Prothrombin complex concentrate for direct factor Xa inhibitor-associated bleeding or before urgent surgery.

INTRODUCTION: Factor Xa inhibitor (FXaI)-associated bleeding events are common and associated with substantial morbidity. Systematic evaluation of widely available, effective, and affordable FXaI bleed management strategies is needed. MATERIALS AND METHODS: We conducted a single-center retrospective cohort study of FXaI-treated patients presenting to a tertiary academic medical center from January 2018 to May 2019 who received 25-50 IU/kg 4F-PCC for either FXaI-associated major bleeding or urgent surgery. The primary outcome was hemostatic efficacy, and the safety outcome was the 30-day risk of thromboembolism. RESULTS: PCC was used to treat FXaI-associated bleeding in 83 cases (79.1 %) and was given before urgent surgery in 22 cases (20.9 %). Sixty-six patients were on apixaban, 38 were on rivaroxaban and one patient was on edoxaban. Intracranial hemorrhage (ICH) and gastrointestinal bleeding accounted for most bleeds (74.7 %). Median interval between last DOAC intake and presentation to triage was 9 h [IQR 5.3-14.8] and median PCC dosing was 40.0 IU/kg [IQR 28.5-46.6]. Forty-two patients (40.0 %) had pre-PCC FXaI levels drawn with median FXaI levels of 114.5 ng/mL [IQR 70.0-175.0]. Effective hemostasis occurred in 66.7 % [95%CI 55.4-76.3] of patients receiving PCC for bleeding and surgical hemostasis was rated as normal in 95.5 % (95%CI 76.5-100.0) for patients having urgent surgery. The 30-day risk of thromboembolism was 7.6 % [95%CI 3.7-14.5] and 22.9 % [95%CI 15.8-31.8] of patients died. CONCLUSIONS: PCC for FXaI-associated bleeding was associated with hemostatic efficacy in two-thirds of patients and thromboembolic events were uncommon. PCC represents a promising treatment strategy for FXaI-associated bleeding.

Effects of Parallax and Distortion in Total Ankle Arthroplasty.

BACKGROUND: Surgeons rely on intraoperative fluoroscopy to assist in placement of implant components during total ankle arthroplasty (TAA). Parallax alters the direction of an object when viewed from two different points, resulting in image distortion. The purpose of this study was to evaluate parallax/distortion in intraoperative fluoroscopic images during TAA. METHODS: A retrospective review of all TAAs performed by two surgeons (R.W.M. and B.S.) from August 2019 to April 2023 were reviewed. Intraoperative fluoroscopic anteroposterior (AP) ankle views were evaluated for any obvious parallax image distortion. Cases with obvious parallax distortion were included for angular evaluation of AP intraoperative fluoroscopic and first postoperative plain films. The tibia was marked at 2-centimeter intervals to create zones from the proximal stem of the implant. The anatomical axis of the tibia (AAT) was drawn at the mid-diaphysis. The anatomic lateral distal tibial angle (aLDTA) and anatomic axis deviation (AAD) were measured for each zone. RESULTS: A total of 22 TAAs were performed during the study period. Four cases were excluded due to inadequate imaging, leaving a total of 18 TAAs for review. We found 6 of 18 (33.3%) cases had obvious parallax distortion. We found the average aLDTA was 90.9° (84°-101°). At the most proximal tibial zone, the average aLDTA was 94° (91°-101°). We found the average AAD was 4.7 (0.5-17.2) mm. The AAD ranged from 0.5 to 17.2 mm lateral to 0.8 to 8.2 mm medial. Postoperative plain film radiographs displayed a normal aLDTA and an AAT centered within the ankle joint. CONCLUSION: Parallax can distort the appearance of the tibia on fluoroscopic images. Deviation from the normal aLDTA and anatomical axis should be anticipated. Surgeons should be aware of the potential impact of parallax and ways to mitigate these effects.

Deep infections after low-velocity ballistic tibia fractures are frequently polymicrobial and recalcitrant.

