Expression of IL-4 in Tumors: A Safety Surrogate to Predict Cancer Survival Associated With Biologic Therapies.

Interleukin (IL)-4-targeted therapies have revolutionized management of inflammatory dermatoses.

Effects of relational and instrumental messaging on human perception of rattlesnakes.

We tested the effects of relational and instrumental message strategies on US residents' perception of rattlesnakes-animals that tend to generate feelings of fear, disgust, or hatred but are nevertheless key members of healthy ecosystems. We deployed an online survey to social media users (n = 1,182) to describe perceptions of rattlesnakes and assess the change after viewing a randomly selected relational or instrumental video message. An 8-item, pre-and post-Rattlesnake Perception Test (RPT) evaluated perception variables along emotional, knowledge, and behavioral gradients on a 5-point Likert scale; the eight responses were combined to produce an Aggregate Rattlesnake Perception (ARP) score for each participant. We found that people from Abrahamic religions (i.e., Christianity, Judaism, Islam) and those identifying as female were associated with low initial perceptions of rattlesnakes, whereas agnostics and individuals residing in the Midwest region and in rural residential areas had relatively favorable perceptions. Overall, both videos produced positive changes in rattlesnake perception, although the instrumental video message led to a greater increase in ARP than the relational message. The relational message was associated with significant increases in ARP only among females, agnostics, Baby Boomers (age 57-75), and Generation-Z (age 18-25 to exclude minors). The instrumental video message was associated with significant increases in ARP, and this result varied by religious group. ARP changed less in those reporting prior experience with a venomous snake bite (to them, a friend, or a pet) than in those with no such experience. Our data suggest that relational and instrumental message strategies can improve people's perceptions of unpopular and potentially dangerous wildlife, but their effectiveness may vary by gender, age, religious beliefs, and experience. These results can be used to hone and personalize communication strategies to improve perceptions of unpopular wildlife species.

The M3 muscarinic acetylcholine receptor can signal through multiple G protein families.

The M3 muscarinic acetylcholine receptor (M3R) is a G protein coupled receptor (GPCR) that regulates important physiological processes including vascular tone, bronchoconstriction, and insulin secretion. It is expressed on a wide variety of cell types, including pancreatic beta, smooth muscle, neuronal, and immune cells. Agonist binding to the M3R is thought to initiate intracellular signaling events primarily through the heterotrimeric G protein Gq. However, reports differ on the ability of M3R to couple to other G proteins beyond Gq. Using members from the four primary G protein families (Gq, Gi, Gs, and G13) in radioligand binding, GTP turnover experiments, and cellular signaling assays including live cell G protein dissociation and second messenger assessment of cAMP and inositol trisphosphate, we show that other G protein families, particularly Gi and Gs, can also interact with the human M3R. We further show that these interactions are productive as assessed by amplification of classical second messenger signaling events. Our findings demonstrate that the M3R is more promiscuous with respect to G protein interactions than previously appreciated. Significance StatementThe study reveals that the human M3 muscarinic acetylcholine receptor (M3R), known for its pivotal roles in diverse physiological processes, not only activates intracellular signaling via Gq as previously known but also functionally interacts with other G protein families, such as Gi and Gs, expanding our understanding of its versatility in mediating cellular responses. These findings signify a broader and more complex regulatory network governed by M3R and have implications for therapeutic targeting.

Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors.

Adhesion G protein-coupled receptor (aGPCR) signaling influences development and homeostasis in a wide range of tissues. In the current model for aGPCR signaling, ligand binding liberates a conserved sequence that acts as an intramolecular, tethered agonist (TA), yet this model has not been evaluated systematically for all aGPCRs. Here, we assessed the TA-dependent activities of all 33 aGPCRs in a suite of transcriptional reporter, G protein activation, and ß-arrestin recruitment assays using a new fusion protein platform. Strikingly, only ∼50% of aGPCRs exhibited robust TA-dependent activation, and unlike other GPCR families, aGPCRs showed a notable preference for G12/13 signaling. AlphaFold2 predictions assessing TA engagement in the predicted intramolecular binding pocket aligned with the TA dependence of the cellular responses. This dataset provides a comprehensive resource to inform the investigation of all human aGPCRs and for targeting aGPCRs therapeutically.

