Sediment subduction in Hadean revealed by machine learning.

Due to the scarcity of rock samples, the Hadean Era predating 4 billion years ago (Ga) poses challenges in understanding geological processes like subaerial weathering and plate tectonics that are critical for the evolution of life. The Jack Hills zircon from Western Australia, the primary Hadean samples available, offer valuable insights into magma sources and tectonic genesis through trace element signatures. However, a consensus on these signatures has not been reached. To address this, we developed a machine learning classifier capable of deciphering the geochemical fingerprints of zircon. This allowed us to identify the oldest detrital zircon originating from sedimentary-derived "S-type" granites. Our results indicate the presence of S-type granites as early as 4.24 Ga, persisting throughout the Hadean into the Archean. Examining global detrital zircon across Earth's history reveals consistent supercontinent-like cycles from the present back to the Hadean. These findings suggest that a significant amount of Hadean continental crust was exposed, weathered into sediments, and incorporated into the magma sources of Jack Hills zircon. Only the early operation of both subaerial weathering and plate subduction can account for the prevalence of S-type granites we observe. Additionally, the periodic evolution of S-type granite proportions implies that subduction-driven tectonic cycles were active during the Hadean, at least around 4.2 Ga. The evidence thus points toward an early Earth resembling the modern Earth in terms of active tectonics and habitable surface conditions. This suggests the potential for life to originate in environments like warm ponds rather than extreme hydrothermal settings.

Optimizing the Use of Dose Error Reduction Software on Intravenous Infusion Pumps.

BACKGROUND AND OBJECTIVES: Intravenous infusions have the potential to cause significant harm in patients and are associated with a high rate of adverse drug events and medication errors. Infusion pumps with dose error reduction software (DERS) can be used to reduce errors by establishing safe infusion parameters. In 2019, a quality improvement project was initiated with the aim to increase DERS compliance from 46% to 75% at our specialty institution by October 1, 2022. METHODS: An interdisciplinary group was tasked with improving compliance with DERS by identifying key drivers, including informed staff, engaged staff, and an accurate smart pump library. We used the Model for Improvement framework to guide this improvement project, and Plan-Do-Study-Act (PDSA) cycles were used to plan for interventions. PDSA cycles included drug library updates, education, and unit-level compliance reporting. Weekly average DERS compliance was monitored as the outcome measure, and weekly pump alerts per 100 infusions were monitored as a balancing measure; statistical process control charts were used to monitor measures from 2018 to 2022. RESULTS: Over the course of 25 months, 8 PDSA cycles resulted in 5 centerline improvements from a baseline mean of 46% to a final mean of 78%. Pump alerts per 100 infusions decreased from 15.9 to 6.4 with the first PDSA cycle and then continued to decrease to 3.9 with subsequent interventions. CONCLUSIONS: Although features like DERS can help ensure safe medication administration, continuous improvement efforts to increase DERS compliance without increasing alert burden are needed to ensure that benefits of this technology are optimized.

Enhanced U-Pb detrital zircon, Lu-Hf zircon, δ18O zircon, and Sm-Nd whole rock global databases.

High-quality global isotopic databases provide Earth scientists with robust means for developing and testing a variety of geological hypotheses. Database design establishes the range of questions that can be addressed, and validation techniques can enhance data quality. Here, six validated global isotopic databases provide extensive records of analyses from U-Pb in detrital zircon, Lu-Hf in zircon, Sm-Nd from whole rocks, and δ18O in zircon. The U-Pb detrital zircon records are segregated into three independently sampled databases. Independent samples are critical for testing the replicability of results, a key requisite for gaining confidence in the validity of a hypothesis. An advantage of our updated databases is that a hypothesis developed from one of the global detrital zircon databases can be immediately tested with the other two independent detrital zircon databases to assess the replicability of results. The independent εHf(t) and εNd(t) values provide similar means of testing for replicable results. This contribution discusses database design, data limitations, and validation techniques used to ensure the data are optimal for subsequent geological investigations.

Church Leaders Share and Implement Solution-Focused Health Strategies During the COVID-19 Pandemic in Rural Alabama.

