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Alpha-gal syndrome develops in some individuals who have had tick bites which result in IgE responses to alpha-gal, a carbohydrate not found in humans. Patients with alpha-gal syndrome develop symptoms when they ingest mammalian meat, which contains this oligosaccharide. Often the response to this exposure is delayed and occurs 2 to 6 hours post-ingestion. Symptoms can include skin rashes, urticaria, gastrointestinal symptoms, and occasionally anaphylaxis. In some patients, the initial site of the skin reaction is at the location of the prior tick bite. The frequency of the syndrome is uncertain but the geographic distribution is predominantly in areas with the lone star tick. The diagnosis depends on careful attention to the time interval between the ingestion of meat and the development of the symptoms. In addition, a history of prior tick bites is important for considering this diagnosis. Diagnostic studies include skin tests, serologic tests for specific IgE, and food challenges, with varying risks for anaphylaxis. The treatment of patients with acute presentations frequently includes intramuscular epinephrine, oral antihistamines, and corticosteroids. Long-term management involves diet modification with the elimination of meat. Patients can also have adverse reactions to medications, such as set cetuximab, heparin, monoclonal antibodies, and pancreatic enzymes, and clinicians will likely have difficulty identifying these reactions. If patients have a good response to diet modification and have a significant reduction in their specific IgE level to alpha-gal, they potentially can resume eating meat in their diet. This should be done under the direction of a specialist., Competing Interests: Conflicts of interest The authors declare no conflicts of interest relevant to this work. No financial support was received for this work., (Copyright © 2024. Published by Elsevier Inc.)

Background: Infectious diseases is a crucial specialty in medicine, yet applications for fellowship have declined even as the United States faces an imminent shortage of infectious disease physicians. Career interests often develop in medical school, but little is known about which interests and experiences are associated with interest in ID., Objective: Evaluate interest in ID among medical students and identify factors associated with interest and disinterest in ID careers., Methods: We developed a 26-question survey to gauge interest in infectious diseases (ID). All 16 medical schools in Texas were contacted and invited to participate., Results: A total of 262 students across 9 medical school campuses completed the survey. Those interested in ID as a career had a significantly higher interest in public health (p<0.0001) and global (p<0.0003) health. The presence of an ID campus interest group (p<0.0015) and direct experience with the ID profession (p<0.0001) were also associated with interest. The most common reasons for lack of interest were lack of interest in pursuing internal medicine or pediatric residency, lack of compensation, and lack of procedures. Those interested in ID expressed interest in a wide variety of career pathways within ID, the most common being general inpatient and outpatient ID, as well as medical microbiology and global health/tropical medicine/travel medicine., Conclusions: Based on this survey, recruitment efforts for new ID fellows might include focusing on students with interests in public and global health, as well as increasing direct exposure to ID at the medical school level., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is an emerging epidemic and a subset of HPV-positive patients experience aggressive disease with metastases. The CYLD gene is frequently altered in HPV-positive HNSCC, but the role of these alterations in disease progression is poorly understood., Methods: We identified 11 HPV-positive HNSCC patients with CYLD alterations and assessed their clinical course. We also characterized a unique, HPV-positive, metastatic, HNSCC patient-derived xenograft (PDX)., Results: All 11 patients developed metastasis with reduced overall survival when compared with metastatic HPV-positive patients with wild-type CYLD. The metastatic PDX harbored a CYLD mutation (S371*) and exhibited reduced expression of connexin 43, a potentially antimetastatic protein. We also investigated the functional impact of the S371* mutation, as well as 2 CYLD mutations from our 11-patient cohort., Conclusion: Our findings indicate that alterations in CYLD in HPV-positive HNSCC are associated with metastasis and poor prognosis., (© 2024 Wiley Periodicals LLC.)

Objectives: Periodically, medical publications are retracted. The reasons vary from minor situations, such as author attributions, which do not undermine the validity of the data or the analysis in the article, to serious reasons, such as fraud. Understanding the reasons for retraction can provide important information for clinicians, educators, researchers, journals, and editorial boards., Methods: The PubMed database was searched using the term "COVID-19" (coronavirus disease 2019) and the term limitation "retracted publication." The characteristics of the journals with retracted articles, the types of article, and the reasons for retraction were analyzed., Results: This search recovered 196 articles that had been retracted. These retractions were published in 179 different journals; 14 journals had >1 retracted article. The mean impact factor of these journals was 8.4, with a range of 0.32-168.9. The most frequent reasons for retractions were duplicate publication, concerns about data validity and analysis, concerns about peer review, author request, and the lack of permission or ethical violation. There were significant differences between the types of article and the reasons for retraction but no consistent pattern. A more detailed analysis of two particular retractions demonstrates the complexity and the effort required to make decisions about article retractions., Conclusions: The retraction of published articles presents a significant challenge to journals, editorial boards, peer reviewers, and authors. This process has the potential to provide important benefits; it also has the potential to undermine confidence in both research and the editorial process.