Local tree cover predicts mosquito species richness and disease vector presence in a tropical countryside landscape.

Context: Land use change drives both biodiversity loss and zoonotic disease transmission in tropical countryside landscapes. Developing solutions for protecting countryside biodiversity, public health, and livelihoods requires understanding the scales at which habitat characteristics such as land cover shape biodiversity, especially for arthropods that transmit pathogens. Evidence increasingly shows that species richness for many taxa correlates with local tree cover. Objectives: We investigated whether mosquito species richness, community composition, and presence of disease vector species responded to land use and tree cover - and if so, whether at spatial scales similar to other taxa. Methods: We paired a field survey of mosquito communities in agricultural, residential, and forested lands in rural southern Costa Rica with remotely sensed tree cover data. We compared mosquito community responses to tree cover surrounding survey sites measured across scales, and analyzed community responses to land use and environmental gradients. Results: Tree cover was positively correlated with mosquito species richness, and negatively correlated with the presence of the common invasive dengue vector Aedes albopictus, particularly at small spatial scales of 80 - 200m. Land use predicted community composition and Ae. albopictus presence. Environmental gradients of tree cover, temperature, and elevation explained 7% of species turnover among survey sites. Conclusions: The results suggest that preservation and expansion of tree cover at local scales can protect biodiversity for a wide range of taxa, including arthropods, and also confer protection against disease vector occurrence. The identified spatial range of tree cover benefits can inform land management for conservation and public health protection.

Optimized 13C-TrEnDi Enhances the Sensitivity of Plasmenyl Ether Glycerophospholipids and Demonstrates Compatibility with Other Derivatization Strategies.

The identification and quantitation of plasmalogen glycerophospholipids is challenging due to their isobaric overlap with plasmanyl ether-linked glycerophospholipids, susceptibility to acid degradation, and their typically low abundance in biological samples. Trimethylation enhancement using diazomethane (TrEnDi) can be used to significantly enhance the signal of glycerophospholipids through the creation of quaternary ammonium groups producing fixed positive charges using 13C-diazomethane in complex lipid extracts. Although TrEnDi requires a strong acid for complete methylation, we report an optimized protocol using 10 mM HBF4 with the subsequent addition of a buffer solution that prevents acidic hydrolysis of plasmalogen species and enables the benefits of TrEnDi to be realized for this class of lipids. These optimized conditions were applied to aliquots of bovine liver extract (BLE) to achieve permethylation of plasmalogen lipids within a complex mixture. Treating aliquots of unmodified and TrEnDi-derivatized BLE samples with 80% formic acid and comparing their liquid chromatography mass spectrometry (LCMS) results to analogous samples not treated with formic acid, enabled the identification of 29 plasmalogen species. On average, methylated plasmalogen species from BLE demonstrated 2.81-fold and 28.1-fold sensitivity gains over unmodified counterparts for phosphatidylcholine and phosphatidylethanolamine plasmalogen species, respectively. Furthermore, the compatibility of employing 13C-TrEnDi and a previously reported iodoacetalization strategy was demonstrated to effectively identify plasmenyl-ether lipids in complex biological extracts at greater levels of sensitivity. Overall, we detail an optimized 13C-TrEnDi derivatization strategy that enables the analysis of plasmalogen glycerophospholipids with no undesired cleavage of radyl groups, boosting their sensitivity in LCMS and LCMS/MS analyses.

From Pre-test and Post-test Probabilities to Medical Decision Making.

