An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma.

Grade IV glioma, formerly known as glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor, and its treatment remains challenging in part due to extensive interpatient heterogeneity in disease driving mechanisms and lack of prognostic and predictive biomarkers. Using mechanistic inference of node-edge relationship (MINER), we have analyzed multiomics profiles from 516 patients and constructed an atlas of causal and mechanistic drivers of interpatient heterogeneity in GBM (gbmMINER). The atlas has delineated how 30 driver mutations act in a combinatorial scheme to causally influence a network of regulators (306 transcription factors and 73 miRNAs) of 179 transcriptional "programs", influencing disease progression in patients across 23 disease states. Through extensive testing on independent patient cohorts, we share evidence that a machine learning model trained on activity profiles of programs within gbmMINER significantly augments risk stratification, identifying patients who are super-responders to standard of care and those that would benefit from 2 nd line treatments. In addition to providing mechanistic hypotheses regarding disease prognosis, the activity of programs containing targets of 2 nd line treatments accurately predicted efficacy of 28 drugs in killing glioma stem-like cells from 43 patients. Our findings demonstrate that interpatient heterogeneity manifests from differential activities of transcriptional programs, providing actionable strategies for mechanistically characterizing GBM from a systems perspective and developing better prognostic and predictive biomarkers for personalized medicine.

Complete mitochondrial genome of the Starhead Topminnow Fundulus dispar (Cyprinodontiformes: Fundulidae).

Topminnows of the Teleost genus Fundulus serve as model organisms in ecotoxicology because of their broad physiological tolerance and propensity to breed in captivity. This research has been primarily limited to intraspecific comparisons, due to incomplete understanding of the evolutionary history of the genus, which is necessary for use of phylogenetic comparative methods. Interspecific relationships of topminnows remain unresolved, despite recent advances in mitochondrial and nuclear genome sequencing. Specifically, interrelationships of a group containing the starhead topminnows (Fundulus blairae, F. dispar, F. escambiae, F. lineolatus, and F. nottii) typically yield low node support values. Here, we present the first annotated mitochondrial genome of the Starhead Topminnow (F. dispar) and provide a phylogenetic hypothesis for starhead topminnows within the genus Fundulus. DNA was isolated from a specimen of F. dispar collected in Kentucky, USA. The circular genome is 16,564 bp long and contains 13 protein-coding genes, two ribosomal RNAs (rRNA), 22 transfer RNAs (tRNA), and one control region (D-loop). Our phylogenetic analysis supports a sister relationship between F. dispar and a group containing F. notatus and F. olivaceus. This data helps to resolve the phylogenetic placement of starhead topminnows.

Differences in incidence, staging, and survival of urologic cancers in patients under 65 living in the US-Mexico border region.

Objectives: To describe and compare the incidence, stage at diagnosis, and survival for genitourinary cancers in the border regions and in Hispanic-Americans. Materials and methods: A population-based search was performed using the Surveillance, Epidemiology, and End Results Program 18 database and the Texas Cancer Registry from 2000 to 2017. Cox regression models were performed with adjusted for age, gender, race, cancer type, cancer stage, insurance status, and cause of death were used to compare cancer-specific survival. Results: A total of 63,236 kidney and renal pelvis, 38,398 bladder, 170,640 prostate, 24,313 testicular cancer cases were identified. Cancer-specific survival was found to be improved in Hispanic-Americans in kidney and renal pelvis (hazard ratio [HR], 0.903, 95% confidence interval [CI], 0.856-0.952, p = 0.0001), and bladder cancers (HR, 0.817, 95% CI, 0.743-0.898, p < 0.001), despite a more advanced stage at diagnosis in Hispanics with bladder cancer (p < 0.0074). Testicular cancer has a survival disadvantage for individuals living in the border region (HR, 1.315, 95% CI, 1.124-1.539, p = 0.0006). Conclusions: Disparities exist between Hispanic-Americans and Non-Hispanic White and also between individuals living in the border counties when compared to other regions. This is most significant in individuals with testicular cancer residing in the border region who demonstrate worse overall survival.

Velocity map imaging spectroscopy of C2H- and C2D-: A benchmark study of vibronic coupling interactions.

High-resolution velocity-map imaged photoelectron spectra of the ethynyl anions C2H- and C2D- are measured at photon wavelengths between 355 and 266 nm to investigate the complex interactions between the closely lying X̃2Σ+ and Ã2Π electronic states. An indicative kinetic energy resolution of 0.4%, together with the full angular dependence of the fast electrons, provides a detailed description of the vibronically coupled structure. It is demonstrated that a modest quadratic vibronic coupling model, parameterized by the quasidiabatic ansatz, is sufficient to accurately recreate all the observed vibronic interactions. Simulated spectra are shown to be in excellent agreement with the experimental data, verifying the proposed model and providing a framework that may be used to accurately simulate spectra of larger C2nH monohydride carbon chains. New spectral assignments are supported by experimental electron anisotropy measurements and Dyson orbital calculations.

