Incorporating Noncovalent Interactions in Transfer Learning Gaussian Process Regression Models for Molecular Simulations.

FFLUX is a quantum chemical topology-based multipolar force field that uses Gaussian process regression machine learning models to predict atomic energies and multipole moments on the fly for fast and accurate molecular dynamics simulations. These models have previously been trained on monomers, meaning that many-body effects, for example, intermolecular charge transfer, are missed in simulations. Moreover, dispersion and repulsion have been modeled using Lennard-Jones potentials, necessitating careful parametrization. In this work, we take an important step toward addressing these shortcomings and show that models trained on clusters, in this case, a dimer, can be used in FFLUX simulations by preparing and benchmarking a formamide dimer model. To mitigate the computational costs associated with training higher-dimensional models, we rely on the transfer of hyperparameters from a smaller source model to a larger target model, enabling an order of magnitude faster training than with a direct learning approach. The dimer model allows for simulations that account for two-body effects, including intermolecular polarization and charge penetration, and that do not require nonbonded potentials. We show that addressing these limitations allows for simulations that are closer to quantum mechanics than previously possible with the monomeric models.

Assessment of Posttransplant Bacteremia Caused by Extended-Spectrum Beta-Lactamase-Producing Gram-Negative Bacteria Among Kidney Transplant Recipients.

BACKGROUND: Extended-spectrum beta-lactamase-producing gram-negative rods (ESBL-GNR) are a rising cause of bacteremia in kidney transplant recipients (KT). The study purpose was to examine patient mortality, allograft survival, estimated glomerular filtration rate (eGFR) at the end of 1 year, and readmission rates while looking at treatment strategies among KTs with ESBL-GNR and non-ESBL-GNR bacteremia at our institution. METHODS: This study was a retrospective, cohort analysis of KTs with gram-negative bacteremia from January 1, 2020, to December 31, 2021. The primary outcome of the study was mortality. Patient outcomes were assessed for 365 days after positive blood cultures. RESULTS: The study included 63 patients. Of these, 18 (29%) patients had bacteremia caused by an ESBL-GNR and 45 (71%) patients had bacteremia caused by a non-ESBL-GNR. Patient survival at 90 days was 94% in the ESBL-GNR group and 96% in the non-ESBL-GNR group. Ciprofloxacin was the most common antimicrobial therapy at discharge (68.9%) in the non-ESBL-GNR group whereas ertapenem was the most common in the ESBL-GNR group (44.5%). Median eGFR at discharge was 41 mL/min/1.73 m2 in the ESBL-GNR group and 48 mL/min/1.73 m2 in the non-ESBL-GNR group. Ninety-day readmission occurred in 9 (50%) ESBL-GNR patients and 14 (32%) non-ESBL-GNR patients. None of the above comparisons are statistically significant (p > 0.05). Eleven (61%) ESBL-GNR and 2 (4%) non-ESBL-GNR patients used outpatient parenteral antimicrobial therapy (p < 0.001). CONCLUSIONS: Among KTs with ESBL-GNR bacteremia, no significant difference was detected in mortality or allograft function compared to non-ESBL-GNR bacteremia.

Probabilistic Finite Element Analysis of Human Rib Biomechanics: A Framework for Improved Generalizability.

In dynamic impact events, thoracic injuries often involve rib fractures, which are closely related to injury severity. Previous studies have investigated the behavior of isolated ribs under impact loading conditions, but often neglected the variability in anatomical shape and tissue material properties. In this study, we used probabilistic finite element analysis and statistical shape modeling to investigate the effect of population-wide variability in rib cortical bone tissue mechanical properties and rib shape on the biomechanical response of the rib to impact loading. Using the probabilistic finite element analysis results, a response surface model was generated to rapidly investigate the biomechanical response of an isolated rib under dynamic anterior-posterior load given the variability in rib morphometry and tissue material properties. The response surface was used to generate pre-fracture force-displacement computational corridors for the overall population and a population sub-group of older mid-sized males. When compared to the experimental data, the computational mean response had a RMSE of 4.28N (peak force 94N) and 6.11N (peak force 116N) for the overall population and sub-group respectively, whereas the normalized area metric when comparing the experimental and computational corridors ranged from 3.32% to 22.65% for the population and 10.90% to 32.81% for the sub-group. Furthermore, probabilistic sensitivities were computed in which the contribution of uncertainty and variability of the parameters of interest was quantified. The study found that rib cortical bone elastic modulus, rib morphometry and cortical thickness are the random variables that produce the largest variability in the predicted force-displacement response. The proposed framework offers a novel approach for accounting biological variability in a representative population and has the potential to improve the generalizability of findings in biomechanical studies.