Background: A central goal of modern evidence-based medicine is the development of simple and easy to use tools that help clinicians integrate quantitative information into medical decision-making. The Bayesian Pre-test/Post-test Probability (BPP) framework is arguably the most well known of such tools and provides a formal approach to quantify diagnostic uncertainty given the result of a medical test or the presence of a clinical sign. Yet, clinical decision-making goes beyond quantifying diagnostic uncertainty and requires that that uncertainty be balanced against the various costs and benefits associated with each possible decision. Despite increasing attention in recent years, simple and flexible approaches to quantitative clinical decision-making have remained elusive. Methods: We extend the BPP framework using concepts of Bayesian Decision Theory. By integrating cost, we can expand the BPP framework to allow for clinical decision-making. Results: We develop a simple quantitative framework for binary clinical decisions (e.g., action/inaction, treat/no-treat, test/no-test). Let p be the pre-test or post-test probability that a patient has disease. We show that r*=(1-p)/p represents a critical value called a decision boundary. In terms of the relative cost of under- to over-acting, r* represents the critical value at which action and inaction are equally optimal. We demonstrate how this decision boundary can be used at the bedside through case studies and as a research tool through a reanalysis of a recent study which found widespread misestimation of pre-test and post-test probabilities among clinicians. Conclusions: Our approach is so simple that it should be thought of as a core, yet previously overlooked, part of the BPP framework. Unlike prior approaches to quantitative clinical decision-making, our approach requires little more than a hand-held calculator, is applicable in almost any setting where the BPP framework can be used, and excels in situations where the costs and benefits associated with a particular decision are patient-specific and difficult to quantify.

High Community-Level Social Vulnerability is Associated with Worse Recurrence-Free Survival (RFS) After Resection of Extremity and Truncal Soft Tissue Sarcoma.

BACKGROUND: Although social vulnerability has been associated with worse postoperative and oncologic outcomes in other cancer types, these effects have not been characterized in patients with soft tissue sarcoma. This study evaluated the association of social vulnerability and oncologic outcomes. METHODS: The authors conducted a single-institution cohort study of adult patients with primary and locally recurrent extremity or truncal soft tissue sarcoma undergoing resection between January 2016 and December 2021. The social vulnerability index (SVI) was measured on a low (SVI 1-39%, least vulnerable) to high (60-100%, most vulnerable) SVI scale. The association of SVI with overall survival (OS) and recurrence-free survival (RFS) was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. RESULTS: The study identified 577 patients. The median SVI was 44 (interquartile range [IQR], 19-67), with 195 patients categorized as high SVI and 265 patients as low SVI. The median age, tumor size, histologic subtype, grade, comorbidities, stage, follow-up time, and perioperative chemotherapy and radiation utilization were similar between the high and low SVI cohorts. The patients with high SVI had worse OS (p = 0.07) and RFS (p = 0.016) than the patients with low SVI. High SVI was independently associated with shorter RFS in the multivariate analysis (hazard ratio, 1.64; 95% confidence interval, 1.06-2.54) but not with OS (HR, 1.47; 95% CI 0.84-2.56). CONCLUSION: High community-level social vulnerability appears to be independently associated with worse RFS for patients undergoing resection of extremity and truncal soft tissue sarcoma. The effect of patient and community-level social risk factors should be considered in the treatment of patients with extremity sarcoma.

Evaluation of luciferase and prefusion-stabilized F protein from respiratory syncytial virus mRNA/LNPs in pre-clinical models using jet delivery compared to needle and syringe.

Described here is the evaluation of a luciferase (luc) and respiratory syncytial virus (RSV) messenger RNA / lipid nanoparticle (mRNA/LNP) vaccine using a Needle-free Injection System, Tropis®, from PharmaJet® (Golden, Colorado USA). Needle-free jet delivery offers an alternative to needle/syringe. To perform this assessment, compatibility studies with Tropis were first performed with a luc mRNA/LNP and compared to needle/syringe. Although minor changes in particle size and encapsulation efficiency were observed when using Tropis on the benchtop, in vitro luciferase activity remained the same. Next, the luc mRNA/LNP was administered to rats intramuscularly using Tropis or needle/syringe and tracking of the injection and distribution was performed. Lastly, an mRNA encoding a prefusion-stabilized F protein from RSV was delivered intramuscularly using both Tropis and needle/syringe at 1 and 5 mcg mRNA. An equivalent IgG response was observed using both Tropis and needle/syringe. The cell mediated immune (CMI) response was also evaluated, and responses to RSV-F were detected from animals immunized with needle/syringe at all dose levels, and from the animals immunized with Tropis in the 5 and 25 ug groups. These results indicated that delivery of mRNA/LNPs with Tropis is a potential means of administration and an alternative to needle/syringe.

Free labial mucocutaneous graft for eyelid reconstruction in four dogs.

