Unique Event Research Articles

Meta-analysis of gastrointestinal adverse effects in patients with non-small cell lung cancer treated with a combination therapy of pembrolizumab and chemotherapy versus chemotherapy alone.

e14634 Background: Pembrolizumab combined with chemotherapy has transformed the treatment of non-small cell lung cancer (NSCLC) and is now the standard of care. It has unique immune-related adverse events (irAE) that have been well defined. There is limited literature reporting its effect on the occurrence of common chemotherapy related AEs such as gastrointestinal adverse effects (GIAEs) (nausea, vomiting and diarrhea). We performed a meta-analysis to evaluate the GIAEs of pembrolizumab in non-small cell lung cancer patients treated with pembrolizumab and chemotherapy (P+C) and drew a comparison with those treated with chemotherapy alone (C). Methods: A literature search was performed in the MEDLINE database for randomized clinical trials of non-small cell lung cancer treated with pembrolizumab reporting gastrointestinal adverse effects. Articles were screened in concordance with PRISMA guidelines. Funnel plots were generated to assess publication bias. The pooled odds ratios (OR) for occurrence of GIAEs with 95% confidence intervals (CI) using random-effects models was calculated. Results: 9 studies (including data from KEYNOTE-021, 407, 189, 604, PROLUNG trial) were included in our analyses (n = 3157 patients). A clear increment in certain GIAEs (constipation (OR 1.16 (0.99- 1.37)), diarrhea (OR 1.51 (1.28- 1.78)), colitis (OR 4.39 (1.81- 10.62)), hepatitis (OR 4.67(1.79-12.18)) was noted the Pembrolizumab plus chemotherapy arm versus chemotherapy alone. No significant differences were noted in the occurrence of nausea, vomiting and pancreatitis. Conclusions: Pembrolizumab plus chemotherapy compared with chemotherapy alone has been studied extensively to highlight the survival advantages of the former therapeutic strategy. The risk of certain GIAEs (constipation, diarrhea, colitis, hepatitis) with pembrolizumab combination therapy for non-small cell lung cancer is significantly higher in comparison to chemotherapy alone. This alludes to the superadded effect of pembrolizumab on the existing AEs of chemotherapy. [Table: see text]

SpliceIO: A robust platform for the discovery and validation of splicing-derived neoantigens.

2581 Background: Splicing dysregulation is a major hallmark of cancer, affecting tumor progression, metastasis, and therapy resistance. Aberrant alternative splicing plays a critical role in generating tumor-specific neoantigens targetable through an arsenal of immunotherapeutic modalities. Such neoantigens cannot be discovered using conventional DNA-based tools; they require specialized software for alternative splicing analysis using RNA-seq data. Methods: Envisagenics has developed SpliceIO, a proprietary software platform for splicing-derived neoantigen discovery. SpliceIO uses RNA-seq data to uncover extracellular neoantigens encoded by transmembrane proteins or presented to immune cells through the MHC complex. This predictive ensemble maximizes the value of RNA-seq data to predict fundamental aspects of neoantigen activity, such as their protein localization, MHC binding affinity, epitope accessibility and cancer pathway relevance. Here, we summarize the discovery and validation of novel splicing-derived neoantigens identified using SpliceIO in acute myeloid leukemia and colorectal cancer. Results: We analyzed >10,000 RNA-seq samples from the four tumor types and controls derived from 32 normal tissues. To maximize the prevalence of neoantigen target candidates in patient subpopulations, RNA-seq samples were pre-stratified using SpliceSlice, a proprietary software for spliceosomal profiling. As a result, patients sharing common spliceosome alterations were grouped into 11 coherent subsets that are distinct from normal tissue. Using this approach, we have discovered several promising candidates that we prioritized for experimental validations. SpliceIO target candidates were validated experimentally in cancer cell lines and primary tumor tissues to confirm RNA expression, translation, and membrane localization. Additionally, we performed proteomics to evaluate the presence of neopeptides generated from the unique splicing events. Using this approach, we have discovered and validated several tumor specific splicing derived neoantigens that are also recurrent in >15 % of the population. Conclusions: Together, our results strongly support the role of aberrant splicing as a major source of tumor-specific neoantigens. Our combined computational and experimental approach promotes novel target discovery, enabling the development of novel immunotherapeutics for cancer treatment.