Fibrocartilaginous Mesenchymoma of the Spine: A Case Report.

CASE: A healthy, 19-year-old woman was incidentally found to have a large, destructive tumor of T11 without neurologic symptoms. Biopsy demonstrated fibrocartilaginous mesenchymoma (FCM). The patient was treated with resection including subtotal corpectomy and T8-L1 fusion with use of cage and allograft strut construct. The patient remained without recurrence over 3 years of follow-up. CONCLUSION: FCM arising from the spine is a rare tumor, of which this is the sixth report. FCM affects primarily young adults and is benign but locally aggressive, requiring complete excision to prevent recurrence.

Life Detection on Icy Moons Using Flow Cytometry and Intrinsically Fluorescent Biomolecules.

In a previous experiment, we demonstrated the capability of flow cytometry as a potential life detection technology for icy moons using exogenous fluorescent stains (Wallace et al., 2023). In this companion experiment, we demonstrated the capability of flow cytometry to detect life using intrinsically fluorescent biomolecules in addition to exogenous stains. We used a method similar to our previous work to positively identify six classes of intrinsically fluorescent biomolecules: flavins, carotenoids, chlorophyll, tryptophan, NAD+, and NAD(P)H. We demonstrated the effectiveness of this method with six known organisms and known abiotic material and showed that the cytometer is easily able to distinguish the known organisms and the known abiotic material by using the intrinsic fluorescence of these six biomolecules. To simulate a life detection experiment on an icy moon lander, we used six natural samples with unknown biotic and abiotic content. We showed that flow cytometry can identify all six intrinsically fluorescent biomolecules and can separate the biotic material from the known abiotic material on scatter plots. The use of intrinsically fluorescent biomolecules in addition to exogenous stains will potentially cast a wider net for life detection on icy moons using flow cytometry.

Mulch Madness: A Community-Academic Partnership for Lead Poisoning Prevention.

BACKGROUND: Soil constitutes a major source of childhood lead exposure, disproportionately affecting communities of color. Mulching offers a low-cost interim control. OBJECTIVES: A community-academic partnership was established for lead poisoning prevention, with a three-fold aim: (1) control soil lead hazards by applying mulch, (2) identify home lead hazards with screening kits, and (3) connect residents to resources to address lead hazards. METHODS: Student volunteers canvassed neighborhoods one month prior to the annual event. They requested consent for mulching, distributed lead screening kits, and screened residents for grant eligibility. Soil samples were collected from each home before mulching. According to principles of community-based participatory research, materials and plans were iterative, guided and adjusted by neighborhood association feedback, and detailed reports about home lead results were shared with each participating resident. Composite neighborhood data and survey results were shared with volunteers and community partners. RESULTS: The project was evaluated in the third (41 homes) and fourth (48 homes) years of implementation. Before mulching, the median soil lead level was over 400 ppm, and after mulching, it was less than 20 ppm. Lead screening kits identified widespread lead hazards in paint, soil, and dust, but not water. Challenges remain in (a) increasing child blood lead testing and (b) increasing submissions for city grant funding for lead abatement. Evaluation surveys indicate a sense of ownership in the project among community partners and high levels of engagement among students. CONCLUSIONS: Community-academic partnerships are an effective tool for lead poisoning prevention, generating evidence for public health action.

Association of ambient air pollution and pesticide mixtures on respiratory inflammatory markers in agricultural communities.