Eco-evolutionary experiments are typically conducted in semi-unnatural controlled settings, such as mesocosms; yet inferences about how evolution and ecology interact in the real world would surely benefit from experiments in natural uncontrolled settings. Opportunities for such experiments are rare but do arise in the context of restoration ecology-where different "types" of a given species can be introduced into different "replicate" locations. Designing such experiments requires wrestling with consequential questions. (Q1) Which specific "types" of a focal species should be introduced to the restoration location? (Q2) How many sources of each type should be used-and should they be mixed together? (Q3) Which specific source populations should be used? (Q4) Which type(s) or population(s) should be introduced into which restoration sites? We recently grappled with these questions when designing an eco-evolutionary experiment with threespine stickleback ( Gasterosteus aculeatus ) introduced into nine small lakes and ponds on the Kenai Peninsula in Alaska that required restoration. After considering the options at length, we decided to use benthic versus limnetic ecotypes (Q1) to create a mixed group of colonists from four source populations of each ecotype (Q2), where ecotypes were identified based on trophic morphology (Q3), and were then introduced into nine restoration lakes scaled by lake size (Q4). We hope that outlining the alternatives and resulting choices will make the rationales clear for future studies leveraging our experiment, while also proving useful for investigators considering similar experiments in the future., Competing Interests: The authors have no conflict of interest to declare., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Chimeric antigen receptor (CAR) T cell therapies have demonstrated immense clinical success for B cell and plasma cell malignancies. We tested their impact on the viral reservoir in a macaque model of HIV persistence, comparing the functions of CD20 CAR T cells between animals infected with simian/human immunodeficiency virus (SHIV) and uninfected controls. We focused on the potential of this approach to disrupt B cell follicles (BCFs), exposing infected cells for immune clearance. In SHIV-infected animals, CAR T cells were highly functional, with rapid expansion and trafficking to tissue-associated viral sanctuaries, including BCFs and gut-associated lymphoid tissue (GALT). CD20 CAR T cells potently ablated BCFs and depleted lymph-node-associated follicular helper T (T FH ) cells, with complete restoration of BCF architecture and T FH cells following CAR T cell contraction. BCF ablation decreased the splenic SHIV reservoir but was insufficient for effective reductions in systemic viral reservoirs. Although associated with moderate hematologic toxicity, CD20 CAR T cells were well tolerated in SHIV-infected and control animals, supporting the feasibility of this therapy in people living with HIV with underlying B cell malignancies. Our findings highlight the unique ability of CD20 CAR T cells to safely and reversibly unmask T FH cells within BCF sanctuaries, informing future combinatorial HIV cure strategies designed to augment antiviral efficacy., Competing Interests: Declaration of interests The authors declare the following competing interests: H.-P.K. is or was a consultant to and has or had ownership interests in Rocket Pharmaceuticals, Homology Medicines, Vor Biopharma, and Ensoma, Inc., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of in vivo persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed. In our studies using the humanized bone marrow/liver/thymus (BLT) mouse model and nonhuman primate (NHP) model of HIV infection, we evaluated two CAR-based gene therapy approaches. In the ACT approach, we used cytokine enhancement and preconditioning to generate greater persistence of anti-HIV CAR + T cells. We observed limited persistence and expansion of anti-HIV CAR T cells, which led to minimal control of the virus. In our stem cell-based approach, we modified hematopoietic stem/progenitor cells (HSPCs) with anti-HIV CAR to generate anti-HIV CAR T cells in vivo. We observed CAR-expressing T cell expansion, which led to better plasma viral load suppression. HSPC-derived CAR cells in infected NHPs showed superior trafficking and persistence in multiple tissues. Our results suggest that a stem cell-based CAR T cell approach may be superior in generating long-term persistence and functional antiviral responses against HIV infection., Competing Interests: Declaration of interests S.G.K. is a founding member of CDR3. H.-P.K. is or was a consultant to and has or had ownership interests in Rocket Pharmaceuticals, Homology Medicines, VOR Biopharma, and Ensoma., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti-PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.

Background: The retraction of medical articles periodically occurs in most medical journals and can involve multiple article types. These retractions are beneficial if they remove flawed or fraudulent information from the medical literature. However, retractions may also decrease confidence in the medical literature and require significant amounts of time by editors., Methods: One publisher (Hindawi) announced that it will retract over 1200 articles. Given this, the PubMed database was searched to identify retracted publications on or related to COVID-19, and articles retracted by journals sponsored by the publisher Hindawi were then identified., Results: These journals retracted 25 articles and, in most cases, did not provide an exact explanation about the particular problem(s) resulting in the retraction. The time to retraction was 468.7 ± 109.8 days (median =  446 days). These articles had 9.3 ± 9.9 citations., Conclusion: Analysis of the titles and abstracts of the articles suggests that their removal from the medical literature would have limited effects on the near-term management decisions during the COVID-19 pandemic. Nevertheless, retraction of medical articles creates uncertainty in medical care and science and in the public regarding the validity of medical research and related publications and the level of professionalism of the individuals submitting these articles., Competing Interests: The authors report no funding or conflicts of interest., (Copyright © 2024 Baylor University Medical Center.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In 2003, the Eastern Cooperative Oncology Group initiated a randomized phase III clinical trial (E4402) comparing two different rituximab dosing strategies for patients with previously untreated low-tumor burden follicular lymphoma. Rituximab-responsive patients (n = 299) were randomly assigned to either a retreatment rituximab (RR) strategy or a maintenance rituximab (MR) strategy. Each dosing strategy was continued until treatment failure. The primary end point of the study was time to treatment failure (TTF). In the original report, there was no difference in TTF between the two dosing strategies. Here, we report on the long-term outcomes for secondary end points of time to first cytotoxic therapy, duration of response, and overall survival (OS). At 7 years, 83% of MR patients had not required first chemotherapy compared with 63% of RR patients (hazard ratio, 2.37 [95% CI, 1.5 to 3.76]). At 7 years, 71% of MR remained in their first remission compared with 37% of RR patients. Despite the improved first remission length with MR, there was no difference in OS at 10 years (83% v 84%). With mature long-term data, we confirm that prolonged maintenance rituximab does not confer an OS advantage in low-tumor burden follicular lymphoma.