The germinal center in the pathogenesis of B cell lymphomas.

The adaptive immune system has evolved to allow effective responses against a virtually unlimited number of invading pathogens. This process requires the transient formation of germinal centers (GC), a dynamic environment that ensures the generation and selection of B cells capable to produce antibodies with high antigen affinity, or to maintain the memory of that antigen for life. However, this comes at a cost, as the unique events accompanying the GC reaction pose a significant risk to the genome of B cells, which must endure elevated levels of replication stress, while proliferating at high rates and undergoing DNA breaks introduced by somatic hypermutation and class switch recombination. Indeed, the genetic/epigenetic disruption of programs implicated in normal GC biology has emerged as a hallmark of most B cell lymphomas. This improved understanding provides a conceptual framework for the identification of cellular pathways that could be exploited for precision medicine approaches.

Generating Personalized Summaries of Day Long Egocentric Videos.

The popularity of egocentric cameras and their always-on nature has lead to the abundance of day long first-person videos. The highly redundant nature of these videos and extreme camera-shakes make them difficult to watch from beginning to end. These videos require efficient summarization tools for consumption. However, traditional summarization techniques developed for static surveillance videos or highly curated sports videos and movies are either not suitable or simply do not scale for such hours long videos in the wild. On the other hand, specialized summarization techniques developed for egocentric videos limit their focus to important objects and people. This paper presents a novel unsupervised reinforcement learning framework to summarize egocentric videos both in terms of length and the content. The proposed framework facilitates incorporating various prior preferences such as faces, places, or scene diversity and interactive user choice in terms of including or excluding the particular type of content. This approach can also be adapted to generate summaries of various lengths, making it possible to view even 1-minute summaries of one's entire day. When using the facial saliency-based reward, we show that our approach generates summaries focusing on social interactions, similar to the current state-of-the-art (SOTA). The quantitative comparisons on the benchmark Disney dataset show that our method achieves significant improvement in Relaxed F-Score (RFS) (29.60 compared to 19.21 from SOTA), BLEU score (0.68 compared to 0.67 from SOTA), Average Human Ranking (AHR), and unique events covered. Finally, we show that our technique can be applied to summarize traditional, short, hand-held videos as well, where we improve the SOTA F-score on benchmark SumMe and TVSum datasets from 41.4 to 46.40 and 57.6 to 58.3 respectively. We also provide a Pytorch implementation and a web demo at https://pravin74.github.io/Int-sum/index.html.

Elevated road segment (ERS) passage design may provide enhanced connectivity for amphibians, reptiles, and small mammals

IntroductionDesigns for safe and effective road crossing structures for small animals are typically under-road microtunnels and culverts which have varying levels of effectiveness reported in the scientific literature. Many species, particularly migratory amphibians, may have limited ability to find and use passages if they are too far apart, resulting in substantial barrier effects.MethodsWe designed a novel open elevated passage (elevated road segment: ERS), similar to a low terrestrial bridge, that could theoretically be built to any length based upon species needs and movement characteristics. A 30 m length prototype ERS was installed along a forest road with a history of amphibian road mortality in Sierra National Forest, Fresno County, CA, USA. From 2018 to 2021, we monitored small animal activity under the ERS in relation to surrounding roadside and forest habitats using active infrared cameras.ResultsWe documented a total of 8,815 unique use events, using species specific independence criteria, across 22 species of amphibians (3), reptiles (4), and small mammals (15). Poisson regression modeling of taxonomic group activity under the ERS, roadside and forest, showed that amphibian activity was highest in the forest habitat, no differences were observed for reptiles, and small mammal activity was highest under the ERS. However, mean activity estimates under the ERS were equal to or greater than the open roadside habitat for all 22 species, suggesting that adding cover objects, such as downed logs and vegetation may further enhance passage use.DiscussionOverall, results showed that the design of the ERS crossing has potential to provide high connectivity for a wide range of amphibian, reptile, and small mammal species while reducing road mortality. ERS systems can also be used in areas with challenging terrain and other hydrological and environmental constraints. Incorporating current road ecology science, we provide supplemental ERS concept designs for secondary roads, primary roads and highways to help increase the options available for road mitigation planning for small animals.