Main COVID-19 information sources in a culturally and linguistically diverse community in Sydney, Australia: A cross-sectional survey.

OBJECTIVE: Describe COVID-19 information-seeking experiences for culturally and linguistically diverse groups in Sydney, Australia. METHODS: Cross-sectional survey, translated into 11 languages; participants recruited from March 21 to July 9, 2021. Regression models identified factors associated with difficulty finding easy-to-understand COVID-19 information. RESULTS: Across 708 participants (88% born overseas, 31% poor English proficiency), difficulty finding easy-to-understand COVID-19 information was rated 4.13 for English (95%CI: 3.85-4.41) and 4.36 for non-English language materials (95%CI: 4.07-4.66) (1 easy to 10 hard). Participants who were older (p < 0.001), had inadequate health literacy (p < 0.001), or poor English proficiency (p < 0.001) found it harder to find easy-to-understand English-language COVID-19 information. Those who had greater difficulty finding easy-to-understand non-English COVID-19 information were younger (p = 0.004), had poor English proficiency (p < 0.001), were university-educated (p = 0.05), and had spent longer living in Australia (p = 0.001). They were more likely to rely on friends and family for COVID-19 information (p = 0.02). There was significant variation in information-seeking experiences across language groups (p's < 0.001). CONCLUSIONS: Easy-to-understand and accessible COVID-19 information is needed to meet the needs of people in culturally and linguistically diverse communities. PRACTICE IMPLICATIONS: COVID-19 communication efforts must involve working alongside these communities to leverage existing communication channels and tailor messages.

PAH Growth in Flames and Space: Formation of the Phenalenyl Radical.

Polycyclic aromatic hydrocarbons (PAHs) are intermediates in the formation of soot particles and interstellar grains. However, their formation mechanisms in combustion and interstellar environments are not fully understood. The production of tricyclic PAHs and, in particular, the conversion of a PAH containing a five-membered ring to one with a six-membered ring are of interest to explain PAH abundances in combustion processes. In the present work, resonant ionization mass spectrometry in conjunction with isotopic labeling is used to investigate the formation of the phenalenyl radical from acenaphthylene and methane in an electrical discharge. We show that in this environment the CH cycloaddition mechanism converts a five-membered ring to a six-membered ring. This mechanism can occur in tandem with other PAH formation mechanisms such as hydrogen abstraction/acetylene addition (HACA) to produce larger PAHs in flames and the interstellar medium.

Velocity Map Imaging Spectroscopy of the Dipole-Bound State of CH2CN-: Implications for the Diffuse Interstellar Bands.

Weakly bound anionic systems present a new domain for negative ion spectroscopy. Here we report on a multifaceted study of the CH2CN- dipole-bound state, employing high-resolution photoelectron spectroscopy from 130 different wavelengths, velocity-map imaging at threshold, and laser scanning photodetachment experiments. This uncovers a wide variety of different vibrational and rotational autodetaching resonances. By examination of both sides of the problem, absorption from the anion to the dipole-bound state and vibrational/rotational autodetachment to the neutral, a complete model of the dipole-bound chemistry is formed. Precise values for the electron affinity EA = 12468.9(1) cm-1, dipole binding energy DBE = 40.2(3) cm-1, and anion inversion splitting ω5 = 115.9(2) cm-1 are obtained. This model is then employed to study possible astronomical implications, revealing good agreement between the K = 1 ← 0 CH2CN- dipole transition and the λ8040 diffuse interstellar band.

Testicular Cancer Incidence and Mortality in New Mexico.

Objective: To examine incidence and survival of testicular cancer in New Mexico, overall and separately for border and non-border counties. Methods: Incidence and 5-year survival rates for testicular cancer were obtained from the SEER18 database using the SEER*Stat program following established NCI protocols. Incidence data were compared using Student's t-test. Age-adjusted 5-year survival and Kaplan-Meier method were used to estimate survival. Log-rank tests were used to compare survival for New Mexico to the remaining17 geographical areas of the SEER 18 and for the New Mexico border counties to the New Mexico non-border counties. Odds ratios were used to compare testicular stage at diagnosis. Cox proportional hazards regression was performed to account for race/ethnicity, and border status. Results: From 2000-2015, New Mexico had a testicular cancer incidence rate of 6.3 per 100,000 people, significantly higher than SEER18 (P<.001). The 5-year survival rate in New Mexico did not differ significantly from the SEER18 (P=.3). Border Hispanics had a lower survival rate than border non-Hispanic populations (P=.03). From 2000-2018, New Mexico had a significantly higher proportion of distant cancers than the SEER18 (OR: 1.29, 95% CI: 1.08 to 1.53, P=.005). Conclusions: The higher incidence of testicular cancer in New Mexico does not appear to have a clear explanation based on the current understanding of risk factors; however, the increased incidence in New Mexico does not appear to be associated with increased mortality. The higher proportion of advanced testicular cancers in New Mexico may represent a delay in diagnosis. The increased mortality rate seen in Hispanic border populations may be due in part to barriers to care.