Objectives: To identify risk factors for developing a fracture-related infection in operatively treated ballistic tibia fractures and to report the microbiologic results of intraoperative cultures. Design: Retrospective review. Setting: Level 1 trauma center. Patients/Participants: One hundred thirty-three adults with operatively treated low-velocity ballistic tibia fractures, from 2011 to 2021. Intervention: One dose of prophylactic cefazolin or equivalent as well as perioperative prophylaxis. Main Outcome Measurements: Deep infection rate. Results: The deep infection rate was 12% (16/134) with no significant difference in injury characteristics, index surgical characteristics, or time to antibiotics between the groups (P > 0.05). Patients who were slightly older (35.5 vs. 27 median years, P = 0.005) and with higher median body mass indexes (BMIs) (30.09 vs. 24.51, P = 0.021) developed a deep infection. 56.3% of patients presented with signs of infection within the first 100 days after injury. Nine patients had polymicrobial infections. There were 29 isolated organisms, 69% were uncovered by first-generation cephalosporin prophylaxis (anaerobes, gram-negative rods, Enterococcus, methicillin resistant Staphylococcus Aureus [MRSA]), and 50% of patients developed recalcitrant infection and required a second reoperation where 6 organisms were isolated, half of which were not covered by first-generation prophylaxis (Enterococcus, Staphylococcus Aureus MRSA). Conclusions: We found a deep infection rate of 12% among ballistic tibia fractures receiving standard-of-care antibiotic prophylaxis. Increased age and body mass index were associated with deep infections. Half became recalcitrant requiring a second reoperation. 66.7% of isolated organisms were not covered by first-generation cephalosporin prophylaxis. Consideration should be given to treatment options such as broader prophylaxis or local antibiotic treatment. Level of Evidence: IV.

Phasing and climate forcing potential of the Millennium Eruption of Mt. Baekdu.

The Millennium Eruption of Mt. Baekdu, one of the largest volcanic eruptions in the Common Era, initiated in late 946. It remains uncertain whether its two main compositional phases, rhyolite and trachyte, were expelled in a single eruption or in two. Investigations based on proximal and medial ash have not resolved this question, prompting us to turn to high-resolution ice-core evidence. Here, we report a suite of glaciochemical and tephra analyses of a Greenlandic ice core, identifying the transition from rhyolitic to trachytic tephra with corresponding spikes in insoluble particle fallout. By modeling annual snow accumulation, we estimate an interval of one to two months between these spikes, which approximates the hiatus between two eruptive phases. Additionally, negligible sulfur mass-independent fractionation, near-synchroneity between particle and sulfate deposition, and peak sulfur fallout in winter all indicate an ephemeral aerosol veil. These factors limited the climate forcing potential of the Millennium Eruption.

Factors associated with facility childbirth and skilled birth attendance in Migori County, Kenya and the effect of Lwala Community Alliance intervention: a cross-sectional assessment from the 2019 and 2021 Lwala household surveys.

Background: Despite evidence of the beneficial effects of skilled birth attendance (SBA) on maternal health and childbirth outcomes, there are disparities in access across counties in Kenya. These include Migori County which has historically recorded high maternal mortality rates. In 2007, the Lwala Community Alliance was founded to improve health outcomes in this county. The objective of this study is to provide a baseline status of facility childbirth and SBA in Migori and to characterize the effect of Lwala intervention on these outcomes. Methods: A cross-sectional household survey was designed for a 10-year study to evaluate the effectiveness of Lwala initiatives. The 2019 and 2021 household surveys were conducted in Lwala intervention wards and in comparison wards with sample sizes of 3,846 and 5,928 mothers, respectively. The survey captured demographic, health, and socioeconomic data at each household, data on SBA and facility childbirth, and explanatory variables. A generalized linear model was used to determine factors associated with SBA. A secondary trend analysis was conducted to determine change over time in the explanatory variables and SBA. To determine the change in SBA rate due to Lwala intervention, controlling for background temporal trends, a difference-in-differences (DiD) model compared SBA rates in intervention wards and comparison wards. Results: SBA increased in all surveyed wards and across all explanatory variables from 2019 to 2021. The DiD analysis showed that the SBA rate increased more in Lwala intervention wards than in comparison wards (Adjusted Prevalence Rate Ratio 1.05, p < 0.001, 95%CI 1.03-1.08). The 2021 survey found the highest rates of both facility childbirths (97.9%, 95%CI 96.5-98.7) and SBA (98.2%, 95%CI 97.0-99.0) in North Kamagambo, the oldest ward of Lwala intervention. Higher educational status, four or more ANC visits, marriage/cohabitation, and wealth were significantly associated with increased SBA. Conclusions: We provide the first quasi-experimental evidence that Lwala interventions are significantly improving SBA which may inform related initiatives in similar settings. The household-survey data provides a baseline for continued evaluation of Lwala programs, and the breakdown by ward allows for development of specific programmatic targets.

