Traumatic Brain Injury as an Independent Predictor of Futility in the Early Resuscitation of Patients in Hemorrhagic Shock.

This review explores the concept of futility timeouts and the use of traumatic brain injury (TBI) as an independent predictor of the futility of resuscitation efforts in severely bleeding trauma patients. The national blood supply shortage has been exacerbated by the lingering influence of the COVID-19 pandemic on the number of blood donors available, as well as by the adoption of balanced hemostatic resuscitation protocols (such as the increasing use of 1:1:1 packed red blood cells, plasma, and platelets) with and without early whole blood resuscitation. This has underscored the urgent need for reliable predictors of futile resuscitation (FR). As a result, clinical, radiologic, and laboratory bedside markers have emerged which can accurately predict FR in patients with severe trauma-induced hemorrhage, such as the Suspension of Transfusion and Other Procedures (STOP) criteria. However, the STOP criteria do not include markers for TBI severity or transfusion cut points despite these patients requiring large quantities of blood components in the STOP criteria validation cohort. Yet, guidelines for neuroprognosticating patients with TBI can require up to 72 h, which makes them less useful in the minutes and hours following initial presentation. We examine the impact of TBI on bleeding trauma patients, with a focus on those with coagulopathies associated with TBI. This review categorizes TBI into isolated TBI (iTBI), hemorrhagic isolated TBI (hiTBI), and polytraumatic TBI (ptTBI). Through an analysis of bedside parameters (such as the proposed STOP criteria), coagulation assays, markers for TBI severity, and transfusion cut points as markers of futilty, we suggest amendments to current guidelines and the development of more precise algorithms that incorporate prognostic indicators of severe TBI as an independent parameter for the early prediction of FR so as to optimize blood product allocation.

Processing speed and executive functioning in relation to off-topic verbosity among young adults and older adults.

PURPOSE: Off-topic verbosity (OTV) is a tendency towards excessive, off-topic speech and has been linked with age-related deficits in executive functioning, particularly inhibition. However, there are numerous disagreements within the literature on what constitutes OTV, and there is a further lack of investigation into alternative cognitive explanations for the link between inhibition and OTV. The purpose of this study was to investigate the speech characteristics of OTV in young and older adults as well as to examine whether variations in OTV are better explained by diminished executive functioning or processing speed, as measured by the D-KEFS Stroop test. METHODS: Young adults (n = 65; age 18-28) and older adults (n = 85; age 60-98) completed the D-KEFS Color-Word Interference Test and provided verbal samples of autobiographical episodic and procedural speech. These speech samples were rated on three facets of OTV: tangentiality, egocentrism and quantity of speech. RESULTS: Procedural autobiographical speech was found to best measure age cohort variations in OTV, and higher OTV was associated with poorer Stroop test performance in older adults but not in young adults. In fact, young adults only displayed associations between poorer Stroop performance and a reduction in speech quantity. Finally, processing speed deficits were more associated with increased OTV in older adults than executive functioning. CONCLUSION: These results provide support for links between age-related cognitive decline and OTV, but the results suggest that processing speed may be more implicated than executive functioning.

The Occurrence of Karenia species in mid-Atlantic coastal waters: Data from the Delmarva Peninsula, USA.

