In this randomized trial involving patients undergoing invasive ventilation, pantoprazole decreased the risk of upper gastrointestinal bleeding as compared with placebo but did not affect mortality.
An estimated 13.9% of Americans currently meet criteria for an alcohol (ethanol; EtOH) use disorder (AUD). While there are 4 medications approved by the Food and Drug Administration (FDA) to treat ...AUD, these treatments have demonstrated poor clinical efficacy. Our ongoing research program encompasses a multi-tiered screening of a natural product library and validation process to provide novel information about the mechanisms underlying EtOH-induced changes in neurobiology and to identify novel chemical scaffolds to be exploited in the development of pharmacological treatments for AUD in a rodent organotypic hippocampal slice culture model. Initial screens of several natural product compounds identified 3 compounds which attenuate 48 h EtOH-induced cytotoxicity in vitro. As analogs of natural products can be developed to have enhanced therapeutic potential over parental structures, Study 1 sought to extend on prior findings via the screening of several natural product analogs for their ability to attenuate EtOH-induced cytoxicity. Nine natural produce analogs demonstrated potent cytoprotective effects against EtOH-induced toxicity at 48 h. Several reports suggest EtOH-induced neurotoxicity may be secondary to the induction of persistent neuroimmune activation, and isoflavonoids have been shown to have effects on neuroimmune signaling. Thus, Study 2 compared the effects of compound 9b, an isoflavonoid analog identified in Study 1, to daidzein (DZ), a prototypical isoflavonoid, in the same 48 h model, with the addition of a neuroimmune component. Specifically, culture media was collected to assess for the release of the neuroimmune mediators HMGB1, TNF-α, IL-6, and IL-10 via ELISA. Compound 9b and DZ protected against EtOH-induced cytotoxicity at 48 h. EtOH exposure significantly increased secretion of HMGB1 and IL-6 into culture media at 48h. Compound 9b and DZ attenuated these increases at all concentrations tested. These results suggest potential neuroimmune modulating properties of isoflavonoids which may contribute to their neuroprotective effects against EtOH in vitro. These findings highlight the potential applications DZ and the novel isoflavonoid analog 9b for use in the treatment of AUD.
An estimated 13.9% of Americans currently meet criteria for an alcohol use disorder. Ultimately, chronic alcohol use may result in neurological deficits, with up to 85% of alcoholics exhibiting signs ...of cognitive decline. However, biochemical and behavioral factors contributing to this decline have remained elusive. Our ongoing research program encompasses a multi-tiered screening of a natural product library and validation process to provide novel information about mechanisms underlying these deficits and to identify novel chemical scaffolds to be exploited in the development of pharmacological treatments for alcohol use disorders in a rodent organotypic hippocampal slice culture mode. Experiment 1 sought to establish a 48 h high throughput model for testing novel scaffolds against ethanol (EtOH) toxicity. Experiment 2 tested multiple natural product compounds for their ability to attenuate ethanol-induced cytotoxicity. Results from Experiment 1 revealed EtOH (100 mM) induced significant cytotoxicity at 48 h. Trolox (100 µM), a potent antioxidant, was found to reduce ethanol-induced cytotoxicity in this assay. Experiment 2 revealed two spoxazomicins (1, 1-1) demonstrated potent cytoprotective effects against ethanol toxicity. These findings highlight the potential applications of these novel scaffolds for use in the treatment of alcohol use disorder.
Citizen science can play an important role in school science education. Citizen science is particularly relevant to addressing current societal environmental sustainability challenges, as it engages ...the students directly with environmental science and gives students an understanding of the scientific process. In addition, it allows students to observe local representations of global challenges. Here, we report a citizen science programme designed to engage school‐age children in real‐world scientific research. The programme used standardized methods deployed across multiple schools through scientist–school partnerships to engage students with an important conservation problem: habitat for pollinator insects in urban environments. Citizen science programmes such as the programme presented here can be used to enhance scientific literacy and skills. Provided key challenges to maintain data quality are met, this approach is a powerful way to contribute valuable citizen science data for understudied, but ecologically important study systems, particularly in urban environments across broad geographical areas.
The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker ...risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants.
In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566.
Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold.
Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies.
Takeda and Zinfandel.