Air pollution exposure is associated with adverse respiratory health outcomes. Evidence from occupational and community-based studies also suggests agricultural pesticides have negative health impacts on respiratory health. Although populations are exposed to multiple inhalation hazards simultaneously, multidomain mixtures (e.g. environmental and chemical pollutants of different classes) are rarely studied. We investigated the association of ambient air pollution-pesticide exposure mixtures with urinary leukotriene E4 (LTE4), a respiratory inflammation biomarker, for 75 participants in four Central California communities over two seasons. Exposures included three criteria air pollutants estimated via the Community Multiscale Air Quality model (fine particulate matter, ozone, and nitrogen dioxide) and urinary metabolites of organophosphate (OP) pesticides (total dialkyl phosphates (DAPs), total diethyl phosphates (DE), and total dimethyl phosphates (DM)). We implemented multiple linear regression models to examine associations in single pollutant models adjusted for age, sex, asthma status, occupational status, household member occupational status, temperature, and relative humidity, and evaluated whether associations changed seasonally. We then implemented Bayesian kernel machine regression (BKMR) to analyse these criteria air pollutants, DE, and DM as a mixture. Our multiple linear regression models indicated an interquartile range (IQR) increase in total DAPs was associated with an increase in urinary LTE4 in winter (ß: 0.04, 95% CI: [0.01, 0.07]). Similarly, an IQR increase in total DM was associated with an increase in urinary LTE4 in winter (ß:0.03, 95% CI: [0.004, 0.06]). Confidence intervals for all criteria air pollutant effect estimates included the null value. BKMR analysis revealed potential non-linear interactions between exposures in our air pollution-pesticide mixture, but all confidence intervals contained the null value. Our analysis demonstrated a positive association between OP pesticide metabolites and urinary LTE4 in a low asthma prevalence population and adds to the limited research on the joint effects of ambient air pollution and pesticides mixtures on respiratory health.

No Revisions Attributable To Wear of Highly Cross-Linked Polyethylene Liners: A Long Term Follow-up Study.

INTRODUCTION: There is a paucity of data beyond 15 years on the survivorship of total hip arthroplasty since the introduction of highly cross-linked polyethylene (HXLPE) liners. Our aim was to evaluate implant survivorship, liner wear rates, and clinical outcomes after primary THA using HXLPE liners implanted between 1999 and 2002. METHODS: Between 1999 and 2002, 690 primary THAs utilizing 28-mm femoral heads and HXLPE liners of a single design were identified using our institutional total joint registry. Femoral heads were made of metal in 96% of cases and ceramic in 4%. The mean age was 56 years, 48% were women, and the mean BMI was 30. Survivorship analyses were performed for the outcomes of implant revision, reoperation, and complications for the entire cohort. Linear HXLPE liner wear rates were determined on 197 hips with radiographs with more than 18.5 years of follow-up. RESULTS: At 20 years, survivorship free of revision was 94%, free of reoperation was 92%, and free of any complication was 81%. There were no documented wear-related revisions. The linear wear rate at a mean of 20.3 years postoperatively was 0.02 mm/year. There was no statistically significant difference in measured wear observed between the first available postoperative radiographs and those taken at the final follow-up. The use of elevated liners, patient BMI, age, preoperative diagnosis, acetabular component inclination, and anteversion angles were not associated with increased wear rates. Mean Harris Hip Scores improved from 52 preoperatively to 90 at greater than 18.5 years. CONCLUSIONS: Primary THAs using a single first generation HXLPE liner demonstrated excellent survivorship and clinical outcomes at long-term follow-up with no wear-related revisions. Wear rates of HXLPE liners at 20 years are exceedingly low and are not significantly impacted by acetabular component position or patient-dependent variables such as BMI. LEVEL OF EVIDENCE: IV.

When to feed after percutaneous endoscopic gastrostomy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Initiation of feeding after percutaneous endoscopic gastrostomy (PEG) placement has been debated. Randomized controlled trials (RCTs) have been performed on early feeding compared with delayed feeding after PEG placement with varying results. Therefore, a meta-analysis was conducted examining early vs delayed feeding after placement of a PEG. METHODS: A comprehensive search of databases was conducted in January 2024. Peer-reviewed published RCTs comparing early feeding (≤4 h) with delayed feeding (>4 h) were identified and included in the meta-analysis. Meta-analysis was completed using pooled estimates of overall complications, individual complications, mortality ≤72 h, and number of day 1 significant gastric residual volumes. RESULTS: Six RCTs (n = 467) were included in the analysis. Comparison of early feeding with delayed feeding after PEG showed no statistically significant differences for overall complications (P = 0.18), mortality ≤72 h (P = 0.3), and number of day 1 significant gastric residual volumes (P = 0.05). No differences were also noted for individual complications, including vomiting, wound infection, bleeding, or diarrhea. CONCLUSION: Feeding ≤4 h after PEG have no differences in minor and major complications compared with that of delayed feeding. Early feeding ≤4 h is safe and should be recommended in future guidelines.

Residential greenspace and COVID-19 Severity: A cohort study of 313,657 individuals in Greater Manchester, United Kingdom.

