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The article discusses the need for improved biosecurity measures in pathogen research and proposes a "bottom-up" approach to enhance safety and security. The authors share their experience implementing a successful program at the University of Texas Medical Branch (UTMB) that requires principal investigators (PIs) to conduct comprehensive risk assessments for proposed studies involving human pathogens. The program involves a formal notification of use (NOU) submission that is extensively reviewed by the Institutional Biosafety Committee (IBC). The authors suggest that this approach can be applied nationally with appropriate policy guidance and support, and emphasize the importance of training, access to biocontainment laboratories, and collaboration between institutions. [Extracted from the article]

BACKGROUND: Aerospace Medicine board eligibility via the American Board of Preventive Medicine requires completion of a Master of Public Health (MPH), or equivalent, degree. The University of Texas Medical Branch (UTMB) Aerospace Medicine Residency has traditionally provided residents with an education resulting in a MPH degree. Recent nationwide changes to the MPH competencies made by the Council on Education for Public Health (CEPH), feedback from recent graduates, and input from potential employers of Flight Surgeons prompted the University of Texas Medical Branch to re-examine the curriculum and adapt it to better suit the needs of our residents. OVERVIEW: A new curriculum comprising a Master of Science in Aerospace Medicine was tailored to UTMB residents based on feedback from identified stakeholders. It includes approximately 100 hours of Aerospace Medicine specific content in addition to the core courses required for board eligibility. Examples of topics covered include complex aeromedical certification, fundamentals of aerospace physiology, women's health in spaceflight, medical operations to include launch and landing efforts, acute care response, risk management, and introductory principles to mishap investigation and response. In addition, UTMB has partnered with a commercial space company that will be providing a customized overview of systems engineering and approach to the development of requirements for non-engineers. We are proud to partner with experts in the field to provide this new curriculum to our residents. DISCUSSION: As mission architectures for space and aviation evolve, so too must the education for physicians in pursuit of Aerospace Medicine. Through the lens of a multi-disciplinary core faculty, and the input of both government and industry stakeholders, the UTMB residency is proactively innovating and preparing for the future. Learning Objectives 1. The participant will be able to identify differences in the former MPH curriculum and the current MS curriculum at UTMB. 2. The participant will have a better understanding of the type of content included in the MS curriculum. [ABSTRACT FROM AUTHOR]

This study aimed to find out whether three Texas state policies restricting opioid prescriptions have influenced the prescribing patterns of the oculoplastic department at the University of Texas Medical Branch (UTMB). This is a retrospective chart review of 520 patients at UTMB between 2019 and 2021, reporting the amount of morphine milliequivalents (MMEs) prescribed to patients undergoing one of eight oculoplastic procedures before and after passage of each state policy. Of 520 patients, 218 received opioids. There were no changes in MMEs/month after the first policy (95% CI: −0.1531–0.1256, p = 0.85), second policy (95% CI: −0.000997–0.00093, p = 0.97), or third policy (95% CI: −0.001431–0.00164, p = 0.096). The passage and implementation of three Texas state antiopioid policies were not associated with significant changes in opioid prescribing patterns following oculoplastic and orbital surgeries at UTMB. Average MMEs/month were driven by orbital-floor fractures, which composed most procedures overall. Limitations included the small population and that only a single provider was reviewed. Future studies would be beneficial in further evaluating the role of state legislation on opioid prescribing patterns and usage among patients. [ABSTRACT FROM AUTHOR]

Background: Heart transplant recipients are a subset of immunocompromised patients at particularly high risk of morbidity and mortality from COVID-19. Acute effects of the viral infection have been well-described in the literature but the chronic effects persisting after recovery from infection have not. The aim of this study is to determine the impact of COVID-19 on heart transplant function both during and after recovery from acute infection. Methods: We retrospectively analyzed the data of 32 heart transplant recipients at the University of Texas Medical Branch (UTMB). Echocardiograms of patients with documented COVID-19 infection were analyzed at three time points including pre-infection, peri-infection, and post-infection. Echocardiograms of patients without history of infection were analyzed as control. Left Ventricular Ejection Fraction (LVEF) and presence or absence of valvular insufficiency were collected from echocardiograms to assess systolic and valvular function. Results: 2 out of 10 COVID-19 positive heart transplant recipients had decreases in LVEF below 20% during the peri-infection period, and one of these patients passed away from complications of infection. Despite this, mean LVEF was not significantly different at peri-infection (p =.3, 95% CI − 11.5 to 27.6) or post-infection (p =.6, 95% CI − 3.6 to 5.8) time points when compared to pre-infection. A statistically significant increase in valvular dysfunction was found among COVID-19 positive patients without documented history of valvular dysfunction on pre-infection echocardiograms (p =.01, 95% CI 19.3% to 96.4%). COVID-19 negative heart transplant recipients did not experience statistically significant changes in LVEF 1, 2, or 3 years after baseline echocardiogram. Conclusion: COVID-19 may induce myocardial dysfunction resulting in decreased systolic function and valvular dysfunction among heart transplant recipients. Severity of systolic dysfunction may be a useful prognostic indicator among this patient population. More research must be conducted to fully elucidate the effects of COVID-19 infection on heart transplant recipients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Upon graduation, many Aerospace Medicine residents are embarking on entirely new career paths compared to their predecessors just a decade ago. To ensure that trainees continue to receive cutting-edge education in this rapidly evolving field, the University of Texas Medical Branch (UTMB) has updated its curriculum to incorporate innovative and invaluable academic and rotational experiences into its Aerospace Medicine residency program. OVERVIEW: This fall, UTMB introduced a Master of Science in Aerospace Medicine into its first-year curriculum. This program provides a multi-faceted foundation of knowledge in Aerospace Medicine and, of note, introduces an approach to systems engineering thru the lens of a commercial space provider. To combine this academic knowledge with real-world experience, the program includes longitudinal rotations at NASA's Johnson Space Center. In the second year, trainees are afforded the opportunity to create unique experiences that will benefit their specific career choices. This year, residents have cared for altitude-related maladies in the Himalayas, collaborated on projects with the UK's Civil Aviation Authority in London, joined USAF colleagues in CBRN training exercises, and drafted emergency medical protocols for new commercial space companies. DISCUSSION: With the advent of the commercial space industry, the field of aerospace medicine is rapidly expanding, requiring training programs to adapt to new educational and training needs. UTMB's program advances the field of aerospace medicine by ensuring that trainees are receiving the experiences and education that they need in these new roles. Learning Objectives 1. During this presentation, the audience will learn about cutting-edge approaches to aerospace medical education. 2. After this presentation, the audience will be familiar with the impact of real-world rotational experiences on creating unique educational pathways for Aerospace Medicine Residents. [ABSTRACT FROM AUTHOR]