PURPOSE: To describe a technique for eyelid margin reconstruction following large mass resection utilizing a free labial mucocutaneous graft. METHODS: Four dogs (4 eyes) underwent en bloc eyelid mass excision under general anesthesia. Measurements were made of the mass followed by free labial mucocutaneous graft retrieval, resection of the mass, and then transplantation of retrieved region of labial mucocutaneous tissue into the resulting defect. RESULTS: Three patients underwent eyelid margin reconstruction with a free labial mucocutaneous graft. One patient received a pedicle advancement graft combined with a free labial mucocutaneous graft. In all cases, a length of 120%-150% of the eyelid defect was retrieved from the oral labia. Postoperative follow-up ranged from 6 weeks to 4 months. All cases had superficial graft necrosis and depigmentation of the donor tissue with total healing time taking up to 8 weeks. All cases had an esthetic and functional reconstruction. CONCLUSIONS: This technique allows reconstruction of the majority of the eyelid margin, greater than that which can be closed primarily. Due to tissue sloughing, the healing time can be extended but cosmetic outcomes are good. Eyelid reconstruction utilizing a free labial graft restored a mucocutaneous margin and recreated a functional eyelid, thus avoiding trichiasis or secondary keratitis.

Contributions of carotid bodies, retrotrapezoid nucleus neurons and preBötzinger complex astrocytes to the CO2 -sensitive drive for breathing.

Current models of respiratory CO2 chemosensitivity are centred around the function of a specific population of neurons residing in the medullary retrotrapezoid nucleus (RTN). However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm-generating region of the medulla oblongata - the preBötzinger complex (preBötC). There is also evidence that astrocytes, non-neuronal brain cells, contribute to central CO2 chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preBötC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO2 in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preBötC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preBötC astrocytes was associated with ∼20% and ∼30% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by ∼25%. Bilateral inhibition of RTN neurons transduced to express Gi-coupled designer receptors exclusively activated by designer drug (DREADDGi ) by application of clozapine-N-oxide reduced the CO2 response by ∼20% and ∼40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preBötC, inhibition of RTN neurons and carotid body denervation reduced the CO2 -induced respiratory response by ∼70%. These data further support the hypothesis that the CO2 -sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preBötC level, astrocytes modulate the activity of the respiratory network in response to CO2 , either by relaying chemosensory information (i.e. they act as CO2  sensors) or by enhancing the preBötC network excitability to chemosensory inputs. KEY POINTS: This study reevaluated the roles played by the carotid bodies, neurons of the retrotrapezoid nucleus (RTN) and astrocytes of the preBötC in mediating the CO2 -sensitive drive to breathe. The data obtained show that disruption of preBötC astroglial signalling, blockade of inputs from the peripheral chemoreceptors or inhibition of RTN neurons similarly reduce the respiratory response to hypercapnia. These data provide further support for the hypothesis that the CO2 -sensitive drive to breathe is mediated by the inputs from the peripheral chemoreceptors and several central chemoreceptor sites.

Trimethylation Enhancement Using Diazomethane (TrEnDi) Enables Enhanced Detection of Glufosinate and 3-(Methylphosphinico)propionic Acid from Complex Canola Samples.

Over the past century, agriculture practices have transitioned from manual cultivation to the use of an array of chemical herbicides for weed control including phosphinothricin, or glufosinate (GLUF). Consequently, the potential for long-term residual GLUF exposure in the food chain has increased, highlighting the need for improved analytical strategies for its detection, as well as the detection of its main breakdown product 3-(methylphosphinico)propionic acid (MPPA). Chemical derivatization strategies have been developed to improve the detection of GLUF and MPPA via liquid chromatography tandem mass spectrometry analyses. Herein, we employ trimethylation enhancement using diazomethane (TrEnDi) for the first time as a means to confer analytical advantages via quantitatively derivatizing these analytes into permethylated GLUF ([GLUFTr]+) and MPPA ([MPPATr+H]+). Comparing [GLUFTr]+ and [MPPATr+H]+ to underivatized counterparts, TrEnDi yields 2.8-fold and 1.7-fold improvements in reversed-phase chromatographic retention, respectively, while MS-based sensitivity is enhanced 4.1-fold and 11.0-fold, respectively. Successful analyte derivatization (with >99% yields) was further demonstrated on a commercial herbicide solution imparting consistent analytical enhancements. To investigate the benefits of TrEnDi in a bona fide agricultural scenario, simple aqueous extractions from distinct parts of field-grown canola plants were performed to quantify GLUF and MPPA before and after TrEnDi derivatization. In their underivatized forms, GLUF and MPPA were undetectable in all field samples, whereas [GLUFTr]+ and [MPPATr+H]+ were readily quantifiable using the same analysis conditions. Our results demonstrate that TrEnDi continues to be a useful tool to enhance the analytical characteristics of organic molecules that are traditionally difficult to detect.

