Management of imatinib-resistant CML patients

Imatinib has had marked impact on outcomes in chronic myelogenous leukemia (CML) patients for all stages of the disease and is endorsed by international treatment guidelines as the first line option. Although imatinib is highly effective and well tolerated, the development of resistance represents a clinical challenge. Since the most frequently identified mechanism of acquired imatinib resistance is bcr-abl kinase domain point mutations, periodic hematologic, cytogenetic, and molecular monitoring is critical throughout imatinib therapy. Once cytogenetic remission is achieved, residual disease can be monitored by bcr-abl transcript levels as assayed by reverse transcription polymerase chain reaction (RT-PCR). Detection of bcr-abl mutants prior to and during imatinib therapy can aid in risk stratification as well as in determining therapeutic strategies. Thus, mutation screening is indicated in patients lacking or losing hematologic response. Moreover, search for mutations should also be performed when a 3-log reduction of bcr-abl transcripts is not achieved or there is a reproducible increase of transcript levels. In patients harboring mutations which confer imatinib resistance, novel second line tyrosine kinase inhibitors have demonstrated encouraging efficacy with low toxicity. Only the T315I bcr-abl mutant has proved totally resistant to all clinically available bcr-abl inhibitors. Strategies to further increase the rates of complete molecular remissions represent the next frontier in the targeted therapy of CML patients

The knowns and unknowns of SSRI treatment in young people with depression and anxiety: efficacy, predictors, and mechanisms of action

The use of SSRIs for the treatment of depression and anxiety in young people is increasing. However, the effects of SSRIs in adolescence, a time when there are substantial changes in neural, cognitive, and social functioning, are not well understood. Here, we review evidence from clinical trials about the benefits and risks of SSRIs in young people and consider their mechanisms of action, as shown through human experimental work and animal models. We emphasise key outstanding questions about the effects of SSRIs in youth, identified through gaps in the literature and in consultation with young people with lived experience. It is crucial to characterise the mechanisms underpinning risks and benefits of SSRIs in this age group to progress the field, and to narrow the chasm between the widespread use of SSRIs in youth and the science on which this use is based

Do social networks affect the use of residential aged care among older Australians?

Background: Older people's social networks with family and friends can affect residential aged care use. It remains unclear if there are differences in the effects of specific (with children, other relatives, friends and confidants) and total social networks upon use of low-level residential care and nursing homes. Methods: Data were drawn from the Australian Longitudinal Study of Ageing. Six waves of data from 1477 people aged ≥ 70 collected over nine years of follow-up were used. Multinomial logistic regressions of the effects of specific and total social networks on residential care use were carried out. Propensity scores were used in the analyses to adjust for differences in participant's health, demographic and lifestyle characteristics with respect to social networks. Results Higher scores for confidant networks were protective against nursing home use (odds ratio [OR] upper versus lower tertile of confidant networks = 0.50; 95%CI 0.33–0.75). Similarly, a significant effect of upper versus lower total network tertile on nursing home use was observed (OR = 0.62; 95%CI 0.43–0.90). Evidence of an effect of children networks on nursing home use was equivocal. Nursing home use was not predicted by other relatives or friends social networks. Use of lower-level residential care was unrelated to social networks of any type. Social networks of any type did not have a significant effect upon low-level residential care use. Discussion: Better confidant and total social networks predict nursing home use in a large cohort of older Australians. Policy needs to reflect the importance of these particular relationships in considering where older people want to live in the later years of life.Lynne C Giles, Gary FV Glonek, Mary A Luszcz and Gary R Andrew

Spin-wave directional anisotropies in antiferromagnetic Ba3NbFe3Si2O14

Ba3NbFe3Si2O14 (langasite) is structurally and magnetically single-domain chiral with the magnetic helicity induced through competing symmetric exchange interactions. Using neutron scattering, we show that the spin waves in antiferromagnetic langasite display directional anisotropy. On applying a time-reversal symmetry breaking magnetic field along the c axis, the spin-wave energies differ when the sign is reversed for either the momentum transfer ±Q or applied magnetic field ±μ0H. When the field is applied within the crystallographic ab plane, the spin-wave dispersion is directionally isotropic and symmetric in ±μ0H. However, a directional anisotropy is observed in the spin-wave intensity. We discuss this directional anisotropy in the dispersion in langasite in terms of a field-induced precession of the dynamic unit cell staggered magnetization resulting from a broken twofold symmetry. Directional anisotropy, often referred to as nonreciprocal responses, can occur in antiferromagnetic phases in the absence of the Dzyaloshinskii-Moriya interaction or other effects resulting from spin-orbit coupling

