Identification of an ANCA-Associated Vasculitis Cohort Using Deep Learning and Electronic Health Records.

Background: ANCA-associated vasculitis (AAV) is a rare but serious disease. Traditional case-identification methods using claims data can be time-intensive and may miss important subgroups. We hypothesized that a deep learning model analyzing electronic health records (EHR) can more accurately identify AAV cases. Methods: We examined the Mass General Brigham (MGB) repository of clinical documentation from 12/1/1979 to 5/11/2021, using expert-curated keywords and ICD codes to identify a large cohort of potential AAV cases. Three labeled datasets (I, II, III) were created, each containing note sections. We trained and evaluated a range of machine learning and deep learning algorithms for note-level classification, using metrics like positive predictive value (PPV), sensitivity, F-score, area under the receiver operating characteristic curve (AUROC), and area under the precision and recall curve (AUPRC). The deep learning model was further evaluated for its ability to classify AAV cases at the patient-level, compared with rule-based algorithms in 2,000 randomly chosen samples. Results: Datasets I, II, and III comprised 6,000, 3,008, and 7,500 note sections, respectively. Deep learning achieved the highest AUROC in all three datasets, with scores of 0.983, 0.991, and 0.991. The deep learning approach also had among the highest PPVs across the three datasets (0.941, 0.954, and 0.800, respectively). In a test cohort of 2,000 cases, the deep learning model achieved a PPV of 0.262 and an estimated sensitivity of 0.975. Compared to the best rule-based algorithm, the deep learning model identified six additional AAV cases, representing 13% of the total. Conclusion: The deep learning model effectively classifies clinical note sections for AAV diagnosis. Its application to EHR notes can potentially uncover additional cases missed by traditional rule-based methods.

A Paper-Based Multiplexed Serological Test to Monitor Immunity against SARS-COV-2 Using Machine Learning.

The rapid spread of SARS-CoV-2 caused the COVID-19 pandemic and accelerated vaccine development to prevent the spread of the virus and control the disease. Given the sustained high infectivity and evolution of SARS-CoV-2, there is an ongoing interest in developing COVID-19 serology tests to monitor population-level immunity. To address this critical need, we designed a paper-based multiplexed vertical flow assay (xVFA) using five structural proteins of SARS-CoV-2, detecting IgG and IgM antibodies to monitor changes in COVID-19 immunity levels. Our platform not only tracked longitudinal immunity levels but also categorized COVID-19 immunity into three groups: protected, unprotected, and infected, based on the levels of IgG and IgM antibodies. We operated two xVFAs in parallel to detect IgG and IgM antibodies using a total of 40 µL of human serum sample in <20 min per test. After the assay, images of the paper-based sensor panel were captured using a mobile phone-based custom-designed optical reader and then processed by a neural network-based serodiagnostic algorithm. The serodiagnostic algorithm was trained with 120 measurements/tests and 30 serum samples from 7 randomly selected individuals and was blindly tested with 31 serum samples from 8 different individuals, collected before vaccination as well as after vaccination or infection, achieving an accuracy of 89.5%. The competitive performance of the xVFA, along with its portability, cost-effectiveness, and rapid operation, makes it a promising computational point-of-care (POC) serology test for monitoring COVID-19 immunity, aiding in timely decisions on the administration of booster vaccines and general public health policies to protect vulnerable populations.

Poly (ADP-ribose) polymerase-1 regulates HIV-1 replication in human CD4+ T cells.

