Investigating ticagrelor in a preclinical pipeline as a novel therapeutic to prevent preterm birth.

In brief: Preterm birth is the leading cause of perinatal morbidity and mortality, and new therapies that delay preterm birth and improve neonatal outcomes are urgently needed. This study investigates whether ticagrelor inhibits uterine contractility and inflammation in preclinical in vitro, ex vivo (human) and in vivo (mouse) studies, to explore the potential of repurposing ticagrelor for the prevention of preterm birth. Abstract: Preterm birth remains a significant global health challenge, affecting approximately 10% of pregnancies and resulting in one million deaths globally every year. Tocolytic agents, used to manage preterm labour, have considerable limitations including lack of efficacy, and adverse side effects, emphasising the urgent need for innovative solutions. Here, we explore repurposing an antiplatelet cardioprotective drug, ticagrelor, as a potential treatment to prevent preterm birth. Ticagrelor has demonstrated pleiotropic actions beyond platelet inhibition, including relaxant effects on smooth muscle cells and anti-inflammatory effects in models of diabetes and sepsis. As preterm birth is underscored by inflammatory processes triggering uterine contractions, these actions position ticagrelor as an attractive candidate for prevention or delay of preterm birth. Utilising primary human myometrial tissue, human myometrial cells, and a mouse model of preterm birth, we investigated ticagrelor's potential as a safe and effective therapy for preterm birth. We showed that ticagrelor did not reduce the frequency or strength of spontaneous muscle contractions of ex vivo myometrial tissue nor did it reduce in vitro inflammation-induced contractility in myometrial cells. Additionally, ticagrelor did not exhibit the anticipated anti-inflammatory effects in myometrial cell culture experiments. In our mouse model of preterm birth, ticagrelor neither improved the preterm birth rate or fetal survival outcomes. Gene expression of pro-inflammatory cytokines and contraction-associated proteins in postpartum mouse uteri were unaltered by ticagrelor. In conclusion, ticagrelor is not a strong candidate to continue investigations in clinical trial for the treatment of preterm labour and prevention of preterm birth.

Child Opportunity Index and Pediatric Intensive Care Outcomes: A Multicenter Retrospective Study in the United States.

OBJECTIVES: To evaluate for associations between a child's neighborhood, as categorized by Child Opportunity Index (COI 2.0), and 1) PICU mortality, 2) severity of illness at PICU admission, and 3) PICU length of stay (LOS). DESIGN: Retrospective cohort study. SETTING: Fifteen PICUs in the United States. PATIENTS: Children younger than 18 years admitted from 2019 to 2020, excluding those after cardiac procedures. Nationally-normed COI category (very low, low, moderate, high, very high) was determined for each admission by census tract, and clinical features were obtained from the Virtual Pediatric Systems LLC (Los Angeles, CA) data from each site. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 33,901 index PICU admissions during the time period, median patient age was 4.9 years and PICU mortality was 2.1%. There was a higher percentage of admissions from the very low COI category (27.3%) than other COI categories (17.2-19.5%, p < 0.0001). Patient admissions from the high and very high COI categories had a lower median Pediatric Index of Mortality 3 risk of mortality (0.70) than those from the very low, low, and moderate COI groups (0.71) ( p < 0.001). PICU mortality was lowest in the very high (1.7%) and high (1.9%) COI groups and highest in the moderate group (2.5%), followed by very low (2.3%) and low (2.2%) ( p = 0.001 across categories). Median PICU LOS was between 1.37 and 1.50 days in all COI categories. Multivariable regression revealed adjusted odds of PICU mortality of 1.30 (95% CI, 0.94-1.79; p = 0.11) for children from a very low versus very high COI neighborhood, with an odds ratio [OR] of 0.996 (95% CI, 0.993-1.00; p = 0.05) for mortality for COI as an ordinal value from 0 to 100. Children without insurance coverage had an OR for mortality of 3.58 (95% CI, 2.46-5.20; p < 0.0001) as compared with those with commercial insurance. CONCLUSIONS: Children admitted to a cohort of U.S. PICUs were often from very low COI neighborhoods. Children from very high COI neighborhoods had the lowest risk of mortality and observed mortality; however, odds of mortality were not statistically different by COI category in a multivariable model. Children without insurance coverage had significantly higher odds of PICU mortality regardless of neighborhood.