A bloom of Karenia papilionacea that occurred along the Delaware coast in late summer of 2007 was the first Karenia bloom reported on the Delmarva Peninsula (Delaware, Maryland, and Virginia, USA). Limited spatial and temporal monitoring conducted by state agencies and citizen science groups since 2007 have documented that several Karenia species are an annual component of the coastal phytoplankton community along the Delmarva Peninsula, often present at background to low concentrations (100 to 10,000 cells L-1). Blooms of Karenia (> 105 cells L-1) occurred in 2010, 2016, 2018, and 2019 in different areas along the Delmarva Peninsula coast. In late summer and early autumn of 2017, the lower Chesapeake Bay experienced a K. papilionacea bloom, the first recorded in Bay waters. Blooms typically occurred summer into autumn but were not monospecific; rather, they were dominated by either K. mikimotoi or K. papilionacea, with K. selliformis, K. brevis-like cells, and an undescribed Karenia species also present. Cell concentrations during these mid-Atlantic Karenia spp. blooms equalled concentrations reported for other Karenia blooms. However, the negative impacts to environmental and human health often associated with Karenia red tides were not observed. The data compiled here report on the presence of multiple Karenia species in coastal waters of the Delmarva Peninsula detected through routine monitoring and opportunistic sampling conducted between 2007 and 2022, as well as findings from research cruises undertaken in 2018 and 2019. These data should be used as a baseline for future phytoplankton community analyses supporting coastal HAB monitoring programs.

CRISPR-Cas immunity is repressed by the LysR-type transcriptional regulator PigU.

Bacteria protect themselves from infection by bacteriophages (phages) using different defence systems, such as CRISPR-Cas. Although CRISPR-Cas provides phage resistance, fitness costs are incurred, such as through autoimmunity. CRISPR-Cas regulation can optimise defence and minimise these costs. We recently developed a genome-wide functional genomics approach (SorTn-seq) for high-throughput discovery of regulators of bacterial gene expression. Here, we applied SorTn-seq to identify loci influencing expression of the two type III-A Serratia CRISPR arrays. Multiple genes affected CRISPR expression, including those involved in outer membrane and lipopolysaccharide synthesis. By comparing loci affecting type III CRISPR arrays and cas operon expression, we identified PigU (LrhA) as a repressor that co-ordinately controls both arrays and cas genes. By repressing type III-A CRISPR-Cas expression, PigU shuts off CRISPR-Cas interference against plasmids and phages. PigU also represses interference and CRISPR adaptation by the type I-F system, which is also present in Serratia. RNA sequencing demonstrated that PigU is a global regulator that controls secondary metabolite production and motility, in addition to CRISPR-Cas immunity. Increased PigU also resulted in elevated expression of three Serratia prophages, indicating their likely induction upon sensing PigU-induced cellular changes. In summary, PigU is a major regulator of CRISPR-Cas immunity in Serratia.

Discovery and verification of extracellular microRNA biomarkers for diagnostic and prognostic assessment of preeclampsia at triage.

We report on the identification of extracellular miRNA (ex-miRNA) biomarkers for early diagnosis and prognosis of preeclampsia (PE). Small RNA sequencing of maternal serum prospectively collected from participants undergoing evaluation for suspected PE revealed distinct patterns of ex-miRNA expression among different categories of hypertensive disorders in pregnancy. Applying an iterative machine learning method identified three bivariate miRNA biomarkers (miR-522-3p/miR-4732-5p, miR-516a-5p/miR-144-3p, and miR-27b-3p/let-7b-5p) that, when applied serially, distinguished between PE cases of different severity and differentiated cases from controls with a sensitivity of 93%, specificity of 79%, positive predictive value (PPV) of 55%, and negative predictive value (NPV) of 89%. In a small independent validation cohort, these ex-miRNA biomarkers had a sensitivity of 91% and specificity of 57%. Combining these ex-miRNA biomarkers with the established sFlt1:PlGF protein biomarker ratio performed better than either set of biomarkers alone (sensitivity of 89.4%, specificity of 91.3%, PPV of 95.5%, and NPV of 80.8%).

High placental expression of FLT1, LEP, PHYHIP and IL3RA - In persons of African ancestry with severe preeclampsia.