Bridging the healthcare access gap and addressing COVID-19 vaccine hesitancy among rural-dwelling Black American adults residing in the Deep South require involvement of faith-based leaders in the community. This study explored perceived barriers and resources to meeting community needs, including vaccination, during the COVID-19 pandemic as reported by 17 Black American church leaders in the rural West Alabama Black Belt geographic region in May 2022. The main themes that emerged included (1) attending to community impact of COVID-19 illness and death; (2) maximizing health literacy and diminishing vaccine hesitancy through engaging in preventive health practices and sharing public health information; (3) addressing challenges created or exacerbated by COVID-19, including reduction in in-person attendance (particularly among adolescents and young adults), limited access to and literacy with technology, and political perceptions influencing engagement in preventive health behaviors; (4) maximizing technological solutions to increase attendance in the church; and (5) engaging in solution-focused and innovative initiatives to meet the identified needs in the congregation and community. Church leaders in West Alabama rural areas facing economic, health, and technological disparities identified "silver linings" as well as challenges created or exacerbated during the pandemic. As the need for COVID-19 vaccination and booster vaccination continues, Black American church leaders play pivotal roles in meeting rural community needs.

Rift-induced disruption of cratonic keels drives kimberlite volcanism.

Kimberlites are volatile-rich, occasionally diamond-bearing magmas that have erupted explosively at Earth's surface in the geologic past1-3. These enigmatic magmas, originating from depths exceeding 150 km in Earth's mantle1, occur in stable cratons and in pulses broadly synchronous with supercontinent cyclicity4. Whether their mobilization is driven by mantle plumes5 or by mechanical weakening of cratonic lithosphere4,6 remains unclear. Here we show that most kimberlites spanning the past billion years erupted about 30 million years (Myr) after continental breakup, suggesting an association with rifting processes. Our dynamical and analytical models show that physically steep lithosphere-asthenosphere boundaries (LABs) formed during rifting generate convective instabilities in the asthenosphere that slowly migrate many hundreds to thousands of kilometres inboard of rift zones. These instabilities endure many tens of millions of years after continental breakup and destabilize the basal tens of kilometres of the cratonic lithosphere, or keel. Displaced keel is replaced by a hot, upwelling mixture of asthenosphere and recycled volatile-rich keel in the return flow, causing decompressional partial melting. Our calculations show that this process can generate small-volume, low-degree, volatile-rich melts, closely matching the characteristics expected of kimberlites1-3. Together, these results provide a quantitative and mechanistic link between kimberlite episodicity and supercontinent cycles through progressive disruption of cratonic keels.

No evidence of supracrustal recycling in Si-O isotopes of Earth's oldest rocks 4 Ga ago.

Identifying the oldest evidence for the recycling of hydrated crust into magma on Earth is important because it is most effectively achieved by subduction. However, given the sparse geological record of early Earth, the timing of first supracrustal recycling is controversial. Silicon and oxygen isotopes have been used as indicators of crustal evolution on Archean igneous rocks and minerals to trace supracrustal recycling but with variable results. We present Si-O isotopes of Earth's oldest rocks [4.0 billion years ago (Ga)] from the Acasta Gneiss Complex, northwest Canada, obtained using multiple techniques applied to zircon, quartz, and whole rock samples. Undisturbed zircon is considered the most reliable recorder of primary Si signatures. By combining reliable Si isotope data from the Acasta samples with filtered data from Archean rocks globally, we observe that widespread evidence for a heavy Si signature is recorded since 3.8 Ga, marking the earliest record of surface silicon recycling.

Barium content of Archaean continental crust reveals the onset of subduction was not global.

Earth's earliest continental crust is dominated by tonalite-trondhjemite-granodiorite (TTG) suites, making these rocks key to unlocking the global geodynamic regime operating during the Archaean (4.0-2.5 billion years ago [Ga]). The tectonic setting of TTG magmatism is controversial, with hypotheses arguing both for and against subduction. Here we conduct petrological modeling over a range of pressure-temperature conditions relevant to the Archaean geothermal gradient. Using an average enriched Archaean basaltic source composition, we predict Ba concentrations in TTG suites, which is difficult to increase after magma generated in the source. The results indicate only low geothermal gradients corresponding to hot subduction zones produce Ba-rich TTG, thus Ba represents a proxy for the onset of subduction. We then identify statistically significant increases in the Ba contents of TTG suites worldwide as recording the diachronous onset of subduction from regional at 4 Ga to globally complete sometime after 2.7 Ga.

Evolving mantle convection from bottom up to top down.