INTRODUCTION: While the primary mission of United States operations in Antarctica is scientific discovery, the Department of Defense (DOD) provides permanent support to the National Science Foundation (NSF) through Operational DEEP FREEZE. One of the major responsibilities of the DOD is to provide logistics and transport capability to the continent, including medical evacuation. Due to logistical challenges, an attempt to comprehensively analyze U.S. aeromedical evacuations from Antarctica, reconciling both civilian and military records across multiple deployment seasons, has not been described in the literature. METHODS: This study was approved by the 59th Medical Wing Institutional Review Board. De-identified aeromedical evacuation records involving a patient within/from Antarctica or labeled "Operation Deep Freeze" was obtained from the DOD TRAC2ES database. NSF records were reviewed in person by DOD medical extractors at the University of Texas Medical Branch (UTMB) Center for Polar Operations. De-identified medical data was extracted, including relevant medical history, diagnosis, medical treatments, destination, and en-route care interventions. Twenty percent of UTMB records were reviewed by both extractors for intra-rater reliability. A third extractor reconciled discrepancies as needed. RESULTS: 71 DOD TRAC2ES records and 93 UTMB records were included in the final analysis. A preliminary review identified a total of 129 distinct patient movements for calendar years 2015 -- 2023. Only 35 records (27.1%) could be reconciled between TRAC2ES and UTMB as the same patient movement. Of the remaining patient movements, 36 were unique TRAC2ES records (27.9%), 58 were unique UTMB records (45.0%). Musculoskeletal pathology (28.9%), genitourinary/reproductive (12.5%), gastrointestinal (14.1%), cardiac (11.7%), and neurologic (9.4%) pathologies were the most common body systems requiring aeromedical evacuation. DISCUSSION: These results show that the NSF, DOD and, UTMB work cooperatively to safely transport patients with a wide variety of medical pathologies out of Antarctica. This project highlights the limitations of retrospective chart reviews, especially those requiring data extraction from paper charts and deidentified databases. This knowledge will facilitate immediate follow-on studies to further analyze trends of medical capabilities in Antarctica. Learning Objectives 1. Understand the differences between DOD and NSF records from Antarctica patient movements. 2. Understanding the trends of United States aeromedical evacuations from Antarctica between 2015 and 2023. 3. Understand the limitations of a retrospective chart review and the next steps planned for data extraction involving United Sates Antarctica medical care. [ABSTRACT FROM AUTHOR]

Clopidogrel is a purinergic receptor P2Y12 (P2RY12)-blocking pro-drug used to inhibit platelet aggregation in patients at risk for major adverse cardiac events (MACE), such as coronary artery disease and stroke. Despite clopidogrel therapy, some patients may still present with recurrent cardiovascular events. One possible cause of recurrence are variants in the cytochrome P450 2C19 (CYP2C19) gene. CYP2C19 is responsible for the metabolism of many drugs including clopidogrel. Recent studies have associated pharmacogenetics testing of CYP2C19 variants to guide clopidogrel therapy with a decreased risk of certain recurrent MACEs. Through a different mechanism, diabetes mellitus (DM) and obesity are also associated with clopidogrel treatment failure. We describe the case of a 64-year-old Caucasian woman with a history of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI), and DM/obesity, who presented to University of Texas Medical Branch (UTMB) in 2019 with a transient ischemic attack (TIA) while on clopidogrel/aspirin dual anti-platelet therapy. After CYP2C19 genetic testing revealed that she was an intermediate metabolizer with a heterozygous *2 genotype, ticagrelor replaced the clopidogrel treatment regimen. No future MACEs were documented in the two-year patient follow-up. Thus, ACS patients with DM/obesity who have undergone PCI and are intermediate CYP2C19 metabolizers may yield better treatment outcomes if prescribed ticagrelor instead of clopidogrel. Whether this improvement was due to genotype-guided therapy or the differing interactions of clopidogrel/ticagrelor in DM/obese patients is unknown based on available data. Regardless, CYP2C19 genotype-guided treatment of ACS/PCI patients, with consideration of DM/obesity status, may provide effective individualized therapy compared to standard treatment. The inclusion of DM/obesity in this study is clinically relevant because DM/obesity has become a major health issue in the United States and worldwide. [ABSTRACT FROM AUTHOR]

The American Osler Society (AOS) traces its origin to a 1970 symposium on Humanism in Medicine in Galveston, Texas. Although John P. McGovern (1921–2007) receives credit for conceiving the symposium and spearheading formation of the AOS, Chester Ray Burns (1937–2006) played a key role that has not been sufficiently recognized. Burns, the first American-born physician to receive a doctorate in the history of medicine from the Johns Hopkins University, did much and perhaps most of the organizational work and brought to the symposium a perspective on the crossroads between medicine and the humanities that proved essential to the nascent organization's success. Burns went on to a productive career at the University of Texas Medical Branch (UTMB) in Galveston, became the 35th president of the AOS, and is among the relatively few physician-historians to have published scholarly articles in the history of medicine, medical biography, medical ethics, and philosophy as related to medicine. [ABSTRACT FROM AUTHOR]

Low-vision rehabilitation (LVR) has significant benefit in improving the quality of life of visually impaired patients. However, these services are highly underutilized in ophthalmology practices. A quality improvement study was performed to investigate barriers to LVR services for patients at the University of Texas Medical Branch (UTMB) between 2010 and 2020. Low vision was defined as the best corrected visual acuity of 20/70 or worse in the better-seeing eye or a visual field less than 20 degrees. Potential subjects were screened (n = 577) from the electronic medical record using International Classification of Disease (ICD) codes for legal blindness, impaired vision, and low vision. Chart review identified 190 subjects who met criteria for low-vision analysis. Patients who received LVR referrals to attend at least one LVR service visit from the eligible subjects were contacted for participation in phone interviews regarding their LVR experience. Practicing eye care providers (ECPs) at UTMB completed a questionnaire to capture their referral patterns. Of the eligible subjects, 64% were referred to LVR services by ECPs. Reported patient barriers included mental health issues (76%), denial of need for low-vision aid (71%), poor physical health (67%), lack of transportation (57.1%), and lack of referrals (36%). EPCs reported patient's overall health (67%), older age (44%), lack of social support (44%), poor cognitive function (44%), and low likelihood of follow-up (44%) as barriers to referring patients to LVR. This study identified several modifiable barriers that can be addressed to access LVR services for low-vision patients. Changing referral patterns, eliminating variations in referral criteria, and increasing patient awareness and knowledge of LVR resources may tremendously improve the quality of life of low-vision patients. [ABSTRACT FROM AUTHOR]

