Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

A Qualitative Study of Workplace Stress and Coping in Secondary Teachers in Ireland

Teacher stress has received scant attention in Ireland. This study examines teachers’ perceptions of their daily stresses and how they attempt to cope with such situations. Interviews were conducted with fifteen secondary teachers from a variety of school types in eastern Ireland. The teachers showed great concern for their students, with some being prepared to ignore school guidelines in order to deal with their pupils’ needs. Several particularly stressful factors were identified, including the maintenance of boundaries (especially when dealing with students with personal problems), dealing with disruptive student behaviour, and the heavy workload. These stresses closely mirrored those described in international literature. Levels of stress and methods of dealing with stress varied widely among the sample, with primary support coming from their colleagues. One strong finding was the lack of suitable training and preparation felt by the participants, particularly in methods of dealing with sensitive and stressful situations in pupils, and in appropriate means of reaction to student misbehaviour. It is recommended that teacher-training courses include explicit training in dealing with such situations

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD): study protocol for establishing a core outcome set in polycystic kidney disease

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life threatening inherited kidney disease and is responsible for 5-10% of cases of end-stage kidney disease (ESKD). Cystic kidneys may enlarge up to 20 times the weight of a normal kidney due to the growth of renal cysts, and patients with ADPKD have an increased risk of morbidity, premature mortality, and other life-time complications including renal and hepatic cyst and urinary tract infection, intracranial aneurysm, diverticulosis, and kidney pain which impair quality of life. Despite some therapeutic advances and the growing number of clinical trials in ADPKD, the outcomes that are relevant to patients and clinicians, such as symptoms and quality of life, are infrequently and inconsistently reported. This potentially limits the contribution of trials to inform evidence-based decision-making. The Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) project aims to establish a consensus-based set of core outcomes for trials in PKD (with an initial focus on ADPKD but inclusive of all stages) that patients and health professionals identify as critically important. METHODS: The five phases of SONG-PKD are: a systematic review to identify outcomes that have been reported in existing PKD trials; focus groups with nominal group technique with patients and caregivers to identify, rank, and describe reasons for their choices; qualitative stakeholder interviews with health professionals to elicit individual values and perspectives on outcomes for trials involving patients with PKD; an international three-round Delphi survey with all stakeholder groups (including patients, caregivers, healthcare providers, policy makers, researchers, and industry) to gain consensus on critically important core outcome domains; and a consensus workshop to review and establish a set of core outcome domains and measures for trials in PKD. DISCUSSION: The SONG-PKD core outcome set is aimed at improving the consistency and completeness of outcome reporting across ADPKD trials, leading to improvements in the reliability and relevance of trial-based evidence to inform decisions about treatment and ultimately improve the care and outcomes for people with ADPKD

Measuring area-level disadvantage in Australia : Development of a locally sensitive indicator

Background In Australia, the Socio-Economic Indexes for Areas (SEIFA), which includes the Index of Relative Socioeconomic Disadvantage (IRSD), captures the socioeconomic characteristics of areas. Because SEIFA rankings are relative to the country or state, the decile categorisations may not reflect an area’s socioeconomic standing relative to areas nearby. Aims The aim of the research was to explore whether IRSD rankings could be re-ranked to become locally sensitive. Data and methods Using existing SEIFA data to redistribute the membership of current decile IRSD groups, we tested three methods to re-rank all SA1 areas relative to the nearest areas capped at: (1) the nearest 99 neighbours, (2) a population threshold of 50,000 (3) a distance threshold of 10 km. Results The reclassification of SEIFA IRSD deciles was largest (up to 8 decile points of change) when comparing the nearest neighbour and population threshold local methods to current state-based rankings. Moreover, compared to using current national and state SEIFA IRSD rankings, the use of local rankings resulted in more evenly distributed deciles between cities, regional, and remote areas. Conclusions Because SEIFA IRSD rankings are used to allocate resources and health services, we encourage the combined use of a state and local ranking to refine areas considered the most disadvantaged

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular Size in Aging Mice

The decline of circulating testosterone levels in aging men is associated with adverse health effects. During studies of probiotic bacteria and obesity, we discovered that male mice routinely consuming purified lactic acid bacteria originally isolated from human milk had larger testicles and increased serum testosterone levels compared to their age-matched controls. Further investigation using microscopy-assisted histomorphometry of testicular tissue showed that mice consuming Lactobacillus reuteri in their drinking water had significantly increased seminiferous tubule cross-sectional profiles and increased spermatogenesis and Leydig cell numbers per testis when compared with matched diet counterparts This showed that criteria of gonadal aging were reduced after routinely consuming a purified microbe such as L. reuteri. We tested whether these features typical of sustained reproductive fitness may be due to anti-inflammatory properties of L. reuteri, and found that testicular mass and other indicators typical of old age were similarly restored to youthful levels using systemic administration of antibodies blocking pro-inflammatory cytokine interleukin-17A. This indicated that uncontrolled host inflammatory responses contributed to the testicular atrophy phenotype in aged mice. Reduced circulating testosterone levels have been implicated in many adverse effects; dietary L. reuteri or other probiotic supplementation may provide a viable natural approach to prevention of male hypogonadism, absent the controversy and side-effects of traditional therapies, and yield practical options for management of disorders typically associated with normal aging. These novel findings suggest a potential high impact for microbe therapy in public health by imparting hormonal and gonad features of reproductive fitness typical of much younger healthy individuals.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant U01 CA164337)National Institutes of Health (U.S.) (Grant RO1CA108854