For sessile organisms at high risk from climate change, phenotypic plasticity can be critical to rapid acclimation. Epigenetic markers like DNA methylation are hypothesized as mediators of plasticity; methylation is associated with the regulation of gene expression, can change in response to ecological cues, and is a proposed basis for the inheritance of acquired traits. Within reef-building corals, gene-body methylation (gbM) can change in response to ecological stressors. If coral DNA methylation is transmissible across generations, this could potentially facilitate rapid acclimation to environmental change. We investigated methylation heritability in Acropora, a stony reef-building coral. Two Acropora millepora and two Acropora selago adults were crossed, producing eight offspring crosses (four hybrid, two of each species). We used whole-genome bisulfite sequencing to identify methylated loci and allele-specific alignments to quantify per-locus inheritance. If methylation is heritable, differential methylation (DM) between the parents should equal DM between paired offspring alleles at a given locus. We found a mixture of heritable and nonheritable loci, with heritable portions ranging from 44% to 90% among crosses. gBM was more heritable than intergenic methylation, and most loci had a consistent degree of heritability between crosses (i.e. the deviation between parental and offspring DM were of similar magnitude and direction). Our results provide evidence that coral methylation can be inherited but that heritability is heterogenous throughout the genome. Future investigations into this heterogeneity and its phenotypic implications will be important to understanding the potential capability of intergenerational environmental acclimation in reef building corals., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Journal editors depend on peer reviewers to make decisions about submitted manuscripts. These reviewers help evaluate the methods, the results, the discussion of the results, and the overall organization and presentation of the manuscript. In addition, reviewers can help identify important mistakes and possible misconduct. Editors frequently have difficulty obtaining enough peer reviews which are submitted in a timely manner. This increases the workload of editors and journal managers and potentially delays the publication of clinical and research studies. This commentary discusses of the importance of peer reviews and make suggestions which potentially can increase the participation of academic faculty and researchers in this important activity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Since the start of the coronavirus disease (COVID-19) pandemic, the residency and fellowship recruitment process has changed significantly with the use of virtual interview (VI) platforms. Pulmonary and critical care medicine (PCCM) candidates reported in a survey that VIs hindered their ability to evaluate their fit within the program. However, the program directors' (PDs') opinion of this process remains unknown., Objective: We aim to provide insight into the PCCM fellowship PDs' perspective regarding the virtual recruitment process since the first class of fellows undergoing this process has now completed 1 year of training., Methods: An anonymous survey was sent to the PDs of PCCM programs participating in the National Resident Matching Program match process in 2020 and 2021. The survey consisted of five sections and 26 closed-ended questions and was distributed via email using the SurveyMonkey platform. The survey was conducted for a total of 6 weeks. A follow-up email to nonrespondents was sent every week. The collected responses were divided into two categories: favoring VIs versus not favoring VIs. A multivariable logistic regression analysis was performed to determine the factors associated with favoring VIs., Results: The survey was sent to 190 email accounts from the Fellowship and Residency Electronic Interactive Database Access System website. Over the course of 6 weeks, 64 respondents participated in the survey, with a response rate of 33.68%. Of 64 respondents, 56 (87.5%) fully completed the survey and 8 (12.5%) partially completed the survey. The final sample size was 59. Thirty-six (61.02%) of the PDs favored VIs for future recruitment, and 23 (38.98%) did not ( P  < 0.001). Ninety-seven percent of PDs who favored VIs versus 72.73% of those who did not perceived the current fellows to fit well in the program ( P  = 0.007). The multivariable logistic regression analysis showed a trend toward higher odds of favoring VIs if PDs believed they were able to represent the program well virtually (adjusted odds ratio, 6.99; 95% confidence interval, 0.79 - 61.58) and if they found that the current fellows fit the program well (adjusted odds ratio, 7.15; 95% confidence interval, 0.76-66.52); however, these results were not statistically significant., Conclusion: In this survey research, we found that the majority of the PCCM fellowship PDs favored a virtual process for future recruitment., (Copyright © 2024 by the American Thoracic Society.)

This paper investigates the integration of multiple geometries present within a ReLU-based neural network. A ReLU neural network determines a piecewise affine linear continuous map, M , from an input space ℝ m to an output space ℝ n . The piecewise behavior corresponds to a polyhedral decomposition of ℝ m . Each polyhedron in the decomposition can be labeled with a binary vector (whose length equals the number of ReLU nodes in the network) and with an affine linear function (which agrees with M when restricted to points in the polyhedron). We develop a toolbox that calculates the binary vector for a polyhedra containing a given data point with respect to a given ReLU FFNN. We utilize this binary vector to derive bounding facets for the corresponding polyhedron, extraction of "active" bits within the binary vector, enumeration of neighboring binary vectors, and visualization of the polyhedral decomposition (Python code is available at https://github.com/cglrtrgy/GoL&#95;Toolbox). Polyhedra in the polyhedral decomposition of ℝ m are neighbors if they share a facet. Binary vectors for neighboring polyhedra differ in exactly 1 bit. Using the toolbox, we analyze the Hamming distance between the binary vectors for polyhedra containing points from adversarial/nonadversarial datasets revealing distinct geometric properties. A bisection method is employed to identify sample points with a Hamming distance of 1 along the shortest Euclidean distance path, facilitating the analysis of local geometric interplay between Euclidean geometry and the polyhedral decomposition along the path. Additionally, we study the distribution of Chebyshev centers and related radii across different polyhedra, shedding light on the polyhedral shape, size, clustering, and aiding in the understanding of decision boundaries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Caglar, Peterson and Kirby.)

Background: Academic article retractions occur across all disciplines, though few studies have examined the association between research topics and retraction rates., Objectives: We assessed and compared the rate of retraction across several important clinical research topics., Methods: Information about the number of publications, the number of retractions, the retraction rate, and the time to retraction was collected for articles identified by 15 Medical Subject Headings (MeSH) terms. These articles were published between 1 January 2010 and 31 December 2020. The searches took place between 18 September 2021 and 24 October 2021. The MeSH terms were selected based on our clinical experience with the expectation that there will be multiple publications during the timeframe to use for the searches. Additional topics were selected based on the frequency of controversy in the public media and were identified by the Altmetric Top 100 report., Results: The mean number of publications for all categories was 181,975 ± 332,245; the median number of publications was 67,991 [Q1, Q3; 31951.5, 138,981.5]. The mean number of retractions was 100.3 ± 251.3, and the median number of retractions was 22 [Q1, Q3; 6.5, 53]. The mean time to retraction ranged from 114 days to 1,409.5 days; the median was 857.3 days [Q1, Q3; 684.7, 1098.6], depending on the topic. The various MeSH term categories used in this study had significant differences in retraction rate and time to retraction. The "Neoplasms" category had the highest total number of retractions (993) and one of the highest retraction rates (75.4 per 100,000 publications)., Discussion: All PubMed categories analyzed in this study had retracted articles. The median time to retraction was 857 days. The long delays in some categories could contribute to potentially misleading information which might have adverse effects on clinical decisions in patient care and on research design., Conclusion: Rate of retraction varies across research topics and further studies are needed to explore this relationship.