The Effects of a National Recall on the Reports to the FDA Manufacturer and User Facility Device Experience Database of a Common Atherectomy Device

The HawkOne Directional Atherectomy System (Medtronic Inc., Minneapolis, MN) is a peripheral arterial disease management system that was recalled in December 2021 secondary to repeated guidewire prolapse. We set forth to analyze the patient problems and device issues that caused the device to be recalled and determine if the recall had a significant impact on the device reports utilizing the US Food and Drug Administration (FDA) database Manufacturer and User Facility Device Experience (MAUDE). MAUDE was queried for all adverse report events for the HawkOne device six months prior to and after its recall date in December 2021. Data collected included patient-based issues, device-based issues, and if the device was evaluated by the manufacturer. Fisher's exact test was utilized. There were 72 unique events reported prior to the device recall and 35 events reported after the recall. The majority of adverse events resulted in no adverse clinical outcomes before (55.6%) and after (21.3%) the recall. The most common reported device issue was detachment both before (54.8%) and after (57.1%) the recall. There was no significant difference in the rate of any patient outcome or device problem after the recall. The number of devices evaluated by the manufacturer after the recall was significantly reduced (69.9% vs 11.4%; P ≤ .001). There was no significant change in the rate of specific patient outcomes or device issues after the HawkOne device recall. The rate at which the devices were evaluated by the manufacturer significantly reduced after the recall. These data indicate possible influences that an official device recall might have on reporting to the MAUDE and warrant further study to understand the complexity of user-based feedback of such endovascular devices.

Nontraditional Occupational Exposures to Crude Oil Combustion Disasters and Respiratory Disease Risk: A Narrative Review of Literature.

Burning of petroleum products has been consistently associated with adverse respiratory health effects. Combustion of crude oil, specifically, produces toxic byproducts, but there have been relatively few studies of health effects. Burning of crude oil is increasingly employed as a means of mitigating environmental disasters despite the potential health risks to workers involved in clean-up efforts. Here, we review epidemiological studies of respiratory effects following unique crude oil burning events to (1) characterize respiratory health effects from this nontraditional occupational exposure and (2) identify approaches used to characterize exposures that could be applied to future disaster-related studies. We searched PubMed and EMBASE for references from inception to January 30, 2023. We also manually screened references cited in eligible articles. We identified 14 eligible publications. Our review suggests that exposure to crude oil combustion has adverse respiratory effects, including reduced lung function and increased occurrence of respiratory symptoms and disease. However, the evidence is inconsistent, and quality of data varied across studies.While some studies used quantitative, modeled exposure estimates, most used self-reported proxies of exposure. Although disasters involving crude oil combustion are relatively rare, limited evidence suggests that some worker populations may be at risk for respiratory effects from burning exposures in disaster settings. Future studies that use improved exposure assessment methods (e.g., personal monitors, remote sensing data) may help further quantify the respiratory risk from crude oil burning exposures.