National-level and state-level prevalence of overweight and obesity among children, adolescents, and adults in the USA, 1990–2021, and forecasts up to 2050

Background Over the past several decades, the overweight and obesity epidemic in the USA has resulted in a significant health and economic burden. Understanding current trends and future trajectories at both national and state levels is crucial for assessing the success of existing interventions and informing future health policy changes. We estimated the prevalence of overweight and obesity from 1990 to 2021 with forecasts to 2050 for children and adolescents (aged 5–24 years) and adults (aged ≥25 years) at the national level. Additionally, we derived state-specific estimates and projections for older adolescents (aged 15–24 years) and adults for all 50 states and Washington, DC. Methods In this analysis, self-reported and measured anthropometric data were extracted from 134 unique sources, which included all major national surveillance survey data. Adjustments were made to correct for self-reporting bias. For individuals older than 18 years, overweight was defined as having a BMI of 25 kg/m2 to less than 30 kg/m2 and obesity was defined as a BMI of 30 kg/m2 or higher, and for individuals younger than 18 years definitions were based on International Obesity Task Force criteria. Historical trends of overweight and obesity prevalence from 1990 to 2021 were estimated using spatiotemporal Gaussian process regression models. A generalised ensemble modelling approach was then used to derive projected estimates up to 2050, assuming continuation of past trends and patterns. All estimates were calculated by age and sex at the national level, with estimates for older adolescents (aged 15–24 years) and adults aged (≥25 years) also calculated for 50 states and Washington, DC. 95% uncertainty intervals (UIs) were derived from the 2·5th and 97·5th percentiles of the posterior distributions of the respective estimates. Findings In 2021, an estimated 15·1 million (95% UI 13·5–16·8) children and young adolescents (aged 5–14 years), 21·4 million (20·2–22·6) older adolescents (aged 15–24 years), and 172 million (169–174) adults (aged ≥25 years) had overweight or obesity in the USA. Texas had the highest age-standardised prevalence of overweight or obesity for male adolescents (aged 15–24 years), at 52·4% (47·4–57·6), whereas Mississippi had the highest for female adolescents (aged 15–24 years), at 63·0% (57·0–68·5). Among adults, the prevalence of overweight or obesity was highest in North Dakota for males, estimated at 80·6% (78·5–82·6), and in Mississippi for females at 79·9% (77·8–81·8). The prevalence of obesity has outpaced the increase in overweight over time, especially among adolescents. Between 1990 and 2021, the percentage change in the age-standardised prevalence of obesity increased by 158·4% (123·9–197·4) among male adolescents and 185·9% (139·4–237·1) among female adolescents (15–24 years). For adults, the percentage change in prevalence of obesity was 123·6% (112·4–136·4) in males and 99·9% (88·8–111·1) in females. Forecast results suggest that if past trends and patterns continue, an additional 3·33 million children and young adolescents (aged 5–14 years), 3·41 million older adolescents (aged 15–24 years), and 41·4 million adults (aged ≥25 years) will have overweight or obesity by 2050. By 2050, the total number of children and adolescents with overweight and obesity will reach 43·1 million (37·2–47·4) and the total number of adults with overweight and obesity will reach 213 million (202–221). In 2050, in most states, a projected one in three adolescents (aged 15–24 years) and two in three adults (≥25 years) will have obesity. Although southern states, such as Oklahoma, Mississippi, Alabama, Arkansas, West Virginia, and Kentucky, are forecast to continue to have a high prevalence of obesity, the highest percentage changes from 2021 are projected in states such as Utah for adolescents and Colorado for adults. Interpretation Existing policies have failed to address overweight and obesity. Without major reform, the forecasted trends will be devastating at the individual and population level, and the associated disease burden and economic costs will continue to escalate. Stronger governance is needed to support and implement a multifaceted whole-system approach to disrupt the structural drivers of overweight and obesity at both national and local levels. Although clinical innovations should be leveraged to treat and manage existing obesity equitably, population-level prevention remains central to any intervention strategies, particularly for children and adolescents.Bill & Melinda Gates Foundation.publishedVersio