Utility of end-tidal carbon dioxide to guide resuscitation termination in prolonged out-of-hospital cardiac arrest.

STUDY OBJECTIVE: To evaluate if the change in end-tidal carbon dioxide (ETCO2) over time has improved discriminatory value for determining resuscitation futility compared to a single ETCO2 value in prolonged, refractory non-shockable out-of-hospital cardiac arrest (OHCA). METHODS: This is a retrospective analysis of adult refractory non-shockable, non-traumatic OHCA patients in the Portland Cardiac Arrest Epidemiologic Registry (PDX Epistry) from 2018 to 2021. We defined refractory non-shockable OHCA cases as patients with lack of a shockable rhythm at any time or return of spontaneous circulation at any time prior to 30-min of on-scene resuscitation. We abstracted ETCO2 values first recorded after advanced airway placement and nearest to the 30-min mark of on-scene resuscitation (30 min-ETCO2) from EMS charts. The primary outcome was survival to hospital discharge. We compared 30 min-ETCO2 cutoffs of 10 mmHg and 20 mmHg to the trend (increasing or not) from initial to 30 min-ETCO2 (delta-ETCO2) using sensitivity, specificity, and area under the receiver operating curves (AUROC). RESULTS: Of 3837 adult OHCA, 2850 were initially non-shockable, and there were 617 (16.1%) cases of refractory non-shockable OHCA at 30-min. We excluded 320 cases without at least two ETCO2 recordings in the EMS chart, leaving 297 cases that met inclusion criteria. Of these, 176 (59.3%) were transported and 2 (0.7%) survived to discharge. Using absolute 30 min-ETCO2 cutoffs, both survivors were in the >10 mmHg group (sensitivity 100.0%, specificity 12.5%), whereas only one survivor was identified in the >20 mmHg group (sensitivity 50.0%, specificity 32.5%). Using delta-ETCO2, both survivors were in the increasing ETCO2 group (sensitivity 100.0%, specificity 60.7%). In comparing the two tests that did not misclassify survivors, the AUROC [95% CI] was higher when using delta-ETCO2 (0.803 [0.775-0.831]) compared to an absolute cutoff of 10 mmHg (0.563 [0.544-0.582]). CONCLUSIONS: Nearly one-sixth of EMS-treated adult OHCA patients had refractory non-shockable arrests after at least 30 min of ongoing resuscitation. In this group, the ETCO2 trend following advanced airway placement may be more accurate in guiding termination of resuscitation than an absolute ETCO2 cutoff of 10 or 20 mmHg.

Local tree cover predicts mosquito species richness and disease vector presence in a tropical countryside landscape.

Context: Land use change drives both biodiversity loss and zoonotic disease transmission in tropical countryside landscapes. Developing solutions for protecting countryside biodiversity, public health, and livelihoods requires understanding the scales at which habitat characteristics such as land cover shape biodiversity, especially for arthropods that transmit pathogens. Evidence increasingly shows that species richness for many taxa correlates with local tree cover. Objectives: We investigated whether mosquito species richness, community composition, and presence of disease vector species responded to land use and tree cover - and if so, whether at spatial scales similar to other taxa. Methods: We paired a field survey of mosquito communities in agricultural, residential, and forested lands in rural southern Costa Rica with remotely sensed tree cover data. We compared mosquito community responses to tree cover surrounding survey sites measured across scales, and analyzed community responses to land use and environmental gradients. Results: Tree cover was positively correlated with mosquito species richness, and negatively correlated with the presence of the common invasive dengue vector Aedes albopictus , particularly at small spatial scales of 80 - 200m. Land use predicted community composition and Ae. albopictus presence. Environmental gradients of tree cover, temperature, and elevation explained 7% of species turnover among survey sites. Conclusions: The results suggest that preservation and expansion of tree cover at local scales can protect biodiversity for a wide range of taxa, including arthropods, and also confer protection against disease vector occurrence. The identified spatial range of tree cover benefits can inform land management for conservation and public health protection.

