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Intranasal medications have been proposed as adjuncts to out‐of‐hospital cardiac arrest (OHCA) care. We sought to quantify the effects of intranasal medication administration (INMA) in OHCA workflows. We conducted separate randomized OHCA simulation trials with lay rescuers (LRs) and first responders (FRs). Participants were randomized to groups performing hands‐only cardiopulmonary resuscitation (CPR)/automated external defibrillator with or without INMA during the second analysis phase. Time to compression following the second shock (CPR2) was the primary outcome and compression quality (chest compression rate (CCR) and fraction (CCF)) was the secondary outcome. We fit linear regression models adjusted for CPR training in the LR group and service years in the FR group. Among LRs, INMA was associated with a significant increase in CPR2 (mean diff. 44.1 s, 95% CI: 14.9, 73.3), which persisted after adjustment (p = 0.005). We observed a significant decrease in CCR (INMA 95.1 compressions per min (cpm) vs control 104.2 cpm, mean diff. −9.1 cpm, 95% CI −16.6, −1.6) and CCF (INMA 62.4% vs control 69.8%, mean diff. −7.5%, 95% CI −12.0, −2.9). Among FRs, we found no significant CPR2 delays (mean diff. −2.1 s, 95% CI −15.9, 11.7), which persisted after adjustment (p = 0.704), or difference in quality (CCR INMA 115.5 cpm vs control 120.8 cpm, mean diff. −5.3 cpm, 95% CI −12.6, 2.0; CCF INMA 79.6% vs control 81.2% mean diff. −1.6%, 95% CI −7.4, 4.3%) INMA in LR resuscitation was associated with diminished resuscitation performance. INMA by FR did not impede key times or quality.

Background Pregnant laboring patients sometimes require interfacility transfer to a higher level of care. There is a paucity of evidence to inform when it is safe to transfer a laboring patient and when delivery may be too imminent to transfer. Methods This is a retrospective study of pregnant patients undergoing interfacility transfer with a specialized obstetric transport team deployed from a large Midwest regional healthcare system. The primary outcome was delivery prior to or within one hour of arrival at the receiving institution due to progression of labor. Data collected included basic demographics, vital signs, gravidity, parity, gestational age, contraction frequency if contractions were present, and cervical dilation. We sought to define the association between these variables and the primary outcome to inform risk assessment for precipitous delivery among patients being considered for interfacility transfer. Results Of the 370 pregnant patients for whom the specialized transfer team was requested, 11 (3%) met the primary outcome. Those with more advanced cervical dilation and those who did not receive regular prenatal care were more likely to meet the criteria for the primary outcome. For every centimeter of cervical dilation, the odds of meeting the primary outcome increased 2.3-fold (95% CI: 1.5-3.4). Conclusions We identified risk factors for early delivery among pregnant patients for whom an interfacility transfer was requested and described patients who were high-risk for obstetric interfacility transport due to the progression of labor. Our results can help inform risk assessments for transferring potentially high-risk laboring patients.

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC) 1 . The extracellular matrix (ECM) contributes to immune exclusion 2 . However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes 3 , 4 . Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity 5 , instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1 -knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM. In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration.

The perceived replication crisis and the reforms designed to address it are grounded in the notion that science is a binary signal detection problem. However, contrary to null hypothesis significance testing (NHST) logic, the magnitude of the underlying effect size for a given experiment is best conceptualized as a random draw from a continuous distribution, not as a random draw from a dichotomous distribution (null vs. alternative). Moreover, because continuously distributed effects selected using a P < 0.05 filter must be inflated, the fact that they are smaller when replicated (reflecting regression to the mean) is no reason to sound the alarm. Considered from this perspective, recent replication efforts suggest that most published P < 0.05 scientific findings are “true” (i.e., in the correct direction), with observed effect sizes that are inflated to varying degrees. We propose that original science is a screening process, one that adopts NHST logic as a useful fiction for selecting true effects that are potentially large enough to be of interest to other scientists. Unlike original science, replication science seeks to precisely measure the underlying effect size associated with an experimental protocol via large-N direct replication, without regard for statistical significance. Registered reports are well suited to (often resource-intensive) direct replications, which should focus on influential findings and be published regardless of outcome. Conceptual replications play an important but separate role in validating theories. However, because they are part of NHST-based original science, conceptual replications cannot serve as the field’s self-correction mechanism. Only direct replications can do that.