Global, regional, and national prevalence of child and adolescent overweight and obesity, 1990–2021, with forecasts to 2050:A forecasting study for the Global Burden of Disease Study 2021

Background: Despite the well documented consequences of obesity during childhood and adolescence and future risks of excess body mass on non-communicable diseases in adulthood, coordinated global action on excess body mass in early life is still insufficient. Inconsistent measurement and reporting are a barrier to specific targets, resource allocation, and interventions. In this Article we report current estimates of overweight and obesity across childhood and adolescence, progress over time, and forecasts to inform specific actions. Methods: Using established methodology from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021, we modelled overweight and obesity across childhood and adolescence from 1990 to 2021, and then forecasted to 2050. Primary data for our models included 1321 unique measured and self-reported anthropometric data sources from 180 countries and territories from survey microdata, reports, and published literature. These data were used to estimate age-standardised global, regional, and national overweight prevalence and obesity prevalence (separately) for children and young adolescents (aged 5–14 years, typically in school and cared for by child health services) and older adolescents (aged 15–24 years, increasingly out of school and cared for by adult services) by sex for 204 countries and territories from 1990 to 2021. Prevalence estimates from 1990 to 2021 were generated using spatiotemporal Gaussian process regression models, which leveraged temporal and spatial correlation in epidemiological trends to ensure comparability of results across time and geography. Prevalence forecasts from 2022 to 2050 were generated using a generalised ensemble modelling approach assuming continuation of current trends. For every age-sex-location population across time (1990–2050), we estimated obesity (vs overweight) predominance using the log ratio of obesity percentage to overweight percentage. Findings: Between 1990 and 2021, the combined prevalence of overweight and obesity in children and adolescents doubled, and that of obesity alone tripled. By 2021, 93·1 million (95% uncertainty interval 89·6–96·6) individuals aged 5–14 years and 80·6 million (78·2–83·3) aged 15–24 years had obesity. At the super-region level in 2021, the prevalence of overweight and of obesity was highest in north Africa and the Middle East (eg, United Arab Emirates and Kuwait), and the greatest increase from 1990 to 2021 was seen in southeast Asia, east Asia, and Oceania (eg, Taiwan [province of China], Maldives, and China). By 2021, for females in both age groups, many countries in Australasia (eg, Australia) and in high-income North America (eg, Canada) had already transitioned to obesity predominance, as had males and females in a number of countries in north Africa and the Middle East (eg, United Arab Emirates and Qatar) and Oceania (eg, Cook Islands and American Samoa). From 2022 to 2050, global increases in overweight (not obesity) prevalence are forecasted to stabilise, yet the increase in the absolute proportion of the global population with obesity is forecasted to be greater than between 1990 and 2021, with substantial increases forecast between 2022 and 2030, which continue between 2031 and 2050. By 2050, super-region obesity prevalence is forecasted to remain highest in north Africa and the Middle East (eg, United Arab Emirates and Kuwait), and forecasted increases in obesity are still expected to be largest across southeast Asia, east Asia, and Oceania (eg, Timor-Leste and North Korea), but also in south Asia (eg, Nepal and Bangladesh). Compared with those aged 15–24 years, in most super-regions (except Latin America and the Caribbean and the high-income super-region) a greater proportion of those aged 5–14 years are forecasted to have obesity than overweight by 2050. Globally, 15·6% (12·7–17·2) of those aged 5–14 years are forecasted to have obesity by 2050 (186 million [141–221]), compared with 14·2% (11·4–15·7) of those aged 15–24 years (175 million [136–203]). We forecasted that by 2050, there will be more young males (aged 5–14 years) living with obesity (16·5% [13·3–18·3]) than overweight (12·9% [12·2–13·6]); while for females (aged 5–24 years) and older males (aged 15–24 years), overweight will remain more prevalent than obesity. At a regional level, the following populations are forecast to have transitioned to obesity (vs overweight) predominance before 2041–50: children and adolescents (males and females aged 5–24 years) in north Africa and the Middle East and Tropical Latin America; males aged 5–14 years in east Asia, central and southern sub-Saharan Africa, and central Latin America; females aged 5–14 years in Australasia; females aged 15–24 years in Australasia, high-income North America, and southern sub-Saharan Africa; and males aged 15–24 years in high-income North America. Interpretation: Both overweight and obesity increased substantially in every world region between 1990 and 2021, suggesting that current approaches to curbing increases in overweight and obesity have failed a generation of children and adolescents. Beyond 2021, overweight during childhood and adolescence is forecast to stabilise due to further increases in the population who have obesity. Increases in obesity are expected to continue for all populations in all world regions. Because substantial change is forecasted to occur between 2022 and 2030, immediate actions are needed to address this public health crisis. Funding: Bill &amp; Melinda Gates Foundation and Australian National Health and Medical Research Council.</p