Association of the Child Opportunity Index and Inpatient Illness Severity in the United States, 2018-2019.

OBJECTIVE: Children residing in impoverished neighborhoods have reduced access to health care resources. Our objective was to identify potential associations between Child Opportunity Index (COI), a composite score of neighborhood characteristics, and inpatient severity of illness and clinical trajectory among United States (US) children. METHODS: This retrospective cohort study assessed data using the Pediatric Health Information System Registry from 2018 to 2019. Primary exposure variable was COI level (range: very low [CO1 1], low [COI 2], moderate [COI 3], high [COI 4], and very high [COI 5]). Markers of inpatient clinical severity included index mortality, Pediatric Intensive Care Unit (PICU) admission, invasive mechanical ventilation (IMV), and hospital length of stay (LOS). Subgroup analysis of COI and clinical outcome variation by United States Census Geographic Regions was conducted. Adjusted regression analysis was utilized to understand associations between COI and inpatient clinical severity outcomes. RESULTS: Of the 132,130 encounters, 44% resided in very low or low COI neighborhoods. In adjusted models, very low COI was associated with increased mortality (aOR: 1.35, 95% CI: 1.05-1.74, P = .018), PICU admission (aOR: 1.06, 95% CI: 1.02-1.11, P = 0.014), IMV (aOR: 1.12, 95% CI: 1.04-1.21, P = .002), and higher hospital LOS (P = .045). Regional variation by COI depicted the East North Central region having the highest rate of mortality (20.5%), P < .001, and PICU admissions (23%), P = .014. CONCLUSIONS: Our multicenter, retrospective study highlights the interaction between neighborhood-level deprivation and worsened health disparities, indicating a need for prospective study.

Proximity Proteome Analysis Reveals Novel TREM2 Interactors in the ER-Mitochondria Interface of Human Microglia.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in microglial biology and the pathogenesis of Alzheimer's disease (AD). Besides DNAX-activating protein 12 (DAP12), a communal adaptor for TREM2 and many other receptors, other cellular interactors of TREM2 remain largely elusive. We employed a 'proximity labeling' approach using a biotin ligase, TurboID, for mapping protein-protein interactions in live mammalian cells. We discovered novel TREM2-proximal proteins with diverse functions, including those localized to the Mitochondria-ER contact sites (MERCs), a dynamic subcellular 'hub' implicated in a number of crucial cell physiology such as lipid metabolism. TREM2 deficiency alters the thickness (inter-organelle distance) of MERCs, a structural parameter of metabolic state, in microglia derived from human induced pluripotent stem cells. Our TurboID-based TREM2 interactome study suggest novel roles for TREM2 in the structural plasticity of the MERCs, raising the possibility that dysregulation of MERC-related TREM2 functions contribute to AD pathobiology.

Discussing pathologic mechanisms of Diabetic retinopathy & therapeutic potentials of curcumin and ß-glucogallin in the management of Diabetic retinopathy.

Diabetic retinopathy (DR) is a form of retinal microangiopathy that occurs as a result of long-term Diabetes mellitus (DM). Patients with Diabetes mellitus typically suffer from DR as a progression of the disease that may be due to initiation and dysregulation of pathways like the polyol, hexosamine, the AGE/RAGE, and the PKC pathway, which all have negative impacts on eye health and vision. In this review, various databases, including PubMed, Google Scholar, Web of Science, and Science Direct, were scoured for data relevant to the aforementioned title. The three most common therapies for DR today are retinal photocoagulation, anti-vascular endothelial growth factor (VEGF) therapy, and vitrectomy, however, there are a number of drawbacks and limits to these methods. So, it is of critical importance and profound interest to discover treatments that may successfully address the pathogenesis of DR. Curcumin and ß-glucogallin are the two potent compounds of natural origin that are already being used in various nutraceutical formulations for several ailments. They have been shown potent antiapoptotic, anti-inflammatory, antioxidant, anticancer, and pro-vascular function benefits in animal experiments. Their parent plant species have been used for generations by practitioners of traditional herbal medicine for the treatment and prevention of various eye ailments. In this review, we will discuss about pathophysiology of Diabetic retinopathy and the therapeutic potentials of curcumin and ß-glucogallin one of the principal compounds from Curcuma longa and Emblica officinalis in Diabetic retinopathy.

