Knowledge and behavioural interventions to reduce human health risk from private groundwater systems: A global review and pooled analysis based on development status

Groundwater contamination constitutes a significant health risk for private well users residing in rural areas. As the responsibility to safeguard rural private domestic groundwater typically rests with non-expert homeowners, interventions promoting risk mitigation and awareness represent the most viable means of preventing supply contamination. However, no global review or pooled analyses of these interventions has been undertaken to date. The current study sought to identify and quantify the performance of private well interventions from 1990 to 2018 via a global systematised review and pooled analysis. The PICO (Population-Intervention-Comparison-Outcome) approach was employed for literature identification. Relevant studies were statistically analysed across two quantitative outcome (performance) types, namely knowledge and behaviour, controlling for intervention characteristics and country development status. Mean behavioural and knowledge attainment across interventions was 53% and 48%, respectively, with interventions in economically developed regions exhibiting higher behavioural outcomes (56% vs. 45%) than those in developing regions. Geographically, interventions were located in southern or southeast Asia (n = 23), North America (n = 15), Central America (n = 1) and Africa (n = 1), with none identified in Australia/Oceania, Europe, or South America. Behavioural outcomes were significantly associated with presence of educational/research coordinator (p = 0.023), with these interventions attaining higher levels of efficacy (+74%) than those implemented by other coordinator types. Findings indicate that instructor-led, practical interventions allied with both large- and local-scale awareness-raising campaigns represent an optimum approach for future private well risk interventions. Subsequent adoption of such interventions may lead to increased levels of private well maintenance and provide a point of reference for myriad water and health communication contexts

Psychological Impairment and Extreme Weather Event (EWE) Exposure, 1980–2020: A Global Pooled Analysis Integrating Mental Health and Well-being Metrics

Extreme Weather Events (EWEs) impose a substantial health and socio-economic burden on exposed populations. Projected impacts on public health, based on increasing EWE frequencies since the 1950s, alongside evidence of human-mediated climatic change represents a growing concern. To date, the impacts of EWEs on mental health remain ambiguous, largely due to the inherent complexities in linking extreme weather phenomena with psychological status. This exploratory investigation provides a new empirical and global perspective on the psychological toll of EWEs by exclusively focusing on psychological morbidity among individuals exposed to such events. Morbidity data collated from a range of existing psychological and well-being measures have been integrated to develop a single (“holistic”) metric, namely, psychological impairment. Morbidity, and impairment, were subsequently pooled for key disorders-, specifically PTSD, anxiety and depression. A “composite” (any impairment) post-exposure pooled-prevalence rate of 23% was estimated, with values of 24% calculated for depression and ⁓17% for both PTSD and anxiety. Notably, calculated pooled odds ratios (pOR = 1.9) indicate a high likelihood of any negative psychological outcome (+90%) following EWE exposure. Pooled analyses of reported risk factors (p \u3c 0.05) highlight the pronounced impacts of EWEs among individuals with higher levels of event exposure or experienced stressors (14.5%) and socio-demographic traits traditionally linked to vulnerable sub-populations, including female gender (10%), previous history (i.e., pre-event) of psychological impairment (5.5%), lower socio-economic status (5.5%), and a lower education level (5.2%). Inherent limitations associated with collating mental health data from populations exposed to EWEs, and key knowledge gaps in the field are highlighted. Study findings provide a robust evidence base for developing and implementing public health intervention strategies aimed at ameliorating the psychological impacts of extreme weather among exposed populations

NCI-MATCH Arms N & P: Phase II study of PI3K beta inhibitor GSK2636771 in patients (pts) with cancers (ca) with PTEN mutation/deletion (mut/del) or PTEN protein loss