Anish Bhardwaj Departments of Neurology, Neurosurgery, and Neurobiology, University of Texas Medical Branch (UTMB), Galveston, TX, 77555, USACorrespondence: Anish Bhardwaj, University of Texas Medical Branch (UTMB), 9.128 John Sealy Annex, Route 0539, 301 University Blvd, Galveston, TX, 77555, USA, Tel +1-409-772-8068, Email anbhardw@UTMB.EDUAbstract: Medical professionalism is critical toward provision of safe, effective, patient-centered, timely, efficient, and equitable clinical care delivery. The basic tenets of medical professionalism are deeply embedded in the historical context via oaths and expectations. However, standardization of professional conduct and its integration by providers have been a challenge due to the evolving complexity of healthcare organizations (HCOs) and academic medical institutions (AMIs). Increasing heterogeneity of the workforce leads to greater complexity in collaborative teamwork. In this evolving landscape, violations of professional conduct demand closer scrutiny along professional and personal lines. Likewise, actions among minority groups pose challenges between integration and inclusion of certain professional interactions and conduct. Recently, in American HCOs and AMIs, there has been a renewed emphasis on accountability and managing unprofessional behaviors in the delivery of clinical care. This descriptive literature-based treatise explicates the professionalism construct in its historical milieu, underscores key facets of professionalism, highlights principal drivers of unprofessional behaviors, and posits solutions for enhancing and nurturing professionalism in the delivery of clinical care in HCOs and AMIs by a diverse workforce of healthcare providers.Keywords: professionalism, workforce, healthcare, diversity, inclusion

Anish Bhardwaj Departments of Neurology, Neurosurgery, Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch (UTMB), Galveston, TX, USACorrespondence: Anish Bhardwaj, Departments of Neurology, Neurosurgery, Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch (UTMB), 9.128 John Sealy Annex, Route 0539, 301 University Blvd, Galveston, TX, 77555, USA, Tel +1-409-772-8068, Email anbhardw@UTMB.EDUAbstract: Artificial Intelligence (AI) and Machine Learning (ML) promise to transform all facets of medicine. Expected changes include more effective clinical triage, enhanced accuracy of diagnostic interpretations, improved therapeutic interventions, augmented workflow algorithms, streamlined data collection and processing, more precise disease prognostication, newer pharmacotherapies, and ameliorated genome interpretation. However, many caveats remain. Reliability of input data, interpretation of output data, data proprietorship, consumer privacy, and liability issues due to potential for data breaches will all have to be addressed. Of equal concern will be decreased human interaction in clinical care, patient satisfaction, affordability, and skepticism regarding cost-benefit. This descriptive literature-based treatise expounds on the promise and provisos associated with the anticipated import of AI and ML into all domains of medicine and healthcare in the very near future.Keywords: artificial intelligence, machine learning, cost-benefit, healthcare

Anish Bhardwaj Department of Neurology, Neurosurgery, Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch (UTMB), Galveston, TX, 77555, USACorrespondence: Anish Bhardwaj, Department of Neurology, University of Texas Medical Branch (UTMB), 9.128 John Sealy Annex, Route 0539, 301 University Blvd, Galveston, TX, 77555, USA, Tel +1-409-772-8068, Email anbhardw@UTMB.EDUAbstract: Across the United States, physician burnout is progressively escalating, with accompanying negative sequelae for myriad stakeholders in healthcare, including communities, patients, physicians, and Healthcare Organizations (HCOs) with essential manpower implications. This ubiquitous trend is due to complex and multifactorial elements, including individual physician-related influences, generational perspectives, sociocultural communal effects, HCOs, and more recently the mounting challenges accompanying the COVID-19 pandemic. To achieve the overarching goals of US healthcare provision (ie, safe, effective, patient-centered, timely, efficient, and equitable patient care), proposed solutions should focus on longitudinal actionable data acquisition to meet workforce needs preemptively, resource allocation for wellness programs geared towards enhancing recruitment and retention, and shared responsibility at the level of individual physician and HCO. This descriptive literature-based treatise expounds on the underlying causality for physician burnout, its consequences for the healthcare workforce in the US, and provides individual- and institution-based solutions for its mitigation.Keywords: burnout, pandemic, workforce, healthcare, COVID-19

Carers were disproportionately harmed in the COVID-19 pandemic. Despite facing an increased risk of contracting the virus, they continued in frontline roles in care services and acted as "shock absorbers" for their families and communities. In this article, we apply an intersectional lens to examine care work and the structural factors disadvantaging carers during COVID-19 through a comparative case study analysis of 16 low-, middle-, and high-income countries. Data on each country was collected through a qualitative framework during 2021–2022. We found that while carers everywhere were predominantly women with low incomes and precarious employment, other factors were at play in shaping their experiences. Moreover, government responses to mitigate the direct impact of the pandemic have created local and global disparities affecting those working in this sector. Our findings reveal how oppressive social structures such as race, class, caste, and migration status converged in contextually specific ways to shape the gendered nature of care within and between different countries. We call for a better understanding of the multiple axes of inequalities experienced by carers to inform crisis mitigations, coupled with long-term strategies to address social inequities in the care economy and to promote gender equality. [ABSTRACT FROM AUTHOR]

Eilat (EILV)/chikungunya virus (CHIKV), an insect-based chimeric alphavirus was previously reported to protect mice months after a single dose vaccination. The underlying mechanisms of host protection are not clearly defined. Here, we assessed the capacity of EILV/CHIKV to induce quick and durable protection in cynomolgus macaques. Both EILV/CHIKV and the live attenuated CHIKV 181/25 vaccine protected macaques from wild-type (WT) CHIKV infection 1 year after a single dose vaccination. Transcriptome and functional analyses reveal that EILV/CHIKV triggered T cell, memory B cell and antibody responses in a dose-dependent manner. EILV/CHIKV induced more robust, durable, and broader repertoire of CHIKV-specific T cell responses than CHIKV 181/25; whereas the latter group induced more durable memory B cells and comparable or higher CHIKV -specific neutralization and binding antibodies. EILV/CHIKV and an inactivated WT CHIKV protected macaques from WT CHIKV infection and CHIK fever (CHIKF) within 6 days post vaccination. Transcriptome analysis showed that the chimeric virus induced multiple innate immune pathways, including Toll-like receptor signaling, antigen presenting cell activation, and NK receptor signaling. EILV/CHIKV triggered quicker and more robust type I interferon and NK cell responses than the inactivated WT virus vaccine. Lastly, we developed a guinea pig sensitization model and demonstrated that the chimeric virus produced in insect cells, did not cause skin hypersensitivity reactions. Overall, EILV/CHIKV is safe, and confers rapid and long-lasting protection in cynomolgus macaques via preferential induction of robust innate immune signaling and superior T cell immunity. [ABSTRACT FROM AUTHOR]