INTRODUCTION: Mortality from preeclampsia (PE) and PE-associated morbidities are 3-to 5-fold higher in persons of African ancestry than in those of Asian and European ancestries. METHODS: To elucidate placental contribution to worse PE outcomes in African ancestry pregnancies, we performed bulk RNA sequencing on 50 placentas from persons with severe PE (sPE) of African (n = 9), Asian (n = 18) and European (n = 23) ancestries and 73 normotensive controls of African (n = 10), Asian (n = 15) and European (n = 48) ancestries. RESULTS: Previously described canonical preeclampsia genes, involved in metabolism and hypoxia/angiogenesis including: LEP, HK2, FSTL3, FLT1, ENG, TMEM45A, ARHGEF4 and HTRA1 were upregulated sPE versus normotensive placentas across ancestries. LTF, NPR3 and PHYHIP were higher in African vs. Asian ancestry sPE placentas. Allograft rejection/adaptive immune response genes were upregulated in placentas from African but not in Asian or European ancestry sPE patients; IL3RA was of particular interest because the patient with the highest placental IL3RA expression, a person of African ancestry with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients with the highest IL3RA expression among persons of Asian and European ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placental IL3RA levels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p = .0005). DISCUSSION: High placental upregulation of both canonical preeclampsia and allograft rejection/adaptive immune response genes may contribute to worse PE outcomes in African ancestry sPE patients.

Identification of Streptococcus pneumoniae genes associated with hypothiocyanous acid tolerance through genome-wide screening.

Streptococcus pneumoniae is a commensal bacterium and invasive pathogen that causes millions of deaths worldwide. The pneumococcal vaccine offers limited protection, and the rise of antimicrobial resistance will make treatment increasingly challenging, emphasizing the need for new antipneumococcal strategies. One possibility is to target antioxidant defenses to render S. pneumoniae more susceptible to oxidants produced by the immune system. Human peroxidase enzymes will convert bacterial-derived hydrogen peroxide to hypothiocyanous acid (HOSCN) at sites of colonization and infection. Here, we used saturation transposon mutagenesis and deep sequencing to identify genes that enable S. pneumoniae to tolerate HOSCN. We identified 37 genes associated with S. pneumoniae HOSCN tolerance, including genes involved in metabolism, membrane transport, DNA repair, and oxidant detoxification. Single-gene deletion mutants of the identified antioxidant defense genes sodA, spxB, trxA, and ahpD were generated and their ability to survive HOSCN was assessed. With the exception of ΔahpD, all deletion mutants showed significantly greater sensitivity to HOSCN, validating the result of the genome-wide screen. The activity of hypothiocyanous acid reductase or glutathione reductase, known to be important for S. pneumoniae tolerance of HOSCN, was increased in three of the mutants, highlighting the compensatory potential of antioxidant systems. Double deletion of the gene encoding glutathione reductase and sodA sensitized the bacteria significantly more than single deletion. The HOSCN defense systems identified in this study may be viable targets for novel therapeutics against this deadly pathogen. IMPORTANCE Streptococcus pneumoniae is a human pathogen that causes pneumonia, bacteremia, and meningitis. Vaccination provides protection only against a quarter of the known S. pneumoniae serotypes, and the bacterium is rapidly becoming resistant to antibiotics. As such, new treatments are required. One strategy is to sensitize the bacteria to killing by the immune system. In this study, we performed a genome-wide screen to identify genes that help this bacterium resist oxidative stress exerted by the host at sites of colonization and infection. By identifying a number of critical pneumococcal defense mechanisms, our work provides novel targets for antimicrobial therapy.

Men's Experiences of Self-Conscious Emotions Following Childhood Sexual Abuse.

