Pulmonary and Critical Care Fellowship Program Directors' Perspective on the Virtual Interview Process.

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.

An analysis of retracted COVID-19 articles published by one medical publisher with multiple journals.

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.

Anti-PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers.

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.

Consumer Protection, Agencies, and the Supreme Court.

This Viewpoint discusses an upcoming US Supreme Court case that could result in the termination of the US Consumer Financial Protection Bureau, which protects the financial well-being of consumers.

Ehrlichiosis: A Unique Presentation of Fatal Sepsis in an Immunocompetent Adult.

Ehrlichiosis is a vector-borne illness transmitted by the lone star tick (Amblyomma americanum). Most patients have risk factors for tick exposure, such as hobbies or careers involving hunting, camping, and hiking. This case exposes a rare case of severe ehrlichiosis, ultimately resulting in fatal sepsis, in an elderly patient without any reported tick bites or exposures. This patient had a history of cognitive impairment, which was confounded by acute encephalopathy at presentation. Unfortunately, this hindered his ability to report any known tick exposures, which posed a challenge in the diagnosis and ultimately delayed treatment as there were no clear findings of a tick bite or known exposures.

Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells.

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.

CD20 CAR T cells safely and reversibly ablate B cell follicles in a non-human primate model of HIV persistence.

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 (TFH) cells, with complete restoration of BCF architecture and TFH 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 TFH cells within BCF sanctuaries, informing future combinatorial HIV cure strategies designed to augment antiviral efficacy.

Long-Term Follow-Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor Burden Follicular Lymphoma.

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.

Mixed Patterns of Intergenerational DNA Methylation Inheritance in Acropora.

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.

Integrating geometries of ReLU feedforward neural networks.

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 ℝm to an output space ℝn. The piecewise behavior corresponds to a polyhedral decomposition of ℝm. 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_Toolbox). Polyhedra in the polyhedral decomposition of ℝm 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.

Furry, Fomite, and Facultative Anaerobe: A Unique Case of Capnocytophaga canimorsus.

Capnocytophaga canimorsus infection is frequently associated with dog and cat bites or scratches in patients who have risk factors such as immunosuppression, asplenia, and alcohol abuse. However, rare instances of C. canimorsus infection in patients without typical risk factors have been reported. Here, we present such a rare and unusual case of C. canimorsus bacteremia in a patient without animal wounds or risk factors. Chronic sinusitis may have contributed to mucosal disruption and served as an entry point for C. canimorsus. Prompt initiation of antibiotics resulted in rapid resolution of symptoms and clearance of bacteremia.

Nonbacterial Thrombotic Endocarditis With Embolic Phenomena Diagnosed by Transesophageal Echocardiogram.

Nonbacterial thrombotic endocarditis (NBTE) is a valvular disorder commonly associated with malignancy and connective tissue diseases. While the disorder is often discovered during autopsy, it is sometimes diagnosed in patients who present with systemic embolization. Here, we discuss the case of a 52-year-old female, with connective tissue disease and malignancy, who presented with symptoms of systemic embolization and was diagnosed with NBTE by transesophageal echocardiogram (TEE). This case highlights the utility of TEE in diagnosing NBTE and its influence in guiding the subsequent management of patients.

Article retraction rates in selected MeSH term categories in PubMed published between 2010 and 2020.

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.

• Article retractions occurred in all subsets of articles classified by the 15 PubMed MeSH terms used in this study.• The time to retraction and the rate of retraction differed significantly across research topics classified by these MeSH terms. This suggests that research content and visibility affect retraction rates.• As an example, the "Neoplasms" category had the highest total number of retractions (993) and one of the highest retraction rates (75.4 per 100,000 publications).• Readers, editors, and authors need to understand that retractions do occur following publication in the medical literature. These retractions potentially have important consequences and require attention from all individuals involved in the multiple steps needed to create high-quality medical and scientific information.

Triple Threat: Triple-Valve Endocarditis Case Report and Literature Review.

Triple valve endocarditis (TVE) is a rare presentation of endocarditis often requiring multivalvular surgery. Here we report a case of S. aureus triple valve endocarditis in a patient with a history of intravenous drug use and provide a literature review of TVE identification, treatment, and prognosis.

Efficient manufacturing and engraftment of CCR5 gene-edited HSPCs following busulfan conditioning in nonhuman primates.

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.

A Case of Chagas Cardiomyopathy in Western Virginia: Worlds Away?

Chagas cardiomyopathy, caused by the parasite Trypanosoma cruzi, is a significant cause of cardiac pathology worldwide. Though most frequently observed in Latin America, Chagas disease is present in the United States and should be considered in patients with heart block or other cardiac abnormalities and previous travel to or residence in endemic areas. Here we describe a new diagnosis of Chagas cardiomyopathy in a patient residing in Virginia with a previous residence in Mexico.

Local adaptation and host specificity to copepod intermediate hosts by the tapeworm Schistocephalus solidus.

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.

Efficient ex vivo expansion of conserved element vaccine-specific CD8+ T-cells from SHIV-infected, ART-suppressed nonhuman primates.

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.

A multiplexed barcode approach to simultaneously evaluate gene delivery by adeno-associated virus capsid variants in nonhuman primates.

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.

Disseminated coccidioidomycosis in a patient on mycophenolate.

Disseminated coccidioidomycosis is a rare but serious complication of fungal illness, with immunocompromised patients more susceptible to severe illness. Here we report a unique case of disseminated coccidioidomycosis in a patient on mycophenolate for treatment of polymyositis.