Hematopoietic stem cell gene therapy has been successfully used for a number of genetic diseases and is also being explored for HIV. However, toxicity of the conditioning regimens has been a major concern. Here we compared current conditioning approaches in a clinically relevant nonhuman primate model. We first customized various aspects of the therapeutic approach, including mobilization and cell collection protocols, conditioning regimens that support engraftment with minimal collateral damage, and cell manufacturing and infusing schema that reflect and build on current clinical approaches. Through a series of iterative in vivo experiments in two macaque species, we show that busulfan conditioning significantly spares lymphocytes and maintains a superior immune response to mucosal challenge with simian/human immunodeficiency virus, compared to total body irradiation and melphalan regimens. Comparative mobilization experiments demonstrate higher cell yield relative to our historical standard, primed bone marrow and engraftment of CRISPR-edited hematopoietic stem and progenitor cells (HSPCs) after busulfan conditioning. Our findings establish a detailed workflow for preclinical HSPC gene therapy studies in the nonhuman primate model, which in turn will support testing of novel conditioning regimens and more advanced HSPC gene editing techniques tailored to any disease of interest., Competing Interests: H.-P.K. has received support as the inaugural recipient of the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Stephanus Family Endowed Chair for Cell and Gene Therapy and is or was a consultant to and has or had ownership interests with Rocket Pharmaceuticals, Homology Medicines, VOR Biopharma, and Ensoma Inc. H.-P.K. has also been a consultant to CSL Behring and Magenta Therapeutics. S.R. is a consultant to Forty Seven Inc. (Gilead Sciences) and Ensoma Inc., (© 2023 The Authors.)

Host-parasite coevolution may lead to patterns of local adaptation in either the host or parasite. For parasites with complex multi-host life cycles, this coevolution may be more challenging as they must adapt to multiple geographically varying hosts. The tapeworm Schistocephalus solidus exhibits some local adaptation to its second intermediate host, threespine stickleback, to which the parasite is strictly specialized. However, the tapeworm's adaptation to its first intermediate host (any of a number of copepod species) is not documented. We investigated if there was local adaptation and host specify in the tapeworm Schistocephalus solidus to its copepod first intermediate hosts. We exposed copepods from five lakes in Vancouver Island (BC, Canada) to local (i.e. same lake) and foreign tapeworms in a reciprocal exposure experiment. Results indicate that the tapeworm is not locally adapted to the copepods. Instead, we observed moderate-effect host specificity, infection rates being higher in certain copepod species than in others. Infection rates also varied among cestode populations. These results show that although S. solidus infects multiple copepod genera, they are not equally competent hosts. Differences in S. solidus epidemiology among lakes is likely to be driven more by this partial specialization, than by local adaptation to first intermediate hosts., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

HIV-specific T cells are necessary for control of HIV-1 replication but are largely insufficient for viral clearance. This is due in part to these cells' recognition of immunodominant but variable regions of the virus, which facilitates viral escape via mutations that do not incur viral fitness costs. HIV-specific T cells targeting conserved viral elements are associated with viral control but are relatively infrequent in people living with HIV (PLWH). The goal of this study was to increase the number of these cells via an ex vivo cell manufacturing approach derived from our clinically-validated HIV-specific expanded T-cell (HXTC) process. Using a nonhuman primate (NHP) model of HIV infection, we sought to determine i) the feasibility of manufacturing ex vivo -expanded virus-specific T cells targeting viral conserved elements (CE, CE-XTCs), ii) the in vivo safety of these products, and iii) the impact of simian/human immunodeficiency virus (SHIV) challenge on their expansion, activity, and function. NHP CE-XTCs expanded up to 10-fold following co-culture with the combination of primary dendritic cells (DCs), PHA blasts pulsed with CE peptides, irradiated GM-K562 feeder cells, and autologous T cells from CE-vaccinated NHP. The resulting CE-XTC products contained high frequencies of CE-specific, polyfunctional T cells. However, consistent with prior studies with human HXTC and these cells' predominant CD8 + effector phenotype, we did not observe significant differences in CE-XTC persistence or SHIV acquisition in two CE-XTC-infused NHP compared to two control NHP. These data support the safety and feasibility of our approach and underscore the need for continued development of CE-XTC and similar cell-based strategies to redirect and increase the potency of cellular virus-specific adaptive immune responses., Competing Interests: Author CB is a scientific cofounder and SAB member of Catamaran Bio and Mana Therapeutics; in addition, she has patent 9,885,021 on HIV-specific T cells licensed to Mana Therapeutics. Author CB also serves on the board of directors of Cabaletta Bio and has stock ownership in Repertoire Immune Medicines and Neximmune. She also served on the DSMB for SOBI. H-PK is a scientific cofounder of Ensoma Bio. Author H-PK is a paid advisor for Ensoma Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dross, Venkataraman, Patel, Huang, Bollard, Rosati, Pavlakis, Felber, Bar, Shaw, Jerome, Mullins, Kiem, Fuller and Peterson.)

