Search

Objective: To determine the influence of self-reported preadmission quality of life, hypothetical quality of life and mortality prognosis, and length and intensity of intensive care on decision making in the seriously ill and elderly.Design: Prospective cohort study.Setting: Medical university.Subjects: Adult inpatients with chronic illness and an estimated 50% 6-month mortality along with patients > or =80 yrs old with an acute illness.Interventions: Patients were presented with two scenarios: a) mechanical ventilation for 14 days; and 2) mechanical ventilation for 1 month with tracheostomy and feeding tube placement. A modified time trade-off was used to vary survival and quality of life over plausible ranges. Patients could consent to intensive care or choose care directed at comfort measures.Measurements and Main Results: Fifty patients were interviewed. As projected intensive care unit mortality rate or postintensive care unit quality of life decreased, patients were less likely to consent to intensive care. Postintensive care quality of life was as important to patients as intensive care survival estimates. However, prehospitalization quality of life did not significantly influence decision making regarding life-extending treatment. When progressing from the acute intensive care scenario to chronic mechanical ventilation with associated interventions, patients demanded a significant increase in survival and quality of life. Neither race nor previous intensive care unit admission was associated with consent to intensive care.Conclusions: There is wide variation in preference for aggressive care that does not appear to be influenced by prehospitalization quality of life. However, predicted quality of life appears to be as important as estimates of intensive care unit survival in decision making. When confronted with extended mechanical ventilation and associated care, a significant proportion of patients would accept this care only for an improved prognosis. Length and intensity of intensive care should be incorporated into discussions regarding intensive care. [ABSTRACT FROM AUTHOR]

Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomic locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities-H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DΔC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1, and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion, and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity., Significance: Histone-mutant pediatric gliomas are a highly heterogeneous tumor entity. Different histone mutations correlate with different ages of onset, survival outcomes, brain regions, and partner alterations. We have developed models of histone-mutant gliomas that reflect this anatomic and genetic heterogeneity and provide evidence of subtype-specific biology and therapeutic targeting. See related commentary by Lubanszky and Hawkins, p. 1516. This article is highlighted in the In This Issue feature, p. 1501., (©2023 The Authors; Published by the American Association for Cancer Research.)

The actual interaction between signaling species in cellular processes is often more important than their expression levels. Förster resonance energy transfer (FRET) is a popular tool for studying molecular interactions, since it is highly sensitive to proximity in the range of 2-10 nm. Spectral spillover-corrected quantitative (3-cube) FRET is a cost effective and versatile approach, which can be applied in flow cytometry and various modalities of fluorescence microscopy, but may be hampered by varying levels of autofluorescence. Here, we have implemented pixel-by-pixel autofluorescence correction in microscopy FRET measurements, exploiting cell-free calibration standards void of autofluorescence that allow the correct determination of all spectral spillover factors. We also present an ImageJ/Fiji plugin for interactive analysis of single images as well as automatic creation of quantitative FRET efficiency maps from large image sets. For validation, we used bead and cell based FRET models covering a range of signal to autofluorescence ratios and FRET efficiencies and compared the approach with conventional average autofluorescence/background correction. Pixel-by-pixel autofluorescence correction proved to be superior in the accuracy of results, particularly for samples with spatially varying autofluorescence and low fluorescence to autofluorescence ratios, the latter often being the case for physiological expression levels., (© 2023. The Author(s).)

DNA alkylation damage is repaired by base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG). Despite its role in DNA repair, AAG-initiated BER promotes cytotoxicity in a process dependent on poly (ADP-ribose) polymerase-1 (PARP-1); a NAD + -consuming enzyme activated by strand break intermediates of the AAG-initiated repair process. Importantly, PARP-1 activation has been previously linked to impaired glycolysis and mitochondrial dysfunction. However, whether alkylation affects cellular metabolism in the absence of AAG-mediated BER initiation is unclear. To address this question, we temporally profiled repair and metabolism in wild-type and Aag -/- cells treated with the alkylating agent methyl methanesulfonate (MMS). We show that, although Aag -/- cells display similar levels of alkylation-induced DNA breaks as wild type, PARP-1 activation is undetectable in AAG-deficient cells. Accordingly, Aag -/- cells are protected from MMS-induced NAD + depletion and glycolysis inhibition. MMS-induced mitochondrial dysfunction, however, is AAG-independent. Furthermore, treatment with FK866, a selective inhibitor of the NAD + salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT), synergizes with MMS to induce cytotoxicity and Aag -/- cells are resistant to this combination FK866 and MMS treatment. Thus, AAG plays an important role in the metabolic response to alkylation that could be exploited in the treatment of conditions associated with NAD + dysregulation.