When it comes to convection, what goes up must come down. Or is it, what goes down must come up? The truth is it depends. Although convection must be mass balanced, there is no reason that it must be force balanced: the positive and negative buoyancy forces driving convection up and down, respectively, do not necessarily need to be balanced. The balance, or imbalance, all depends on the top and bottom boundary layers. Thus, convection in Earth's mantle depends on the temperature differences across the core-mantle boundary below and the lithosphere-asthenosphere boundary above. Convective asymmetry predominated by positive buoyancy, or bottom-up convection, would be driven by plume ascent, whereas if it were predominated by negative buoyancy, or top-down convection, it would be driven by plate subduction. Symmetric convection would balance plume ascent and plate subduction. Is mantle convection on Earth balanced, dominantly top down or bottom up, or time dependent?

Community Perspectives and Environmental Justice Issues in an Unincorporated Black Township.

Through each era, the southeastern United States was and continues to be an epicenter for industrial companies to establish factories and plants. Though this development attracts economic gain for the companies and surrounding areas, low-income and predominantly Black communities bear the brunt of the environmental consequences while frequently remaining stagnant economically. This qualitative, community-based participatory research study grew out of a larger study designed to recruit lay community advisors from communities labeled as hard to reach in research. We focus on Holt, Alabama, an unincorporated community in the southeastern United States region. The primary goal of this research inquiry is to thematically analyze community interviews stemming from a topic of research, practice, and policy interest to community members: the effects of industrial pollution on Holt citizens' daily lives. Content analysis of focus-group transcripts revealed four emergent themes, including: (1) how the pollution affects their water, soil, and air quality; (2) illness related to pollution; (3) community engagement and empowerment; and (4) suggestions regarding what government officials could do to address this area of need. Building upon the prior research regarding environmental justice, human flourishing, and the definition of nurturing environments, suggestions are made regarding the creation, implementation, and maintenance of project advisory councils focused on issues of environmental justice. Community advocacy and empowerment as well as community and scientific partnerships are imperative to alleviate problems associated with environmental justice.

Data integrity within the biopharmaceutical sector in the era of Industry 4.0.

Data Integrity (DI) in the highly regulated biopharmaceutical sector is of paramount importance to ensure decisions on meeting product specifications are accurate and hence assure patient safety and product quality. The challenge of ensuring DI within this sector is becoming more complex with the growing amount of data generated given increasing adoption of process analytical technology (PAT), advanced automation, high throughput microscale studies, and managing data models created by machine learning (ML) tools. This paper aims to identify DI risks and mitigation strategies in biopharmaceutical manufacturing facilities as the sector moves towards Industry 4.0. To achieve this, the paper examines common DI violations and links them to the ALCOA+ principles used across the FDA, EMA, and MHRA. The relevant DI guidelines from the ISPE's GAMP5 and ISA-95 standards are also discussed with a focus on the role of validated computerised and automated manufacturing systems to avoid DI risks and generate compliant data. The paper also highlights the importance of DI whilst using data analytics to ensure the developed models meet the required regulatory standards for process monitoring and control. This includes a discussion on possible mitigation strategies and methodologies to ensure data integrity is maintained for smart manufacturing operations such as the use of cloud platforms to facilitate the storage and transfer of manufacturing data, and migrate away from paper-based records.

Incidental TEE finding of aberrant chordae tendineae insertion into the basal septum.

A 65-year-old female with severe mitral regurgitation presenting for mitral valve replacement was found to have a previously undiagnosed aberrant papillary muscle with thickened chordae tendineae inserting into the basal septum during intra-operative TEE. Despite its anatomic location, there was no evidence that the aberrant papillary muscle was contributing to the mitral regurgitation or causing left ventricular outflow tract (LVOT) obstruction. The aberrant papillary muscle was resected during the operation and the patient was separated from cardiopulmonary bypass without complications.

Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.

AIMS: Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety. METHODS: This double-blind, randomized, placebo-controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single-ascending doses up to 1000 mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 3:1 ratio. P218 was administered in the fasted state with standardized lunch served 4 hours after dosing. 12-lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240 hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration-effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals. RESULTS: Concentration-effect analysis showed that P218 does not prolong the QTcF, J-Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two-sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal. CONCLUSION: Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia.

A decade in review: use of data analytics within the biopharmaceutical sector.