We aim to develop an in vivo hematopoietic stem cell (HSC) gene therapy approach for persistent control/protection of HIV-1 infection based on the stable expression of a secreted decoy protein for HIV receptors CD4 and CCR5 (eCD4-Ig) from blood cells. HSCs in mice and a rhesus macaque were mobilized from the bone marrow and transduced by an intravenous injection of HSC-tropic, integrating HDAd5/35++ vectors expressing rhesus eCD4-Ig. In vivo HSC transduction/selection resulted in stable serum eCD4-Ig levels of ∼100 μg/mL (mice) and >20 μg/mL (rhesus) with half maximal inhibitory concentrations (IC 50 s) of 1 μg/mL measured by an HIV neutralization assay. After simian-human-immunodeficiency virus D (SHIV.D) challenge of rhesus macaques injected with HDAd-eCD4-Ig or a control HDAd5/35++ vector, peak plasma viral load levels were ∼50-fold lower in the eCD4-Ig-expressing animal. Furthermore, the viral load was lower in tissues with the highest eCD4-Ig expression, specifically the spleen and lymph nodes. SHIV.D challenge triggered a selective expansion of transduced CD4 + CCR5 + cells, thereby increasing serum eCD4-Ig levels. The latter, however, broke immune tolerance and triggered anti-eCD4-Ig antibody responses, which could have contributed to the inability to eliminate SHIV.D. Our data will guide us in the improvement of the in vivo approach. Clearly, our conclusions need to be validated in larger animal cohorts., Competing Interests: Declaration of interests A.L. and H.-P.K. are academic co-founders of Ensoma Bio. H.-P.K. is a paid scientific advisor for Ensoma Bio. A.L. and H.-P.K. receive research funding from Ensoma Bio., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Enterovirus A71 can cause serious neurological disease in young children. Animal models for EV-A71 are needed to evaluate potential antiviral therapies. Existing models have limitations, including lack of lethality or crucial disease signs. Here we report the development of an EV-A71 model in 28-day-old mice. Virus was serially passaged until it produced consistent lethality and rear-limb paralysis. Onset of disease occurred between days 6-9 post-infection, with mortality following weight loss and neurological signs on days 9-14. In addition, a single administration of human intravenous immunoglobulin at doses of 200, 400 and 800 mg/kg at 4h post-infection was evaluated in the model. Protection from weight loss, neurological signs, and mortality (between 50 and 89%) were observed at doses of 400 mg/kg or greater. Based on these results, IVIG was selected for use as a positive control in this acute model, and suggest that IVIG is a potential therapeutic for EV-A71 infections., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The use of marijuana by middle and high school students could have important consequences, including physical harm, poor decision making, increased use of tobacco products, and involvement in the legal system. Determining the level of use by students provides the initial information needed to understand the extent of the problem and possible approaches to reducing student use., Methods: The National Youth Tobacco Surveys provide important information about the frequency of use of nicotine and tobacco products by a representative sample of students in schools in the United States. The 2020 survey included a question about the use of marijuana by survey respondents. The results from the survey were analyzed using descriptive statistics and logistic regression to model the association between the use of marijuana and the use of electronic or conventional cigarettes., Results: The final survey from 2020 included 13,357 students, with 6537 male respondents and 6820 female respondents. Ages ranged from younger than 12 to 18 and older years; 961 students used both cigarettes and marijuana, and 1880 students used both electronic cigarettes (e-cigarettes) and marijuana. The adjusted odds ratio for the use of marijuana increased in female students, in non-Hispanic Black students, Hispanic students, and all ages from 13 through 18 and older. The perception of harm associated with either e-cigarettes or cigarettes did not change the odds ratio for using marijuana. Students who did not smoke cigarettes or did not smoke e-cigarettes had significantly lower odds ratios for using marijuana., Conclusions: The 2020 National Youth Tobacco Survey indicates that approximately 18.4% of middle school and high school students have used marijuana. Parents, educators, public health officials, and policymakers need to understand that there is a relatively high use of marijuana among students and that education programs should focus on its use with or without other tobacco products.

Vaccinations against COVID-19 infection have become a contentious issue in the United States. Multiple segments of society, including healthcare workers, have expressed concerns regarding the need for vaccination and the safety of current vaccines. Many hospital-based nurses have helped care for patients with severe COVID-19 infections. An anonymous online survey was sent to the nursing staff at University Medical Center in Lubbock, TX, USA, through a hospital-based email system to determine vaccination status and attitudes towards the COVID-19 vaccine and other routine vaccines. Multivariable regression analysis was used to determine factors associated with vaccination. A total of 251 nurses responded to this survey; 211 nurses (83.7%) had received the vaccine. Almost all nurses (242, 96%) had received all childhood vaccinations, and 231 (91.7%) had received an influenza vaccination in the prior year. A minority of nurses (75, 29.8%) supported mandatory vaccination for healthcare workers. The reasons for declining vaccination included the possibility that diet and alternative medications provided better protection against COVID-19. This survey demonstrates that over 80% of nurses working in a hospital managing very sick patients with COVID-19 infection had been vaccinated. However, nurses who did not take the annual influenza vaccine and did not consider other protective measures useful (such as mask-wearing) were significantly less likely to vaccinate. Nurses can provide an important resource for conversations with the public and patients about vaccine initiatives.

Background and Aims: Adeno-associated virus (AAV) vectors are widely used to deliver therapeutic transgenes to distinct tissues, including the liver. Vectors based on naturally occurring AAV serotypes as well as vectors using engineered capsids have shown variations in tissue tropism and level of transduction between different mouse models. Moreover, results obtained in rodents frequently lack translatability into large animal studies. In light of the increasing interest in AAV vectors for human gene therapy, an increasing number of studies are being performed in nonhuman primates. To keep animal numbers to a minimum and thus optimize the process of AAV capsid selection, we developed a multiplex barcoding approach to simultaneously evaluate the in vivo vector performance for a set of serotypes and capsid-engineered AAV vectors across multiple organs., Approach and Results: Vector biodistribution and transgene expression were assessed by quantitative PCR, quantitative reverse transcription PCR, vector DNA amplicon Illumina sequencing and vRNAseq in male and female rhesus macaques simultaneously dosed with a mixture of barcoded naturally occurring or engineered AAV vectors encoding the same transgene. As expected, our findings show animal-to-animal variation in both the biodistribution and tissue transduction pattern, which was partly influenced by each animal's distinctive serological status., Conclusions: This method offers a robust approach to AAV vector optimization that can be used to identify and validate AAV vectors for gene delivery to potentially any anatomical site or cell type., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

