Characteristics and outcomes of reversible platypnoea-orthodeoxia syndrome in COVID-19 pneumonia.

INTRODUCTION: Platypnoea-orthodeoxia syndrome (POS) is an uncommon clinical entity characterised by dyspnoea and platypnoea (oxygen desaturation that follows the assumption of an upright position from recumbency). Since the coronavirus disease 2019 (COVID-19) outbreak, increasing reports of COVID-19-related POS and its associated morbidity have been reported around the world. We aimed to study the characteristics of COVID-19-related POS and orthodeoxia (including associations leading to a more prolonged orthodeoxia), and the postdischarge functional outcomes of patients with COVID-19-related POS. METHODS: An observational cohort study was conducted in a tertiary hospital that managed post-COVID-19 patients. Twenty-four participants with severe-to-critical COVID-19 disease/pneumonia and POS, who received inpatient pulmonary rehabilitation, were enrolled. Descriptive analysis of the data was performed to describe POS/orthodeoxia characteristics and functional outcomes in these participants. Correlation analyses were carried out to identify significant factors associated with a prolonged orthodeoxia. RESULTS: The mean duration of POS and orthodeoxia was 12.9 ± 8.3 days and 28.5 ± 14.6 days, respectively. All participants demonstrated resolution of POS and orthodeoxia by hospital discharge. On multivariable analysis, intensive care unit admission and maximal level of respiratory support were significantly associated with a prolonged duration of orthodeoxia. One participant was lost to follow-up. The remaining 23 participants achieved independence in self-care. With the exception of one patient, who was recovering from a hip fracture, the rest achieved independence in ambulation and independent community access. CONCLUSION: Resolution of orthodeoxia was observed in all our participants with COVID-19-related POS. Good functional outcome can be attained with timely and effective rehabilitation interventions.

Preliminary Validity and Acceptability of Motion Tape for Measuring Low Back Movement: Mixed Methods Study.

BACKGROUND: Low back pain (LBP) is a significant public health problem that can result in physical disability and financial burden for the individual and society. Physical therapy is effective for managing LBP and includes evaluation of posture and movement, interventions directed at modifying posture and movement, and prescription of exercises. However, physical therapists have limited tools for objective evaluation of low back posture and movement and monitoring of exercises, and this evaluation is limited to the time frame of a clinical encounter. There is a need for a valid tool that can be used to evaluate low back posture and movement and monitor exercises outside the clinic. To address this need, a fabric-based, wearable sensor, Motion Tape (MT), was developed and adapted for a low back use case. MT is a low-profile, disposable, self-adhesive, skin-strain sensor developed by spray coating piezoresistive graphene nanocomposites directly onto commercial kinesiology tape. OBJECTIVE: The objectives of this study were to (1) validate MT for measuring low back posture and movement and (2) assess the acceptability of MT for users. METHODS: A total of 10 participants without LBP were tested. A 3D optical motion capture system was used as a reference standard to measure low back kinematics. Retroreflective markers and a matrix of MTs were placed on the low back to measure kinematics (motion capture) and strain (MT) simultaneously during low back movements in the sagittal, frontal, and axial planes. Cross-correlation coefficients were calculated to evaluate the concurrent validity of MT strain in reference motion capture kinematics during each movement. The acceptability of MT was assessed using semistructured interviews conducted with each participant after laboratory testing. Interview data were analyzed using rapid qualitative analysis to identify themes and subthemes of user acceptability. RESULTS: Visual inspection of concurrent MT strain and kinematics of the low back indicated that MT can distinguish between different movement directions. Cross-correlation coefficients between MT strain and motion capture kinematics ranged from -0.915 to 0.983, and the strength of the correlations varied across MT placements and low back movement directions. Regarding user acceptability, participants expressed enthusiasm toward MT and believed that it would be helpful for remote interventions for LBP but provided suggestions for improvement. CONCLUSIONS: MT was able to distinguish between different low back movements, and most MTs demonstrated moderate to high correlation with motion capture kinematics. This preliminary laboratory validation of MT provides a basis for future device improvements, which will also involve testing in a free-living environment. Overall, users found MT acceptable for use in physical therapy for managing LBP.

Staphylococcus aureus subcapsular splenic abscess and associated empyema in the setting of tocilizumab therapy: A case report.