Impalpable breast lesions generally require image-guided localisation for breast-conserving surgery. A standard technique is to place a hook wire (HW) within the lesion. Radioguided occult lesion ...localisation using iodine seeds (ROLLIS) involves inserting a 4.5 mm iodine-125 seed (seed) into the lesion. We hypothesised that a seed could be more precisely positioned in relation to the lesion than a HW and that this may be associated with a lower re-excision rate.
Retrospective review of consecutive participant data from three ROLLIS RCT (ACTRN12613000655741) sites. Participants underwent preoperative lesion localisation (PLL) with seed or HW between September 2013 and December 2017. Lesion and procedural characteristics were recorded. Distances between (1) any part of the seed or thickened segment of the HW ('TSHW') and the lesion/clip ('distance to device' DTD) and (2) centre of the TSHW/seed and centre of the lesion/clip (device centre to target centre 'DCTC') were measured on immediate postinsertion mammograms. Pathological margin involvement and re-excision rates were compared.
A total of 390 lesions (190 ROLLIS and 200 HWL) were analysed. Lesion characteristics and guidance modality used were similar between groups. Ultrasound-guided DTD and DCTC for seed were smaller than for HW (77.1% and 60.6%, respectively, P-value < 0.001). Stereotactic-guided DCTC for seeds was 41.6% smaller than for HW (P-value = 0.001). No statistically significant difference in the re-excision rates was found.
Iodine-125 seeds can be more precisely positioned for preoperative lesion localisation than HW, however, no statistically significant difference in re-excision rates was detected.
IMPORTANCE: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. OBJECTIVE: To determine whether vitamin C improves outcomes for patients with COVID-19. DESIGN, SETTING, ...AND PARTICIPANTS: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. INTERVENTIONS: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of organ support–free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from –1 organ support–free days for patients experiencing in-hospital death to 22 organ support–free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support–free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. RESULTS: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years IQR, 50-70 years; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years IQR, 51-72 years; 39.6% were female). Among critically ill patients, the median number of organ support–free days was 7 (IQR, −1 to 17 days) for the vitamin C group vs 10 (IQR, −1 to 17 days) for the control group (adjusted proportional OR, 0.88 95% credible interval {CrI}, 0.73 to 1.06) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support–free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 95% CrI, 0.60 to 1.01) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 95% CrI, 0.73 to 1.17) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 95% CrI, 0.61 to 1.17) and the posterior probability was 17.8% for efficacy. CONCLUSIONS AND RELEVANCE: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support–free days and hospital survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP)
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•Ultra-low fO2 reflects fluxing of basaltic differentiates by mantle-derived CH4.•Fractionation involved progressive reduction + multiple stages of melt immiscibility.•Upper-mantle ...CH4-H2 fluids accompany magmatism in many tectonic settings worldwide.
Oxygen fugacity (ƒO2) controls the speciation of COH fluids in Earth’s mantle; a major question is whether the sublithospheric mantle is metal-saturated, maintaining ƒO2 near the Iron-Wüstite (IW) buffer reaction. If so, then COH fluids from this source will be dominated by CH4 + H2, rather than the more oxidized CO2-H2O fluids commonly considered in petrological studies. A key to this question is found in rare but widespread examples of natural mineral assemblages that require unusually low ƒO2. We summarize an investigation of super-reduced mineral assemblages in corundum xenocrysts from Late Cretaceous alkali-basalt volcanoes on Mt Carmel, northern Israel and related Plio-Pleistocene alluvial deposits. P-T estimates indicate that the corundum xenocrysts crystallized in the uppermost mantle. The well-documented geological controls on the origin of these deposits, and radiometric dating of the super-reduced phases, ensure the “naturalness” of the controversial assemblages and make these mineral parageneses a benchmark for evaluation of related occurrences worldwide.
The tuffs contain a “basalt-megacryst” mineral suite (zircon, sapphire, ilmenite, spinel). The megacryst chemistry and the geochronology of the zircons indicate that the megacrysts crystallized from broadly syenitic melts that differentiated at subcrustal levels (P ca 1 GPa) within a thick gabbroic underplate built up from Permian through Pliocene time and perhaps into the Pleistocene. Reaction of mantle-derived CH4-H2 fluids with these syenitic melts led to the separation of immiscible Fe0 and Fe-Ti oxide melts near fO2 = IW. Trace-element distributions suggest the syenitic melts then separated into immiscible Si-Al-Na-K-rich and FeO-rich oxide melts; the latter were enriched in HFSE, REE, P and Zr as in other natural and synthetic examples of melt-melt immiscibility.