Safety of Pregnancy and Delivery With Shunted Hydrocephalus.

This cohort study examines the safety of cerebrospinal fluid shunts during pregnancy.

A multi-sample examination of the relationship between athlete burnout and sport performance.

Athlete burnout potentially has negative consequences for sport performance. However, to the best of our knowledge, empirical studies have yet to examine the relationship between athlete burnout and objective sport performance. Consequently, we aimed to provide a first such examination. To do so, we recruited three samples. We used Sample 1 (n = 106: track and field athletes) to examine the predictive utility of athlete burnout on a single performance, Sample 2 (n = 181: swimmers) to examine whether the findings from Sample 1 can be replicated in a different sport, and Sample 3 (n = 169: track and field athletes) to examine the predictive utility of athlete burnout on peak performance in a three-month period. Finally, having captured three samples each assessing the athlete burnout-performance relationship, we also sought to quantify the combined effect across these samples using a relatively new analytical technique - mini meta-analysis. Results from regression analyses showed that in at least two of the three samples total burnout, reduced sense of accomplishment, and sport devaluation each negatively predicted performance, whereas emotional and physical exhaustion was unrelated to performance. When we combined the samples, mini meta-analysis showed that total burnout, reduced sense of accomplishment, and sport devaluation each displayed a small-to-medium negative and significant meta-correlation with performance. The findings suggest that certain athlete burnout symptoms may indeed have negative consequences for sport performance, and that this is the case when considering a single performance and peak performance.

Influence of Diet on Bowel Function and Abdominal Symptoms in Children and Adolescents with Hirschsprung Disease-A Multinational Patient-Reported Outcome Survey.

Introduction: This study aimed to understand the influence of diet and nutrition items on gastrointestinal symptoms in patients with Hirschsprung Disease (HD). Method: An online questionnaire was created to obtain patient-reported outcomes using the multinational Holistic Care in Hirschsprung Disease Network. This was distributed in Dutch, English, German, Italian, Polish, and Swedish via patient associations. Information on demographics, the extension of disease, current diet, and the influence of food ingredients on bowel function were obtained. Results: In total, 563 questionnaires were answered by parents or patients themselves. The length of the aganglionic segment was short in 33%, long in 45%, total colonic aganglionosis (TCA) in 11%, and involved the small intestine in 10%. Overall, 90% reported following a mixed diet, and 31% reported taking probiotics, with twice as many patients taking probiotics in the TCA group compared to standard HD. Mealtimes and behaviours around eating were affected by 61%, while 77% had established food items that worsened symptoms, and of these, 80% stated that they had worked these items out themselves. A high-fibre diet was followed by 24% and 18% a low-fibre diet. Symptoms were reported, particularly from dairy in 30%, fruits in 39%, pulses in 54%, and sugar in 48%. Conclusions: This first multinational survey on diet and bowel function in HD reports an association between certain dietary items with gastrointestinal symptoms. This study can support an improved understanding of the interaction between food items and bowel function in children with HD. We suggest a multidisciplinary approach to balance dietary exclusions and support adequate growth, preventing nutrition deficiencies and enhancing quality of life.

Traumatic Periprosthetic Fractures Following Total Ankle Replacement A Systematic Review and Proposed Classification.

Total ankle replacements (TAR) are increasingly utilized, but postoperative traumatic periprosthetic fractures remain a rare yet challenging complication. This systematic review aims to address the gap in literature by proposing a comprehensive classification system for these fractures, considering implant stability, fracture location, and surrounding bone quality. A systematic review identified 13 cases from 9 studies meeting inclusion criteria. Fractures were categorized using the proposed Hill-Brown classification: Type A (talus or fibula), Type B (distal tibial component), and Type C (diaphysis/proximal tibial metaphysis). Implant stability was a key factor, with Type B fractures further classified as B1 (stable), B2 (unstable with adequate bone stock), and B3 (unstable with poor bone stock). Most fractures occurred at or near the distal tibial component (Type B), with implant stability largely dependent on fracture location and bone quality. Surgical fixation, particularly minimally invasive plate osteosynthesis (MIPO) with locking plates, was the preferred treatment for stable implants, showing low complication rates. Unstable implants often required revision TAR or conversion to arthrodesis. Surgical intervention is recommended following all traumatic periprosthetic fractures in the setting of a TAR. Bone quality, particularly in patients with rheumatoid arthritis or osteoporosis, significantly impacted treatment decisions. Our findings emphasize the importance of fracture location, implant stability, and bone quality in managing these fractures. Future multicenter studies are necessary to validate this classification system and refine treatment protocols.Level of Evidence: Level III.