Background Gut microbiome characteristics associated with HIV infection are of intense research interest but a deep understanding has been challenged by confounding factors across studied populations. Notably, a Prevotella -rich microbiome described in HIV-infected populations is now understood to be common in men who have sex with men (MSM) regardless of HIV status, but driving factors and potential health implications are unknown. Results Here, we further define the MSM-associated gut microbiome and describe compositional differences between the fecal microbiomes of Prevotella -rich MSM and non-MSM that may underlie observed pro-inflammatory properties. Furthermore, we show relatively subtle gut microbiome changes in HIV infection in MSM and women that include an increase in potential pathogens that is ameliorated with antiretroviral therapy (ART). Lastly, using a longitudinal cohort, we describe microbiome changes that happen after ART initiation. Conclusions This study provides an in-depth characterization of microbiome differences that occur in a US population infected with HIV and demonstrates the degree to which these differences may be driven by lifestyle factors, ART, and HIV infection itself. Understanding microbiome compositions that occur with sexual behaviors that are high risk for acquiring HIV and untreated and ART-treated HIV infection will guide the investigation of immune and metabolic functional implications to ultimately target the microbiome therapeutically.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis 1 . Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis 2 , 3 – 4 ; by contrast, small molecules can provide spatiotemporal control of the chemistry at work 5 . Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron—fentomycin-1—to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44 high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation 6 , 7 while conferring vulnerability to ferroptosis 8 , 9 . Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states 10 . Some cancer cells exhibit high loads of reactive iron in lysosomes, and this feature is exploited by using fentomycin-1, a newly developed small molecule, to induce ferroptosis.

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

Despite the integral role of ice nucleators (IN) in atmospheric processes leading to precipitation, their sources and distributions have not been well established. We examined IN in snowfall from mid- and high-latitude locations and found that the most active were biological in origin. Of the IN larger than 0.2 micrometer that were active at temperatures warmer than -7°C, 69 to 100% were biological, and a substantial fraction were bacteria. Our results indicate that the biosphere is a source of highly active IN and suggest that these biological particles may affect the precipitation cycle and/or their own precipitation during atmospheric transport

Background Nurse care managers (NCM) operate through care management programs to provide care for persons living with dementia (PLWD) and interact regularly with their family caregivers; however, most do not receive formal instruction in dementia care or caregiver support. CRESCENT (CaReEcoSystem primary Care Embedded demeNtia Treatment) is a telephone-based dementia care intervention adapted from the Care EcoSystem model designed to equip NCMs with these tools. For this study, we aimed to measure intervention fidelity and understand how dementia care training impacted NCMs’ provision of dementia care management services during interactions with caregivers of PLWD. Methods We recruited 30 active NCMs; 15 were randomly assigned to receive training. For each nurse, we randomly selected 1–3 patients with a diagnosis of dementia in each nurse’s care during January-June 2021 for a total of 54 medical charts. To assess training uptake and fidelity, we identified documentation by NCMs of CRESCENT protocol implementation in the medical records. To understand how the training impacted the amount and types of dementia care management services provided in interactions with family caregivers, we compared attention to key dementia topic areas between trained NCMs (intervention) and untrained NCMs (control). Results Within the trained group only, community resources for PLWD, followed by safety, medication reconciliation, and advanced care planning topic areas were addressed most frequently (> 30%), while behavior management was addressed least frequently (12%). Trained NCMs were more likely to document addressing aspects of caregiver wellbeing ( p  = 0.03), community resources ( p  = 0.002), and identification of behavior ( p  = 0.03) and safety issues ( p  = 0.02) compared to those without training. There was no difference between groups in the amount of care coordination provided ( p  = 0.64). Conclusion Results from this study demonstrate that focused dementia care training enriches care conversations in important topic areas for PLWD and family caregivers. Future research will clarify how best to sustain and optimize high quality dementia care in care management programs with special attention to the NCM-family caregiver relationship. Trial number NCT04556097.

Although eusociality evolved independently within several orders of insects, research into the molecular underpinnings of the transition towards social complexity has been confined primarily to Hymenoptera (for example, ants and bees). Here we sequence the genome and stage-specific transcriptomes of the dampwood termite Zootermopsis nevadensis (Blattodea) and compare them with similar data for eusocial Hymenoptera, to better identify commonalities and differences in achieving this significant transition. We show an expansion of genes related to male fertility, with upregulated gene expression in male reproductive individuals reflecting the profound differences in mating biology relative to the Hymenoptera. For several chemoreceptor families, we show divergent numbers of genes, which may correspond to the more claustral lifestyle of these termites. We also show similarities in the number and expression of genes related to caste determination mechanisms. Finally, patterns of DNA methylation and alternative splicing support a hypothesized epigenetic regulation of caste differentiation. Although termites are major human pests, they have an important role in maintaining ecosystem function and biodiversity. Here, the authors sequence the genome and transcriptomes of a dampwood termite and highlight genes that may be involved in the mechanisms underlying insect social behaviour.