Quality of life improvement in older patients with heart failure initiated on ivabradine: Results from the UK multi-centre LIVE:LIFE prospective cohort study.

AIMS: LIVE:LIFE is a multi-centre, open-label, prospective observational cohort study assessing health-related quality of life (HRQoL) in older patients with chronic heart failure (CHF) following initiation of ivabradine. The primary endpoint is change in Minnesota Living with Heart Failure Questionnaire (MLWHFQ) total score after 6months. METHODS AND RESULTS: Consenting patients aged ≥70years with CHF, in whom ivabradine was initiated within its licensed indication, were enrolled. Demographic, clinical and HRQoL (MLWHFQ, SF-12) data were collected at baseline (V1), 2 (V2) and 6months (V3). Over 14months, 240 patients were recruited from 44 UK centres. Ninety-nine (41%) were female and 28% aged ≥80years. Aetiology was ischaemic in 152 (63%) and 59% had been diagnosed with CHF for ≤2yrs. 52% of patients were New York Heart Association (NYHA) Class III and 57% had left ventricular ejection fraction <35%. 57% received beta-blockers. Patients had multiple comorbidities (144 (60%) hypertension, 105 (44%) asthma/COPD, 80 (33%) diabetes) and were prescribed a mean of 9±3 daily medications. Resting heart rate was 83bpm at baseline and fell 13bpm by V3. In patients completing both visits (n=187), comparing V3 to baseline: MLWHFQ total score improved by 9 points (p<0.0001, 95% CI: 7-12); 30% of patients improved ≥1 NYHA class and global assessment improved from patient (59%) and physician (60%) perspectives. 88% of patients completing V3 were still taking ivabradine. CONCLUSIONS: These contemporary prospective UK data demonstrate improvements in HRQoL and functional status with ivabradine therapy in typical older CHF patients. Despite comorbidities and polypharmacy, ivabradine was well tolerated.

Sudden cardiac death in end stage renal disease: unlocking the mystery.

Sudden cardiac death (SCD) is a major cause of concern in end stage renal disease (ESRD), contributing to 70% of cardiovascular mortality and 27% of all-cause mortality in dialysis patients. Yet its mechanisms and pathogenesis remain largely obscure. This review discusses the potential reasons for an exaggerated risk of SCD in ESRD populations taking into account recent studies and registry data and additionally explores the reasons for the reported recent decline in SCD. The types of arrhythmias typical of the hemodialysis population are yet to be fully characterised and in this paper, we introduce an ongoing implantable loop recorder (ILR) based study in hemodialysis patients--CRASH ILR (Cardio Renal Arrhythmia Study in Haemodialysis patients using Implantable Loop Recorders). The findings of this study will hopefully guide the design and implementation of larger ILR based studies before undertaking larger scale interventional therapeutic trials in this high risk population.

The impact of age and chronic kidney disease on secondary prevention post-primary percutaneous coronary intervention.

OBJECTIVE: Historical data suggest elderly patients and those with chronic kidney disease (CKD) receive suboptimal secondary prevention following myocardial infarction (MI). We evaluated the impact of age and CKD on secondary prevention following primary percutaneous coronary intervention (PPCI) in a contemporary unselected cohort. DESIGN: We studied 1169 consecutive patients from five UK centres receiving PPCI for ST elevation MI, with use of evidence-based secondary prevention at discharge assessed by age (<60, 60-75 and >75 years) and estimated glomerular filtration rate (eGFR). Follow-up prescribing practice was assessed in 567 patients. RESULTS: One-fifth of patients receiving PPCI were >75 years. This group received fewer secondary prevention drugs at discharge compared to younger patients (P < 0.01 for ß-blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) and statins). By 6 weeks post-PPCI, there was a small drop-off in evidence-based therapy; ß-blocker and statin use in those >75 years fell from 90% to 86% and 96% to 93%, respectively. CKD (eGFR<60 ml/min/1.73 m(2)) was seen in 17.6%. Declining renal function was associated with age, female sex and lower use of ACE inhibitor/ARB. At discharge 83.5% of patients with eGFR<60 ml/min/1.73 m(2) were receiving ACE inhibitors/ARB, dropping to 77.5% at 6 weeks (compared with 95% and 92%, respectively, in patients with eGFR >60 ml/min/1.73 m(2)). CONCLUSION: The uptake of secondary prevention medication is high following PPCI in the UK, even in the elderly and in those with renal dysfunction. A focus on strategies to improve up-titration and continuation of drugs following discharge is required.

