to 0.4%) and neonatal complications (respiratory distress syndrome, 43.8% to 2.6%; maternofetal infections, 7.2% to 2.6%; and severe white matter injury, 5.5% to 1.3%). Although infants at 33 and 34 weeks of gestation rarely experienced necrotizing enterocolitis, bronchopulmonary dysplasia, or nosocomial infections, they still required endotracheal ventilation, antibiotics, or parenteral nutrition. At 5 years of age, older gestational age was associated with significant decreases in rates of cerebral palsy (6.3% at 30 weeks and 0.7% at 34 weeks) and mild to severe cognitive impairments (35.3% at 30 weeks and 23.9% at 34 weeks). In singletons, preterm rupture of membranes or preterm labor carried an increased risk of cerebral palsy but not of cognitive impairment. CONCLUSION: Neonates born at 30-34 weeks experienced substantial morbidity and often required admission to neonatal intensive care units. These outcomes suggest that prolonging pregnancies beyond 34 weeks may be desirable whenever possible. Infants born at 30-34 weeks should be carefully monitored to ensure prompt detection and management of neurodevelopmental impairment.     

How important is consent in maternal serum screening for Down syndrome in France? Information and consent evaluation in maternal serum screening for Down syndrome: a French study

OBJECTIVES: To evaluate the level of information and informed consent for maternal serum screening (MSS) for Down syndrome (DS) in the second trimester of pregnancy and analyse the exercise of autonomy towards the test by the women concerned. METHODS: We studied the population of pregnant women attending obstetric consultations in two French hospitals over a 3-month period. The women were assigned to three groups according to MSS results for DS: women at high risk of having a child with DS (group 1), women at low risk (group 2) and women who did not undergo the test (group 3). A questionnaire was completed before the medical consultation, to assess the quality of consent before amniocentesis for the group at high risk and before the second-trimester ultrasound scan for the other two groups. RESULTS: We analysed 305 questionnaires for 89, 137 and 79 women belonging to groups 1, 2 and 3 respectively. In total, 123 women (40.3% [IC 95%, 35-46%]) were considered to be well informed; 33 (10%, [IC 95%, 8-12%]) had a high level of knowledge, but made choices not consistent with their stated attitude, and 149 (49.7% [IC 95%, 45-56%]) were considered uninformed. Logistic regression analysis showed that maternal consent depended on three independent components: The score attributed to the doctor for information about MSS (t = 4.216, p < 0.001).Whether the patient belonged to group 1 (t = -2.631, p < 0.009).Educational level (< high-school diploma, high-school diploma or at least two years of higher education after high school) (t = 2.324, p < 0.02). The rate of consent increased with educational level and was highest for the women in group 1 and for those whose doctor had a high information score. CONCLUSIONS: Our findings clearly show that women are provided with insufficient information concerning MSS screening for DS in the second trimester of pregnancy for real and valid consent to be obtained.     

Out-Of-Pocket Expenditure Associated with Physical Inactivity,Excessive Weight,and Obesity in China: Quantile Regression Approach

IntroductionPrevious studies exploring associations of physical inactivity, obesity, and out-of-pocket expenditure (OOPE) mainly used traditional linear regression, and little is known about the effect of both physical inactivity and obesity on OOPE across the percentile distribution. This study aims to assess the effects of physical inactivity and obesity on OOPE in China using a quantile regression approach.MethodsStudy participants included 10,687 respondents aged 45 years and older from the recent wave of the China Health and Retirement Longitudinal Study in 2015. Linear regression and quantile regression models were used to examine the association of physical activity, body weight with annual OOPE.ResultsOverall, the proportion of overweight and obesity was 33.2% and 5.8%, respectively. The proportion of individuals performing high-level, moderate-level, and low-level physical activity was 55.2%, 12.7%, and 32.1%, respectively. The effects of low-level physical activity on annual OOPE were small at the bottom quantiles but more pronounced at higher quantiles. Respondents with low-level activity had an increased annual OOPE of 26.9 USD, 150.3 USD, and 1,534.4 USD, at the 10th, 50th, and 90th percentiles, respectively, compared with those with high-level activity. The effects of overweight and obesity on OOPE were also small at the bottom quantiles but more pronounced at higher quantiles.ConclusionInterventions that improve the lifestyles and unhealthy behaviors among people with obesity and physical inactivity are likely to yield substantial financial gains for the individual and health systems in China.     

Experiences of parents whose children participated in a longitudinal follow‐up study

BackgroundLong‐term follow‐up is necessary to understand the impact of perinatal interventions. Exploring parents'' motives and experiences in consenting to their children taking part in longitudinal studies and understanding what outcomes are important to families may enhance participation and mitigate the loss to follow‐up. As existing evidence is largely based on investigators'' perspectives using Western samples, the present pilot study explored parents'' perspectives in a multicultural New Zealand context.MethodsData were generated using semi‐structured interviews with parents whose children had participated in a longitudinal study after neonatal recruitment. Parents'' experiences of being part of the study were analysed thematically using an inductive approach.ResultsParents (n = 16) were generally happy with the outcomes measured. Additionally, parents were interested in lifelong goals such as the impact of parental diabetes. We identified three themes: (1) Facilitators: Research participation was aided by motives and parent and research characteristics such as wishing to help others and straightforward recruitment; (2) Barriers: A hesitancy to participate was due to technical and clinical research aspects, participation burden and cultural barriers, such as complex wording, time commitment and nonindigenous research and (3) Benefits: Children and parents experienced advantages such as the opportunity for education.ConclusionsParents reported positive experiences and described the unexpected benefit of increasing families'' health knowledge through participation. Improvements for current follow‐up studies were identified. Different ethnicities reported different experiences and perspectives, which warrants ongoing research, particularly with indigenous research participants.Patient or Public ContributionNo active partnership with parents of patients took place.     

A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.     

Hemagglutinin Subtype Specificity and Mechanisms of Highly Pathogenic Avian Influenza Virus Genesis

Highly Pathogenic Avian Influenza Viruses (HPAIVs) arise from low pathogenic precursors following spillover from wild waterfowl into poultry populations. The main virulence determinant of HPAIVs is the presence of a multi-basic cleavage site (MBCS) in the hemagglutinin (HA) glycoprotein. The MBCS allows for HA cleavage and, consequently, activation by ubiquitous proteases, which results in systemic dissemination in terrestrial poultry. Since 1959, 51 independent MBCS acquisition events have been documented, virtually all in HA from the H5 and H7 subtypes. In the present article, data from natural LPAIV to HPAIV conversions and experimental in vitro and in vivo studies were reviewed in order to compile recent advances in understanding HA cleavage efficiency, protease usage, and MBCS acquisition mechanisms. Finally, recent hypotheses that might explain the unique predisposition of the H5 and H7 HA sequences to obtain an MBCS in nature are discussed.