We report a case of Staphylococcus aureus subcapsular splenic abscess and associated empyema after recent commencement of tocilizumab, masquerading as musculoskeletal pain. This highlights the importance of considering unusual underlying infections in patients on tocilizumab.

Levels of autonomy in FDA-cleared surgical robots: a systematic review.

The integration of robotics in surgery has increased over the past decade, and advances in the autonomous capabilities of surgical robots have paralleled that of assistive and industrial robots. However, classification and regulatory frameworks have not kept pace with the increasing autonomy of surgical robots. There is a need to modernize our classification to understand technological trends and prepare to regulate and streamline surgical practice around these robotic systems. We present a systematic review of all surgical robots cleared by the United States Food and Drug Administration (FDA) from 2015 to 2023, utilizing a classification system that we call Levels of Autonomy in Surgical Robotics (LASR) to categorize each robot's decision-making and action-taking abilities from Level 1 (Robot Assistance) to Level 5 (Full Autonomy). We searched the 510(k), De Novo, and AccessGUDID databases in December 2023 and included all medical devices fitting our definition of a surgical robot. 37,981 records were screened to identify 49 surgical robots. Most surgical robots were at Level 1 (86%) and some reached Level 3 (Conditional Autonomy) (6%). 2 surgical robots were recognized by the FDA to have machine learning-enabled capabilities, while more were reported to have these capabilities in their marketing materials. Most surgical robots were introduced via the 510(k) pathway, but a growing number via the De Novo pathway. This review highlights trends toward greater autonomy in surgical robotics. Implementing regulatory frameworks that acknowledge varying levels of autonomy in surgical robots may help ensure their safe and effective integration into surgical practice.

Flecainide causing elevated capture thresholds on pacemaker implantation.

Flecainide is a Vaughan Williams class 1c antiarrhythmic used to treat supraventricular and ventricular arrhythmias. It has been described as a rare cause for increased pacemaker capture thresholds. We describe a report of a patient, in her early 80s, presenting with tachy-brady syndrome on a background of permanent atrial fibrillation. She was treated with metoprolol and flecainide by her private cardiologist. Permanent right ventricular chamber pacing was recommended for her slow heart rate. At insertion of her single chamber pacemaker, she was noted to have elevated capture thresholds despite appropriate lead positioning. A flecainide level was elevated at 1.1 µg/mL, and it was subsequently ceased. This was associated with a rapid improvement in her capture threshold. Flecainide should be considered as a cause for elevated pacing thresholds at the time of implant. Particular care should be taken for at-risk groups such as the elderly and patients with renal impairment.

Physical Therapists' Acceptance of a Wearable, Fabric-Based Sensor System (Motion Tape) for Use in Clinical Practice: Qualitative Focus Group Study.

BACKGROUND: Low back pain (LBP) is a costly global health condition that affects individuals of all ages and genders. Physical therapy (PT) is a commonly used and effective intervention for the management of LBP and incorporates movement assessment and therapeutic exercise. A newly developed wearable, fabric-based sensor system, Motion Tape, uses novel sensing and data modeling to measure lumbar spine movements unobtrusively and thus offers potential benefits when used in conjunction with PT. However, physical therapists' acceptance of Motion Tape remains unexplored. OBJECTIVE: The primary aim of this research study was to evaluate physical therapists' acceptance of Motion Tape to be used for the management of LBP. The secondary aim was to explore physical therapists' recommendations for future device development. METHODS: Licensed physical therapists from the American Physical Therapy Association Academy of Leadership Technology Special Interest Group participated in this study. Overall, 2 focus groups (FGs; N=8) were conducted, in which participants were presented with Motion Tape samples and examples of app data output on a poster. Informed by the Technology Acceptance Model, we conducted semistructured FGs and explored the wearability, usefulness, and ease of use of and suggestions for improvements in Motion Tape for PT management of LBP. FG data were transcribed and analyzed using rapid qualitative analysis. RESULTS: Regarding wearability, participants perceived that Motion Tape would be able to adhere for several days, with some variability owing to external factors. Feedback was positive for the low-profile and universal fit, but discomfort owing to wires and potential friction with clothing was of concern. Other concerns included difficulty with self-application and potential skin sensitivity. Regarding usefulness, participants expressed that Motion Tape would enhance the efficiency and specificity of assessments and treatment. Regarding ease of use, participants stated that the app would be easy, but data management and challenges with interpretation were of concern. Physical therapists provided several recommendations for future design improvements including having a wireless system or removable wires, customizable sizes for the tape, and output including range of motion data and summary graphs and adding app features that consider patient input and context. CONCLUSIONS: Several themes related to Motion Tape's wearability, usefulness, and ease of use were identified. Overall, physical therapists expressed acceptance of Motion Tape's potential for assessing and monitoring low back posture and movement, both within and outside clinical settings. Participants expressed that Motion Tape would be a valuable tool for the personalized treatment of LBP but highlighted several future improvements needed for Motion Tape to be used in practice.