Background: The NCI-MATCH trial is the largest national study (1173 sites) for ptswith relapsed/ refractory solid tumors, lymphomas and myeloma, which assigns tar-geted therapies based on individual tumor molecular alterations detected using theadapted Oncomine AmpliSeq panel (143 genes) and immunohistochemistry (IHC).We hypothesized that patients with PTEN-deficient cancers enrolled to Arms N and Pmay benefit from treatment with the PI3K beta-selective inhibitor GSK2636771. Methods: Eligibility: relapsed/refractory ca, good end-organ function, and ECOG PS ≤ 1. Pts were screened for molecular alterations by centralized testing on fresh tumor biopsy and had deleterious PTEN mut/del without loss of expression (Arm N) or complete loss of cytoplasmic and nuclear PTEN staining on IHC (Arm P), and no other aberrations activating the PI3K/MTOR and MAPK pathways (mut in PIK3CA, PIK3R1, BRAF, KRAS, AKT1, TSC1/2, mTOR, RHEB, NF2, NRAS, HRAS). Pts received GSK2636771 400mg/day (28-days cycles). RECIST 1.1 overall response rate (ORR) was the primary endpoint. Results: Of 59 enrolled pts, 56 were eligible and received treatment. Of 22 pts with PTEN mut/del (Arm N: 6 uterine, 2 breast, 2 prostate, 2 head/neck ca, 10 other), all are off treatment as of analysis (14 disease progression, 4 for adverse events [AEs], 4 other). One pt (4.5%) with prostate ca (PTEN deletion, MPRSS2-ERG fusion) attained a partial response (-42%). Of 7 (32%) pts with stable disease (SD), 2 had SD \u3e 6 months (uterine leiomyosarcoma; endometrial carcinoma). Of 34 pts with loss of PTEN protein by IHC (Arm P: 7 prostate, 6 breast, 3 squamous anal ca, 2 cholangiocarcinoma, 16 other), all are off treatment as of analysis (26 disease progression, 4 for AE, 4 other). Of 9 (37.5%) pts with SD, 3 had SD \u3e 6 months (prostate cancer; squamous bladder cancer, squamous anal cancer). Median progression-free survival was 1.8 months for both arms. Gr ≥ 3 treatment-related (tr) reversible toxicities were experienced by 30% (7) and 20% (7) of pts in arms N and P, respectively. No tr Gr 5 toxicities were observed in either arm. Conclusions: Single agent GSK2636771 has very modest activity in ca with PTEN gene mutation/deletion and/or PTEN protein loss

Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting

Phase II Study of Palbociclib (PD-0332991) in CCND1, 2, or 3 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1B

Purpose: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3. Patients and methods: Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles. Results: Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%). Conclusions: Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification

Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH).

PURPOSE: Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols. PATIENTS AND METHODS: Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared. RESULTS: Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, \u3e 35% for urothelial cancers and \u3c 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so. CONCLUSION: We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens

Validation Of 13 Hot And Potentially Terrestrial TESS Planets

The James Webb Space Telescope will be able to probe the atmospheres and surface properties of hot, terrestrial planets via emission spectroscopy. We identify 18 potentially terrestrial planet candidates detected by the Transiting Exoplanet Survey Satellite (TESS) that would make ideal targets for these observations. These planet candidates cover a broad range of planet radii (Rp ∼ 0.6–2.0R⊕) and orbit stars of various magnitudes (Ks = 5.78–10.78, V = 8.4–15.69) and effective temperatures (Teff ∼ 3000–6000 K). We use ground-based observations collected through the TESS Follow-up Observing Program (TFOP) and two vetting tools—DAVE and TRICERATOPS—to assess the reliabilities of these candidates as planets. We validate 13 planets: TOI-206 b, TOI-500 b, TOI-544 b, TOI-833 b, TOI-1075 b, TOI-1411 b, TOI-1442 b, TOI-1693 b, TOI-1860 b, TOI-2260 b, TOI-2411 b, TOI-2427 b, and TOI-2445 b. Seven of these planets (TOI-206 b, TOI-500 b, TOI-1075 b, TOI-1442 b, TOI-2260 b, TOI-2411 b, and TOI-2445 b) are ultra-short-period planets. TOI-1860 is the youngest (133 ± 26 Myr) solar twin with a known planet to date. TOI-2260 is a young (321 ± 96 Myr) G dwarf that is among the most metal-rich ([Fe/H] = 0.22 ± 0.06 dex) stars to host an ultra-short-period planet. With an estimated equilibrium temperature of ∼2600 K, TOI-2260 b is also the fourth hottest known planet with Rp \u3c 2 R⊕

Lower coronary plaque burden in patients with HIV presenting with acute coronary syndrome

Objective: Treated HIV infection is associated with a higher incidence of coronary artery disease and myocardial infarction, although the mechanisms remain unclear. We sought to characterise the burden of coronary artery disease in men with HIV using retrospective data from invasive coronary angiograms in patients presenting with acute coronary syndrome (ACS). Methods: Demographic and coronary angiographic data were obtained from 160 men with ST elevation myocardial infarction, non-STEMI or high-risk chest pain; 73 HIV-infected cases and 87 age-matched controls. The burden of coronary disease was calculated using the Gensini Angiographic Scoring System by 2 independent cardiologists blinded to HIV status. Results:The 2 groups were matched for age, sex and cardiac event subtype and there was no difference in rates of smoking or cholesterol levels. Compared with control participants, patients with HIV had higher usage of antihypertensives (46 (63%) vs 30 (35%), p Conclusions Men with HIV presenting with ACS paradoxically had a lower burden of coronary plaque than matched controls, despite more aggressive risk factor management, suggesting that plaque vulnerability, rather than total burden of atherosclerosis, may be important in the pathophysiology of coronary artery disease in men with HIV