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Lower age at menarche affects survival in older Australian women: results from the Australian Longitudinal Study of Ageing

Extent: 10p.Background: While menarche indicates the beginning of a woman's reproductive life, relatively little is known about the association between age at menarche and subsequent morbidity and mortality. We aimed to examine the effect of lower age at menarche on all-cause mortality in older Australian women over 15 years of follow-up. Methods: Data were drawn from the Australian Longitudinal Study of Ageing (n = 1,031 women aged 65-103 years). We estimated the hazard ratio (HR) associated with lower age at menarche using Cox proportional hazards models, and adjusted for a broad range of reproductive, demographic, health and lifestyle covariates. Results: During the follow-up period, 673 women (65%) died (average 7.3 years (SD 4.1) of follow-up for decedents). Women with menses onset < 12 years of age (10.7%; n = 106) had an increased hazard of death over the follow-up period (adjusted HR 1.28; 95%CI 0.99-1.65) compared with women who began menstruating aged ≥ 12 years (89.3%; n = 883). However, when age at menarche was considered as a continuous variable, the adjusted HRs associated with the linear and quadratic terms for age at menarche were not statistically significant at a 5% level of significance (linear HR 0.76; 95%CI 0.56 - 1.04; quadratic HR 1.01; 95%CI 1.00-1.02). Conclusion: Women with lower age at menarche may have reduced survival into old age. These results lend support to the known associations between earlier menarche and risk of metabolic disease in early adulthood. Strategies to minimise earlier menarche, such as promoting healthy weights and minimising family dysfunction during childhood, may also have positive longer-term effects on survival in later life.Lynne C Giles, Gary FV Glonek, Vivienne M Moore, Michael J Davies and Mary A Luszc

Longevity and relationships with children: the importance of the parental role

<p>Abstract</p> <p>Background</p> <p>Social networks predict longevity across societies but specific mechanisms are largely unknown. The aim of this work was to examine the role of children in the longevity of elderly men and women in a cohort of community dwelling elderly people in Spain.</p> <p>Methods</p> <p>The data were taken from the "Aging in Leganes" cohort study with 15 years of follow-up. The baseline population was an age- and sex-stratified random sample of community dwelling people over 65 living in Leganés (Madrid) in 1993. Poor relationship with at least one child, emotional support and the perceived roles elders play in the lives of their children, extended family, spouse and friends were assessed at baseline. Cox proportional hazards models were fit to investigate the effects of social roles variables on longevity, adjusting for a wide range of socioeconomic, behavioural and health covariates.</p> <p>Results</p> <p>In the fully adjusted model, having a poor relationship with at least one child increased mortality by 30%. Elderly persons who felt their role in their children's lives was important (HR = 0.70; 95% CI 0.54; 0.91) had a lower mortality risk than those who felt they played a small role. Feeling loved and listened to by one's children did not have an effect on survival. Maintaining an important role in the extended family was also significantly associated with survival.</p> <p>Conclusion</p> <p>In this Mediterranean population, maintaining an important role in the lives of one's children is associated with survival. Functions of social networks related to meaning of life and different forms of social support may have important effects on mortality, and these functions may vary across cultures according to family norms and values.</p

The choice of self-rated health measures matter when predicting mortality: evidence from 10 years follow-up of the Australian longitudinal study of ageing

<p>Abstract</p> <p>Background</p> <p>Self-rated health (SRH) measures with different wording and reference points are often used as equivalent health indicators in public health surveys estimating health outcomes such as healthy life expectancies and mortality for older adults. Whilst the robust relationship between SRH and mortality is well established, it is not known how comparable different SRH items are in their relationship to mortality over time. We used a dynamic evaluation model to investigate the sensitivity of time-varying SRH measures with different reference points to predict mortality in older adults over time.</p> <p>Methods</p> <p>We used seven waves of data from the Australian Longitudinal Study of Ageing (1992 to 2004; N = 1733, 52.6% males). Cox regression analysis was used to evaluate the relationship between three time-varying SRH measures (global, age-comparative and self-comparative reference point) with mortality in older adults (65+ years).</p> <p>Results</p> <p>After accounting for other mortality risk factors, poor global SRH ratings increased mortality risk by 2.83 times compared to excellent ratings. In contrast, the mortality relationship with age-comparative and self-comparative SRH was moderated by age, revealing that these comparative SRH measures did not independently predict mortality for adults over 75 years of age in adjusted models.</p> <p>Conclusions</p> <p>We found that a global measure of SRH not referenced to age or self is the best predictor of mortality, and is the most reliable measure of self-perceived health for longitudinal research and population health estimates of healthy life expectancy in older adults. Findings emphasize that the SRH measures are not equivalent measures of health status.</p