BACKGROUND: Greenspaces contribute positively to mental and physical well-being, promote social cohesion, and alleviate environmental stressors, such as air pollution. Ecological studies suggest that greenspace may affect incidence and severity of Coronavirus Disease 2019 (COVID-19). OBJECTIVE: This study examines the association between residential greenspace and COVID-19 related hospitalization and death. METHOD: In this retrospective cohort based on patient records from the Greater Manchester Care Records, all first COVID-19 cases diagnosed between March 1, 2020, and May 31, 2022 were followed until COVID-19 related hospitalization or death within 28 days. Residential greenspace availability was assessed using the Normalized Difference Vegetation Index per lower super output area in Greater Manchester. The association of greenspace with COVID-19 hospitalization and mortality were estimated using multivariate logistic regression models after adjusting for potential individual, temporal, and spatial confounders. We explored potential effect modifications of the associations with greenspace and COVID-19 severity by age, sex, body mass index, smoking, deprivation, and certain comorbidities. Combined effects of greenspace and air pollution (NO2 and PM2.5) were investigated by mutually adjusting pairs with correlation coefficients ≤ 0·7. RESULTS: Significant negative associations were observed between greenspace availability and COVID-19 hospitalization and mortality with odds ratios [OR] (95 % Confidence Intervals [CI]) of 0·96 (0·94-0·97) and 0·84 (0·80-0·88) (per interquartile range [IQR]), respectively. These were significantly modified by deprivation (P-value for interaction < 0.05), showing that those most deprived obtained largest benefits from greenspace. Inclusion of NO2 and PM2.5 diminished associations to null for COVID-19 hospitalization, but only reduced them slightly for mortality, where inverse associations remained. CONCLUSION: In the Greater Manchester area, residential greenspace is associated with reduced risk of hospitalization or death in individuals with COVID-19, with deprived groups obtaining the greatest benefits. Associations were strongest for COVID-19 mortality, which were robust to inclusion of air pollutants in the models.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

The Influence of the Extracorporeal Membrane Oxygenation Circuit and Components on Anticoagulation Management: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the influence of extracorporeal membrane oxygenation (ECMO) circuit components on anticoagulation practices for pediatric ECMO for the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Management of ECMO anticoagulation in the setting of different ECMO circuit components. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Twenty-nine references were used for data extraction and informed recommendations, evidence-based consensus statements, and good practice statements. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for the influence of ECMO circuit and components on anticoagulation management. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One good practice statement, 2 weak recommendations, and 2 consensus statements are presented. CONCLUSIONS: The incorporation of new component technologies into clinical practice has outpaced clinical investigations of anticoagulation strategies for pediatric ECMO. Future investigations should leverage academic and industrial collaborations, translational platforms, and modern biostatistical methods to improve patient outcomes.

A "Prime and Expand" strategy using the multifunctional fusion proteins to generate memory-like NK cells for cell therapy.

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming ("Prime" step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 ("Expand" step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting "Prime and Expand" ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the "Prime and Expand" strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT.

CSF1R Inhibition in Patients With Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase 1 Study of Vimseltinib.

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label, phase 1/2 study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase 2 dose (RP2D), and characterize the pharmacokinetics (PK); exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were grade 1/2. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The RP2D was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7 to 46.9), and the objective response rate as assessed by independent radiological review using Response Evaluation Criteria in Solid Tumors version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.

The association between social risks and days at home for older veterans.

BACKGROUND: Many health systems are trying to support the ability of older adults to remain in their homes for as long as possible. Little is known about the relationship between patient-reported social risks and length of time spent at home. We assessed how social risks were associated with days at home for a cohort of older Veterans at high risk for hospitalization and mortality. METHODS: A prospective cross-sectional study using a 2018 survey of 3479 high-risk Veterans aged ≥65 linked to Veterans Health Administration data. Social risks included measures of social resources (i.e., no partner present, low social support), material resources (i.e., not employed, financial strain, medication insecurity, food insecurity, and transportation barriers), and personal resources (i.e., low medical literacy and less than high school education). We estimated how social risks were associated with days at home, defined as the number of days spent outside inpatient, long-term care, observation, or emergency department settings over a 12-month period, using a negative binomial regression model. RESULTS: Not having a partner, not being employed, experiencing transportation barriers, and low medical literacy were respectively associated with 2.57, 3.18, 3.39, and 6.14 fewer days at home (i.e., 27% more facility days, 95% confidence interval [CI] 8%-50%; 42% more facility days, 95% CI 7%-89%; 34% more facility days, 95% CI 7%-68%; and 63% more facility days, 95% CI 27%-109%). Experiencing food insecurity was associated with 2.62 more days at home (i.e., 24% fewer facility days, 95% CI 3%-59%). CONCLUSIONS: Findings suggest that screening older Veterans at high risk of community exit for social risks (i.e., social support, material resources, and medical literacy) may help identify patients likely to benefit from home- and community-based health and social services that facilitate remaining in home settings. Future research should focus on understanding the mechanisms by which these associations occur.