The Haven Clinic: The Planning and Implementation of a Medical Home for Child Trafficking Survivors.

The authors describe the planning and implementation of a survivor-informed medical home for child trafficking survivors. Key partnerships necessary for establishing clinical infrastructure are highlighted. The trauma-informed clinical practices are described in detail. An overview of next steps for evaluation of this clinical program is provided.

Melamine-Formaldehyde Polymer-Based Nanocomposite for Sunlight-Driven Photodegradation of Multiple Dyes and Their Mixture.

Cadmium sulfide (CdS)-decorated, cross-linked melamine-formaldehyde polymer-based nanocomposite (MFP-CdS) has been synthesized. MFP-CdS is utilized here as a photoactive material for the photodegradation of six model organic dyes and their mixture in an aqueous medium in the presence of sunlight. The half-life values from the kinetic study of multiple dyes strongly support the importance of sunlight on the fast degradation of all six dyes compared to bulb light and control (dark) conditions. A comparative 1H NMR analysis of the dyes and their degraded products has been performed to support the breakdown of the aromatic framework of organic dyes using MFP-CdS in sunlight. The mechanisms involved in the photodegradation of dyes have been investigated based on radical trapping studies that support the significant involvement of superoxide radicals along with holes. Moreover, the dye removal efficiency using MFP-CdS from real industrial wastewater samples is evaluated via the external spiking of organic dyes and their mixture in unknown industrial effluents where they showed similar photodegradation results. Based on the high recyclability of MFP-CdS, these are used for multiple cycles.

Pulmonary Manifestations in Patients of Rheumatoid Arthritis and its Correlation with Severity of Disease.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology marked by symmetric, peripheral polyarthritis. RA has a prevalence of 1-2% in the general adult population. The mortality rate in patients with RA increases during the course of the disease, with a tendency to accelerate after 15 yearsAim: To study the pulmonary manifestations and their severity using [Disease Activity Score (DAS)-28 score] in patients of RAMaterials and methods: Present study was conducted in the Department of Medicine, Sardar Patel Medical College and Associated Group of Hospitals Bikaner, Bikaner, Rajasthan, India, on 100 patients. This study was a cross-sectional, observational study conducted over 1 year. Consecutive cases of RA patients attending the outpatient department or admitted to the medicine wards were selected according to the inclusion and exclusion criteriaResults: Pulmonary manifestation was present in a total of 38% of cases, while the remaining 62% of cases had no pulmonary manifestation. The presence of comorbidity and C-reactive protein (CRP) was significantly associated with pulmonary manifestation in RA patients. On high-resolution computed tomography (HRCT), the most common finding was interstitial lung disease (ILD) (60.5%), with usual interstitial pneumonia (UIP) as the most common pattern. On performing a pulmonary function test (PFT), 33 patients (86.84%) had an abnormal result, with restrictive as the most common patternConclusion: The patients of RA, especially those with advanced age, long duration of disease, male sex, and associated comorbidity, should be screened for pulmonary complications of RA using X-ray chest and PFT, supplemented by HRCT chest wherever required.

Social Determinants of Health in Pediatric Rehabilitation for Children with Traumatic Injury: A Systematic Review.

OBJECTIVE: To examine the current evidence regarding health care disparities in pediatric rehabilitation after hospitalization with traumatic injury. STUDY DESIGN: This systematic review utilized both PubMed and EMBASE, and each was searched with key MESH terms. Studies were included in the systematic review if they (1) addressed social determinants of health including, but not limited to, race, ethnicity, insurance status, and income level; (2) focused on inpatient and outpatient rehabilitation services posthospital stay; (3) were based in the pediatric population; and (4) addressed traumatic injury requiring hospitalization. Only studies from within the US were included. RESULTS: From 10 169 studies identified, 455 abstracts were examined for full-text review, and 24 studies were chosen for data extraction. Synthesis of the 24 studies revealed 3 major themes: (1) access to services; (2) outcomes from rehabilitation; and (3) service provision. Patients with public insurance had decreased availability of service providers and had longer outpatient wait times. Non-Hispanic Black and Hispanic children were more likely to have greater injury severity and decreased functional independence after discharge. Lack of interpreter services was associated with decreased utilization of outpatient services. CONCLUSIONS: This systematic review identified significant effects of health care disparities on the rehabilitation process in pediatric traumatic injury. Social determinants of health must be thoughtfully addressed to identify key areas of improvement for the provision of equitable health care.

