COATI: Multimodal Contrastive Pretraining for Representing and Traversing Chemical Space.

Creating a successful small molecule drug is a challenging multiparameter optimization problem in an effectively infinite space of possible molecules. Generative models have emerged as powerful tools for traversing data manifolds composed of images, sounds, and text and offer an opportunity to dramatically improve the drug discovery and design process. To create generative optimization methods that are more useful than brute-force molecular generation and filtering via virtual screening, we propose that four integrated features are necessary: large, quantitative data sets of molecular structure and activity, an invertible vector representation of realistic accessible molecules, smooth and differentiable regressors that quantify uncertainty, and algorithms to simultaneously optimize properties of interest. Over the course of 12 months, Terray Therapeutics has collected a data set of 2 billion quantitative binding measurements of small molecules to therapeutic targets, which directly motivates multiparameter generative optimization of molecules conditioned on these data. To this end, we present contrastive optimization for accelerated therapeutic inference (COATI), a pretrained, multimodal encoder-decoder model of druglike chemical space. COATI is constructed without any human biasing of features, using contrastive learning from text and 3D representations of molecules to allow for downstream use with structural models. We demonstrate that COATI possesses many of the desired properties of universal molecular embedding: fixed-dimension, invertibility, autoencoding, accurate regression, and low computation cost. Finally, we present a novel metadynamics algorithm for generative optimization using a small subset of our proprietary data collected for a model protein, carbonic anhydrase, designing molecules that satisfy the multiparameter optimization task of potency, solubility, and drug likeness. This work sets the stage for fully integrated generative molecular design and optimization for small molecules.

COVID-19 Testing Among Out-of-Hospital Cardiac Arrest Patients: Implications for Public Health.

OBJECTIVE: The objective of this study was to compare COVID-19 test positivity among out-of-hospital cardiac arrest patients whose resuscitative efforts were terminated in the field with the surrounding community. METHODS: This was a retrospective cohort study of out-of-hospital cardiac arrest patients for whom unsuccessful resuscitative efforts were terminated in the field. Emergency medical services (EMS) personnel obtained postmortem COVID-19 nasal swab specimens from these patients between July 1, 2020 and February 28, 2022 to facilitate patient contact tracing and awareness of potential occupational exposure. A chi-square (n-1) was used to compare test result proportions between cardiac arrest patients and the community at large. A Pearson correlation was used to correlate test positivity among the two groups. RESULTS: EMS personnel obtained postmortem specimens from 648 cardiac arrest patients; 20 (3.1%) were inconclusive. Of the 628 specimens successfully tested, 69 (11.0%) were positive, and 559 (89.0%) were negative. Monthly positivity ranged from 0.0% to 34.0%. For the community at large, overall test positivity during the same period was 5.1%, with a monthly range from 0.4% to 15.2%. Overall, expired and tested cardiac arrest patients had 5.9% (95%CI 3.68 - 8.59) greater COVID-19 test positivity than the general community. There was significant correlation in monthly positivity rates between the groups (r = 0.778, p < .001, 95%CI0.51 - 0.91). CONCLUSIONS: Compared to the general population, COVID-19 was over-represented among EMS cardiac arrest patients who died in the field. Postmortem testing by EMS personnel, not typical practice, identified infectious disease cases that would have otherwise gone undetected, indicating potential for future surveillance applications.

An EMS Transport Destination Officer is Associated with Reductions in Simultaneous Emergency Department Arrivals.