In a model magma chamber the FeO-rich melts would sink, leaving the Si-Al-Na-K melts in an upper zone, both still fluxed by CH4-H2 fluids. At fO2 of ΔIW-6 to -7 the removal of immiscible Fe-Ti-Si-C silicide melts from the FeO-rich melt would leave a desilicated Ca-Al-Si oxide melt that crystallized high-Ti corundum hibonite cumulates with inclusions requiring fO2 from ΔIW + 2 to ΔIW-9, while the less-reduced conjugate silicate melts in the upper levels crystallized low-Ti corundum. Aggregates of skeletal, strongly Ti-zoned corundum crystals. reflect rapid crystallization from very reduced melt-fluid mixtures, probably in fluid-escape channels. Explosive eruptions sampled individual magma chambers at different depths and with different initial compositions, fluid mixtures and fluid dynamics to produce Mt Carmel’s mineralogical diversity.
A review of similar occurrences worldwide suggests that the Mt Carmel assemblages reflect a fundamental process – the rise of CH4-H2 fluids into the upper mantle -- that accompanies mantle-derived magmatism in many tectonic settings. The interaction of these fluids with lithospheric mantle rocks and melts can lead to extreme fractionation via the separation of immiscible Fe-Ti-Si-C melts and residual desilicated melts. The oxidation of CH4-H2 fluids in the lithospheric mantle may be the ultimate source of metasomatic fluids dominated by CO2 + H2O, and of many diamonds. More attention should be paid to the role of methane and other reduced fluids in mantle petrology, and their relevance to metasomatic processes and global carbon cycles.
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Background: Continued smoking after a diagnosis of cancer negatively impacts cancer outcomes but the impact of tobacco on many innovative treatments has not yet been well ...established. Collecting and evaluating tobacco use in cancer clinical trials may advance understanding of the consequences of tobacco use on specific treatment modalities. We performed a systematic scoping review of the frequency of reporting and analysis of tobacco use in clinical trials run by cancer cooperative clinical trial groups. Methods: A comprehensive literature search was conducted to identify cancer cooperative group clinical trials published from January 2017 to October 2019 using Medline, Epub Ahead of Print and In-Process & Other Non-Indexed Citations, Embase, Cochrane Central Register of Controlled Trials using OvidSP. Eligible studies evaluated either systemic and/or radiation therapies, involved at least one cancer cooperative group, included > 100 adult patients and reported on at least one primary or secondary endpoint, which included overall survival (OS), disease/progression-free survival (DFS/PFS), response rates, toxicities/adverse events, or quality of life (QoL). Secondary analyses of previously published trials were excluded. Results: Among 14843 identified studies, 91 studies representing 90 trials met inclusion criteria. 24% were phase II trials, 2% phase II/III and 74% phase III. Trial start dates ranged from 1995-2015 with most (29%) between 2007-2008; median trial sample size was 406 (range: 100-4994); 86% involved systematic therapy, 35% involved radiation; 14% were lung and 5% were head and neck trials. 51% of trials had a curative intent, 33% were palliative and 16% involved hematologic cancers. 74 studies reported on OS, 73 DFS/PFS, and 88 toxicity/QoL. 19 studies reported baseline tobacco use information, while two reported collecting follow-up tobacco use. Of those collecting baseline tobacco use, only 7 reported any analysis of the impact of tobacco on clinical outcomes. There was significant heterogeneity in the reporting of baseline tobacco use: 5 reported never/ever status, 10 reported never/ex-smoker/current smoker status; 4 reported some measure of smoking intensity; none reported on verifying smoking status or second hand smoke exposure. Trials of tobacco related (lung and head and neck) cancers were more likely to report baseline tobacco use compared to non-tobacco related cancers (83% vs 6% p < 0.001). Conclusions: Few cancer cooperative group clinical trials report and analyze trial participants’ baseline tobacco use, and even fewer collect follow up information. Significant heterogeneity exists in reporting tobacco use. Routine standardized collection and reporting of tobacco use, both at baseline and follow up in clinical trials, should be implemented to enable investigators to evaluate the clinical impact of tobacco use on new cancer therapies.
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