Outcomes of Patients Receiving Thrombolysis in a Mobile Stroke Unit: A 4-Year Retrospective, Observational, Single-Center Study.

BACKGROUND AND PURPOSE: Patients with acute ischemic stroke (AIS) eligible for thrombolysis benefit when thrombolysis is administered quickly, and mobile stroke units (MSU) can facilitate timely thrombolysis. We sought to compare time metrics and clinical outcomes of AIS patients receiving thrombolysis in an MSU compared with patients arriving via local emergency medical services (EMS). METHODS: We performed a retrospective, non-randomized, cohort study comparing MSU-arriving to EMS-arriving AIS patients from January 20, 2017 through November 30, 2020. The primary outcome was rate of return to baseline functional status as measured by the modified Rankin Score (mRS) 90 days after thrombolysis. Secondary outcomes included evaluation and treatment intervals from last known well, treatment rate in the first hour of symptoms, hospital length of stay, and mortality. Chi square and Student's t-test were used to compare groups. RESULTS: Of 1752 total patients with prehospital suspected stroke, 975 (55.7%) were transported via MSU, of whom 431 (44.2%) were diagnosed with stroke, including 368 (85.4%) with AIS, and 69 AIS patients (18.8%) received thrombolysis. Of 777 (44.3%) EMS-arriving patients, 373 (48%) were diagnosed with stroke, including 305 (81.8%) with AIS, and 74 (24.3%) received thrombolysis. Though not statistically significant, point estimates of the proportion of AIS patients treated with thrombolysis returning to baseline functional status were more commonly observed for MSU than for EMS transports when the baseline mRS was 0-2 (45.8% vs 33.3%), 0-3 (41.9% vs 33.3%), and 4-5 (71.4% vs 20.0%). MSU patients were more likely to receive thrombolysis in the first 60 minutes of symptom onset (31.9% vs 12.2%, p = 0.006). Overall mortality rates regardless of baseline mRS were similar between groups. CONCLUSIONS: AIS patients received thrombolysis faster in the MSU compared with EMS and more frequently within 60 minutes of stroke onset. Point estimates for 90-day clinical outcomes of AIS patients treated with thrombolysis favored MSU without a statistically significant difference.

CSM-peptides: A computational approach to rapid identification of therapeutic peptides.

Peptides are attractive alternatives for the development of new therapeutic strategies due to their versatility and low complexity of synthesis. Increasing interest in these molecules has led to the creation of large collections of experimentally characterized therapeutic peptides, which greatly contributes to development of data-driven computational approaches. Here we propose CSM-peptides, a novel machine learning method for rapid identification of eight different types of therapeutic peptides: anti-angiogenic, anti-bacterial, anti-cancer, anti-inflammatory, anti-viral, cell-penetrating, quorum sensing, and surface binding. Our method has shown to outperform existing approaches, achieving an AUC of up to 0.92 on independent blind tests, and consistent performance on cross-validation. We anticipate CSM-peptides to be of great value in helping screening large libraries to identify novel peptides with therapeutic potential and have made it freely available as a user-friendly web server and Application Programming Interface at https://biosig.lab.uq.edu.au/csm_peptides.

Insights into the human gut virome by sampling a population from the Indian subcontinent.