Rates of detection and disclosure of childhood sexual abuse (CSA) are believed to be lower in males due to gender socialization fears. The experience of CSA is thought to increase negative self-conscious emotions (shame, guilt, embarrassment, anger, and fear). Such self-conscious emotions have been associated with a range of mental and public health issues. As there has been no research to date that has explored the experience of shame and guilt within the wider context of self-conscious emotional states for males, this research aimed to explore men's experiences of self-conscious emotions following CSA. Nine semi-structured interviews with males were completed. Interpretative Phenomenological Analysis identified three themes: "Invisible In This World" captures participants' isolating circumstances surrounding their CSA, and how this impacted their perception of not being protected or able to speak out; "The Emotional Fallout" describes the overwhelming emotions experienced as a result of the CSA and how such emotions have impacted participants lives, and "Learning To Live With The Wound That May Never Heal" addresses how participants have spent their lives living with the abuse and how it's a process to learn how to adapt and live with the abuse. Findings suggest there is a clear need to recognize the role and power of self-conscious emotions in male CSA, especially for healthcare professionals and services supporting males with CSA. Without addressing such self-conscious emotions, males who have experienced CSA are at risk of enduring the emotional fallout throughout their lives.

Mast Cell and Innate Immune Cell Communication in Cholestatic Liver Disease.

Mast cells (MCs) contribute to the pathogenesis of cholestatic liver diseases (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). PSC and PBC are immune-mediated, chronic inflammatory diseases, characterized by bile duct inflammation and stricturing, advancing to hepatobiliary cirrhosis. MCs are tissue resident immune cells that may promote hepatic injury, inflammation, and fibrosis formation by either direct or indirect interactions with other innate immune cells (neutrophils, macrophages/Kupffer cells, dendritic cells, natural killer, and innate lymphoid cells). The activation of these innate immune cells, usually through the degranulation of MCs, promotes antigen uptake and presentation to adaptive immune cells, exacerbating liver injury. In conclusion, dysregulation of MC-innate immune cell communications during liver injury and inflammation can lead to chronic liver injury and cancer.

Reframing Bilingual Acquisition and Theory: An Insider Perspective Through a Translanguaging Lens.

PURPOSE: This exploratory study developed a process for reinterpreting previously published research studies in the bilingual literature. Three previously published studies on bilingual phonological acquisition were revisited due to the following characteristics: (a) they applied a theoretical framework for bilingual speech production developed by white bilingual researchers, the dual-systems hypothesis, and (b) project data were interpreted without the input and perspective of researchers representative of the community being studied. This study aims to provide a guide for the readership to reinterpret developmental speech and language studies on bilingual children through (a) the theoretical framework of translanguaging, which was developed by minoritized bilingual scholars and members of the community being studied, and (b) community Insider lenses, or the perspectives of research team members whose lived linguistic experiences match those of the target population studied. METHOD: Original interpretations of data were reexamined and reinterpreted incorporating (a) a research team member from the target community and (b) a novel theoretical lens developed by members of the target community called translanguaging. RESULTS: Original findings were extended through the application of translanguaging as a theoretical lens. New interpretations of original data were uncovered when a researcher from the Latinx community was involved in the data interpretation process. New insights were gained on phonological acquisition in bilingual Spanish-English-speaking preschoolers by applying a reinterpretation framework. CONCLUSIONS: Differences in data interpretation reveal that translanguaging may improve understanding of languaging in bilingual/multilingual communities. Implications for development of representative research teams when examining minoritized pediatric populations are also discussed.

A Complexity Approach to Promoting Within- and Cross-Language Generalization in Bilingual Children With Phonological Delays.

PURPOSE: The purpose of this study was to explore the effects of generalization when treating complex targets with shared sounds in Spanish for a 5-year-old Spanish-English bilingual child with a phonological delay. METHOD: Two complex clusters (/fl/ and /fɾ/) and one additional target (/l/) were chosen for treatment. Intervention sessions were held in Spanish over the course of 1 year on a weekly basis. The accuracy of the treated and untreated targets was monitored using a single-subject case design and was assessed using visual analysis. RESULTS: The accuracy of the production of treated targets increased upon administering the intervention. Accuracy also increased for untreated /fl/ targets in Spanish and English, /l/ in English, and untreated /fɾ/ clusters in Spanish. CONCLUSIONS: The results suggest that choosing complex targets consisting of shared sounds helps promote the generalization of skills within and across languages. Future studies should examine the outcomes of selecting additional forms of complex targets for bilingual children.