The cellular enzyme poly (ADP-ribose) polymerase-1 (PARP-1) regulates multiple processes that are potentially implicated in HIV-1 infection. However, the role of PARP-1 in HIV-1 infection remains controversial, with reports indicating or excluding that PARP-1 influence early steps of the HIV-1 life cycle. Most of these studies have been conducted with Vesicular Stomatitis virus Glycoprotein G (VSV-G)-pseudotyped, single-round infection HIV-1; limiting our understanding of the role of PARP-1 in HIV-1 replication. Therefore, we evaluated the effect of PARP-1 deficiency or inhibition in HIV-1 replication in human CD4+ T cells. Our data showed that PARP-1 knockout increased viral replication in SUP-T1 cells. Similarly, a PARP-1 inhibitor that targets PARP-1 DNA-binding activity enhanced HIV-1 replication. In contrast, inhibitors affecting the catalytic activity of the enzyme were inactive. In correspondence with the pharmacological studies, mutagenesis analysis indicated that the DNA-binding domain was required for the PARP-1 anti-HIV-1 activity, but the poly-ADP-ribosylation activity was dispensable. Our results also demonstrated that PARP-1 acts at the production phase of the viral life cycle since HIV-1 produced in cells lacking PARP-1 was more infectious than control viruses. The effect of PARP-1 on HIV-1 infectivity required Env, as PARP-1 deficiency or inhibition did not modify the infectivity of Env-deleted, VSV-G-pseudotyped HIV-1. Furthermore, virion-associated Env was more abundant in sucrose cushion-purified virions produced in cells lacking the enzyme. However, PARP-1 did not affect Env expression or processing in the producer cells. In summary, our data indicate that PARP-1 antagonism enhances HIV-1 infectivity and increases levels of virion-associated Env. Importance: Different cellular processes counteract viral replication. A better understanding of these interfering mechanisms will enhance our ability to control viral infections. We have discovered a novel, antagonist effect of the cellular enzyme poly (ADP-ribose) polymerase-1 (PARP-1) in HIV-1 replication. Our data indicate that PARP-1 deficiency or inhibition augment HIV-1 infectivity in human CD4+ T cells, the main HIV-1 target cell in vivo . Analysis of the mechanism of action suggested that PARP-1 antagonism increases in the virus the amounts of the viral protein mediating viral entry to the target cells. These findings identify for the first time PARP-1 as a host factor that regulates HIV-1 infectivity, and could be relevant to better understand HIV-1 transmission and to facilitate vaccine development.

Patient perceptions underlying ctDNA molecular surveillance for HPV(+) oropharyngeal squamous cell carcinoma.

OBJECTIVE: Circulating tumor DNA assays have robust potential as molecular surveillance tools. They may also exacerbate patient distress without improving outcomes. We investigate patient acceptability of a validated ctHPVDNA assay (NavDx) during cancer surveillance for HPV(+) oropharyngeal cancer (OPC). METHODS: Consented HPV(+) OPC participants completed the NCCN Distress Thermometer, the Hospital Anxiety Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-General (FACT-G) scale both (1) before NavDx blood draw, and (2) after results were provided. Patients then completed a series of focused questions related to their perceptions of the assay. RESULTS: Overall, 55 patients completed the study, with 98.2 % showing no recurrence. For the NCCN Distress Thermometer, median patient distress decreased (2.0 (IQR 1-5) vs. 1.0 (IQR 0-3)) (p < 0.001) in association with NavDx. Using scores ≥ 4 as a cutoff point to define clinically elevated distress, scores also improved (36.4 % vs. 18.2 %, p = 0.031). For HADS, anxiety significantly improved (5.0 (IQR 2.0-7.0) vs. 3.0 (IQR 1.0-6.5)) (p = 0.037), but not depression (3.0 (IQR 1.0-7.0) vs. 3.0 (IQR 1.0-6.5)) (p = 0.870). FACT-G scores showed no substantial differences. On survey questionnaires, 95.5 % of patients believed the test to be helpful, and 100 % felt "somewhat" or "extremely" confident in the assay as a monitoring tool. While 59.1 % felt that it reduced anxiety, 88.4 % concordantly felt that it did not introduce anxiety. CONCLUSION: ctHPVDNA as a molecular surveillance tool reduced distress levels in HPV(+) OPC patients, with notably high patient confidence in the approach. Further investigation is warranted to judiciously incorporate this emerging modality in surveillance guidelines.

Investigating the Impact of Blunt Force Trauma: A Probabilistic Study of Behind Armor Blunt Trauma Risk.