Gα12 signaling regulates transcriptional and phenotypic responses that promote glioblastoma tumor invasion.

In silico interrogation of glioblastoma (GBM) in The Cancer Genome Atlas (TCGA) revealed upregulation of GNA12 (Gα12), encoding the alpha subunit of the heterotrimeric G-protein G12, concomitant with overexpression of multiple G-protein coupled receptors (GPCRs) that signal through Gα12. Glioma stem cell lines from patient-derived xenografts also showed elevated levels of Gα12. Knockdown (KD) of Gα12 was carried out in two different human GBM stem cell (GSC) lines. Tumors generated in vivo by orthotopic injection of Gα12KD GSC cells showed reduced invasiveness, without apparent changes in tumor size or survival relative to control GSC tumor-bearing mice. Transcriptional profiling of GSC-23 cell tumors revealed significant differences between WT and Gα12KD tumors including reduced expression of genes associated with the extracellular matrix, as well as decreased expression of stem cell genes and increased expression of several proneural genes. Thrombospondin-1 (THBS1), one of the genes most repressed by Gα12 knockdown, was shown to be required for Gα12-mediated cell migration in vitro and for in vivo tumor invasion. Chemogenetic activation of GSC-23 cells harboring a Gα12-coupled DREADD also increased THBS1 expression and in vitro invasion. Collectively, our findings implicate Gα12 signaling in regulation of transcriptional reprogramming that promotes invasiveness, highlighting this as a potential signaling node for therapeutic intervention.

Boosting SNR of cascaded FBGs in a sapphire fiber through a rapid heat treatment.

This Letter reports the performance of femtosecond (fs) laser-written distributed fiber Bragg gratings (FBGs) under high-temperature conditions up to 1600°C and explores the impact of rapid heat treatment on signal-to-noise ratio (SNR) enhancement. FBGs are essential for reliable optical sensing in extreme temperature environments. Comprehensive tests demonstrate the remarkable performance and resilience of FBGs at temperatures up to 1600°C, confirming their suitability for deployment in such conditions. The study also reveals significant fringe visibility improvements of up to ∼10 dB on a 1-m-long sapphire optical fiber through rapid heat treatment, representing a first-time achievement to the best of our knowledge. These enhancements are vital for improving the SNR and overall performance of optical fiber systems in extreme temperatures. Furthermore, the research attains long-term stability for the cascaded FBGs over a 24-hr period at 1600°C. This research expands our understanding of the FBG behavior in high-temperature environments and opens avenues for developing robust optical fiber systems for energy, aerospace, oil and gas, and high-temperature distributed sensing applications.

A research agenda to improve incidence and outcomes of assisted vaginal birth.

Access to emergency obstetric care, including assisted vaginal birth and caesarean birth, is crucial for improving maternal and childbirth outcomes. However, although the proportion of births by caesarean section has increased during the last few decades, the use of assisted vaginal birth has declined. This is particularly the case in low- and middle-income countries, despite an assisted vaginal birth often being less risky than caesarean birth. We therefore conducted a three-step process to identify a research agenda necessary to increase the use of, or reintroduce, assisted vaginal birth: after conducting an evidence synthesis, which informed a consultation with technical experts who proposed an initial research agenda, we sought and incorporated the views of women's representatives of this agenda. This process has allowed us to identify a comprehensive research agenda, with topics categorized as: (i) the need to understand women's perceptions of assisted vaginal birth, and provide appropriate and reliable information; (ii) the importance of training health-care providers in clinical skills but also in respectful care, effective communication, shared decision-making and informed consent; and (iii) the barriers to and facilitators of implementation and sustainability. From women's feedback, we learned of the urgent need to recognize labour, childbirth and postpartum experiences as inherently physiological and dignified human processes, in which interventions should only be implemented if necessary. The promotion and/or reintroduction of assisted vaginal birth in low-resource settings requires governments, policy-makers and hospital administrators to support skilled health-care providers who can, in turn, respectfully support women in labour and childbirth.