The hepatorenal syndrome develops in a small percentage of patients with advanced liver disease. The pathogenesis involves intravascular volume contraction secondary to pooling of blood in the splanchnic vessels, stimulation of the sympathetic nervous system and the renin-angiotensin-aldosterone pathway, and increased intra-abdominal pressure secondary to the formation of large volumes of ascitic fluid. The treatment options are limited, and liver transplant is the only definitive form of management. Here we suggest an alternative approach to treating hepatorenal syndrome based on the unexpected continuous peritoneal drainage in a 36-year-old man hospitalized with hepatic encephalopathy and hepatorenal syndrome. A total of 11.2 L ascitic fluid drained over 5 days from a paracentesis puncture site with marked improvement in renal function; the creatinine decreased from 3.3 mg/dL to 0.7 mg/dL and the BUN decreased from 42 mg/dL to 10 mg/dL. The discussion with this case report summarizes the pathogenesis, including the effect of intra-abdominal pressure, of the hepatorenal syndrome, outlines medical management, and makes a proposal for clinical study based on this case., Competing Interests: Declaration of competing interest None, (Copyright © 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

The colon has a very large surface area that is covered by a dense mucus layer. The biomass in the colon includes 500-1000 bacterial species at concentrations of ~10 12 colony-forming units per gram of feces. The intestinal epithelial cells and the commensal bacteria in the colon have a symbiotic relationship that results in nutritional support for the epithelial cells by the bacteria and maintenance of the optimal commensal bacterial population by colonic host defenses. Bacteria can form biofilms in the colon, but the exact frequency is uncertain because routine methods to undertake colonoscopy (i.e., bowel preparation) may dislodge these biofilms. Bacteria in biofilms represent a complex community that includes living and dead bacteria and an extracellular matrix composed of polysaccharides, proteins, DNA, and exogenous debris in the colon. The formation of biofilms occurs in benign colonic diseases, such as inflammatory bowel disease and irritable bowel syndrome. The development of a biofilm might serve as a marker for ongoing colonic inflammation. Alternatively, the development of biofilms could contribute to the pathogenesis of these disorders by providing sanctuaries for pathogenic bacteria and reducing the commensal bacterial population. Therapeutic approaches to patients with benign colonic diseases could include the elimination of biofilms and restoration of normal commensal bacteria populations. However, these studies will be extremely difficult unless investigators can develop noninvasive methods for measuring and identifying biofilms. These methods that might include the measurement of quorum sensing molecules, measurement of bile acids, and identification of bacteria uniquely associated with biofilms in the colon., Competing Interests: The authors declare no conflicts of interest.

Purpose: Increased activity of STAT3 is associated with progression of head and neck squamous cell carcinoma (HNSCC). Upstream activators of STAT3, such as JAKs, represent potential targets for therapy of solid tumors, including HNSCC. In this study, we investigated the anticancer effects of ruxolitinib, a clinical JAK1/2 inhibitor, in HNSCC preclinical models, including patient-derived xenografts (PDX) from patients treated on a window-of-opportunity trial., Experimental Design: HNSCC cell lines were treated with ruxolitinib, and the impact on activated STAT3 levels, cell growth, and colony formation was assessed. PDXs were generated from patients with HNSCC who received a brief course of neoadjuvant ruxolitinib on a clinical trial. The impact of ruxolitinib on tumor growth and STAT3 activation was assessed., Results: Ruxolitinib inhibited STAT3 activation, cellular growth, and colony formation of HNSCC cell lines. Ruxolitinib treatment of mice bearing an HNSCC cell line-derived xenograft significantly inhibited tumor growth compared with vehicle-treated controls. The response of HNSCC PDXs derived from patients on the clinical trial mirrored the responses seen in the neoadjuvant setting. Baseline active STAT3 (pSTAT3) and total STAT3 levels were lower, and ruxolitinib inhibited STAT3 activation in a PDX from a patient whose disease was stable on ruxolitinib, compared with a PDX from a patient whose disease progressed on ruxolitinib and where ruxolitinib treatment had minimal impact on STAT3 activation., Conclusions: Ruxolitinib exhibits antitumor effects in HNSCC preclinical models. Baseline pSTAT3 or total STAT3 levels in the tumor may serve as predictive biomarkers to identify patients most likely to respond to ruxolitinib., (©2022 American Association for Cancer Research.)

Editors of medical journals have important responsibilities and depend on peer reviewers to evaluate the quality of submitted manuscripts. However, invitations to undertake peer review are often declined, and in some cases the reviewer fails to provide a review in a reasonable timeframe. Baylor University Medical Center Proceedings surveyed recent reviewers to determine their motivations for undertaking a review and possible benefits associated with reviewing. Sixty-seven reviewers (12.4%) out of 540 responded to the survey request. Reviewer characteristics included long-standing involvement in research (50 reviewers in research ≥11 years) and prior publication (50 reviewers ≥6 articles). Many reviewers thought that reviewing articles represented a responsibility and provided an opportunity for them to contribute to scientific efforts and medical publications and to learn new information. Survey respondents suggested that recognition by the journal was an adequate benefit. This survey, like others, indicates that editors will continue to depend on a core set of reviewers who consider this activity both an opportunity and a responsibility., Competing Interests: No potential conflict of interest was reported by the author(s)., (Copyright © 2022 Baylor University Medical Center.)

The COVID-19 pandemic and its associated vaccine have highlighted vaccine hesitancy among healthcare workers (HCWs). Vaccine hesitancy among this group existed prior to the pandemic and particularly centered around influenza vaccination. Being a physician, having more advanced education, and previous vaccination habits are frequently associated with vaccine acceptance. The relationship between age and caring for patients on COVID-19 vaccination is unclear, with studies providing opposing results. Reasons for hesitancy include concerns about safety and efficacy, mistrust of government and institutions, waiting for more data, and feeling that personal rights are being infringed upon. Many of these reasons reflect previous attitudes about influenza vaccination as well as political beliefs and views of personal autonomy. Finally, several interventions to encourage vaccination have been studied, including education programs and non-monetary incentives with the most effective studies using a combination of methods.

Objective: The coronavirus disease 2019 pandemic has produced an unprecedented amount of scientific research as well as a high number of article retractions. Social and news media have been used to disseminate scientific research, and this can include retracted or withdrawn research. This risks the persistence of low-quality research and may contribute to controversial ideas or conspiracy theories., Methods: We examined 34 retracted or withdrawn coronavirus disease 2019 articles using alternative metrics., Results: These articles continued to receive social and news media mentions up to 180 days postremoval, although most mentions occurred within 30 days postremoval. Articles available on preprint servers accounted for 45.5% of total mentions., Conclusions: A significant, positive correlation was observed among Scimago Journal Rank, Immediacy Index, and Journal Citation Index, and total article mentions.