Evaluating Behind Armor Blunt Trauma (BABT) is a critical step in preventing non-penetrating injuries in military personnel, which can result from the transfer of kinetic energy from projectiles impacting body armor. While the current NIJ Standard-0101.06 standard focuses on preventing excessive armor backface deformation, this standard does not account for the variability in impact location, thorax organ and tissue material properties, and injury thresholds in order to assess potential injury. To address this gap, Finite Element (FE) human body models (HBMs) have been employed to investigate variability in BABT impact conditions by recreating specific cases from survivor databases and generating injury risk curves. However, these deterministic analyses predominantly use models representing the 50th percentile male and do not investigate the uncertainty and variability inherent within the system, thus limiting the generalizability of investigating injury risk over a diverse military population. The DoD-funded I-PREDICT Future Naval Capability (FNC) introduces a probabilistic HBM, which considers uncertainty and variability in tissue material and failure properties, anthropometry, and external loading conditions. This study utilizes the I-PREDICT HBM for BABT simulations for three thoracic impact locations-liver, heart, and lower abdomen. A probabilistic analysis of tissue-level strains resulting from a BABT event is used to determine the probability of achieving a Military Combat Incapacitation Scale (MCIS) for organ-level injuries and the New Injury Severity Score (NISS) is employed for whole-body injury risk evaluations. Organ-level MCIS metrics show that impact at the heart can cause severe injuries to the heart and spleen, whereas impact to the liver can cause rib fractures and major lacerations in the liver. Impact at the lower abdomen can cause lacerations in the spleen. Simulation results indicate that, under current protection standards, the whole-body risk of injury varies between 6 and 98% based on impact location, with the impact at the heart being the most severe, followed by impact at the liver and the lower abdomen. These results suggest that the current body armor protection standards might result in severe injuries in specific locations, but no injuries in others.

Sex as a predictor of clinical phenotype and determinant of immune response in IgG4-related disease: a retrospective study of patients fulfilling the American College of Rheumatology-European League Against Rheumatism classification criteria.

BACKGROUND: IgG4-related disease is a multiorgan fibroinflammatory disease considered to have an autoimmune origin. Case series describing individual organ involvement have suggested differences in phenotypic expression between males and females. We aimed to characterise differences in IgG4-related disease manifestations between male and female patients in a large single-centre cohort. METHODS: In this retrospective, single-centre cohort study, patients were recruited from the Massachusetts General Hospital Rheumatology Clinic (Boston, MA, USA) and classified according to the American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria. Only patients satisfying the ACR-EULAR classification criteria were included in the study. Data on age at diagnosis, organ involvement at baseline, treatment status, and pre-treatment laboratory values were collected. Circulating plasmablasts and B-cell subsets were quantitated by flow cytometry. Active disease was defined by an IgG4-related disease Responder Index score of more than 0. Laboratory values were analysed for patients who were untreated at baseline and had active IgG4-related disease. The main outcomes were assessed in all participants with available data. FINDINGS: Of the 564 participants enrolled in the Massachusetts General Hospital Rheumatology Clinic IgG4-related disease Registry, 328 fulfilled ACR-EULAR classification criteria and were included between January, 2008, and May, 2023. There was a strong male predominance (male:female ratio 2·2:1) with 226 (69%) males and 102 (31%) females, which contrasted markedly with our general rheumatology clinic population (0·4:1; p<0·001). The male predominance increased with each decade of life starting at age 40 years. On average, male patients were 5·5 years older at diagnosis than female patients (63·7 years vs 58·2 years; p=0·0031). We observed male patients to have higher ACR-EULAR classification criteria scores at baseline with a median score of 35·0 (IQR 28·0-46·0), compared with 29·5 (25·0-39·0) for females (p=0·0010). The proportion of male patients with pancreatic and renal involvement was almost double the proportion observed in female patients (50% of the male patients had pancreatic involvement, compared with about 26% of the female patients; p<0·0001). Male patients were more likely to have serological abnormalities at baseline. The distribution of IgG4 values differed significantly between male an female sexes, favouring higher values in males. We found that male patients with IgG4-related disease were more likely to have active B-cell responses in the blood as defined by plasmablast expansions. INTERPRETATION: IgG4-related disease is unusual among autoimmune diseases in that it is more likely to affect males than females and to present with a striking sex-dependent organ distribution and degree of B-cell response. These findings highlight important variation between IgG4-related disease and other conditions generally believed to have an autoimmune basis. Most autoimmune diseases, by contrast to IgG4-related disease, demonstrate pronounced predilections for affecting females more frequently than males. Hypotheses surrounding the cause and pathophysiology of this condition need to consider this unusual sex distribution among patients with IgG4-related disease. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Multilevel thrombotic or embolic burden and its role in sex-related outcomes in acute limb ischemia.