While the importance of medical professionalism is widely recognized, strategies for incentivizing positive professionalism have not been formally reviewed. We reviewed available literature on interventions to promote professionalism in training and practice to identify common themes and differentiate extrinsic vs intrinsic motivators. Among 24 relevant articles identified for review, 4 programmatic themes emerged: recognition and rewards (extrinsic motivators), and review of performance and reflection (intrinsic motivators). Most incentive programs were geared toward medical students or faculty, and few studies included outcomes data, although the reported findings suggested a positive impact. Incentive programs, such as awards programs, recognition of role models, feedback, coaching, and reflection, appear to promote positive professional behaviors, though further study is needed to facilitate optimal integration of best practices across training and practice. [Pediatr Ann. 2024;53(12):e446–e451.] [ABSTRACT FROM AUTHOR]

The jigsaw method which utilises peer-teaching in small-group settings permits a facilitator to incorporate active learning strategies into their educational toolbox. In November 2022, we evaluated the impact of the jigsaw method with groups stratified by post-graduate year (PGY) level. We assessed pre and post learner confidence and medical knowledge during a facilitator-led workshop. Participants were stratified into three groups who presented on the following subtopics about osteoporosis in men: (1) history and physical examination (PGY1s), (2) lab work and imaging studies (PGY2s) and (3) management and interventions (PGY3s). We evaluated if stratifying by PGY level impacted learner medical knowledge and confidence in November 2022. We had an 80% response rate from 16 actual participants from a total of 20 possible participants. Authors found a statistically significant increases in residents' confidence and medical knowledge after the training for all questions, but broad application across a variety of learners is still needed. The jigsaw method showed improvement in learner confidence about osteoporosis in men and may be implemented in teams distributed by PGY levels. Distribution by PGY level allows each team to building on their current training level to educate their peers. [ABSTRACT FROM AUTHOR]

Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4′-fluorouridine (4′-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4′-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4′-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4′-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4′-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4′-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens. Editor's summary: There are no approved therapies for pathogenic hemorrhagic fever viruses, such as Lassa virus or Junín virus, that cause high morbidity and mortality in humans. Welch et al. now report that 4′-fluorouridine (4′-FlU; EIDD-2749), an oral ribonucleoside analog, has potent antiviral activity against pathogenic hemorrhagic fever viruses in vitro. When given orally to infected guinea pigs, 4′-FlU protected the animals against lethal disease due to Lassa virus or Junín virus. Protection was seen even with reduced doses of drug and when treatment was started after the onset of clinical disease signs. These findings suggest that further investigation into 4′-FlU as a potential treatment for arenavirus infections is warranted. —Orla Smith [ABSTRACT FROM AUTHOR]

Background: Blood metabolites have emerged as promising candidates in the search for biomarkers for Alzheimer's disease (AD), as evidence shows that various metabolic derangements contribute to neurodegeneration in AD. Objective: We aim to identify metabolic biomarkers for AD diagnosis. Methods: We conducted an in-depth analysis of the serum metabolome of AD patients and age, sex-matched cognitively unimpaired older adults using ultra-high-performance liquid chromatography-high resolution mass spectrometry. The biomarkers associated with AD were identified using machine learning algorithms. Results: Using the discovery dataset and support vector machine (SVM) algorithm, we identified a panel of 14 metabolites predicting AD with a 1.00 area under the curve (AUC) of receiver operating characteristic (ROC). The SVM model was tested against the verification dataset using an independent cohort and retained high predictive accuracy with a 0.97 AUC. Using the random forest (RF) algorithm, we identified a panel of 13 metabolites that predicted AD with a 0.96 AUC when tested against the verification dataset. Conclusions: These findings pave the way for an efficient, blood-based diagnostic test for AD, holding promise for clinical screenings and diagnostic procedures. [ABSTRACT FROM AUTHOR]

COVID-19 presents with a plethora of neurological signs and symptoms despite being characterized as a respiratory disease, including seizures, anxiety, depression, amnesia, attention deficits, and alterations in consciousness. The olfactory nerve is widely accepted as the neuroinvasive route by which the etiological agent SARS-CoV-2 enters the brain, but the trigeminal nerve is an often-overlooked additional route. Based on this consensus, we initially conducted a pilot experiment investigating the olfactory nerve route of SARS-CoV-2 neuroinvasion via intranasal inoculation in AC70 human ACE2 transgenic mice. Notably, we found that the trigeminal ganglion is an early and highly efficient site of viral replication, which then rapidly spread widely throughout the brain where neurons were primarily targeted. Despite the extensive viral infection across the brain, obvious evidence of tissue pathology including inflammatory infiltration, glial activation, and apoptotic cell deaths were not consistently observed, albeit inflammatory cytokines were significantly induced. However, the expression levels of different genes related to neuronal function, including the neurotransmitter dopamine pathway as well as synaptic function, and markers of neuronal damage were altered as compared to mock-infected mice. Our findings suggest that the trigeminal nerve may serve as a neuroinvasive route complementary to the olfactory nerve and that the ensuing neuroinvasion presented a unique neuropathological profile. This study provides insights into potential neuropathogenic mechanisms utilized by coronaviruses. [ABSTRACT FROM AUTHOR]

Anish Bhardwaj Department of Neurology, University of Texas Medical Branch (UTMB), Galveston, Texas, 77555, USACorrespondence: Anish Bhardwaj, Department of Neurology, University of Texas Medical Branch (UTMB), 9.128 John Sealy Annex, Route 0539, 301 University Blvd, Galveston, Texas, 77555, USA, Tel +1-409-772-8068, Email anbhardw@UTMB.EDUAbstract: In the US, a heterogeneity in archetypes of leadership augments the success of an Academic Medical Institution (AMI) in fulfilling its key missions of clinical service, teaching, training, mentoring, research and scholarship, community engagement, inclusion, and diversity. Effective leadership is profoundly influenced by organizational culture with its dominant foundations in shared attitudes, beliefs, mores, behaviors—scripted and unscripted, as well as explicit and tacit rules and policies that become entrenched in the operational repertoire over time. Modulating organizational culture are an AMI’s mission, vision, core and affirmed values, formal governance and its complexity, informal influencers, historical precedent, the rapidly evolving landscape of healthcare, regional and institutional socioeconomics, and faculty prototypes. It is paramount that AMIs endeavor to recruit and position leaders whose values align with those of the institution (“cultural fit”). This treatise highlights the crucial influences that affect organizational culture and its interface with AMI leadership and ensure the success of the organization and its leaders.Keywords: academic, leadership, culture, medical, institution