Evaluating the implementation of the Pediatric Acute Care Education (PACE) program in northwestern Tanzania: a mixed-methods study guided by normalization process theory.

BACKGROUND: In low- and middle-income countries (LMICs), such as Tanzania, the competency of healthcare providers critically influences the quality of pediatric care. To address this issue, we introduced Pediatric Acute Care Education (PACE), an adaptive learning program to enhance provider competency in Tanzania's guidelines for managing seriously ill children. Adaptive learning is a promising alternative to current in-service education, yet optimal implementation strategies in LMIC settings are unknown. OBJECTIVES: (1) To evaluate the initial PACE implementation in Mwanza, Tanzania, using the construct of normalization process theory (NPT); (2) To provide insights into its feasibility, acceptability, and scalability potential. METHODS: Mixed-methods study involving healthcare providers at three facilities. Quantitative data was collected using the Normalization MeAsure Development (NoMAD) questionnaire, while qualitative data was gathered through in-depth interviews (IDIs) and focus groups discussions (FGDs). RESULTS: Eighty-two healthcare providers completed the NoMAD survey. Additionally, 24 senior providers participated in IDIs, and 79 junior providers participated in FGDs. Coherence and cognitive participation were high, demonstrating that PACE is well understood and resonates with existing healthcare goals. Providers expressed a willingness to integrate PACE into their practices, distinguishing it from existing educational methods. However, challenges related to resources and infrastructure, particularly those affecting collective action, were noted. Early indicators point toward the potential for long-term sustainability of the PACE, but assessment of reflexive monitoring was limited due to the study's focus on PACE's initial implementation. CONCLUSION: This study offers vital insights into the feasibility and acceptability of implementing PACE in a Tanzanian context. While PACE aligns well with healthcare objectives, addressing resource and infrastructure challenges as well as conducting a longer-term study to assess reflexive monitoring is crucial for its successful implementation. Furthermore, the study underscores the value of the NPT as a framework for guiding implementation processes, with broader implications for implementation science and pediatric acute care in LMICs.

A Suicide Prevention Digital Technology for Individuals Experiencing an Acute Suicide Crisis in Emergency Departments: Naturalistic Observational Study of Real-World Acceptability, Feasibility, and Safety.

BACKGROUND: Emergency departments (EDs) are the front line in providing suicide care. Expert consensus recommends the delivery of several suicide prevention evidence-based interventions for individuals with acute suicidal ideation in the ED. ED personnel demands and staff shortages compromise delivery and contribute to long wait times and unnecessary hospitalization. Digital technologies can play an important role in helping EDs deliver suicide care without placing further demands on the care team if their use is safe to patients in a routine care context. OBJECTIVE: This study evaluates the safety and effectiveness of an evidence-based digital technology (Jaspr Health) designed for persons with acute suicidal ideation seeking psychiatric crisis ED services when used as part of routine ED-based suicide care. This study deployed Jaspr Health for real-world use in 2 large health care systems in the United States and aimed to evaluate (1) how and whether Jaspr Health could be safely and effectively used outside the context of a researcher-facilitated clinical trial, and (2) that Jaspr's use would be associated with improved patient agitation and distress. METHODS: Under the auspices of a nonsignificant risk device study, ED patients with acute suicidal ideation (N=962) from 2 health care systems representing 10 EDs received access to Jaspr Health as part of their routine suicide care. Primary outcome measures included how many eligible patients were assigned Jaspr Health, which modules were assigned and completed, and finally, the number of adverse events reported by patients or by medical staff. Secondary outcome measures were patient agitation, distress, and satisfaction. RESULTS: The most frequent modules assigned were Comfort and Skills (98% of users; n=942) and lethal means assessment (90% of patient users; n=870). Patient task completion rates for all modules ranged from 51% to 79%. No adverse events were reported, suggesting that digital technologies can be safely used for people seeking ED-based psychiatric services. Statistically significant (P<.001) reductions in agitation and distress were reported after using the app. Average patient satisfaction ratings by site were 7.81 (SD 2.22) and 7.10 (SD 2.65), with 88.8% (n=325) and 84% (n=90) of patients recommending the app to others. CONCLUSIONS: Digital technologies such as Jaspr Health may be safely and effectively integrated into existing workflows to help deliver evidence-based suicide care in EDs. These findings hold promise for the use of digital technologies in delivering evidence-based care to other vulnerable populations in complex environments.