OBJECTIVE: The impact of sex upon outcomes in acute limb ischemia (ALI) remains disputed. We aim to quantify the effect of sex upon amputation-free survival (AFS) after a percutaneous-first approach for ALI. METHODS: This was a two-center retrospective review of ALI managed via a percutaneous-first approach. Demographics, comorbidities, and clinical characteristics were analyzed. The Kaplan-Meier and Cox regression were used to estimate AFS, limb salvage, and overall survival. RESULTS: Over 9 years, 170 patients (n = 87, 51% males; median age, 67 [interquartile range (IQR), 59-77 years) presented with ALI. Rutherford classification was I in 56 (33%); IIa in 85 (50%); IIb in 20 (12%), and III in 9 (5%). Thirty-day mortality, major amputation rate, and fasciotomy rates were 8% (n = 13); 6.5% (n = 11), and 4.7% (n = 8), respectively. Among revascularized limbs, 92% were patent at 30 days. Length of stay was 7 days (IQR, 3-11 days). Complications included 13 bleeding episodes (8%), four cases of atrial fibrillation (2%), and three re-thrombosis/clot extension events (1.7%). No differences were noted in complication rates when stratified by sex. Females were older than males (median age, 70 [IQR, 62-79] vs 65 [IQR, 56-76 years]; P = .02) and more likely to present with atrial fibrillation (20.5% vs 8%; P = .02) and hyperlipidemia (72% vs 57%; P = .04). Females also more frequently presented with multi-level thrombotic/embolic burden compared with males (56% vs 43%; P = .03) and required both aspiration thrombectomy and thrombolysis (27% vs 14%; P = .02). Kaplan-Meier estimated median AFS, limb salvage, and overall survival were 425 days (IQR, 140-824 days); 314 days (IQR, 72-727 days); and 342 days (IQR, 112-762 days). When stratified by sex, females had worse survival (median, 270 days [IQR, 92-636 days] vs 406 days [IQR, 140-937 days]; P = .005) and limb salvage (median, 241 days [IQR, 88-636 days] vs 363 days [IQR, 49-822 days]; P = .04) compared with males. Univariate Cox regression showed female sex (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.04-2.05; P = .03), multi-level thrombotic/embolic burden (HR, 1.64; 95% CI, 1.17-2.31; P = .004), and Rutherford class (HR, 1.37; 95% CI, 1.08-1.73; P = .009) predicted major amputation/death. By multivariable Cox regression, multi-level thrombotic/embolic burden (HR, 1.54; 95% CI, 1.09-2.17; P = .01), Rutherford class (HR, 1.34; 95% CI, 1.07-1.69; P = .01), and female sex (HR, 1.45; 95% CI, 1.03-2.05; P = .03) were each independently predictive of major amputation/death. CONCLUSIONS: A percutaneous-first strategy is safe and efficacious in the overall ALI population. Similar to prior works, female vs male patients with ALI in our cohort have higher rates of mortality and major amputation. In our multivariable model, multi-level thrombotic/embolic burden was independently associated with a greater than 45% increased hazard of major amputation/death at last follow-up. Further prospective analysis is warranted to elucidate the underlying factors contributing to the higher prevalence of multi-level thrombotic/embolic burden in female patients with ALI, and to further define the optimal percutaneous-first approach for ALI in consideration of patient sex and extent of clot burden.

Obstetric outcomes of women with congenital uterine anomalies in the United States.