BCG vaccination stimulates integrated organ immunity by feedback of the adaptive immune response to imprint prolonged innate antiviral resistance.

Bacille Calmette-Guérin (BCG) vaccination can confer nonspecific protection against heterologous pathogens. However, the underlying mechanisms remain mysterious. We show that mice vaccinated intravenously with BCG exhibited reduced weight loss and/or improved viral clearance when challenged with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 B.1.351) or PR8 influenza. Protection was first evident between 14 and 21 d post-vaccination and lasted ∼3 months. Notably, BCG induced a biphasic innate response and robust antigen-specific type 1 helper T cell (TH1 cell) responses in the lungs. MyD88 signaling was essential for innate and TH1 cell responses, and protection against SARS-CoV-2. Depletion of CD4+ T cells or interferon (IFN)-γ activity before infection obliterated innate activation and protection. Single-cell and spatial transcriptomics revealed CD4-dependent expression of IFN-stimulated genes in lung myeloid and epithelial cells. Notably, BCG also induced protection against weight loss after mouse-adapted SARS-CoV-2 BA.5, SARS-CoV and SHC014 coronavirus infections. Thus, BCG elicits integrated organ immunity, where CD4+ T cells feed back on tissue myeloid and epithelial cells to imprint prolonged and broad innate antiviral resistance.

Impacts of a COVID-19 Educational Video: Evaluation of the Influence of Race, Gender, Political Affiliation, Study Major, and Age on Vaccine Acceptance among University Students.

BACKGROUND: The World Health Organization (WHO) warns that vaccine hesitancy is an ongoing major global health threat. While vaccination against severe acute respiratory syndrome coronavirus (SARS-CoV-2) proves to be an effective strategy in protecting against the disease, vaccine hesitancy represents a major barrier to stopping the spread of the virus. Willingness for vaccination can be influenced by several factors, including education level and health literacy. Although several studies demonstrate the value of video educational programs in improving coronavirus disease 2019 (COVID-19) vaccine knowledge and acceptance, no studies to date have evaluated if race, gender, and other demographic factors impact the influence of an educational video on COVID-19 vaccine knowledge and hesitancy among university students in the United States (U.S.). AIMS: This study was conducted to determine the impact of an educational video on U.S. university undergraduate students' COVID-19 vaccine perception and acceptance. It also aims to evaluate whether demographic factors affect the influence of the video. METHODS: An online survey was used to measure perceived understanding and acceptance of COVID-19 vaccines before and after viewing a video regarding the effectiveness and safety of COVID-19 vaccinations. The impact of demographic factors on the Video Influence Score was analyzed. KEY RESULTS: After viewing the video, respondents' (n = 285) perceived awareness and acceptance of COVID-19 vaccines significantly increased (p < 0.05). In addition, gender, political party affiliation, age, study major, and influenza vaccination history did not significantly impact the Video Influence Score (p > 0.05). However, African American/Black respondents (3.81 ± 4.24) were significantly more influenced by the video compared to respondents of other races (p < 0.05), such as White/Caucasian (1.91 ± 3.75), Hispanic/Latino (0.17 ± 3.67), Asian (0.29 ± 1.53), and Indigenous American (0.64 ± 2.52). CONCLUSIONS: This study suggests the potential impact of an educational video on COVID-19 vaccine perception and acceptance among university students. Despite limitations such as a modest survey response rate, this study provides valuable insight concerning the influential factors affecting vaccine acceptance in diverse student populations. Future studies are warranted to explore how student response to vaccine educational videos may vary depending on students' racial and cultural backgrounds. IMPLICATIONS: A targeted educational video to promote vaccine acceptance is a valuable tool for public health campaigns to combat vaccine hesitancy. The study also highlights the importance of tailoring interventions to specific demographic groups such as considering racial factors to maximize the impact of educational interventions on vaccine attitudes.