Gut virome plays an important role in human physiology but remains poorly understood. This study reports an investigation of the human gut DNA-virome of a previously unexplored ethnic population through metagenomics of faecal samples collected from individuals residing in Northern India. Analysis shows that, similar to the populations investigated earlier, majority of the identified virome belongs to bacteriophages and a smaller fraction (<20 %) consists of viruses that infect animals, archaea, protists, multiple domains or plants. However, crAss-like phages, in this population, are dominated by the genera VI, VII and VIII. Interestingly, it also reveals the presence of a virus family, Sphaerolipoviridae, which has not been detected in the human gut earlier. Viral families, Siphoviridae, Myoviridae, Podoviridae, Microviridae, Herelleviridae and Phycodnaviridae are detected in all of the analysed individuals, which supports the existence of a core virome. Lysogeny-associated genes were found in less than 10 % of the assembled genomes and a negative correlation was observed in the richness of bacterial and free-viral species, suggesting that the dominant lifestyle of gut phage is not lysogenic. This is in contrast to some of the earlier studies. Further, several hundred high-quality viral genomes were recovered. Detailed characterization of these genomes would be useful for understanding the biology of these viruses and their significance in human physiology.

Assessing the effect of COVID-19 stay-at -home orders on firearm injury in Maryland.

This study sought to characterize frequency and demographic characteristics of firearm injury and penetrating trauma in Maryland over the first year of the pandemic, by comparing these characteristics to those of the three years prior to stay-at-home order issuance. Patients were identified in the Maryland Health Services Cost Review Commission database using ICD-10 codes for firearm injury by all intents and assaults by penetrating trauma. Cases from July 1, 2017 to March 31, 2020 ("pre-stay-at-home") were compared to those from April 1, 2020 to March 31, 2021 ("post-stay-at-home") using descriptive statistics. There was no significant change overall in frequency or demographics of firearm injury or penetrating trauma in the year after stay-at-home orders were issued. Youth between ages 15 and 24, overwhelmingly male, comprise a disproportionately high percentage of firearm injuries and assaults, and most penetrating trauma occurs in urban environments where Black non-Hispanic youth and children of low socioeconomic status are at high risk. Our study also found unintentional firearm injury among adults was significantly increased during the pandemic. While increased unintentional firearm injury among adults was the major significant change found in our study, the persistence of firearm injury, particularly in youth, racial and ethnic minority groups, and those in urban environments, should be deeply concerning. Stay-at-home policies did not keep youth safer from firearm injury. With continued high rates of firearm injury and the national debate over how to prevent these incidents, increased education and comprehensive strategies for prevention are needed.

Non-aqueous onion like nano-carbons from waste diesel-soot used as FRET-based sensor for sensing of nitro-phenols.

Herein, a simple-functionalization method is described to prepare the oleylamine functionalized non-aqueous version of onion-like nanocarbons (ONC-OA), where ONC was isolated from the waste pollutant soot exhausted from the diesel engine. The surface group analysis of ONC-OA has been investigated via Nuclear Magnetic Resonance and X-ray Photoelectron Spectroscopy. ONC-OA shows blue fluorescence with a quantum yield of ∼6% in tetrahydrofuran (THF). The fluorescence-based sensing applications of ONC-OA has been investigated for selective sensing of toxic aromatic nitro-phenols compounds (para-nitro, dinitro, and trinitro phenols) from the tested many nitro organic compounds. Based on the limit of detection values, ONC-OA shows much better results for tri-nitro phenol compared to di and mono nitrophenol. To understand the quenching mechanism, a time-resolved photoluminescence analysis of the sensor with and without the addition of quenchers is performed. The effective lowering in fluorescence lifetime of the sensor after the addition of quenchers concludes that the quenching observed is majorly due to the Förster Resonance Energy Transfer (FRET) mechanism. The real-life application of ONC-OA was analyzed by external spiking of N-PhOHs in soil samples.

Investigating the disordered regions (MoRFs, SLiMs and LCRs) and functions of mimicry proteins/peptides in silico.