Background: Interest in incorporating research into the medical school curriculum has grown over the years. One of the challenges involved with providing research to medical students is developing programs that allow a large number of students to perform research. This involves securing faculty to mentor students in the design of research projects. In order to accommodate students with research interests, well-established research programs must be implemented. Objective: This article describes the design and implementation of a curriculum-based research program for medical students at the University of Texas Medical Branch (UTMB) at Galveston. The main objective of this article is to describe the program for the purpose of assisting other medical schools to develop a similar student research program. Design: At UTMB we established a Medical Student Summer Research Program (MSSRP) that occurred between the first year and the second year of medical school. Between the years 2000–2017, MSSRP accommodated a minimum of 39 and a maximum of 90 students during an 8 week period. Two surveys were conducted to collect students' views on how MSSRP affected their interest in research. We performed a proportion statistical analysis on the data from both surveys in order to determine the significance of the responses. Results: The benefit of MSSRP is that it provided medical students with an exposure to research. According to the proportions test, the responses were statistically significant with 85% of 26 third and fourth year students stating they would continue to incorporate research into their medical careers; 75% stating that MSSRP increased their interest in research; and 85% responding that MSSRP helped them to understand research methodology. Conclusions: MSSRP is a curriculum-based program that provides a framework to other medical institutions interested in the development of similar student research programs and provides students the exposure and option to continue with research as a component of their medical profession. [ABSTRACT FROM AUTHOR]

The article details the University of Texas Medical Branch's (UTMB) advancements in aerospace medicine over the past 30 years.

Burkholderia pseudomallei (Bpm) is the causative agent of the disease melioidosis. As a facultative intracellular pathogen, Bpm has a complex lifestyle that culminates in cell-to-cell fusion and multinucleated giant cells (MNGCs) formation. The virulence factor responsible for MNGC formation is the type 6 secretion system (T6SS), a contractile nanomachine. MNGC formation is a cell-to-cell spread strategy that allows the bacteria to avoid the extracellular immune system and our previous data highlighted cell death, apoptosis, and inflammation as pathways significantly impacted by T6SS activity. Thusly, we investigated how the T6SS influences these phenotypes within the macrophage and pulmonary models of infection. Here we report that the T6SS is responsible for exacerbating apoptotic cell death during infection in both macrophages and the lungs of infected mice. We also demonstrate that although the T6SS does not influence differential macrophage polarization, the M2 polarization observed is potentially beneficial for Bpm pathogenesis and replication. Finally, we show that the T6SS contributes to the severity of inflammatory nodule formation in the lungs, which might be potentially connected to the amount of apoptosis that is triggered by the bacteria. Author summary: Burkholderia pseudomallei (Bpm) is an intracellular pathogen and is the etiological agent of melioidosis. This neglected tropical disease results in an estimated 89,000 fatalities a year, however, this number is believed to be severely underreported. The complex intracellular lifestyle and host response to infection is poorly understood, basic cell interactions and responses are critical to defense against infection. Bpm utilizes an array of virulence factors to successfully replicate and disseminate cell-to-cell, one of these is the T6SS which is responsible for MNGC formation and cell-to-cell spread. In this work, we characterized how macrophages respond to infection in the presence or absence of the critical T6SS virulence factor. Macrophages are a primary replicative niche for Bpm but how intracellular replication disrupts macrophages response to infection is poorly understood. By understanding macrophage cell death patterns and polarization, we can dissect responses that are triggered by T6SS activity with the expectation of finding exploitable responses for host directed therapies. [ABSTRACT FROM AUTHOR]

Advances in fire safety and building construction have made fires in modern health care facilities uncommon and easily contained. Therefore, emergent hospital evacuations resulting from an internal fire are rare. On January 4, 2017, a fire occurred at the John Sealy Hospital, part of the University of Texas Medical Branch at Galveston, resulting in emergent evacuation of the hospital building and an adjacent office and patient care building. The internal emergency response system was quickly activated, and more than 100 patients and 200 staff members were evacuated within 27 minutes with no fire- or smoke-related injuries. Obstacles encountered during the evacuation process included difficulties with communication and confirming patient count in a timely manner. This article describes the emergent hospital evacuation during the fire, summarizes the subsequent reflections of a multiagency after-action review, and issues a call to action for further research and publication on emergency patient evacuation. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results in acute damage and triggers secondary injury responses with sustained neuronal loss and dysfunction. However, the underlying mechanisms for these delayed neuronal pathologies are not entirely understood. SCI results in the swelling of spinal neurons, but the contribution of cell swelling to neuronal loss and functional deficits after SCI has not been systematically characterized. In this study, we devised a three-dimensional image analysis pipeline to evaluate spinal neurons, examining their types, quantities, volumes, and spatial distribution in a double-lateral hemisection SCI mouse model. We found that both excitatory and inhibitory neurons swell and are lost, albeit with distinct temporal patterns. Inhibitory neurons demonstrated marked swelling and decline in number on day 2 after SCI, which resolved by day 14. In contrast, excitatory neurons maintained persistent swelling and continued cell loss for at least 35 days after SCI in mice. Excitatory neurons exhibited sustained expression of the Na+-K+-Cl− cotransporter 1 (NKCC1), whereas inhibitory neurons down-regulated the protein by day 14 after SCI. Treatment with a Food and Drug Administration–approved NKCC1 inhibitor, bumetanide, mitigated swelling of excitatory neurons and reduced their loss in the secondary injury phase after SCI. The administration of bumetanide after SCI in mouse improved locomotor recovery, with functional benefits persisting for at least 4 weeks after treatment cessation. This study advances our understanding of SCI-related pathology and introduces bumetanide as a potential treatment to mitigate sustained neuronal swelling and enhance recovery after SCI. Editor's summary: Spinal neuron swelling occurs after spinal cord injury (SCI), but the mechanisms, dynamics, and relationship of neural swelling to long-term locomotor deficits remain unclear. Here, Li et al. visualized neuronal swelling after SCI in mice using whole-mount tissue and a three-dimensional image analysis pipeline. They found that both excitatory and inhibitory neurons undergo swelling and loss after SCI, but with differing kinetics. Targeting overall tissue edema did not reduce neuronal swelling; however, inhibition of the Na+-K+-Cl− cotransporter 1 (NKCC1) with the FDA-approved drug bumetanide reduced excitatory neuron swelling. Bumetanide given in the first 4 weeks after injury improved recovery of motor function in the presence of excitatory neurons. These findings in mice suggest that excitatory neuronal swelling may be a therapeutic target for reducing functional deficits after SCI. —Molly Ogle [ABSTRACT FROM AUTHOR]