The bulk-boundary correspondence, which links a bulk topological property of a material to the existence of robust boundary states, is a hallmark of topological insulators. However, in crystalline topological materials the presence of boundary states in the insulating gap is not always necessary since they can be hidden in the bulk energy bands, obscured by boundary artifacts of non-topological origin, or, in the case of higher-order topology, they can be gapped altogether. Recently, exotic defects of translation symmetry called partial dislocations have been proposed to trap gapless topological modes in some materials. Here we present experimental observations of partial-dislocation-induced topological modes in 2D and 3D insulators. We particularly focus on multipole higher-order topological insulators built from circuit-based resonator arrays, since crucially they are not sensitive to full dislocation defects, and they have a sublattice structure allowing for stacking faults and partial dislocations., (© 2022. The Author(s).)

We describe 73 patients with coccidioidomycosis diagnosed or treated at a regional referral center in West Texas, USA. Patients most at risk worked in oil production or agriculture; the most-associated health factors were smoking and diabetes. Patient demographics suggest that access to care may affect coccidioidomycosis diagnosis in this region.

Radon is an established human lung carcinogen naturally released as an odorless, colorless gas from soil and rocks. It is a major environmental source of ionizing radiation and can cause oxidative damage to DNA, increasing the risk of lung cancer. Although the association between radon and lung cancer is well established, the association between radon and other cancers is not. Based on reported studies, there is no consistent evidence indicating an association between radon and non-solid and solid cancers, but limited literature, heterogenous study design, and confounding variables preclude definitive conclusions. More research is needed to evaluate the association between residential radon and non-lung cancers, particularly with regard to skin cancer, central nervous system (CNS) cancer, renal, and stomach cancer, in which existing literature suggests potential associations with residential radon may exist. However, the literature largely demonstrates that lung cancer is the primary concern associated with residential radon exposure; the lack of association with nonlung cancers could reflect the lack of studies which have an adequate sample size, establish accurate levels of radon exposure, and control for confounders. These results should be considered in residential radon mitigation efforts which should focus on smokers with high radon exposures., Competing Interests: Conflict of interest: The authors declare no potential conflict of interest., (©Copyright: the Author(s).)

Orally delivered drugs offer significant benefits in the fight against viral infections, and cost-effective production is critical to their impact on pandemic response in low- and middle-income countries. One example, molnupiravir, a COVID-19 therapy developed by Emory, Ridgeback, and Merck & Co., had potential to benefit from significant cost of goods (COGs) reductions for its active pharmaceutical ingredient (API), including starting materials. A holistic approach to identifying, developing, and evaluating optimized synthetic routes, which includes detailed COGs modeling, provides a rapid means to increase the availability, uptake and application of molnupiravir and other antivirals in global markets. Identification and development of alternate processes for the synthesis of molnupiravir has been conducted by the Medicines for All Institute at Virginia Commonwealth University (M4ALL) and the Green and Turner Labs at the University of Manchester. Both groups developed innovative processes based on synthetic route design and biocatalysis aimed at lowering costs and improving global access. The authors then performed COGs modeling to assess cost saving opportunities. This included a focus on manufacturing environments and facilities amenable to global public health and the identification of key parameters using sensitivity analyses. While all of the evaluated routes provide efficiency benefits, the best options yielded 3-6 fold API COGs reductions leading to treatment COGs as low as <$3/regimen. Additionally, key starting materials and cost drivers were quantified to evaluate the robustness of the savings. Finally, COGs models can continue to inform the focus of future development efforts on the most promising routes for additional cost savings. While the full price of a treatment course includes other factors, these alternative API synthetic approaches have significant potential to help facilitate broader access in low- and middle-income countries. As other promising therapeutics are developed, a similar process could enable rapid cost reductions while enhancing global access., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Peterson C et al.)

Peer review continues to be a crucial part of the scientific publishing process. Many editors have reported difficulty recruiting potential reviewers and receiving timely recommendations. Poor reviewer acceptance and completion rates can complicate and delay publication. However, few studies have examined these rates in detail. Here we analyze reviewer invitation, acceptance, and completion data from the Baylor University Medical Proceedings ., (Copyright © 2022 Baylor University Medical Center.)

Rlip76 (Rlip) is a multifunctional membrane protein that facilitates the high metabolic rates of cancer cells through the efflux of toxic metabolites and other functions. Rlip inhibition or depletion results in broad-spectrum anti-cancer effects in vitro and in vivo. Rlip depletion effectively suppresses malignancy and causes global reversion of characteristic CpG island methylomic and transcriptomic aberrations in the p53-null mouse model of spontaneous carcinogenesis through incompletely defined signaling and transcriptomic mechanisms. The methylome and transcriptome are normally regulated by the concerted actions of several mechanisms that include chromatin remodeling, promoter methylation, transcription factor interactions, and miRNAs. The present studies investigated the interaction of Rlip depletion or inhibition with the promoter methylation and transcription of selected cancer-related genes identified as being affected by Rlip depletion in our previous studies. We constructed novel promoter CpG island/luciferase reporter plasmids that respond only to CpG methylation and transcription factors. We found that Rlip depletion regulated expression by a transcription factor-based mechanism that functioned independently of promoter CpG methylation, lipid peroxidation, and p53 status.

Idiopathic inflammatory myopathies (IIMs) are a rare, heterogeneous group of diseases with a characteristic clinical presentation consisting of muscle inflammation and weakness. They often present with accompanying extra-muscular findings, most notably in the skin, lungs, and joints. Inflammatory myopathies are also identified by their characteristic laboratory abnormalities, including a 10- to 50-fold increase in creatinine kinase, elevated liver enzymes, and characteristic electromyography and magnetic resonance imaging findings. Distinct autoimmune markers and clinical phenotypes have advanced our understanding of IIMs and have led to the recognition of 5 distinct entities, each with its unique pathophysiology, autoimmune markers, and clinical features. While autoimmune panels and muscle biopsies help clinicians distinguish one entity from the other, their sensitivity and specificity vary. Of the various inflammatory myopathies, polymyositis remains the most elusive. Often, the diagnosis is ultimately made by combining clinical findings and laboratory data. As our case report illustrates, clinicians must use this constellation of data to initiate treatment for suspected polymyositis despite negative autoimmune panels and negative muscle biopsy.