L'accès aux soins obstétriques d'urgence, y compris l'accouchement vaginal assisté et la césarienne, est essentiel pour améliorer les effets de la maternité et de l'accouchement. Toutefois, bien que la proportion de césariennes ait augmenté ces dernières décennies, le recours à l'accouchement vaginal assisté a diminué. C'est particulièrement le cas dans les pays à revenu faible ou intermédiaire, bien que l'accouchement vaginal assisté soit souvent moins risqué qu'une césarienne. Nous avons donc mené un processus en trois étapes afin d'imaginer un programme de recherche qui permettrait d'augmenter le recours à l'accouchement vaginal assisté ou de le réintroduire. Après avoir réalisé une synthèse des données probantes, qui a servi de base à une consultation avec des experts techniques qui ont proposé un programme de recherche initial, nous avons sollicité et incorporé les avis des représentantes des femmes pour ce programme. Ce processus nous a permis d'imaginer un programme de recherche complet, avec des sujets classés comme suit: (i) la nécessité de comprendre la perception qu'ont les femmes de l'accouchement vaginal assisté et de fournir des informations appropriées et fiables; (ii) l'importance de la formation des prestataires de soins de santé en matière de compétences cliniques, mais aussi de respect dans les soins de santé, de communication efficace, de prise de décision partagée et de consentement éclairé; ou (iii) les obstacles à la mise en œuvre et à la durabilité et les facteurs qui les facilitent. Les réactions de femmes nous ont appris qu'il était urgent de reconnaître que l'accouchement, la naissance et le post-partum sont des processus humains intrinsèquement physiologiques et dignes au cours desquels les interventions ne devraient être mises en œuvre qu'en cas de nécessité. La promotion et/ou la réintroduction de l'accouchement vaginal assisté dans les régions à faibles ressources nécessitent que les pouvoirs publics, les décideurs politiques et les administrations d'hôpitaux soutiennent les prestataires de soins de santé qualifiés, qui pourront à leur tour soutenir respectueusement les femmes pendant l'accouchement.

El acceso a la atención obstétrica de emergencia, incluido el parto vaginal asistido y el parto por cesárea, es crucial para mejorar los resultados de la maternidad y el parto. No obstante, aunque el porcentaje de partos por cesárea ha aumentado en las últimas décadas, el uso del parto vaginal asistido ha disminuido. Esto ocurre especialmente en los países de ingresos bajos y medios, a pesar de que un parto vaginal asistido suele ser menos arriesgado que un parto por cesárea. Por lo tanto, llevamos a cabo un proceso de tres pasos para identificar un programa de investigación necesario para aumentar el uso del parto vaginal asistido o volver a incorporarlo: tras realizar una síntesis de la evidencia, que sirvió de base para una consulta con expertos técnicos que propusieron un programa de investigación inicial, buscamos e integramos las opiniones de las representantes de las mujeres sobre este programa. Este proceso nos ha permitido identificar un programa de investigación exhaustivo, con temas categorizados como: (i) la necesidad de comprender las percepciones de las mujeres sobre el parto vaginal asistido, y proporcionar información adecuada y fiable; (ii) la importancia de formar a los profesionales sanitarios en habilidades clínicas, pero también en atención respetuosa, comunicación efectiva, toma de decisiones compartida y consentimiento informado; o (iii) las barreras y los facilitadores de la implementación y la sostenibilidad. A partir de las opiniones de las mujeres, nos enteramos de la urgente necesidad de reconocer las experiencias del parto, el alumbramiento y el posparto como procesos humanos inherentemente fisiológicos y dignos, en los que las intervenciones solo deben aplicarse si son necesarias. La promoción o la reincoporación del parto vaginal asistido en regiones de escasos recursos exige que los gobiernos, los responsables de formular políticas y los administradores de hospitales apoyen a los profesionales sanitarios capacitados que, a su vez, pueden ayudar a las mujeres en el trabajo de parto y el alumbramiento de manera respetuosa.

Outcomes with Tibial and Humeral Intraosseous Access Compared to Peripheral Intravenous Access in Out-of-Hospital Cardiac Arrest.