The diagnosis of liver antibody-mediated rejection (AMR) is challenging and likely underrecognized. The association of AMR with donor-specific antibodies (DSA), and its clinical course in relation to pathologic findings and treatment are ill defined. We identified cases of liver AMR by following the criteria outlined by the 2016 Banff Working Group. Patient demographics, native liver disease, histopathologic findings, treatment type, clinical outcome, and transaminase levels during AMR diagnosis, treatment, and resolution were determined. Patients (n = 8) with AMR average age was 55.2 years (range: 19-68). Seven of eight cases met the Banff criteria for AMR. Personalized treatment regimens consisted of optimization of immunosuppression, intravenous pulse steroids, plasmapheresis, IVIG, rituximab, and bortezomib. Five patients experienced complete resolution of AMR, return of transaminases to baseline, and decreased DSA at long-term follow-up. One patient developed chronic AMR and two patients required retransplantation. Follow-up after AMR diagnosis ranged from one to 11 years. Because AMR can present at any time, crossmatch, early biopsy, and routine monitoring of DSA levels should be implemented following transaminase elevation to recognize AMR. Furthermore, treatment should be immediately implemented to reverse AMR and prevent graft failure, chronic damage, re-transplantation, and possibly mortality. [ABSTRACT FROM AUTHOR]

Background: Accurate prediction of subject recruitment, which is critical to the success of a study, remains an ongoing challenge. Previous prediction models often rely on parametric assumptions which are not always met or may be difficult to implement. We aim to develop a novel method that is less sensitive to model assumptions and relatively easy to implement. Methods: We create a weighted resampling-based approach to predict enrollment in year two based on recruitment data from year one of the completed GRIPS and PACE clinical trials. Different weight functions accounted for a range of potential enrollment trajectory patterns. Prediction accuracy was measured by Euclidean distance for enrollment sequence in year two, total enrollment over time, and total weeks to enroll a fixed number of subjects, against the actual year two enrollment data. We compare the performance of the proposed method with an existing Bayesian method. Results: Weighted resampling using GRIPS data resulted in closer prediction evidenced by better coverage of observed enrollment with the prediction intervals and smaller Euclidean distance from actual enrollment in year 2, especially when enrollment gaps were filled prior to the weighted resampling. These scenarios also produced more accurate predictions for total enrollment and number of weeks to enroll 50 participants. These same scenarios outperformed an existing Bayesian method for all 3 accuracy measures. In PACE data, using a reduced year 1 enrollment resulted in closer prediction evidenced by better coverage of observed enrollment with the prediction intervals and smaller Euclidean distance from actual enrollment in year 2, with the weighted resampling scenarios better reflecting the seasonal variation seen in year (1) The reduced enrollment scenarios resulted in closer prediction for total enrollment over 6 and 12 months into year (2) These same scenarios also outperformed an existing Bayesian method for relevant accuracy measures. Conclusion: The results demonstrate the feasibility and flexibility for a resampling-based, non-parametric approach for prediction of clinical trial recruitment with limited early enrollment data. Application to a wider setting and long-term prediction accuracy require further investigation. [ABSTRACT FROM AUTHOR]

During pregnancy, two fetomaternal interfaces, the placenta–decidua basalis and the fetal membrane–decidua parietals, allow for fetal growth and maturation and fetal–maternal crosstalk, and protect the fetus from infectious and inflammatory signaling that could lead to adverse pregnancy outcomes. While the placenta has been studied extensively, the fetal membranes have been understudied, even though they play critical roles in pregnancy maintenance and the initiation of term or preterm parturition. Fetal membrane dysfunction has been associated with spontaneous preterm birth (PTB, < 37 weeks gestation) and preterm prelabor rupture of the membranes (PPROM), which is a disease of the fetal membranes. However, it is unknown how the individual layers of the fetal membrane decidual interface (the amnion epithelium [AEC], the amnion mesenchyme [AMC], the chorion [CTC], and the decidua [DEC]) contribute to these pregnancy outcomes. In this study, we used a single-cell transcriptomics approach to unravel the transcriptomics network at spatial levels to discern the contributions of each layer of the fetal membranes and the adjoining maternal decidua during the following conditions: scheduled caesarian section (term not in labor [TNIL]; n = 4), vaginal term in labor (TIL; n = 3), preterm labor with and without rupture of membranes (PPROM; n = 3; and PTB; n = 3). The data included 18,815 genes from 13 patients (including TIL, PTB, PPROM, and TNIL) expressed across the four layers. After quality control, there were 11,921 genes and 44 samples. The data were processed by two pipelines: one by hierarchical clustering the combined cases and the other to evaluate heterogeneity within the cases. Our visual analytical approach revealed spatially recognized differentially expressed genes that aligned with four gene clusters. Cluster 1 genes were present predominantly in DECs and Cluster 3 centered around CTC genes in all labor phenotypes. Cluster 2 genes were predominantly found in AECs in PPROM and PTB, while Cluster 4 contained AMC and CTC genes identified in term labor cases. We identified the top 10 differentially expressed genes and their connected pathways (kinase activation, NF-κB, inflammation, cytoskeletal remodeling, and hormone regulation) per cluster in each tissue layer. An in-depth understanding of the involvement of each system and cell layer may help provide targeted and tailored interventions to reduce the risk of PTB. [ABSTRACT FROM AUTHOR]

The collaborative care model (CCM) was created to improve the delivery of mental health care and is reported to improve access, enhance treatment outcomes, and reduce healthcare costs. To understand the impacts of the CCM on symptom management, diverse populations, and sustainability in healthcare systems, a systematic review was conducted. Several databases were searched for articles assessing the CCM. The inclusion criteria limited the studies to those (1) published between January 2008 and January 2024; (2) written in the English language; (3) analyzing adult patients; (4) analyzing symptom improvement in major depressive disorder, generalized anxiety disorder, or post-traumatic stress disorder; and (5) fitting the given definition of a CCM. We identified 9743 articles. Due to missing information or duplication, 4702 were excluded. The remaining articles were screened, yielding 468 articles for full-text analysis, of which 16 articles met the inclusion criteria. Of these articles, five primarily focused on individual patient outcomes, five focused on specific populations, and six reviewed system impacts; eleven articles studied US populations and five studied international populations. An analysis revealed that in 12 of the final articles, the CCM led to a statistically significant improvement in anxiety and depression symptoms with viable implementation and sustainability strategies. The CCM is an effective method for improving patient symptoms and can be potentially affordable in healthcare systems. [ABSTRACT FROM AUTHOR]