The survey of planetary nebulae in Andromeda (M 31) VI. Kinematics of M 31 inner-halo substructures and comparison with major-merger simulation predictions

ABSTRACT M 31 has experienced a recent tumultuous merger history, as evidenced from the many substructures that are still present in its inner halo, particularly the G1-Clump, NE-, and W-shelves and the Giant Stream (GS). We present planetary nebulae (PNe) line-of-sight velocity (LOSV) measurements covering the entire spatial extent of these four substructures. We further use predictions for the satellite and host stellar particle phase space distributions for a major merger (mass ratio = 1:4) simulation to help interpret the data. The measured PN LOSVs for the two shelves and GS are consistent with those from red giant branch stars. Their projected radius versus LOSV phase space, links the formation of these substructures in a single unique event, consistent with a major merger. We find the G1-clump to be dynamically cold compared to the M 31 disc ($\rm \sigma _{LOS, PN}=27$ km s−1), consistent with pre-merger disc material. Such a structure can not form in a minor merger (mass ratio ∼1:20) and is therefore a smoking gun for the recent major merger event in M 31. The simulation also predicts the formation of a predominantly in situ halo from splashed-out pre-merger disc material, in qualitative agreement with observations of a metal-rich inner halo in M 31. Juxtaposed with previous results for its discs, we conclude that M 31 has had a recent (2.5–4 Gyr ago) ‘wet’ major merger with the satellite falling along the GS, heating the pre-merger disc to form the M 31 thicker disc, rebuilding the M 31 thin disc, and creating the aforementioned inner-halo substructures.

Lesbutantes, Guerilla Queers, and Dyke Nights: Transgressing Heteronormative Borders and the Folklore of Queer Resistance

Abstract: Recent publications have lamented the death of lesbian bars and the absence of distinct urban gayborhoods. The Lesbian Bar Project points out that there are just fifteen lesbian bars left in the United States as of 2021. The rise of social-sexual mobile applications, the impact of gentrification, and a cultural shift in attitudes surrounding acceptance have all contributed to the decline of dedicated lesbian spaces. Comparing the popularity and availability of mobile applications and social-sexual outlets for gay men, such as Grindr, with those designed for queer women—as well as new and unique queer pop-up events, social media forums, and networking opportunities—reveals the ways queer women are subverting authority, resisting changes, and disrupting space through shared practices and experiences. New opportunities and sites for queer spatial resistance have emerged and mobile applications like Meetup facilitate the literal takeover of popular urban spaces. Though technology may have reterritorialized certain sexual geographies for the lesbian community, this essay shows how queer practices are now informing place in ways that assert a queer spatial justice.

Lesbutantes, Guerilla Queers, and Dyke Nights: Transgressing Heteronormative Borders and the Folklore of Queer Resistance

Abstract: Recent publications have lamented the death of lesbian bars and the absence of distinct urban gayborhoods. The Lesbian Bar Project points out that there are just fifteen lesbian bars left in the United States as of 2021. The rise of social-sexual mobile applications, the impact of gentrification, and a cultural shift in attitudes surrounding acceptance have all contributed to the decline of dedicated lesbian spaces. Comparing the popularity and availability of mobile applications and social-sexual outlets for gay men, such as Grindr, with those designed for queer women—as well as new and unique queer pop-up events, social media forums, and networking opportunities—reveals the ways queer women are subverting authority, resisting changes, and disrupting space through shared practices and experiences. New opportunities and sites for queer spatial resistance have emerged and mobile applications like Meetup facilitate the literal takeover of popular urban spaces. Though technology may have reterritorialized certain sexual geographies for the lesbian community, this essay shows how queer practices are now informing place in ways that assert a queer spatial justice.

Maveropepimut-S, a DPX-based immune-educating therapy, shows promising and durable clinical benefit in patients with recurrent ovarian cancer, a phase 2 trial.