Circular RNA vaccine induces potent T cell responses.

Circular RNAs (circRNAs) are a class of RNAs commonly found across eukaryotes and viruses, characterized by their resistance to exonuclease-mediated degradation. Their superior stability compared to linear RNAs, combined with previous work showing that engineered circRNAs serve as efficient protein translation templates, make circRNA a promising candidate for RNA medicine. Here, we systematically examine the adjuvant activity, route of administration, and antigen-specific immunity of circRNA vaccination in mice. Potent circRNA adjuvant activity is associated with RNA uptake and activation of myeloid cells in the draining lymph nodes and transient cytokine release. Immunization of mice with engineered circRNA encoding a protein antigen delivered by a charge-altering releasable transporter induced innate activation of dendritic cells, robust antigen-specific CD8 T cell responses in lymph nodes and tissues, and strong antitumor efficacy as a therapeutic cancer vaccine. These results highlight the potential utility of circRNA vaccines for stimulating potent innate and T cell responses in tissues.

A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes.

Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This deleterious effect is mediated by pathological cleavage of the Cdk5 activator p35 into the truncated product p25, leading to prolonged Cdk5 activation and altered substrate specificity. Elevated p25 levels have been reported in humans and rodents with neurodegeneration, and the benefit of genetically blocking p25 production has been demonstrated previously in rodent and human neurodegenerative models. Here, we report a 12-amino-acid-long peptide fragment derived from Cdk5 (Cdk5i) that is considerably smaller than existing peptide inhibitors of Cdk5 (P5 and CIP) but shows high binding affinity toward the Cdk5/p25 complex, disrupts the interaction of Cdk5 with p25, and lowers Cdk5/p25 kinase activity. When tagged with a fluorophore (FITC) and the cell-penetrating transactivator of transcription (TAT) sequence, the Cdk5i-FT peptide exhibits cell- and brain-penetrant properties and confers protection against neurodegenerative phenotypes associated with Cdk5 hyperactivity in cell and mouse models of neurodegeneration, highlighting Cdk5i's therapeutic potential.

Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses.

Systems vaccinology has defined molecular signatures and mechanisms of immunity to vaccination. However, comparative analysis of immunity to different vaccines is lacking. We integrated transcriptional data of over 3,000 samples, from 820 adults across 28 studies of 13 vaccines and analyzed vaccination-induced signatures of antibody responses. Most vaccines induced signatures of innate immunity and plasmablasts at days 1 and 7, respectively, after vaccination. However, the yellow fever vaccine induced an early transient signature of T and B cell activation at day 1, followed by delayed antiviral/interferon and plasmablast signatures that peaked at days 7 and 14-21, respectively. Thus, there was no evidence for a 'universal signature' that predicted antibody response to all vaccines. However, accounting for the asynchronous nature of responses, we defined a time-adjusted signature that predicted antibody responses across vaccines. These results provide a transcriptional atlas of immunity to vaccination and define a common, time-adjusted signature of antibody responses.

Assessing Preceptor and Student Perceptions of Remote Advanced Pharmacy Practice Experience Learning during the COVID-19 Pandemic.

The coronavirus disease 2019 pandemic created a major shift in learning modalities in the Advanced Pharmacy Practice Experience program. This descriptive study aimed to evaluate preceptor and student perceptions of remote learning experiences and student practice readiness upon completion of remote rotations. Preceptors and students who participated in partial to full remote experiential rotations between 17 August 2020 and 26 March 2021 were invited to complete an on-line survey. A cross-sectional survey consisted of closed-ended questions using a 5-point Likert scale assessing perception on adaptability, effectiveness of remote learning in advancing practice knowledge and skills, and confidence in students' practice readiness. A total of 29 preceptors and 43 students completed the survey (response rates of 67% and 57%, respectively). Approximately 70% of the remote rotations were practice-based, with ambulatory care representing the most frequently reported rotation by preceptors (38%) and students (28%). A high level of confidence in preceptor perception of their ability to adapt and provide effective remote experiences (average 4.28) matched with the students' high level of confidence with their preceptors' abilities (86% agree or strongly agree). Upon the completion of remote rotations, both preceptors and students felt confident in student practice readiness based on student ability to design and initiate individualized patient care plans or complete projects using evidence-based resources (79% and 86%, respectively). Most preceptors (69%) reported that students achieved the rotation objectives at the same level as students engaged in-person experiences. The limitations of remote learning included the absence of direct interactions. Overall, both preceptors and students reported achieving practice readiness with remote experiential learning experiences and felt the remote activities should be continued post-pandemic.

Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration.

DNA double-strand breaks (DSBs) are linked to neurodegeneration and senescence. However, it is not clear how DSB-bearing neurons influence neuroinflammation associated with neurodegeneration. Here, we characterize DSB-bearing neurons from the CK-p25 mouse model of neurodegeneration using single-nucleus, bulk, and spatial transcriptomic techniques. DSB-bearing neurons enter a late-stage DNA damage response marked by nuclear factor κB (NFκB)-activated senescent and antiviral immune pathways. In humans, Alzheimer's disease pathology is closely associated with immune activation in excitatory neurons. Spatial transcriptomics reveal that regions of CK-p25 brain tissue dense with DSB-bearing neurons harbor signatures of inflammatory microglia, which is ameliorated by NFκB knockdown in neurons. Inhibition of NFκB in DSB-bearing neurons also reduces microglia activation in organotypic mouse brain slice culture. In conclusion, DSBs activate immune pathways in neurons, which in turn adopt a senescence-associated secretory phenotype to elicit microglia activation. These findings highlight a previously unidentified role for neurons in the mechanism of disease-associated neuroinflammation.

Cryptococcal Antigen Screening and Missed Opportunities for Earlier Diagnosis Among People With HIV and Poor Virologic Control in the Bronx, NY.

BACKGROUND: There is no established cryptococcal antigen (CrAg) screening guideline for people with HIV who are antiretroviral therapy experienced but have poor virologic control. We assessed factors associated with CrAg screening and describe missed opportunities for earlier testing. SETTING: Ambulatory clinics affiliated with Montefiore Medical Center, Bronx, NY. METHODS: This was a retrospective chart review of CrAg screening among asymptomatic people with HIV with absolute CD4 counts 200 cells/mm 3 and HIV viral loads (VLs) > 200 copies/mL receiving HIV care from 2015 to 2020. We used Cox proportional hazards regression to identify predictors of screening, including longitudinal CD4 count and HIV VL as time-varying covariables. Among cases of diagnosed cryptococcosis, we assessed for opportunities for earlier diagnosis. RESULTS: Screening CrAg was performed in 2.9% of 2201 individuals meeting the inclusion criteria. Compared with those not screened, those who were screened had a shorter duration of HIV infection (0.09 vs. 5.1 years; P = 0.001) and lower absolute CD4 counts (12 vs. 24 cells/mm 3 ; P < 0.0001). In a multivariable model stratified by median HIV duration, CD4 < 100 [hazard ratio (HR), 7.07; 95% confidence interval (CI): 2.43 to 20.6], VL > 10,000 (HR, 15.0; 95% CI: 4.16 to 54.0), and a shorter duration of HIV infection (HR, 0.60; 95% CI: 0.42 to 0.86) were associated with screening for those with HIV < 5 years. Among those diagnosed with cryptococcosis (n = 14), 6 individuals had an ambulatory visit in the preceding 6 months but did not undergo screening. CONCLUSION: CrAg screening was infrequently performed in this at-risk population. Those with a longer duration of HIV infection were less likely to undergo CrAg screening, highlighting potential missed opportunities for earlier diagnosis.

Adjuvanting a subunit SARS-CoV-2 vaccine with clinically relevant adjuvants induces durable protection in mice.