Filoviruses, like the Marburg (MARV) and Ebola (EBOV) viruses, have caused outbreaks associated with significant hemorrhagic morbidity and high fatality rates. Vaccines offer one of the best countermeasures for fatal infection, but to date only the EBOV vaccine has received FDA licensure. Given the limited cross protection between the EBOV vaccine and Marburg hemorrhagic fever (MHF), we analyzed the protective efficacy of a similar vaccine, rVSV-MARV, in the lethal cynomolgus macaque model. NHPs vaccinated with a single dose (as little as 1.6 × 107 pfu) of rVSV-MARV seroconverted to MARV G-protein prior to challenge on day 42. Vaccinemia was measured in all vaccinated primates, self-resolved by day 14 post vaccination. Importantly, all vaccinated NHPs survived lethal MARV challenge, and showed no significant alterations in key markers of morbid disease, including clinical signs, and certain hematological and clinical chemistry parameters. Further, apart from one primate (from which tissues were not collected and no causal link was established), no pathology associated with Marburg disease was observed in vaccinated animals. Taken together, rVSV-MARV is a safe and efficacious vaccine against MHF in cynomolgus macaques. [ABSTRACT FROM AUTHOR]

The rodent-borne Andes virus (ANDV) causes a severe disease in humans. We developed an ANDV mRNA vaccine based on the M segment of the viral genome, either with regular uridine (U-mRNA) or N1-methylpseudouridine (m1Ψ-mRNA). Female mice immunized by m1Ψ-mRNA developed slightly greater germinal center (GC) responses than U-mRNA-immunized mice. Single cell RNA and BCR sequencing of the GC B cells revealed similar levels of activation, except an additional cluster of cells exhibiting interferon response in animals vaccinated with U-mRNA but not m1Ψ-mRNA. Similar immunoglobulin class-switching and somatic hypermutations were observed in response to the vaccines. Female Syrian hamsters were immunized via a prime–boost regimen with two doses of each vaccine. The titers of glycoprotein-binding antibodies were greater for U-mRNA construct than for m1Ψ-mRNA construct; however, the titers of ANDV-neutralizing antibodies were similar. Vaccinated animals were challenged with a lethal dose of ANDV, along with a naïve control group. All control animals and two animals vaccinated with a lower dose of m1Ψ-mRNA succumbed to infection whereas other vaccinated animals survived without evidence of virus replication. The data demonstrate the development of a protective vaccine against ANDV and the lack of a substantial effect of m1Ψ modification on immunogenicity and protection in rodents. Modified nucleosides are often used in mRNA vaccines and can affect protein expression and immunogenicity. Here, the authors compare M segment based Andes virus mRNA vaccines, either with regular uridine or N1-methylpseudouridine, and characterize immune response and protection in rodents. [ABSTRACT FROM AUTHOR]

The article focuses on Awards Night Ceremonies at the 94th Annual Scientific Meeting of the Aerospace Medical Association, including recognition of Serena Aunon-Chancellor for her extensive contributions to aerospace medicine and William Hoffman, received the Boothby-Edwards Award.

The article focuses on the emergence of clade 2.3.4.4b avian influenza A(H5N1) in North America and its potential impact on mammalian hosts, including humans, contrasting with the susceptibility of cattle primarily to influenza D virus. Topics include the investigation into influenza virus infections among dairy cattle in Texas, where veterinary diagnostic laboratories initially explored other pathogens before considering influenza A virus as a possible cause.

Immune activation is essential for lung control of viral and bacterial infection, but an overwhelming inflammatory response often leads to the onset of acute respiratory distress syndrome. IL-10 plays a crucial role in regulating the balance between antimicrobial immunity and immunopathology. In the present study, we investigated the role of IL-10 in acute lung injury induced by influenza A virus and methicillin-resistant Staphylococcus aureus coinfection. This unique coinfection model resembles patients with acute pneumonia undergoing appropriate antibiotic therapies. Using global IL-10 and IL-10 receptor gene-deficient mice, as well as in vivo neutralizing antibodies, we show that IL-10 deficiency promotes IFN-γ–dominant cytokine responses and triggers acute animal death. Interestingly, this extreme susceptibility is fully preventable by IFN-γ neutralization during coinfection. Further studies using mice with Il10ra deletion in selective myeloid subsets reveal that IL-10 primarily acts on mononuclear phagocytes to prevent IFN-γ/TNF-α hyperproduction and acute mortality. Importantly, this antiinflammatory IL-10 signaling is independent of its inhibitory effect on antiviral and antibacterial defense. Collectively, our results demonstrate a key mechanism of IL-10 in preventing hypercytokinemia and acute respiratory distress syndrome pathogenesis by counteracting the IFN-γ response. [ABSTRACT FROM AUTHOR]

Background In recent years, Vietnam has suffered multiple epizootics of influenza in poultry. Methods From 10 January 2019 to 26 April 2021, we employed a One Health influenza surveillance approach at live bird markets (LBMs) and swine farms in Northern Vietnam. When the COVID-19 pandemic permitted, each month, field teams collected oral secretion samples from poultry and pigs, animal facility bioaerosol and fecal samples, and animal worker nasal washes at 4 LBMs and 5 swine farms across 5 sites. Initially samples were screened with molecular assays followed by culture in embryonated eggs (poultry swabs) or Madin-Darby canine kidney cells (human or swine swabs). Results Many of the 3493 samples collected had either molecular or culture evidence for influenza A virus, including 314 (37.5%) of the 837 poultry oropharyngeal swabs, 144 (25.1%) of the 574 bioaerosol samples, 438 (34.9%) of the 1257 poultry fecal swab samples, and 16 (1.9%) of the 828 human nasal washes. Culturing poultry samples yielded 454 influenza A isolates, 83 of which were H5, and 70 (84.3%) of these were highly pathogenic. Additionally, a positive human sample had a H9N2 avian-like PB1 gene. In contrast, the prevalence of influenza A in the swine farms was much lower with only 6 (0.4%) of the 1700 total swine farm samples studied, having molecular evidence for influenza A virus. Conclusions This study suggests that Vietnam's LBMs continue to harbor high prevalences of avian influenza A viruses, including many highly pathogenic H5N6 strains, which will continue to threaten poultry and humans. [ABSTRACT FROM AUTHOR]

The escalation of antibiotic resistance, pandemics, and nosocomial infections underscores the importance of research in both animal and human infectious diseases. Recent advancements in three-dimensional tissue cultures, or "organoids", have revolutionized the development of in vitro models for infectious diseases. Our study conducts a bibliometric analysis on the use of organoids in modeling infectious diseases, offering an in-depth overview of this field's current landscape. We examined scientific contributions from 2009 onward that focused on organoids in host‒pathogen interactions using the Web of Science Core Collection and OpenAlex database. Our analysis included temporal trends, reference aging, author, and institutional productivity, collaborative networks, citation metrics, keyword cluster dynamics, and disruptiveness of organoid models. VOSviewer, CiteSpace, and Python facilitated this analytical assessment. The findings reveal significant growth and advancements in organoid-based infectious disease research. Analysis of keywords and impactful publications identified three distinct developmental phases in this area that were significantly influenced by outbreaks of Zika and SARS-CoV-2 viruses. The research also highlights the synergistic efforts between academia and publishers in tackling global pandemic challenges. Through mostly consolidating research efforts, organoids are proving to be a promising tool in infectious disease research for both human and animal infectious disease. Their integration into the field necessitates methodological refinements for better physiological emulation and the establishment of extensive organoid biobanks. These improvements are crucial for fully harnessing the potential of organoids in understanding infectious diseases and advancing the development of targeted treatments and vaccines. [ABSTRACT FROM AUTHOR]