Patients with platinum resistant ovarian cancer (OvCa) respond poorly to existing therapies. Hence there is a need for more effective treatments. The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase 2 study to evaluate the safety and effectiveness of maveropepimut-S (MVP-S) with cyclophosphamide (CPA) in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL MVP-S 3 weeks apart, followed by one 0.1 mL doses, every 8 weeks up to progression. Oral CPA, 50 mg twice daily, was administered in repeating weekly on and off cycles. Twenty-two patients were enrolled. Median age was 58 years (38-78 years). Among the evaluable population, ORR was 21% (90% CI, 7.5%-41.9%), with a DCR of 63% (90% CI, 41.8%-81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum-sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four stable disease patients maintained clinical benefit up to 25 months. Most treatment related adverse events (TRAEs) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T cell responses were observed in treated patients with clinical benefit. MVP-S with intermittent low-dose CPA is well-tolerated, with clinical benefit for patients with recurrent OvCa. Observed responses are irrespective of the platinum status.

A Novel, Low-Fidelity, Low-Cost Residency “Simulation Festival” Competition: An Opportunity for Scholarly Innovation [ID: 1381241

INTRODUCTION: Simulation has rapidly expanded in obstetrics and gynecology for teaching medical knowledge, surgical skills, and maintenance of certification. Low-fidelity simulations are typically lower cost to produce and have been proven beneficial for surgical training. METHODS: The Junior Fellows of the American College of Obstetricians and Gynecologists District X created a competition at their Annual District Meeting in October 2022. All nine residency programs submitted and showcased a low-cost, novel simulation in obstetrics and gynecology at a 1-hour event open to all attendees. After IRB exemption was obtained, a postevent survey was completed by the participants at the event. RESULTS: A total of 77 individuals completed our postevent survey (medical students 12.99%, residents 58.44%, staff or fellows 28.57%). The majority of respondents felt simulation is valuable to ob-gyn training (96.10%). All respondents reported they would like to see the event repeated at future Annual District Meetings. The majority of resident responders reported they would be very likely (79.07%) or likely (18.60%) to use one of the simulations presented at the festival in future teaching or training. Fifteen respondents were involved in creating a simulation for the festival. Most simulations were very easy (60.00%) or easy (33.33%) to make, and all were reported to be very reproducible (100.00%). CONCLUSION: This unique event for Junior Fellows was successful in fostering innovative, low-cost, low-fidelity, highly reproducible simulations in obstetrics and gynecology. Our goals are to continue this event in future years, expand to other districts, foster reproduction of simulations at residency programs and medical schools, and support the publication of novel ideas.

Background incidence rates of selected adverse events of special interest (AESI) to monitor the safety of COVID-19 vaccines.

Determining background rates of medical conditions identified as adverse events of special interest (AESI) that may occur following COVID-19 vaccination is important for contextualising and investigating potential vaccine safety signals. We conducted a retrospective population-based cohort study using linked emergency department, hospitalisation and death data for 2017 and 2018 from Australia's most populous state, New South Wales. Incident cases of select neurological conditions, arterial or venous thromboembolic conditions, secondary thrombocytopenia, myocarditis/pericarditis, and unique events of anaphylaxis and generalised convulsions were identified using internationally agreed upon diagnostic (ICD-10) codes. State-specific rates per 100,000 person-years were calculated, with further stratification by age group and sex where clinically relevant to the condition, and the number of expected cases nationally in one and 6weeks was estimated. Background rates of selected neurological conditions were low with the exception of generalised convulsions for which 1,599-1,872 cases were estimated nationally in a 1-week period in the absence of vaccination. Using a narrow case definition, rates of Guillain-Barré Syndrome (3.9 per 100,000 person-years) were higher than international rates reported elsewhere. Thromboembolic and cerebral venous sinus thrombosis event rates increased with age. Myocarditis occurred more commonly in males, and was highest in males aged 18-24years, with an estimated 1-4 cases expected nationally in a 1-week period. Using routinely collected linked healthcare data provides localised estimates of background rates of new onset or periodic AESI which enables rapid estimation of observed-versus-expected rates of events reported following COVID-19 vaccination. This Australian-specific analysis contributes AESI background rates which can be compared with those from other countries to enhance understanding of geographic variability in the frequency of specific AESI in the absence of vaccination, and can be utilised for signal detection during program implementation.