BACKGROUND: Due to the rarity, congenital uterine anomaly type-specific evaluation of pregnant women has been relatively understudied. OBJECTIVE: To describe national-level obstetric outcomes in women with congenital uterine anomalies. STUDY DESIGN: This cross-sectional study queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample. Pregnant women with diagnosis of congenital uterine anomalies who had hospital delivery between 2016 and 2019 were examined. The World Health Organization's International Classification of Disease, 10th revision coding was used to delineate type of congenital uterine anomaly, diagnoses, and procedures performed during the index admission. Primary outcomes included pregnancy outcome, which was classified as full-term live birth, preterm live birth, abortion/stillbirth, or ectopic pregnancy. Secondary outcomes included obstetric comorbidities and severe maternal mortality, which were compared between different subtypes of congenital uterine anomalies with multivariable logistic regression model. RESULTS: A total of 50,180 pregnant women with congenital uterine anomalies were identified. Bicornuate was the most common subtype (73.5%), followed by arcuate (13.5%) and unicornuate (10.0%). 70.6% of women with congenital uterine anomalies had a full-term live birth, 26.8% had a preterm live birth, 2.1% had an abortion or stillbirth, and 0.4% had an ectopic pregnancy. 61.8% of preterm births occurred between 33 and 36 weeks, 16.9% between 30 and 32 weeks, and 21.3% at <30 weeks. There were 1,440 (2.9%) periviable births. The preterm (34.5%) and periviable (6.9%) birth rates were highest in the uterine didelphys group. Overall, two-thirds (65.7%) of patients with congenital uterine anomalies were delivered via cesarean section. When compared to arcuate uterus, risk of severe maternal morbidity in septate uterus (4.8% vs 2.6%, adjusted-odds ratio [aOR] 2.60, 95% confidence interval [CI] 1.49-4.52) was increased, including hemorrhage (14.5% vs 7.7%, aOR 2.16, 95% CI 1.51-3.07). This was followed by uterine didelphys (4.2% vs 2.6%, aOR 1.75, 95% CI 1.24-2.47), unicornuate uterus (3.8% vs 2.6%, aOR 1.61, 95% CI 1.29-2.01), and bicornuate uterus (3.0% vs 2.6%, aOR 1.23, 95% CI 1.04-1.47). CONCLUSION: While the majority of patients with congenital uterine anomalies result in full-term viable deliveries, each subtype of congenital uterine anomalies confers different obstetric risks. Uterine didelphys was associated with the highest risk of preterm birth, while septate uterus was associated with the highest risk of severe maternal morbidity. While this hospital delivery dataset likely overrepresents bicornuate uteri, this populational data may help inform patients with congenital anomalies considering pregnancy.

Intravenous Administration of Anti-CD47 Antibody Augments Hematoma Clearance, Mitigates Acute Neuropathology, and Improves Cognitive Function in a Rat Model of Penetrating Traumatic Brain Injury.

Traumatic brain injury (TBI)-induced intracerebral hematoma is a major driver of secondary injury pathology such as neuroinflammation, cerebral edema, neurotoxicity, and blood-brain barrier dysfunction, which contribute to neuronal loss, motor deficits, and cognitive impairment. Cluster of differentiation 47 (CD47) is an antiphagocytic cell surface protein inhibiting hematoma clearance. This study was designed to evaluate the safety and efficacy of blockade of CD47 via intravenous (i.v.) administration of anti-CD47 antibodies following penetrating ballistic-like brain injury (PBBI) with significant traumatic intracerebral hemorrhage (tICH). The pharmacokinetic (PK) profile of the anti-CD47 antibody elicited that antibody concentration decayed over 7 days post-administration. Blood tests and necropsy analysis indicated no severe adverse events following treatment. Cerebral hemoglobin levels were significantly increased after injury, however, anti-CD47 antibody administration at 0.1 mg/kg resulted in a significant reduction in cerebral hemoglobin levels at 72 h post-administration, indicating augmentation of hematoma clearance. Immunohistochemistry assessment of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA1) demonstrated a significant reduction of GFAP levels in the lesion core and peri-lesional area. Based on these analyses, the optimal dose was identified as 0.1 mg/kg. Lesion volume showed a reduction following treatment. Rotarod testing revealed significant motor deficits in all injured groups but no significant therapeutic benefits. Spatial learning performance revealed significant deficits in all injured groups, which were significantly improved by the last testing day. Anti-CD47 antibody treated rats showed significantly improved attention deficits, but not retention scores. These results provide preliminary evidence that blockade of CD47 using i.v. administration of anti-CD47 antibodies may serve as a potential therapeutic for TBI with ICH.

Iron Olefin Metathesis: Unlocking Reactivity and Mechanistic Insights.

Olefin metathesis catalyzed by iron complexes has garnered substantial interest due to iron's abundance and nontoxicity relative to ruthenium, yet its full potential remains untapped, largely because of the propensity of iron carbenes to undergo cyclopropanation instead of cycloreversion from a metallacycle intermediate. In this report, we elucidate the reactions of [{PC(sp2)P}Fe(L)(N2)], ([PC(sp2)P] = bis[2-(diisopropylphosphino)phenyl]methylene) with strained olefins, unveiling their capability to yield metathesis-related products. Our investigations led to the isolation of a structurally characterized metallacyclobutane during the reaction with norbornadiene derivatives, ultimately leading to a ring-opened iron alkylidene. These findings provide compelling evidence that iron complexes adhere to the Chauvin olefin metathesis mechanism.

The Tissue-Specific Eco-Exposome: Differential Pharmaceutical Bioaccumulation and Disposition in Fish among Trophic Positions.