Background: As of July 2022, there have been more than 91.3 million cases of COVID-19 and nearly 1.03 million deaths in the United States alone. In addition, many people who survived COVID-19 had long-term symptoms, such as fatigue, dyspnea, loss of smell and taste, depression, and anxiety., Objectives: The purpose of our study is to evaluate the status of COVID-19 patients who were previously hospitalized., Methods: We conducted a single-center retrospective cohort study at Texas Tech University Health Sciences Center and its affiliated University Medical Center under IRB of L21-144. We included all patients hospitalized for COVID-19 and followed up in our Internal Medicine Clinic at any time between April 1, 2020, and April 1, 2021, and reviewed follow-up data for these patients after discharge., Results: A total of 128 patients were included; 59 (46%) were men, and 69 (54%) were women with an average age of 59.7 ± 14.8 years. Most of the patients (n = 78, 60.9%) identified their race as Hispanic or Latino origin; the next largest group was Caucasian (n = 29, 22.65%). The average number of days until post-hospitalization follow-up was 36 ± 38 days. The 50% of the patients (n = 64) used telemedicine for follow-up visits. Important comorbidities in these patients included diabetes (n = 84, 65.6%) and hypertension (n = 94, 73.4%). Thirty-four patients (26.6%) reported respiratory symptoms at their follow-up appointments, 24 patients (18.8%) reported constitutional symptoms, 12 patients (9.4%) reported GI symptoms, and 25 patients (19.5%) reported other symptoms, such as paresthesia, lower extremity edema, or psychological symptoms. After hospital discharge, 54 patients had follow-up chest x-rays, and 41 (75.9%) still had abnormal findings consistent with COVID-19 imaging characteristics. Follow-up laboratory tests identified 44 patients (77.2%, 57 tested) with elevated D-dimer levels, 44 patients (78.6%, 56 tested) with high ferritin levels, and 21patients (35.6%, 59 tested) with elevated troponin T HS levels., Conclusion: Long-lasting COVID-19 symptoms in these patients included respiratory symptoms (26.6%), constitutional symptoms (18.8%), GI symptoms (9.4%), and other symptoms, such as paresthesia, lower extremity edema, or psychological symptoms (19.5%). The rate of telehealth follow-up was 50%. Many patients had elevated inflammatory markers that will need follow up to determine the clinical implications.

Over the past decade, numerous gene-editing platforms which alter host DNA in a highly specific and targeted fashion have been described. Two notable examples are zinc finger nucleases (ZFNs), the first gene-editing platform to be tested in clinical trials, and more recently, CRISPR/Cas9. Although CRISPR/Cas9 approaches have become arguably the most popular platform in the field, the therapeutic advantages and disadvantages of each strategy are only beginning to emerge. We have established a nonhuman primate (NHP) model that serves as a strong predictor of successful gene therapy and gene-editing approaches in humans; our recent work shows that ZFN-edited hematopoietic stem and progenitor cells (HSPCs) engraft at lower levels than CRISPR/Cas9-edited cells. Here, we investigate the mechanisms underlying this difference. We show that optimized culture conditions, including defined serum-free media, augment engraftment of gene-edited NHP HSPCs in a mouse xenograft model. Furthermore, we identify intracellular RNases as major barriers for mRNA-encoded nucleases relative to preformed enzymatically active CRISPR/Cas9 ribonucleoprotein (RNP) complexes. We conclude that CRISPR/Cas9 RNP gene editing is more stable and efficient than ZFN mRNA-based delivery and identify co-delivered RNase inhibitors as a strategy to enhance the expression of gene-editing proteins from mRNA intermediates., Competing Interests: H.P.K. has received support as the inaugural recipient of the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Stephanus Family Endowed Chair for Cell and Gene Therapy, and is or was a consultant to and has or had ownership interests with Rocket Pharmaceuticals, Homology Medicines, VOR Biopharma, and Ensoma Inc. H.P.K. has also been a consultant to CSL Behring and Magenta Therapeutics. S.R. is a consultant to Forty Seven Inc. (Gilead Sciences) and Ensoma Inc., (© 2021.)

Although genome editing technologies have the potential to revolutionize the way we treat human diseases, barriers to successful clinical implementation remain. Increasingly, preclinical large animal models are being used to overcome these barriers. In particular, the immunogenicity and long-term safety of novel gene editing therapeutics must be evaluated rigorously. However, short-lived small animal models, such as mice and rats, cannot address secondary pathologies that may arise years after a gene editing treatment. Likewise, immunodeficient mouse models by definition lack the ability to quantify the host immune response to a novel transgene or gene-edited locus. Large animal models, including dogs, pigs, and non-human primates (NHPs), bear greater resemblance to human anatomy, immunology, and lifespan and can be studied over longer timescales with clinical dosing regimens that are more relevant to humans. These models allow for larger scale and repeated blood and tissue sampling, enabling greater depth of study and focus on rare cellular subsets. Here, we review current progress in the development and evaluation of novel genome editing therapies in large animal models, focusing on applications in human immunodeficiency virus 1 (HIV-1) infection, cancer, and genetic diseases including hemoglobinopathies, Duchenne muscular dystrophy (DMD), hypercholesterolemia, and inherited retinal diseases., Competing Interests: Declaration of interests H.P.K. has received support as the inaugural recipient of the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Stephanus Family Endowed Chair for Cell and Gene Therapy, and is or was a consultant to and has or had ownership interests with Rocket Pharmaceuticals, Homology Medicines, VOR Biopharma and Ensoma Inc. H.P.K. has also been a consultant to CSL Behring and Magenta Therapeutics. Other authors have no competing interests., (Copyright © 2021. Published by Elsevier Inc.)