Conditions and Magmas Sources of Summit and Flank Eruptions of the Klyuchevskoy Volcano in 2020–2021: Isotope (Sr-Nd-Pb-O)-Geochemical Data

In 2021 a unique event occurred on Klyuchevskoy volcano (Kamchatka). After more than 30 years dominance of terminal eruptions a flank vent was formed. It was named after corresponding member of the Academy of Sciences USSR G.S. Gorshkov. The eruption began immediately after the end of the summit crater activation in 2020–2021 at an altitude of 2850 m in the northwestern part of the volcano, where no manifestations of flank volcanism were observed earlier. This paper presents geochemical and isotopic Sr-Nd-Pb-O data for lavas of the summit and flank eruptions of the Klyuchevskoy volcano in 2020–2021. A comparative petrographic analysis was carried out and the chemical composition of the Ol, Cpx, Pl phenocrysts of these lavas was analyzed. The lavas of both eruptions are alumina andesitic basalts of normal alkalinity. Variations of basic oxides in the lavas of the summit eruption and in the lavas of the G.S. Gorshkov vent are SiO2 53.1–53.2 wt. % and 51.6–53.2 wt. %, MgO 5.6 wt. % and 5.5–6.0 wt. %; respectively. Estimates of temperatures and pressures of plagioclase crystallization showed that for lavas of the summit eruption they were 1210–1118°С and 12.3–3.6 kbar, for lavas of the flank vent 1203–1119°С and 9.0–3.3 kbar. The content of the main elements, the proximity of the conditions of plagioclase generations, and the features of variations in the chemical composition of Ol, Cpx, and Pl phenocrysts in the lavas of both eruptions indicate the genetic relationship of the magmas that fed the summit and flank eruptions. The lavas of the summit eruptions of 2016, 2020–2021, as well as the lavas of the previous summit eruptions of the Klyuchevsky volcano, are characterized by highly sustained Sr-Nd-Pb isotopic characteristics: 87Sr/86Sr = 0.703625–0.703626, 143Nd/144Nd = 0.513085–0.513102, 206Pb/204Pb = 18.3148–18.3179). Isotopic ratios 207Pb/204Pb (15.5022–15.5107) and 208Pb/204Pb (37.9597–38.0143) are significantly higher for the lavas of the last summit and flank eruptions than for all Klyuchevskoy’s lavas of the past, which indicates more complex processes of magma evolution at crustal levels. The values of δ18O = 6.49–7.39 rel. units (SMOW) in the lavas of the considered eruptions are consistent with previously published data on the Klyuchevsky volcano. The lavas of the Gorshkov vent are enriched with Ba, Zr, Sr and other incompatible elements at constant values of MgO in comparison with the lavas of the last summit eruptions, which indicates differences in the ways of evolution of their magmas. Sharply increased values of the 87Sr/86Sr ratio (0.703673–0.703743) in the lavas of the G.S. Gorshkov vent, not previously observed in the lavas of the Klyuchevsky volcano, testifies to intensive assimilation of crustal matter by the initial melts in the northwestern part of the volcano.

Expanding the legal common good via sustainable urban mobility

PurposeThe purpose of this paper is to examine the 2015 Union Cycliste Internationale (UCI) Road World Cycling Championship in Richmond, Virginia.Design/methodology/approachAn array of eclectic methods included in situ witness observations of several of the races, 21 semi-structured random interviews and multiple discussions with elements of UCI, the city of Richmond’s planners, residents and business owners during and after the championship in fall 2015.FindingsThis paper has uncovered five findings: First, the material investment was considerably smaller than that of other events (common good criterion CGC i – good governance); second, pre-planning was critical to successfully hosting the event; third, this event included not only two entities as one would expect at first glance, but many (common good criterion CGC ii – good management); fourth, a filière approach to community service and the exploitation of clustered thematic activities was of critical importance to successfully hosting the 2015 UCI Road World Cycling Championship; and fifth, this event enabled the opportunity to market other city and regional assets (common good criterion CGC iii – good outcomes).Practical implicationsCities hoping to bid for events ought to consider hosting unique events such as road championships. Those cities will benefit from careful event pre-planning, responsible event hosting and post-event legacies in the form of socio-economic and mindscape memories.Social implicationsBidding and pre-event planning is increasingly seen as an opportunity to locate, create and develop support for common good urban projects, which will remain valuable after the event is over or which will need to be built in spite of the bid’s result.Originality/valueThis study fills an unresearched gap on the impact of events on a city’s future non-motorized sustainable transportation priorities.