Adjuvants enhance the magnitude and the durability of the immune response to vaccines. However, there is a paucity of comparative studies on the nature of the immune responses stimulated by leading adjuvant candidates. In this study, we compared five clinically relevant adjuvants in mice-alum, AS03 (a squalene-based adjuvant supplemented with α-tocopherol), AS37 (a TLR7 ligand emulsified in alum), CpG1018 (a TLR9 ligand emulsified in alum), O/W 1849101 (a squalene-based adjuvant)-for their capacity to stimulate immune responses when combined with a subunit vaccine under clinical development. We found that all four of the adjuvant candidates surpassed alum with respect to their capacity to induce enhanced and durable antigen-specific antibody responses. The TLR-agonist-based adjuvants CpG1018 (TLR9) and AS37 (TLR7) induced Th1-skewed CD4+ T cell responses, while alum, O/W, and AS03 induced a balanced Th1/Th2 response. Consistent with this, adjuvants induced distinct patterns of early innate responses. Finally, vaccines adjuvanted with AS03, AS37, and CpG1018/alum-induced durable neutralizing-antibody responses and significant protection against the B.1.351 variant 7 months following immunization. These results, together with our recent results from an identical study in non-human primates (NHPs), provide a comparative benchmarking of five clinically relevant vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV-2 subunit vaccines to provide durable protection against the B.1.351 variant. Furthermore, these results reveal differences between the widely-used C57BL/6 mouse strain and NHP animal models, highlighting the importance of species selection for future vaccine and adjuvant studies.

Epigenetic adjuvants: durable reprogramming of the innate immune system with adjuvants.

Development of effective vaccines is a critical global health priority. Stimulating antigen-specific B and T cells to elicit long-lasting protection remains the central paradigm of vaccinology. Adjuvants are components that enhance vaccine immunogenicity by targeting specific innate immune receptors and pathways. Recent data highlight the capacity of adjuvants to induce durable epigenetic reprogramming of the innate immune system to engender heightened resistance against pathogens. This raises the prospect of developing epigenetic adjuvants that, in addition to stimulating robust T and B cell responses, convey broad protection against diverse pathogens by training the innate immune system. In this review, we discuss our emerging understanding of the various vaccines and adjuvants and their effects on durable reprogramming of the innate immune response, their putative mechanisms of action, and the promise and challenges of developing epigenetic adjuvants as a universal vaccine strategy.

Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine.

Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.

A molecular atlas of innate immunity to adjuvanted and live attenuated vaccines, in mice.

Adjuvants hold great potential in enhancing vaccine efficacy, making the understanding and improving of adjuvants critical goals in vaccinology. The TLR7/8 agonist, 3M-052, induces long-lived humoral immunity in non-human primates and is currently being evaluated in human clinical trials. However, the innate mechanisms of 3M-052 have not been fully characterized. Here, we perform flow cytometry, single cell RNA-seq and ATAC-seq to profile the kinetics, transcriptomics and epigenomics of innate immune cells in murine draining lymph nodes following 3M-052-Alum/Ovalbumin immunization. We find that 3M-052-Alum/OVA induces a robust antiviral and interferon gene program, similar to the yellow fever vaccine, which is known to confer long-lasting protection. Activation of myeloid cells in dLNs persists through day 28 and single cell analysis reveals putative TF-gene regulatory programs in distinct myeloid cells and heterogeneity of monocytes. This study provides a comprehensive characterization of the transcriptomics and epigenomics of innate populations in the dLNs after vaccination.

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia.

Immune aplastic anemia (AA) features somatic loss of HLA class I allele expression on bone marrow cells, consistent with a mechanism of escape from T-cell-mediated destruction of hematopoietic stem and progenitor cells. The clinical significance of HLA abnormalities has not been well characterized. We examined the somatic loss of HLA class I alleles and correlated HLA loss and mutation-associated HLA genotypes with clinical presentation and outcomes after immunosuppressive therapy in 544 AA patients. HLA class I allele loss was detected in 92 (22%) of the 412 patients tested, in whom there were 393 somatic HLA gene mutations and 40 instances of loss of heterozygosity. Most frequently affected was HLA-B*14:02, followed by HLA-A*02:01, HLA-B*40:02, HLA-B*08:01, and HLA-B*07:02. HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 were also overrepresented in AA. High-risk clonal evolution was correlated with HLA loss, HLA-B*14:02 genotype, and older age, which yielded a valid prediction model. In 2 patients, we traced monosomy 7 clonal evolution from preexisting clones harboring somatic mutations in HLA-A*02:01 and HLA-B*40:02. Loss of HLA-B*40:02 correlated with higher blood counts. HLA-B*07:02 and HLA-B*40:01 genotypes and their loss correlated with late-onset of AA. Our results suggest the presence of specific immune mechanisms of molecular pathogenesis with clinical implications. HLA genotyping and screening for HLA loss may be of value in the management of immune AA. This study was registered at clinicaltrials.gov as NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167.