Following SARS‐CoV‐2 infection, some patients develop lingering neurologic symptoms of post‐acute sequelae of COVID‐19 (PASC) that commonly include fatigue and "brain fog." PASC symptoms are also linked with reduced growth hormone (GH) secretion, but GH treatment has not been tested to relieve symptoms. We enrolled 13 adults with neurologic PASC symptoms and peak stimulated GH secretion less than 10 ng/mL (glucagon stimulation) in a pilot study to receive 9 months of daily GH injections and an additional 3 months of off‐treatment assessment. We compared peak stimulated GH secretion at baseline and 12 months and assessed measures of cognition, metabolism, body composition, and physical performance over the first 6 months of treatment. Patient‐reported outcomes of fatigue, quality of life, sleep, and mood were recorded at baseline and compared with timepoints at 6, 9, and 12 months. GH treatment was associated with significantly improved scores for Brief Fatigue Inventory, Multidimensional Fatigue Symptom Inventory, Quality of Life Assessment of Growth Hormone Deficiency in Adults, Profile of Mood States, and Beck Depression Inventory‐II, with no significant change in Pittsburgh Sleep Quality Index. Six months of adjunct GH treatment was not associated with significant changes in cognition, body composition, resting energy expenditure, or physical performance. Peak stimulated GH secretion was not altered at 12 months following 9 months of GH treatment. GH treatment significantly improved neurologic symptoms in PASC patients but cognition, sleep, and physical performance were not significantly altered. [ABSTRACT FROM AUTHOR]

The article announces the appointment of new presidents for constituent organizations in the aerospace medicine field for the years 2024-2025, and it reports that Tamara Averett-Brauer will serve as the incoming president for the Allied Health Professionals Society, among others.

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. In the brain, no detectable viral RNA and minimal residential immune cell activation was observed in the surviving mice post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and gene expression levels associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent systemic Thelper 1 prone cellular immune responses and strong sera neutralizing antibodies against Delta and Omicron variants months post-acute infection. Overall, our findings suggest that infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long-COVID patients and provides new insights into the role of systemic and brain residential immune factors in PASC pathogenesis. [ABSTRACT FROM AUTHOR]

Scrub typhus is an acute febrile disease due to Orientia tsutsugamushi (Ot) infection and can be life-threatening with organ failure, hemorrhage, and fatality. Yet, little is known as to how the host reacts to Ot bacteria at early stages of infection; no reports have addressed the functional roles of type I versus type II interferon (IFN) responses in scrub typhus. In this study, we used comprehensive intradermal (i.d.) inoculation models and two clinically predominant Ot strains (Karp and Gilliam) to uncover early immune events. Karp infection induced sequential expression of Ifnb and Ifng in inflamed skin and draining lymph nodes at days 1 and 3 post-infection. Using double Ifnar1-/-Ifngr1-/- and Stat1-/- mice, we found that deficiency in IFN/STAT1 signaling resulted in lethal infection with profound pathology and skin eschar lesions, which resembled to human scrub typhus. Further analyses demonstrated that deficiency in IFN-γ, but not IFN-I, resulted in impaired NK cell and macrophage activation and uncontrolled bacterial growth and dissemination, leading to metabolic dysregulation, excessive inflammatory cell infiltration, and exacerbated tissue damage. NK cells were found to be the major cellular source of innate IFN-γ, contributing to the initial Ot control in the draining lymph nodes. In vitro studies with dendritic cell cultures revealed a superior antibacterial effect offered by IFN-γ than IFN-β. Comparative in vivo studies with Karp- and Gilliam-infection revealed a crucial role of IFN-γ signaling in protection against progression of eschar lesions and Ot infection lethality. Additionally, our i.d. mouse models of lethal infection with eschar lesions are promising tools for immunological study and vaccine development for scrub typhus. Author summary: Scrub typhus can lead to severe complications and even fatality if not treated properly; however, the early host immune responses to Ot bacterium infection remain unclear. This study focused on the functional roles of IFNs in i.d. inoculation mouse models of scrub typhus. We found that mice lacking IFN receptors were highly susceptible to Ot infection, which resulted in severe pathology and skin eschar lesions that resembled to human scrub typhus. Further investigation revealed that the lack of IFN-γ, but not IFN-I, resulted in dysregulated innate immune responses, leading to uncontrolled bacterial burdens and tissue damage. Using IFN-γ reporter mice and neutralizing antibody treatment, we confirmed that NK cells were the major source of early IFN-γ, and thus contributed to the bacterial control in the draining lymph nodes. Moreover, our comparative studies with two Ot strains revealed bacterium strain- and dose-dependent eschar formation and disease severity. In conclusion, our study highlights the crucial role of IFN-γ signaling in ensuring host protection against Ot infection. Our mouse models resemble skin eschar lesions and lethal infections observed in human disease, offering potential for future immunological studies on scrub typhus. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has raised the standard regarding the current vaccine development pace, as several messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines have proved their ability to induce strong immunogenicity and protective efficacy. We developed 1-methylpseudouridine-containing mRNA-LNP vaccines, expressing either the more conserved SARS-CoV-2 nucleoprotein (mRNA-N) or spike protein (mRNA-S), both based on the prototypic viral sequences. When combining both mRNA-S and mRNA-N together (mRNA-S+N), the vaccine showed high immunogenicity and broad protection against different SARS-CoV-2 variants, including wildtype, Delta, BA.1, BA.5, and BQ.1. To better understand the mechanisms behind this broad protection obtained by mRNA-S+N, we analyzed innate and adaptive immune parameters following vaccination in mice. Compared to either mRNA-S or mRNA-N alone, mice vaccinated with mRNA-S+N exhibited an increase in the innate immune response, as depicted by the higher cytokine (IL-6 and chemokine (MCP-1) levels. In addition, lymph node immunophenotyping showed the maturation and activation of dendritic cells and natural killer cells, respectively. To understand the adaptive immune response, RNA-Seq analyses of the lung and spleen samples of the vaccinated mice were performed in parallel and revealed a stronger immune gene-expression profile in the lung than that in the spleen. Compared to mRNA-S alone, mRNA-S+N vaccination elicited higher levels of expression for genes involved in multiple immune pathways, including T cells, cytokine signaling, antigen presentation, B cells, and innate immunity. Together, our studies provide immunological insights into the mechanisms of broad protection conferred by dual mRNA vaccination against SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]