Microbial mimicry of the host proteins/peptides can elicit host auto-reactive T- or B-cells resulting in autoimmune disease(s). Since intrinsically disordered protein regions (IDPRs) are involved in several host cell signaling and PPI networks, molecular mimicry of the IDPRs can help the pathogens in substituting their own proteins in the host cell-signaling and PPI networks and, ultimately hijacking the host cellular machinery. Thus, the present study was conducted to discern the structural disorder and intrinsically disordered protein regions (IDPRs) like, molecular recognition features (MoRFs), short linear motifs (SLiMs), and low complexity regions (LCRs) in the experimentally verified mimicry proteins and peptides (mimitopes) of bacteria, viruses and host. Also, functional characteristics of the mimicry proteins were studied in silico. Our results indicated that 78% of the bacterial host mimicry proteins and 45% of the bacterial host mimitopes were moderately/highly disordered while, 73% of the viral host mimicry proteins and 31% of the viral host mimitopes were moderately/highly disordered. Among the pathogens, 27% of the bacterial mimicry proteins and 13% of the bacterial mimitopes were moderately/highly disordered while, 53% of the viral mimicry proteins and 21% of the viral mimitopes were moderately/highly disordered. Though IDPR were frequent in host, bacterial and viral mimicry proteins, only a few mimitopes overlapped with the IDPRs like, MoRFs, SLiMs and LCRs. This suggests that most of the microbes cannot use molecular mimicry to modulate the host PPIs and hijack the host cell machinery. Functional analyses indicated that most of the pathogens exhibited mimicry with the host proteins involved in ion binding and signaling pathways. This is the first report on the disordered regions and functional aspects of experimentally proven host and microbial mimicry proteins.

Human Trafficking ICD-10 Code Utilization in Pediatric Tertiary Care Centers Within the United States.

BACKGROUND: Human trafficking is a global public health issue that affects pediatric patients widely. The International Labor Organization estimates children comprise approximately 25% of the identified trafficked persons globally, with domestic estimates including over 2000 children a year. Trafficked children experience a broad range of health consequences leading to interface with healthcare systems during their exploitation. In June 2018, International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) released diagnostic codes for human trafficking. OBJECTIVE: To use a large, multicenter database of US pediatric hospitalizations to describe the utilization of the ICD-10-CM codes related to child trafficking, as well as the demographic and clinical characteristics of these children. METHODS: This study was descriptive in nature. Encounters using data from the Pediatric Health Information System database (PHIS) with ICD-10-CM codes indicating trafficking from June 1, 2018 to March 1st, 2020 were included in the study cohort, with data collection continuing for 30 days after first hospital encounter, until March 31st, 2020. Patients 19 years old and younger were included. Condition-specific prevalence as well as demographic and clinical characteristics for patient encounters were analyzed. Study subjects were followed for 30 days after first hospital encounter to describe healthcare utilization patterns. RESULTS: During the study period, 0.005% (n = 293) of patient encounters in the PHIS database were identified as trafficked children. The children of our cohort were mostly female (90%), non-Hispanic Black (38%), and had public insurance (59%). Nearly two-thirds of patients (n = 190) had a documented mental health disorder at the initial encounter, with 32.1% classified as the principal diagnosis. Our cohort had a 30-day hospital inpatient, overnight observation, or emergency department readmission rate of 16% (n = 48). DISCUSSION: Our study demonstrates a low utilization of human trafficking ICD-10-CM codes in academic children's health centers, with code usage predominantly assigned to Non-Hispanic Black teenage girls. As comparison, in 2019 the National Human Trafficking Hotline identified 2,582 trafficked US children in a single year. These results suggest widespread under-recognition of child trafficking in health care settings, including the intensive care unit, in addition to racial and socioeconomic disparities amongst trafficked children.

Sodium channel expression and transcript variation in the developing brain of human, Rhesus monkey, and mouse.

Genetic variation in voltage-gated sodium (NaV) channels is a significant contributor to neurodevelopmental disorders. NaV channel alpha subunits are encoded by the SCNxA family and four are predominately expressed in the brain: SCN1A, SCN2A, SCN3A, and SCN8A. Gene expression is developmentally regulated, and they are known to express functionally distinct transcript variants. Precision therapies targeting these genes and their transcript variants are currently in preclinical development, yet the developmental expression of these transcripts in the human brain is yet to be fully understood. Additionally, the functional consequences of some mutations differ depending on the studied channel isoform, suggesting differential transcript variant expression can affect disease prognoses. We characterise the expression of the four SCNxAs and their transcript variants in human, Rhesus monkey and mouse brain using publicly available RNA-sequencing data and analysis tools, demonstrating that this approach can be used to answer important biological questions of gene and transcript developmental regulation. We find that gene expression and transcript variant regulation are conserved across species at similar developmental stages and determine the developmental milestones for transcript variant expression. Our study provides a guide to researchers testing therapies and clinicians advising prognoses based on the expression of channel isoforms.