BACKGROUND: The optimal initial vascular access strategy for out-of-hospital cardiac arrest (OHCA) remains unknown. Our objective was to evaluate the association between peripheral intravenous (PIV), tibial intraosseous (TIO), or humeral intraosseous (HIO) as first vascular attempt strategies and outcomes for patients suffering OHCA. METHOD: This was a secondary analysis of the Portland Cardiac Arrest Epidemiologic Registry, which included adult patients (≥18 years-old) with EMS-treated, non-traumatic OHCA from 2018-2021. The primary independent variable in our analysis was the initial vascular access strategy, defined as PIV, TIO, or HIO based on the first access attempt. The primary outcome for this study was the return of spontaneous circulation (ROSC) at emergency department (ED) arrival (a palpable pulse on arrival to the hospital). Secondary outcomes included survival to: admission, discharge, and discharge with a favorable outcome (Cerebral Perfusion Category score of ≤2). We conducted multivariable logistic regressions, adjusting for confounding variables and for clustering using a mixed-effects approach, with prespecified subgroup analyses by initial rhythm. RESULTS: We included 2,993 patients with initial vascular access strategies of PIV (822 [27.5%]), TIO (1,171 [39.1%]), and HIO (1,000 [33.4%]). Multivariable analysis showed lower odds of ROSC at ED arrival (adjusted odds ratio [95% CI]) with TIO (0.79 [0.64-0.98]) or HIO (0.75 [0.60-0.93]) compared to a PIV-first strategy. These associations remained in stratified analyses for those with shockable initial rhythms (0.60 [0.41-0.88] and 0.53 [0.36-0.79]) but not in patients with asystole or pulseless electrical activity for TIO and HIO compared to PIV, respectively. There were no statistically significant differences in adjusted odds for survival to admission, discharge, or discharge with a favorable outcome for TIO or HIO compared to the PIV-first group in the overall analysis. Patients with shockable initial rhythms had lower adjusted odds of survival to discharge (0.63 [0.41-0.96] and 0.64 [0.41-0.99]) and to discharge with a favorable outcome (0.60 [0.39-0.93] and 0.64 [0.40-1.00]) for TIO and HIO compared to PIV, respectively. CONCLUSIONS: TIO or HIO as first access strategies in OHCA were associated with lower odds of ROSC at ED arrival compared to PIV.

An In Silico Database for Automated Feature Identification of High-Resolution Tandem Mass Spectrometry 13C-Trimethylation Enhancement Using Diazomethane (13C-TrEnDi)-Modified Lipid Data.

13C-Trimethylation enhancement using diazomethane (13C-TrEnDi) is a chemical derivatization technique that uses 13C-labeled diazomethane to increase mass spectrometry (MS) signal intensities for phosphatidylcholine (PC) and phosphatidylethanolamine (PE) lipid classes, both of which are of major interest in biochemistry. In silico mass spectrometry databases have become mainstays in lipidomics experiments; however, 13C-TrEnDi-modified PC and PE species have altered m/z and fragmentation patterns from their native counterparts. To build a database of 13C-TrEnDi-modified PC and PE species, a lipid extract from nutritional yeast was derivatized and fragmentation spectra of modified PC and PE species were mined using diagnostic fragmentation filtering by searching 13C-TrEnDi-modified headgroups with m/z 199 (PC) and 202 (PE). Identities of 25 PC and 10 PE species were assigned after comparing to predicted masses from the Lipid Maps Structure Database with no false positive identifications observed; neutral lipids could still be annotated after derivatization. Collision energies from 16 to 52 eV were examined, resulting in three additional class-specific fragment ions emerging, as well as a combined sn-1/sn-2 fragment ion, allowing sum-composition level annotations to be assigned. Using the Lipid Blast templates, a NIST-compatible 13C-TrEnDi database was produced based on fragmentation spectra observed at 36 eV and tested on HEK 293T cell lipid extracts, identifying 47 PC and 24 PE species, representing a 1.8-fold and 2.2-fold increase in annotations, respectively. The 13C-TrEnDi database is freely available, MS vendor-independent, and widely compatible with MS data processing pipelines, increasing the throughput and accessibility of TrEnDi for lipidomics applications.