An OmpW-dependent T4-like phage infects Serratia sp. ATCC 39006.

Serratia sp. ATCC 39006 is a Gram-negative bacterium that has been used to study the function of phage defences, such as CRISPR-Cas, and phage counter-defence mechanisms. To expand our phage collection to study the phage-host interaction with Serratia sp. ATCC 39006, we isolated the T4-like myovirus LC53 in Otepoti Dunedin, Aotearoa New Zealand. Morphological, phenotypic and genomic characterization revealed that LC53 is virulent and similar to other Serratia, Erwinia and Kosakonia phages belonging to the genus Winklervirus. Using a transposon mutant library, we identified the host ompW gene as essential for phage infection, suggesting that it encodes the phage receptor. The genome of LC53 encodes all the characteristic T4-like core proteins involved in phage DNA replication and generation of viral particles. Furthermore, our bioinformatic analysis suggests that the transcriptional organization of LC53 is similar to that of Escherichia coli phage T4. Importantly, LC53 encodes 18 tRNAs, which likely compensate for differences in GC content between phage and host genomes. Overall, this study describes a newly isolated phage infecting Serratia sp. ATCC 39006 that expands the diversity of phages available to study phage-host interactions.

Histopathologic and Transcriptomic Profiling Identifies Novel Trophoblast Defects in Patients With Preeclampsia and Maternal Vascular Malperfusion.

Preeclampsia (PE) is a heterogeneous disease for which the current clinical classification system is based on the presence or absence of specific clinical features. PE-associated placentas also show heterogeneous findings on pathologic examination, suggesting that further subclassification is possible. We combined clinical, pathologic, immunohistochemical, and transcriptomic profiling of placentas to develop integrated signatures for multiple subclasses of PE. In total, 303 PE and 1388 nonhypertensive control placentas were included. We found that maternal vascular malperfusion (MVM) in the placenta was associated with preterm PE with severe features and with small-for-gestational-age neonates. Interestingly, PE placentas with either MVM or no histologic pattern of injury showed a linear decrease in proliferative (p63+) cytotrophoblast per villous area with increasing gestational age, similar to placentas obtained from the nonhypertensive patient cohort; however, PE placentas with fetal vascular malperfusion or villitis of unknown etiology lost this phenotype. This is mainly because of cases of fetal vascular malperfusion in placentas of patients with preterm PE and villitis of unknown etiology in placentas of patients with term PE, which are associated with a decrease or increase, respectively, in the cytotrophoblast per villous area. Finally, a transcriptomic analysis identified pathways associated with hypoxia, inflammation, and reduced cell proliferation in PE-MVM placentas and further subclassified this group into extravillous trophoblast-high and extravillous trophoblast-low PE, confirmed using an immunohistochemical analysis of trophoblast lineage-specific markers. Our findings suggest that within specific histopathologic patterns of placental injury, PE can be subclassified based on specific cellular and molecular defects, allowing the identification of pathways that may be targeted for diagnostic and therapeutic purposes.

Phage capsid recognition triggers activation of a bacterial toxin-antitoxin defense system.

Zhang et al.1 reveal a previously unknown route to toxin activation whereby bacteriophage capsid proteins bind the antitoxin domain of the CapRel fused toxin-antitoxin system, triggering translational inhibition via pyrophosporylation of tRNAs and culminating in abortive infection-mediated phage resistance.

Loneliness and Off-Topic Verbosity Among Young Adults and Older Adults.

OBJECTIVES: Off-topic verbosity (OTV) refers to prolonged speech that derails from the initial conversational topic by including more loosely associated speech and becoming increasingly more unfocused and distant from the initial topic. Previous research has suggested that, among older adults, loneliness may be associated with greater OTV. The purpose of this study was to investigate the nature of the relationship between loneliness and OTV among young adults (n = 62) and older adults (n = 80). METHODS: Participants completed a measure of loneliness and provided speech samples, which were transcribed and rated for OTV. RESULTS: Results indicated some relationship between loneliness and tangentiality of speech, particularly among older adults. DISCUSSION: Overall, loneliness may be associated with greater OTV in older adults, which could further explain the connection between increased loneliness and worse health outcomes in older adulthood.