Comparisons of urban and rural heat stress conditions in a hot-humid tropical city.

BACKGROUND: In recent years the developing world, much of which is located in the tropical countries, has seen dramatic growth of its urban population associated with serious degradation of environmental quality. Climate change is producing major impacts including increasing temperatures in these countries that are considered to be most vulnerable to the impact of climate change due to inadequate public health infrastructure and low income status. However, relevant information and data for informed decision making on human health and comfort are lacking in these countries. OBJECTIVE: The aim of this paper is to study and compare heat stress conditions in an urban (city centre) and rural (airport) environments in Akure, a medium-sized tropical city in south-western Nigeria during the dry harmattan season (January-March) of 2009. MATERIALS AND METHODS: We analysed heat stress conditions in terms of the mean hourly values of the thermohygrometric index (THI), defined by simultaneous in situ air temperature and relative humidity measurements at both sites. RESULTS: The urban heat island (UHI) exists in Akure as the city centre is warmer than the rural airport throughout the day. However, the maximum UHI intensity occurs at night between 1900 and 2200 hours local time. Hot conditions were predominant at both sites, comfortable conditions were only experienced in the morning and evenings of January at both sites, but the rural area has more pleasant morning and evenings and less of very hot and torrid conditions. January has the lowest frequency of hot and torrid conditions at both sites, while March and February has the highest at the city centre and the airport, respectively. The higher frequencies of high temperatures in the city centre suggest a significant heat stress and health risk in this hot humid environment of Akure. CONCLUSIONS: More research is needed to achieve better understanding of the seasonal variation of indoor and outdoor heat stress and factors interacting with it in order to improve the health, safety, and productivity of Akure city dwellers.

Is there a Failure to Optimize theRapy in anGina pEcToris (FORGET) study?

BACKGROUND: In the management of chronic stable angina, percutaneous coronary intervention (PCI) provides symptomatic relief of angina rather than improvement of prognosis. Current guidelines recommend optimization of medical therapy prior to elective PCI. It is not clear if these guidelines are adhered to in clinical practice. AIM: The aim of this multi-centre study was to determine the extent to which these treatment guidelines are being implemented in the UK. DESIGN: This was a multi-centre study involving six hospitals in the UK. METHODS: The medical treatment and extent of risk factor modification was recorded for consecutive patients undergoing elective PCI for chronic stable angina at each site. Data collected included anti-anginal drug therapy, lipid levels and blood pressure (BP). Data on heart rate (HR) control were also collected, since this represents a fundamental part of medical anti-anginal therapy. Target HR is <60 b.p.m. for symptomatic angina. RESULTS: A total of 500 patients [74% male; mean age +/- SD (64.4 +/- 10.1 years)] were included. When considering secondary prevention, 85% were receiving a statin and 76% were on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. In terms of medical anti-ischaemic therapy, 78% were receiving beta-blockers [mean equivalent dose of bisoprolol 3.1 mg (range 1.25-20 mg)], 11% a rate limiting calcium antagonist, 35% a nitrate or nicorandil and one patient was receiving ivabradine. The mean total cholesterol (95% confidence interval) was 4.3 mmol/l (4.2-4.4), mean systolic BP of 130 +/- 24 mmHg and mean diastolic BP of 69 +/- 13 mmHg. Serum cholesterol was <5 mmol/l in 77% and <4 mmol/l in 42% of the patients, 62% of the patients had systolic BP < 140 mmHg and 92% had diastolic BP < 90 mmHg. Considering European Society of Cardiology targets, 50% had systolic BP < 130 mmHg and 76% had diastolic BP < 80 mmHg. A large proportion of patients did not achieve target resting HR; 27% of patients had a resting HR of >or=70 b.p.m., 40% had a resting HR between 60 and 69 b.p.m. and 26% had a resting HR between 50 and 59 b.p.m. The resting HR was not related to the dose of beta-blocker. CONCLUSION: A significant proportion of the patients with chronic stable angina undergoing elective PCI did not achieve therapeutic targets for lipid, BP and HR control. Over 50% of patients did not receive adequate HR lowering anti-anginal therapy to achieve recommended target resting HR.