The provision of toilets and menstrual supplies has emerged as a promising programmatic strategy to support adolescent girls' school attendance and performance in less developed countries. We use the first round of the Malawi Schooling and Adolescent Survey (MSAS) to examine the individual- and school-level factors associated with menstruation-related school absenteeism. The MSAS is a school-based longitudinal survey of adolescent students enrolled in coed public primary schools in the southern districts of Machinga and Balaka who were aged 14-16 in 2007. Although one-third of female students report missing at least one day of school at their last menstrual period, our data suggest that menstruation only accounts for a small proportion of all female absenteeism and does not create a gender gap in absenteeism. We find no evidence for school-level variance in menstruation-related absenteeism, suggesting that absenteeism is not sensitive to school environments. Rather, co-residence with a grandmother and spending time on school work at home reduce the odds of absence during the last menstrual period.

With the spread of formal schooling in sub-Saharan Africa and delays in the age at marriage, a growing proportion of adolescents remain enrolled in school when they "come of age." As a consequence, more and more adolescents have to negotiate sexual maturation and sexual initiation in a vastly different context from that of prior generations. Using data from the 2004 National Survey of Adolescents conducted in Burkina Faso, Ghana, Malawi, and Uganda, we investigate the empirical association between premarital sex and leaving school among those who were enrolled in school at the outset of adolescence (age 12). Discrete-time logistic regression models show that, in general, girls are more likely than boys to leave school before completing secondary school, before completing primary school, and, among those completing primary school, before progressing to secondary school. Girls who complete primary school, however, do so at the same age as or a younger age than their male peers. Girls appear more vulnerable to leaving school once they engage in premarital sex. These findings can assist researchers, policymakers, program managers, and educators in understanding and addressing the challenges to educational attainment posed by the increasing proportion of school-aged adolescents engaging in premarital sex.

Leaving school prematurely is often claimed to be among the most negative consequences of early marriage and pregnancy for girls in less developed countries. However, an analysis of the relative frequency with which these events actually occur or are named as reasons for leaving school reveals that, at least in the case of francophone Africa, they explain no more than 20 per cent of dropouts. To the extent that demographic events trump school or family factors as determinants of school-leaving, our data indicate that it is union formation--defined by the DHS as first marriage or cohabitation--rather than childbirth that is more likely to have this effect. 'Schoolgirl pregnancy' typically accounts for only between 5 and 10 per cent of girls' departures from school. Furthermore, the risks of leaving school because of pregnancy or marriage have declined over time with the decline in rates of early marriage and childbearing.

Using data from nearly 600 adolescents aged 12-19 in combination with data collected from 33 primary schools that the adolescents attended, this report explores whether certain aspects of the school environment affect the initiation of premarital sex among girls and boys in three districts of Kenya. The results suggest that, although neither the school nor the home appears to influence whether boys engage in sex prior to marriage, for girls, a school characterized by a gender-neutral atmosphere appears to reduce the risk of their engaging in premarital sex. Furthermore, although policymakers in Kenya are clearly concerned with the problem of "schoolgirl pregnancy," the data indicate that in this sample, pregnancy is not the primary reason that girls leave school.

Although a growing proportion of young people is spending some time in school between puberty and marriage, little research on education in developing countries has been focused on adolescent issues. This article examines the school environment in Kenya and the ways it can help or hinder adolescents. Gender differences are considered with a view toward illuminating some factors that may present particular obstacles or opportunities for girls. Using both qualitative and quantitative data, 36 primary schools in rural areas in three districts of Kenya are studied. These schools are chosen to reflect the spectrum of school quality in the country. The focus in this study is on primary schools because the majority of adolescents in school attend primary school. In these schools, where considerable variation in performance and parental educational status is found, disorganization coexists with strict punishment, minimal comforts are lacking, learning materials are scare, learning is by rote, and sex education is not provided. In the primary-school-leaving exam, girls' performance is poorer than that of boys. Teachers' attitudes and behavior reveal lower expectations for adolescent girls, traditional assumptions about gender roles, and a double standard about sexual activity.

A consistent negative association between women's paid work and fertility in developed countries has emerged from many years of research. Results from research in developing countries are more ambiguous, with as many examples of a positive association as of a negative one. Lack of data comparability has often hampered interpretation of results. The World Fertility Surveys (WFS)--undertaken in 40 developing countries between 1974-81, using a common core questionnaire that included numerous questions on women's work--have created a unique opportunity to evaluate this association in a comparative framework. This article reviews and interprets the major findings on the work-fertility relationship from this and other published research on women's work and fertility, and assesses the data limitations. The article concludes with recommendations for the treatment of women's work in the design of future fertility and family planning surveys.

The relationship between improvements in child survival, family planning, and fertility is viewed here as the outcome of a process of family building that evolves through distinct phases as the mortality transition progresses. The speed with which family building strategies evolve from "family building by fate" to "family building by design" and from "insurance" to "replacement" as child survival improves depends on the pattern (by age and causes of death) of mortality decline and the sociocultural context. While child survival improvements will not lead to compensatory declines in fertility when fate or replacement behavior govern family building, more than compensatory fertility declines can result when families shift to family building by design, which, in its initial phases, is manifested by so-called insurance behavior. A literature review supports these hypotheses and identifies family planning availability as a critical additional factor. These results provide strong support for an integrated approach to the delivery of health and family planning services.