A Descriptive Analysis of the Use of Chemical, Biological, Radiological, and Nuclear Weapons by Violent Non-State Actors and the Modern-Day Environment of Threat.

The use of chemical, biological, radiation, and nuclear (CBRN) weapons is not new, and though rare, it is an issue of concern around the world due to their ability to cause large-scale mass-casualty events and their potential threat to global stability. The purpose of this study is to explore the use of CBRN weapons by non-state actors through analysis of the Violent Non-State Actor (VNSA) CBRN Event database, and aims to better inform health care systems of the potential risks and consequences of such events. Data collection was performed using a retrospective database search through the VNSA CBRN Event database. A total of 565 events were recorded. Five hundred and five (505) events (89.4%) involved single agents while 60 events (10.6%) involved multiple agents. Fatalities numbered 965 for chemical agents, 19 for biological agents, and none for radiological and nuclear events. Injuries numbered 7,540 for chemical agents, 59 for biological agents, 50 for radiological events, and none for nuclear attacks. Fatality and injury per attack was 2.22 and 17.37, respectively, for chemical event agents and 0.15 and 0.48, respectively, for biological event agents. Violent Non-State Actors were responsible for 565 unique events around the world involving the use of CBRN weapons from 1990-2020. The United States (118), Russia (49), and Iraq (43) accounted for the top three countries where these events occurred. While CBRN events remain relatively rare, technological advances have the potential to facilitate the use of such weapons as part of a hybrid warfare strategy with significant repercussions for civilian health and health care systems.

Profiling spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin

The spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. In this study, by performing integrated analysis of single-cell and spatial multi-omics data, we used 16 prenatal human samples to create a comprehensive developmental cell atlas of the spinal cord during post-conceptional weeks 5–12. This revealed how the cell fate commitment of neural progenitor cells and their spatial positioning are spatiotemporally regulated by specific gene sets. We identified unique events in human spinal cord development relative to rodents, including earlier quiescence of active neural stem cells, differential regulation of cell differentiation and distinct spatiotemporal genetic regulation of cell fate choices. In addition, by integrating our atlas with pediatric ependymomas data, we identified specific molecular signatures and lineage-specific genes of cancer stem cells during progression. Thus, we delineate spatiotemporal genetic regulation of human spinal cord development and leverage these data to gain disease insight.

Identifying gravity waves launched by the Hunga Tonga–Hunga Ha′apai volcanic eruption in mesosphere/lower-thermosphere winds derived from CONDOR and the Nordic Meteor Radar Cluster

Abstract. The Hunga Tonga–Hunga Ha′apai volcano eruption was a unique event that caused many atmospheric phenomena around the globe. In this study, we investigate the atmospheric gravity waves in the mesosphere/lower-thermosphere (MLT) launched by the volcanic explosion in the Pacific, leveraging multistatic meteor radar observations from the Chilean Observation Network De Meteor Radars (CONDOR) and the Nordic Meteor Radar Cluster in Fennoscandia. MLT winds are computed using a recently developed 3DVAR+DIV algorithm. We found eastward- and westward-traveling gravity waves in the CONDOR zonal and meridional wind measurements, which arrived 12 and 48 h after the eruption, and we found one in the Nordic Meteor Radar Cluster that arrived 27.5 h after the volcanic detonation. We obtained observed phase speeds for the eastward great circle path at both locations of about 250 m s−1, and they were 170–150 m s−1 for the opposite propagation direction. The intrinsic phase speed was estimated to be 200–212 m s−1. Furthermore, we identified a potential lamb wave signature in the MLT winds using 5 min resolved 3DVAR+DIV retrievals.

Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: A retrospective study.

Although immune checkpoint inhibitor (ICI) therapy has improved the prognosis of unresectable hepatocellular carcinoma (HCC), it has also resulted in unique immune-related adverse events (irAEs). The relationship between irAE and treatment outcomes in ICI-treated unresectable HCC patients remains unknown. To elucidate the correlation between immune-related toxic effects and prognosis in patients with unresectable HCC treated with pembrolizumab. From March 2019 to February 2021, a total of 190 unresectable HCC (Barcelona Clinic Liver Cancer C) patients receiving pembrolizumab treatment were retrospectively reviewed. Overall survival (OS) was the primary endpoint, while objective response rate (ORR), disease control rate (DCR), and time to progression (TTP) were secondary evaluation indexes. We assessed demographics, irAEs, and outcomes by retrospective review. One hundred and forty-three males and 47 females were included in the study. The ORR and DCR were 12.1% (23/190) and 52.1% (99/190), respectively. The median OS was 376 d [95% confidence interval (CI): 340-411 d] and the median TTP was 98 d (95%CI: 75-124 d). The overall incidence of treatment-related adverse events was 72.6% (138/190) and 10.0% of them were severe irAEs (grade ≥ 3). Child-Pugh B class, portal vein tumor thrombus, extrahepatic metastasis, and hypothyroidism were the independent risk factors for survival. Patients with hypothyroidism showed a longer OS [517 d (95%CI: 423-562) vs 431 d (95%CI: 412-485), P = 0.011] and TTP [125 d (95%CI: 89-154) vs 87 d (95%CI: 61-98), P = 0.004] than those without irAEs. Pembrolizumab-treated patients with unresectable HCC who experienced hypothyroidism have promising ORR and durable response. Hypothyroidism, an irAE, may be used as a clinical evaluation parameter of response to ICIs in unresectable HCC.

Predicting Cardiac Arrest in Children with Heart Disease: A Novel Machine Learning Algorithm

Children with congenital and acquired heart disease are at a higher risk of cardiac arrest compared to those without heart disease. Although the monitoring of cardiopulmonary resuscitation quality and extracorporeal resuscitation technologies have advanced, survival after cardiac arrest in this population has not improved. Cardiac arrest prevention, using predictive algorithms with machine learning, has the potential to reduce cardiac arrest rates. However, few studies have evaluated the use of these algorithms in predicting cardiac arrest in children with heart disease. We collected demographic, laboratory, and vital sign information from the electronic health records (EHR) of all the patients that were admitted to a single-center pediatric cardiac intensive care unit (CICU), between 2010 and 2019, who had a cardiac arrest during their CICU admission, as well as a comparator group of randomly selected non-cardiac-arrest controls. We compared traditional logistic regression modeling against a novel adaptation of a machine learning algorithm (functional gradient boosting), using time series data to predict the risk of cardiac arrest. A total of 160 unique cardiac arrest events were matched to non-cardiac-arrest time periods. Using 11 different variables (vital signs and laboratory values) from the EHR, our algorithm's peak performance for the prediction of cardiac arrest was at one hour prior to the cardiac arrest (AUROC of 0.85 [0.79,0.90]), a performance that was similar to our previously published multivariable logistic regression model. Our novel machine learning predictive algorithm, which was developed using retrospective data that were collected from the EHR and predicted cardiac arrest in the children that were admitted to a single-center pediatric cardiac intensive care unit, demonstrated a performance that was similar to that of a traditional logistic regression model. While these results are encouraging, future research, including prospective validations with multicenter data, is warranted prior to the implementation of this algorithm as a real-time clinical decision support tool.