There are large amounts of data generated within the biopharmaceutical sector. Traditionally, data analysis methods labelled as multivariate data analysis have been the standard statistical technique applied to interrogate these complex data sets. However, more recently there has been a surge in the utilisation of a broader set of machine learning algorithms to further exploit these data. In this article, the adoption of data analysis techniques within the biopharmaceutical sector is evaluated through a review of journal articles and patents published within the last ten years. The papers objectives are to identify the most dominant algorithms applied across different applications areas within the biopharmaceutical sector and to explore whether there is a trend between the size of the data set and the algorithm adopted.

Molybdenum isotopes unmask slab dehydration and melting beneath the Mariana arc.

How serpentinites in the forearc mantle and subducted lithosphere become involved in enriching the subarc mantle source of arc magmas is controversial. Here we report molybdenum isotopes for primitive submarine lavas and serpentinites from active volcanoes and serpentinite mud volcanoes in the Mariana arc. These data, in combination with radiogenic isotopes and elemental ratios, allow development of a model whereby shallow, partially serpentinized and subducted forearc mantle transfers fluid and melt from the subducted slab into the subarc mantle. These entrained forearc mantle fragments are further metasomatized by slab fluids/melts derived from the dehydration of serpentinites in the subducted lithospheric slab. Multistage breakdown of serpentinites in the subduction channel ultimately releases fluids/melts that trigger Mariana volcanic front volcanism. Serpentinites dragged down from the forearc mantle are likely exhausted at >200 km depth, after which slab-derived serpentinites are responsible for generating slab melts.

TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.

Reducing Time to Discharge after Chemotherapy by Standardizing Workflow and Providing Outpatient Intravenous Hydration.

INTRODUCTION: Patients receiving cyclophosphamide or ifosfamide chemotherapy require intravenous fluid hydration to prevent hemorrhagic cystitis. In selected patients without medical contraindications (ie, excess nausea/vomiting), this hydration may be completed after discharge. We aimed to reduce the time to discharge after completing mesna in patients receiving cyclophosphamide or ifosfamide therapy on an inpatient chemotherapy service. METHODS: The quality improvement team performed a medical record review to capture the time to discharge after mesna therapy and the readmission rate and used quality improvement methods to redesign discharge workflow and increase patient involvement with the discharge process. RESULTS: From August 2017 through July 2018, there were 160 admission encounters (73 patients) for cyclophosphamide or ifosfamide on a dedicated chemotherapy service. Of those encounters, 89 (55.6%) were appropriate for outpatient hydration; 48 (53.9%) of these encounters involved a patient who elected to receive outpatient hydration. Although the median time to discharge for the whole cohort did not change, in encounters where patients chose intravenous outpatient hydration, the median time to discharge was reduced from 2.82 to 0.66 hours (76.6% reduction) after implementing the new discharge workflow. No patients experienced readmission within 48 hours. CONCLUSIONS: Discharge workflow redesign and standardization reduced the time to discharge after chemotherapy in patients who chose outpatient hydration. Outpatient intravenous hydration after cyclophosphamide or ifosfamide appears safe and feasible in selected patient populations.

A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.

Comparing the consistency of electrocardiogram interval measurements by resting ECG versus 12-lead Holter.

In clinical trials, traditionally only a limited number of 12-lead resting electrocardiograms (ECGs) can be recorded and, thus, long intervals may elapse between assessment timepoints and valuable information may be missed during times when patients' cardiac electrical activity is not being monitored. These limitations have led to the increasing use of Holter recorders which provide continuous data registrations while reducing the burden on patients and freeing up time for clinical trial staff to perform other tasks. However, there is a shortage of data comparing the two approaches. In this study, data from a randomized, double-blind, four-period, crossover thorough QT study in 40 healthy subjects were used to compare continuous 12-lead Holter recordings to standard 12-lead resting ECGs which were recorded in parallel. Heart rate and QT interval data were estimated by averaging three consecutive heartbeats. Values exceeding the sample average by more than 5% were tagged as outliers and excluded from the analysis. Visual comparisons of the ECG waveforms of the Holter signal showed a good correlation with resting ECGs at matching timepoints. Resting ECG data revealed sex differences that Holter data did not show. Specifically, women were found to have a longer QTcF of 20 ms, while men had a lower heart rate. We found that continuous recordings provided a more accurate reflection of changes in cardiac electrical activity over 24 hr. However, manual adjudication is still required to ensure the quality and accuracy of ECG data, and that only artifacts are removed thereby avoiding loss of true signals.