Objective: A centralized transport destination officer (TDO) is one technique used by EMS systems to distribute patients. This retrospective analysis examines the effect of a TDO on simultaneous arrivals and consecutive simultaneous arrivals at emergency departments in a suburban EMS system, and their relationship to transport unit throughput.Methods: Each system hospital arrival from July 1, 2020 to February 28, 2022, at six study hospitals was evaluated. An arrival within 300 seconds of the previous arrival at the same hospital was designated as a simultaneous arrival. Any simultaneous arrival where the previous arrival was also a simultaneous arrival was further designated as a consecutive simultaneous arrival. Simultaneous and consecutive simultaneous arrivals were aggregated by day to produce countywide daily totals. Median and interquartile ranges were calculated and a Wilcoxon rank-sum test was used to compare each outcome, with the presence of the TDO as the grouping variable. A Pearson correlation was used to assess the relationship between daily total simultaneous and consecutive simultaneous arrivals to median daily hospital turnaround interval.Results: Median simultaneous arrivals showed a 15% reduction from 21 [IQR: 17 - 26] to 18 [IQR: 15 - 22] (p < 0.001). Consecutive simultaneous arrivals decreased 33%, from 6 [IQR: 4 - 9] to 4 per day [IQR: 2 - 6] on days when the TDO was in place (p < 0.001). Increased total daily simultaneous and consecutive simultaneous arrivals also showed statistically significant correlation with increased median daily hospital turnaround interval (simultaneous r = 0.488, p < 0.001; consecutive simultaneous r = 0.360 p < 0.001).Conclusions: A centralized EMS transport destination officer is associated with a reduction in simultaneous and consecutive simultaneous arrivals of patients in the emergency department. Further analysis also shows a significant correlation between the number of simultaneous and consecutive simultaneous arrivals and transport unit hospital turnaround interval. This technique to achieve load balancing across transport destinations appears to be effective and can be considered in systems experiencing throughput difficulties.

Decreases in out of hospital cardiac arrest (OHCA) outcome metrics persist when known COVID patients are excluded from analysis.

OBJECTIVE: A decline in OHCA performance metrics during the pandemic has been reported in the literature but the cause is still not known. The Montgomery County Fire and Rescue Service (MCFRS) observed a decline in both the rate of return of spontaneous circulation (ROSC) and the proportion of resuscitations that resulted in cerebral performance category (CPC) 1 or 2 discharge of the patient beginning in March of 2020. This study examines whether the decline in these performance metrics persists when known COVID positive patients are excluded from the analysis. METHODS: Two samples of OHCA patients for similar time periods (one year apart) before and after the start of the COVID pandemic were developed. A database of known COVID positive patients among EMS encounters was used to identify and exclude COVID positive patients. OHCA outcomes in these two groups were then compared using a Chi-square test and Fisher's exact test for difference in proportions and Analysis of Variance (ANOVA) for difference in means. A two-stage multivariable logistic regression model was used to develop odds ratios for achieving ROSC and CPC 1 or 2 discharge in each period. RESULTS: After excluding known COVID patients, 32.5% of the patients in the pre-COVID period achieved ROSC compared to 25.1% in the COVID period (p = 0.007). 6% of patients in the pre-COVID period were discharged with CPC 1 or 2 compared to 3.2% from the COVID era (p = 0.026). Controlling for all available patient characteristics, patients undergoing OHCA resuscitation prior to be beginning of the pandemic were 1.2 times more likely to achieve ROSC and 1.6 times more likely to be discharged with CPC 1 or 2 than non-COVID patients in the pandemic era sample. CONCLUSIONS: When known COVID patients are excluded, pre-pandemic OHCA resuscitation patients were more likely to achieve ROSC and CPC 1 or 2 discharge. The prevalence of known COVID positive patients among all OHCA resuscitations during the pandemic was not sufficient to fully account for the marked decrease in both ROSC and CPC 1 or 2 discharges. Other causative factors must be sought.

Shifting Power in Practice: The Importance of Contextual and Experiential Evidence in Guiding MCH Decision Making.