First-Trimester Cell-Free DNA Fetal Fraction and Birth Weight in Twin Pregnancies.

OBJECTIVE: The relationship between fetal fraction and birth weight in twin gestations is poorly understood. This study aimed to investigate the relationship between first-trimester cell-free DNA (cfDNA) fetal fraction and birth weight <10th percentile in twin gestations. STUDY DESIGN: This is a planned secondary analysis of the Twin cfDNA Study, a 17-center retrospective cohort of twin pregnancies screened for aneuploidy using cfDNA in the first trimester from December 2011 to February 2022, excluding those with positive screen results for chromosomal aneuploidy. cfDNA testing was performed by a single laboratory using massively parallel sequencing. Baseline characteristics and birth weight of pregnancies with normal fetal fraction were compared with those with low (<5%) and high (>95%) fetal fraction using univariable analyses and multivariable regression. RESULTS: A total of 1,041 twin pregnancies were included. Chronic hypertension, elevated body mass index, and self-identified Black race were associated with fetal fraction <5th percentile. There was no difference in median fetal fraction between those with birth weight <10th percentile in at least one twin (median [interquartile range (IQR)] fetal fraction: 12.2% [9.8, 14.8] vs. those with normal birth weight (≥10th percentile) in both twins (median [IQR] fetal fraction: 12.3% [9.7, 15.2] for normal birth weight, p = 0.49). There was no association between high or low fetal fraction and birth weight <10th percentile for one (p = 0.45) or both (p = 0.81) twins, and there was no association between high or low fetal fraction and birth weight <5th percentile for one (p = 0.44) or both (p = 0.74) twins. The results were unchanged after adjustment for potential confounders. CONCLUSION: In this large cohort, there was no association between the extremes of cfDNA fetal fraction and birth weight <10th percentile, suggesting that first-trimester fetal fraction may not predict impaired fetal growth in twin gestations. KEY POINTS: · No association between fetal fraction and small for gestational age birth weight in twins.. · Results suggest that fetal fraction does not predict birth weight in twin gestations.. · These results differ from the relationship between fetal fraction and birth weight in singletons..

Aldehydes alter TGF-ß signaling and induce obesity and cancer.

Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor ß (TGF-ß) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (ß2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2-/- and Aldh2-/-Sptbn1+/- mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

Anatomy of Summertime Upslope Events in Northeastern Colorado: Ammonia (NH3) Transport to the Rocky Mountains.

The Transport and Transformation of Ammonia (TRANS2Am) airborne field campaign occurred over northeastern Colorado during the summers of 2021 and 2022. A subset of the TRANS2Am flights investigated easterly wind conditions capable of moving agricultural emissions of ammonia (NH3) through urban areas and into the Rocky Mountains. TRANS2Am captured 6 of these events, unveiling important commonalities. (1) NH3 enhancements are present over the mountains on summer afternoons when easterly winds are present in the foothills region. (2) The abundance of gas-phase NH3 is 1 and 2 orders of magnitude higher than particle-phase NH4+ over the mountains and major agricultural sources, respectively. (3) During thermally driven circulation periods, emissions from animal husbandry sources closer to the mountains likely contribute more to the NH3 observed over the mountains than sources located further east. (4) Transport of plumes from major animal husbandry sources in northeastern Colorado westward across the foothills requires ∼5 h. (5) Winds drive variability in the transport of NH3 into nearby mountain ecosystems, producing both direct plume transport and recirculation. A similar campaign in other seasons, including spring and autumn, when synoptic scale events can produce sustained upslope transport, would place these results in context.

Automatic Speech Recognition in Primary Progressive Apraxia of Speech.