Recommendations to improve the patient experience and avoid bias when prenatal screening/testing.

While prenatal screening and testing have expanded substantially over the past decade and provide access to more genetic information, expectant parents are more likely to describe the diagnosis experience as negative than positive. In addition, the conversations that take place during these experiences sometimes reflect unconscious bias against people with disabilities. Consequently, an interdisciplinary committee of experts, including people with disabilities, family members, disability organization leaders, healthcare and genetics professionals, and bioethicists, reviewed selected published and gray literature comparing the current state of the administration of prenatal testing to the ideal state. Subsequently, the interdisciplinary team created recommendations for clinicians, public health agencies, medical organizations, federal agencies, and other stakeholders involved with administering prenatal screening and testing to create better patient experiences; conduct training for healthcare professionals; create, enforce, and fund policies and guidelines; and engage in more robust data collection and research efforts.

The Development of Normal Fetal External Genitalia Throughout Gestation.

In this review, we describe normal development of fetal genitalia throughout gestation as well as the identification of normal male and female genitalia on ultrasound. We use abnormal and ambiguous genitalia as illustrative tools to assist with the identification of normal genitalia and recognition of some of the most common abnormalities in external genitalia development.

Type III CRISPR-Cas provides resistance against nucleus-forming jumbo phages via abortive infection.

Bacteria have diverse defenses against phages. In response, jumbo phages evade multiple DNA-targeting defenses by protecting their DNA inside a nucleus-like structure. We previously demonstrated that RNA-targeting type III CRISPR-Cas systems provide jumbo phage immunity by recognizing viral mRNA exported from the nucleus for translation. Here, we demonstrate that recognition of phage mRNA by the type III system activates a cyclic triadenylate-dependent accessory nuclease, NucC. Although unable to access phage DNA in the nucleus, NucC degrades the bacterial chromosome, triggers cell death, and disrupts phage replication and maturation. Hence, type-III-mediated jumbo phage immunity occurs via abortive infection, with suppression of the viral epidemic protecting the population. We further show that type III systems targeting jumbo phages have diverse accessory nucleases, including RNases that provide immunity. Our study demonstrates how type III CRISPR-Cas systems overcome the inaccessibility of jumbo phage DNA to provide robust immunity.

Gaps in Framing and Naming: Commentary to "A Viewpoint on Accent Services".

PURPOSE: In this commentary, we offer a critique of "A Viewpoint on Accent Services: Framing and Terminology Matter" (Grover et al., 2022). We argue that the authors' proposal to rename and reframe accent modification lacks criticality, which actually hinders-rather than advances-the movement toward equitable, culturally sustaining, and emancipatory practices. METHOD: We offer an analysis of the shortfall between the authors' calls for linguistic justice in "A Viewpoint on Accent Services" and the actual changes they proposed. We break down major gaps in criticality, reflexivity, practice, and vision and discuss their potential for undercutting meaningful progress as it relates to linguistic justice. RESULTS: We found that the frameworks for the pursuit of equity, cultural sustenance, and emancipatory practices were misrepresented in the article in such a way that suggests that these goals could be achieved through superficial changes in terminology and attitudes. "A Viewpoint on Accent Services" upholds a power-neutral frame of operation that does not address the deeper systemic forces that make accent modification problematic. The lack of criticality toward accent intervention fosters complacency toward real transformation. CONCLUSION: We advocate for a serious and critical interrogation of accent practices and commitment to an emancipatory practice that addresses linguistic discrimination above all else. We emphasize the need to decenter standardized languages and to co-envision linguistic liberation using critical methods in scholarship, pedagogy, clinical practice, and policy.