BACKGROUND: Evidence is central to all maternal and child health (MCH) decision-making processes, continuously interacting with and influencing our work. There is a growing emphasis in MCH on using evidence-based approaches when addressing public health challenges, but the field lacks a unified understanding of what constitutes evidence. MCH must operate from an expansive understanding of evidence that centers community voice and acknowledges the role of evidence prioritization in achieving equitable population-level outcomes. CALL TO ACTION: What we consider valid evidence has immense implications for MCH practice, including whose work is deemed worthy of funding and replication. The authors advocate for shifting the field's evidence paradigm from being primarily focused on research findings to also recognize the importance of community-rooted evidence. Contextual and experiential evidence, alongside research evidence, should be considered for two purposes: (1) to support the effectiveness of a given practice generally, and (2) to support that the practice will work in specific contexts. Putting this shift into practice requires explicit power shifting - the MCH workforce must cede power to those who have been historically barred from participating in and guiding research. To facilitate this, MCH professionals must build skills in communication, equitable leadership, and change management. CONCLUSION: The MCH workforce should position communities to set their own priorities and define, develop, and disseminate evidence representative of their priorities. Evidence co-creation is key to establishing and sustaining transformative relationships between community members and Title V programs, shifting power structures to build upon existing community leadership and assets.

A Call to Transform Maternal and Child Health Mentorship to Build Inclusivity, Honor Diversity of Experiences, and Tackle the Root of Health Disparities.

INTRODUCTION: Mentorship should be a transformative experience that propels mentees from one point in their career to another and drives personal growth. Within the field of maternal and child health (MCH), it is considered a critical professional duty. However, MCH has yet to explicitly embrace mentorship practice as a means to address workforce challenges including turnover, knowledge loss, and undue burden on the part of historically oppressed individuals and communities to overturn oppressive systems. CALL TO ACTION: We advocate for public calls for diversity and equity to be met with strategic enhancement of the practice of MCH mentorship. Transformative MCH mentorship should be used to promote positive identity formation, understanding of self in context, efficacy, and sustained commitment to working with MCH populations in ways that are inclusive and prevent the perpetration of the problematic power dynamics that lead to inequitable outcomes. RECOMMENDATIONS: We present recommendations to strengthen MCH mentorship practice. At the individual level, there should be a refreshment of norms and expectations, where mentorship is seen as a uniquely flexible opportunity for mutual learning. At the organizational level, embedding mentorship in all aspects of practice helps establish and sustain a culture of belonging. This transformative organizational culture can attract and retain future generations of professionals that are not only more representative of the populations that MCH programs support but are prepared to authentically elevate the needs and strengths of those populations. These suggestions incorporate best practices from other fields and include ideas for the MCH field in particular.

Machine learning and AI-based approaches for bioactive ligand discovery and GPCR-ligand recognition.

In the last decade, machine learning and artificial intelligence applications have received a significant boost in performance and attention in both academic research and industry. The success behind most of the recent state-of-the-art methods can be attributed to the latest developments in deep learning. When applied to various scientific domains that are concerned with the processing of non-tabular data, for example, image or text, deep learning has been shown to outperform not only conventional machine learning but also highly specialized tools developed by domain experts. This review aims to summarize AI-based research for GPCR bioactive ligand discovery with a particular focus on the most recent achievements and research trends. To make this article accessible to a broad audience of computational scientists, we provide instructive explanations of the underlying methodology, including overviews of the most commonly used deep learning architectures and feature representations of molecular data. We highlight the latest AI-based research that has led to the successful discovery of GPCR bioactive ligands. However, an equal focus of this review is on the discussion of machine learning-based technology that has been applied to ligand discovery in general and has the potential to pave the way for successful GPCR bioactive ligand discovery in the future. This review concludes with a brief outlook highlighting the recent research trends in deep learning, such as active learning and semi-supervised learning, which have great potential for advancing bioactive ligand discovery.

Enhanced and sustained T cell activation in response to fluid shear stress.