INTRODUCTION: Transcribing disordered speech can be useful when diagnosing motor speech disorders such as primary progressive apraxia of speech (PPAOS), who have sound additions, deletions, and substitutions, or distortions and/or slow, segmented speech. Since transcribing speech can be a laborious process and requires an experienced listener, using automatic speech recognition (ASR) systems for diagnosis and treatment monitoring is appealing. This study evaluated the efficacy of a readily available ASR system (wav2vec 2.0) in transcribing speech of PPAOS patients to determine if the word error rate (WER) output by the ASR can differentiate between healthy speech and PPAOS and/or among its subtypes, whether WER correlates with AOS severity, and how the ASR's errors compare to those noted in manual transcriptions. METHOD: Forty-five patients with PPAOS and 22 healthy controls were recorded repeating 13 words, 3 times each, which were transcribed manually and using wav2vec 2.0. The WER and phonetic and prosodic speech errors were compared between groups, and ASR results were compared against manual transcriptions. RESULTS: Mean overall WER was 0.88 for patients and 0.33 for controls. WER significantly correlated with AOS severity and accurately distinguished between patients and controls but not between AOS subtypes. The phonetic and prosodic errors from the ASR transcriptions were also unable to distinguish between subtypes, whereas errors calculated from human transcriptions were. There was poor agreement in the number of phonetic and prosodic errors between the ASR and human transcriptions. CONCLUSIONS: This study demonstrates that ASR can be useful in differentiating healthy from disordered speech and evaluating PPAOS severity but does not distinguish PPAOS subtypes. ASR transcriptions showed weak agreement with human transcriptions; thus, ASR may be a useful tool for the transcription of speech in PPAOS, but the research questions posed must be carefully considered within the context of its limitations. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26359417.

Evaluating Methods for the Prediction of Cell Type-Specific Enhancers in the Mammalian Cortex.

Identifying cell type-specific enhancers in the brain is critical to building genetic tools for investigating the mammalian brain. Computational methods for functional enhancer prediction have been proposed and validated in the fruit fly and not yet the mammalian brain. We organized the 'Brain Initiative Cell Census Network (BICCN) Challenge: Predicting Functional Cell Type-Specific Enhancers from Cross-Species Multi-Omics' to assess machine learning and feature-based methods designed to nominate enhancer DNA sequences to target cell types in the mouse cortex. Methods were evaluated based on in vivo validation data from hundreds of cortical cell type-specific enhancers that were previously packaged into individual AAV vectors and retro-orbitally injected into mice. We find that open chromatin was a key predictor of functional enhancers, and sequence models improved prediction of non-functional enhancers that can be deprioritized as opposed to pursued for in vivo testing. Sequence models also identified cell type-specific transcription factor codes that can guide designs of in silico enhancers. This community challenge establishes a benchmark for enhancer prioritization algorithms and reveals computational approaches and molecular information that are crucial for the identification of functional enhancers for mammalian cortical cell types. The results of this challenge bring us closer to understanding the complex gene regulatory landscape of the mammalian brain and help us design more efficient genetic tools and potential gene therapies for human neurological diseases.

Vaccine Development Should Be Polytheistic, Not Monotheistic.

Vaccines based on mRNA technology have been tremendously successful, but their properties are not necessarily ideal for all pathogens. There is a risk that concentration on that technology alone for new vaccine development will ignore older technologies that have properties giving broader and more persistent protection.

Poor Prognostic Factors in Long-Term Survivors of Resected Pancreatic Ductal Adenocarcinoma: An International, Multicenter Cohort Study.

OBJECTIVE: To measure the rate of LTS in resected PDAC and determine the association between predictors of OS and LTS. SUMMARY BACKGROUND DATA: Long-term survival (>5 y, LTS) remains rare in pancreatic ductal adenocarcinoma (PDAC). Multiple predictors of overall survival (OS) are known but their association with LTS remains unclear. METHODS: An international, multicenter retrospective study was conducted. Included were patients from 2012-2019 with resected PDAC. Excluded were those with metastases at diagnosis or resection, R2 resections, and 90-day mortality. Predictors of OS were identified using multivariable Cox regression and their prevalence in patients with LTS assessed. LTS was calculated by excluding patients with shorter follow-up and predictors of LTS were identified using multivariable logistic regression. RESULTS: 3,003 patients were included (27.4% received neoadjuvant chemotherapy). Elevated baseline CA19-9, high tumor grade, nodal disease, and perineural and lymphovascular invasion were negative independent predictors of OS, while receipt of adjuvant chemotherapy predicted improved OS (all P<0.05). LTS was observed in 220/2,436 patients (9.0%), of whom 198 (90%) harbored poor prognostic factors: elevated baseline CA19-9 (58.1%), poor tumor differentiation (51.0%), nodal disease (46.8%), and perineural invasion (76.0%). Of those without any of these four features, 50.0% achieved LTS as compared to 21.3%, 13.3%, 5.2%, and 3.5% in those with 1, 2, 3, or 4 features. CONCLUSIONS: This bi-national cohort demonstrates a true LTS rate of 9.0% in resected PDAC. Clinicians should remain aware that presence of poor prognostic factors does not preclude LTS.