Precision arbovirus serology with a pan-arbovirus peptidome.

Arthropod-borne viruses represent a crucial public health threat. Current arboviral serology assays are either labor intensive or incapable of distinguishing closely related viruses, and many zoonotic arboviruses that may transition to humans lack any serologic assays. In this study, we present a programmable phage display platform, ArboScan, that evaluates antibody binding to overlapping peptides that represent the proteomes of 691 human and zoonotic arboviruses. We confirm that ArboScan provides detailed antibody binding information from animal sera, human sera, and an arthropod blood meal. ArboScan identifies distinguishing features of antibody responses based on exposure history in a Colombian cohort of Zika patients. Finally, ArboScan details epitope level information that rapidly identifies candidate epitopes with potential protective significance. ArboScan thus represents a resource for characterizing human and animal arbovirus antibody responses at cohort scale.

Molecular profiling of 888 pediatric tumors informs future precision trials and data-sharing initiatives in pediatric cancer.

To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children's Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.

Combined First-Principles and Experimental Investigation into the Reactivity of Codeposited Chromium-Carbon under Pressure.

High-pressure synthesis in the diamond anvil cell suffers from the lack of a general approach for the control of precursor stoichiometry and homogeneity. Here, we present results from a new method we have developed that uses magnetron cosputtering to prepare stoichiometrically precise and atomically mixed amorphous films of Cr:C. Laser-heated diamond anvil cell experiments carried out on a flake of this sample at pressures between 13.5 and 24.3 GPa lead to the observation of Cr3C (Pnma) over the entire pressure range-in good agreement with our in-house theoretical predictions-but also reveal two other metastable phases that were not expected: a novel monoclinic chromium carbide phase and the NaCl-type CrC (Fm3̅m) phase. The unexpected stability of CrC is investigated by using first-principles methods, revealing a large stabilizing effect tied to substoichiometry at the carbon site. These results offer an important case study into the current limitations of crystal structure prediction methods with regard to phase complexity and bolster the growing need for advanced theoretical approaches that can more completely survey experimentally unexplored phase space.

Rapid, Portable, and Electricity-free Sample Extraction Method for Enhanced Molecular Diagnostics in Resource-Limited Settings.

The COVID-19 pandemic has highlighted the need for rapid and reliable diagnostics that are accessible in resource-limited settings. To address this pressing issue, we have developed a rapid, portable, and electricity-free method for extracting nucleic acids from respiratory swabs (i.e. nasal, nasopharyngeal and buccal swabs), successfully demonstrating its effectiveness for the detection of SARS-CoV-2 in residual clinical specimens. Unlike traditional approaches, our solution eliminates the need for micropipettes or electrical equipment, making it user-friendly and requiring little to no training. Our method builds upon the principles of magnetic bead extraction and revolves around a low-cost plastic magnetic lid, called SmartLid, in combination with a simple disposable kit containing all required reagents conveniently prealiquoted. Here, we clinically validated the SmartLid sample preparation method in comparison to the gold standard QIAamp Viral RNA Mini Kit from QIAGEN, using 406 clinical isolates, including 161 SARS-CoV-2 positives, using the SARS-CoV-2 RT-qPCR assays developed by the US Centers for Disease Control and Prevention (CDC). The SmartLid method showed an overall sensitivity of 95.03% (95% CI: 90.44-97.83%) and a specificity of 99.59% (95% CI: 97.76-99.99%), with a positive agreement of 97.79% (95% CI: 95.84-98.98%) when compared to QIAGEN's column-based extraction method. There are clear benefits to using the SmartLid sample preparation kit: it enables swift extraction of viral nucleic acids, taking less than 5 min, without sacrificing significant accuracy when compared to more expensive and time-consuming alternatives currently available on the market. Moreover, its simplicity makes it particularly well-suited for the point-of-care where rapid results and portability are crucial. By providing an efficient and accessible means of nucleic acid extraction, our approach aims to introduce a step-change in diagnostic capabilities for resource-limited settings.