The efficacy of T cell therapies in treating solid tumors is limited by poor in vivo persistence, proliferation, and cytotoxicity, which can be attributed to limited and variable ex vivo activation. Herein, we present a 10-day kinetic profile of T cells subjected to fluid shear stress (FSS) ex vivo, with and without stimulation utilizing bead-conjugated anti-CD3/CD28 antibodies. We demonstrate that mechanical stimulation via FSS combined with bead-bound anti-CD3/CD28 antibodies yields a synergistic effect, resulting in amplified and sustained downstream signaling (NF-κB, c-Fos, and NFAT), expression of activation markers (CD69 and CD25), proliferation and production of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2). This study represents the first characterization of the dynamic response of primary T cells to FSS. Collectively, our findings underscore the critical role of mechanosensitive ion channel-mediated mechanobiological signaling in T cell activation and fitness, enabling the development of strategies to address the current challenges associated with poor immunotherapy outcomes.

Disaster Preparedness for Clinics - Further Study from Haiti.

OBJECTIVE: This team created a manual to train clinics in low- and middle-income countries (LMICs) to effectively respond to disasters. This study is a follow-up to a prior study evaluating disaster response. The team returned to previously trained clinics to evaluate retention and performance in a disaster simulation. BACKGROUND: Local clinics are the first stop for patients when disaster strikes LMICs. They are often under-resourced and under-prepared to respond to patient needs. Further effort is required to prepare these crucial institutions to respond effectively using the Incident Command System (ICS) framework. METHODS: Two clinics in the North East Region of Haiti were trained through a disaster manual created to help clinics in LMICs respond effectively to disasters. This study measured the clinic staff's response to a disaster drill using the ICS and compared the results to prior responses. RESULTS: Using the prior study's evaluation scale, clinics were evaluated on their ability to set up an ICS. During the mock disaster, staff was evaluated on a three-point scale in 13 different metrics, grading their ability to mitigate, prepare, respond, and recover in a disaster. By this scale, both clinics were effective (36/39; 92%) in responding to a disaster. CONCLUSION: The clinics retained much prior training, and after repeat training, the clinics improved their disaster response. Future study will evaluate the clinics' ability to integrate disaster response with country-wide health resources to enable an effective outcome for patients.

Assessment of Acute Obstetrical Needs and the Potential Utility of Point-Of-Care Ultrasound in the North East Region of Haiti: A Cross-Sectional Study.

Background: Point-of-care ultrasound (POCUS) implemented through task shifting to nontraditional users has potential as a diagnostic adjuvant to enhance acute obstetrical care in resource-constrained environments with limited access to physician providers. Objective: This study evaluated acute obstetrical needs and the potential role for POCUS programming in the North East region of Haiti. Methods: Data was collected on all women presenting to the obstetrical departments of two Ministry of Public Health and Population (MSPP)-affiliated public hospitals in the North East region of Haiti: Fort Liberté Hospital and Centre Medicosocial de Ouanaminthe. Data was obtained via retrospective review of hospital records from January 1 through March 31, 2016. Trained personnel gathered data on demographics, obstetrical history, diagnoses, clinical care and outcomes using a standardized tool. Diagnoses a priori, defined as those diagnoses whose detection could be assisted with POCUS, included multi-gestations, non-vertex presentation, cephalopelvic disproportion, placental abruption, placenta previa, spontaneous abortions, retained products and ectopic pregnancy. Results: Data were collected from 589 patients during the study period. Median maternal age was 26 years and median gestational age was 38 weeks. The most common reason for seeking care was pelvic pain (85.2%). Sixty-seven (11.5%) women were transferred to other facilities for higher-level care. Among cases not transferred, post-partum hemorrhage, infant mortality and maternal mortality occurred in 2.4%, 3.0% and 0.6% of cases, respectively. There were 69 cases with diagnoses that could have benefited from POCUS use. Between sites, significantly more cases had the potential for improved diagnostics with POCUS at Fort Liberté Hospital (19.8%) than Centre Medicosocial de Ouanaminthe (8.2%) (p < 0.001). Conclusion: Acute obstetrical care is common and POCUS has the potential to impact the care of obstetrical patients in the North East region of Haiti. Future programs evaluating the feasibility of task shifting and the sustainable impacts of acute obstetric POCUS in Haiti will be important.

Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

Individuals at Risk for Suicide.

BACKGROUND: Individuals experiencing suicidal ideation and/or behaviors are often difficult to engage in treatment. Up to 50% of individuals presenting to an ER for treatment of a suicidal crisis refuse outpatient treatment referrals. This study examined outpatient mental health clinicians' perceptions of the barriers to and facilitators of mental health treatment engagement of individuals at risk for suicide. METHOD: Thirty-six mental health clinicians working with clients with past and/or current suicidality (ideation, behaviors) in outpatient mental health centers participated in four focus groups. Data were collected using semistructured interview. A process of content analysis was utilized in which data were analyzed thematically. RESULTS: Five main domains of barriers and facilitators emerged including (a) client-level, (b) clinician-level, (c) service-level, (d) agency-level, and (e) intervention-level variables. In all, 38 barriers and 31 facilitators were identified. The most frequently identified facilitator was the clinician's own sense of engagement with the client, identified by 31% of the clinicians. The most frequently identified barrier was housing instability, identified by 34% of the clinicians. CONCLUSION: Knowledge of clinicians' perspective on treatment engagement of clients at risk for suicide may inform the development and implementation of interventions and guide training/supervision programs for those working with this vulnerable population.

Anti-mullerian hormone is higher in seizure-free women with epilepsy compared to those with ongoing seizures.

OBJECTIVE: To determine if anti-mullerian hormone (AMH), a neuroactive peptide hormone and a measure of ovarian reserve, is different between women with epilepsy (WWE) and healthy controls (HC) seeking pregnancy and to evaluate epilepsy-related factors associated with AMH concentrations. METHODS: Subjects were participants in Women with Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD), a multi-center prospective, observational cohort study evaluating fecundity in WWE compared to HC, ages 18-40 years. WWE were divided into a Sz+ group or a Sz- group, dependent on whether they had seizures within the 9 months prior to enrollment. Serum was collected, and AMH concentrations were measured as an exploratory analysis. Linear and logistic regression models were used to assess associations and control for covariates. RESULTS: Serum AMH concentrations were measured in 72 out of 90 enrolled WWE and 97 out of 109 HC; the remaining subjects became pregnant before serum was obtained. Thirty WWE were in the Sz+ group and 40 in the Sz- group (retrospective seizure information was missing for two). All AMH concentrations were within the range, however, the normal inverse correlation between age and AMH was present in the HC and in the Sz- groups, but was lacking in the Sz+ group. Mean AMH concentration was higher in the Sz- group (3982pg/ml (SD+/-2452)) compared to the Sz+ group of WWE (2776pg/ml (SD+/-2308)) and HCs (3241 (SD±2647)). All values were within the expected range for age. In WWE, by linear regression, after controlling for age and BMI, seizure occurrence remained associated with AMH (p=0.025). In the prospective phase of the study, AMH concentrations were also associated with seizure occurrence during the menstrual cycle in which the serum sample was obtained (p=0.012). Antiepileptic drugs and other epilepsy factors were not associated with AMH concentrations. When analyzing the Sz- WWE group and the HC group by linear regression with AMH as the dependent variable, after controlling for age and BMI, the association with AMH was also present (p=0.017). AMH concentrations of the Sz+ group and HCs did not differ. SIGNIFICANCE: In this exploratory analysis, seizure freedom was associated with higher AMH concentrations compared to women with ongoing seizures and to HCs. Future studies should further investigate the mechanism of the association of AMH with seizure occurrence, whether AMH could have a direct seizure-protective neuroactive hormone effect, as well as implications of AMH concentrations as a biomarker for ovarian reserve in women with epilepsy.