Though bioaccumulation of pharmaceuticals by aquatic organisms continues to receive scientific attention, the internal disposition of these contaminants among different tissue compartments of fish species has been infrequently investigated, particularly among fish at different trophic positions. We tested a human to fish biological read-across hypothesis for contaminant disposition by examining tissue-specific accumulation in three understudied species, longnose gar (Lepisosteus osseus; piscivore), gizzard shad (Dorosoma cepedianum; planktivore/detritivore), and smallmouth buffalo (Ictiobus bubalus; benthivore), from a river influenced by municipal effluent discharge. In addition to surface water, fish plasma, and brain, gill, gonad, liver, and lateral muscle fillet tissues were analyzed via isotope dilution liquid chromatography tandem mass spectrometry. Caffeine and sucralose, two common effluent tracers, were quantitated at low micrograms per liter levels in surface water, while an anticonvulsant, carbamazepine, was observed at levels up to 37 ng/L. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and primary metabolites were detected in at least one tissue of all three species at low micrograms per kilogram concentrations. Within each species, brain and liver of select fish contained the highest levels of SSRIs compared to plasma and other tissues, which is generally consistent with human tissue disposition patterns. However, we observed differential accumulation among specific tissue types and species. For example, mean levels of sertraline in brain and liver tissues were 13.4 µg/kg and 1.5 µg/kg in gizzard shad and 1.3 µg/kg and 7.3 µg/kg in longnose gar, respectively. In contrast, smallmouth buffalo did not consistently accumulate SSRIs to detectable levels. Tissue-specific eco-exposome efforts are necessary to understand mechanisms associated with such marked bioaccumulation and internal dispositional differences among freshwater fish species occupying different trophic positions. Environ Toxicol Chem 2024;00:1-9. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Rheumatoid arthritis and changes on spirometry by smoking status in two prospective longitudinal cohorts.

OBJECTIVE: To compare longitudinal changes in spirometric measures between patients with rheumatoid arthritis (RA) and non-RA comparators. METHODS: We analysed longitudinal data from two prospective cohorts: the UK Biobank and COPDGene. Spirometry was conducted at baseline and a second visit after 5-7 years. RA was identified based on self-report and disease-modifying antirheumatic drug use; non-RA comparators reported neither. The primary outcomes were annual changes in the per cent-predicted forced expiratory volume in 1 s (FEV1%) and per cent predicted forced vital capacity (FVC%). Statistical comparisons were performed using multivariable linear regression. The analysis was stratified based on baseline smoking status and the presence of obstructive pattern (FEV1/FVC <0.7). RESULTS: Among participants who underwent baseline and follow-up spirometry, we identified 233 patients with RA and 37 735 non-RA comparators. Among never-smoking participants without an obstructive pattern, RA was significantly associated with more FEV1% decline (ß=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV1% decline than non-RA comparators (ß=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (ß=1.12, p=0.01). Results were similar for FEV1/FVC decline. No difference was observed in the annual FVC% change in RA versus non-RA. CONCLUSIONS: Smokers with RA, especially those with baseline obstructive spirometric patterns, experienced lower FEV1% and FEV1/FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV1% decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA.

CD28-CD57+ T cells from head and neck cancer patients produce high levels of cytotoxic granules and type II interferon but are not senescent.

T lymphocytes expressing CD57 and lacking costimulatory receptors CD27/CD28 have been reported to accumulate with aging, chronic infection, and cancer. These cells are described as senescent, with inability to proliferate but enhanced cytolytic and cytokine-producing capacity. However, robust functional studies on these cells taken directly from cancer patients are lacking. We isolated these T cells and their CD27/28+ counterparts from blood and tumor samples of 50 patients with previously untreated head and neck cancer. Functional studies confirmed that these cells have enhanced ability to degranulate and produce IFN-γ. They also retain the ability to proliferate, thus are not senescent. These data suggest that CD27/28-CD57+ CD8+ T cells are a subset of highly differentiated, CD45RA+ effector memory (TEMRA) cells with retained proliferative capacity. Patients with > 34% of these cells among CD8+ T cells in the blood had a higher rate of locoregional disease relapse, suggesting these cells may have prognostic significance.

Anxiety sensitivity and COVID-19 mental health, fatigue, and well-being: a longitudinal examination among adults from the United States during March-October 2020.

There is widespread empirical evidence that the COVID-19 pandemic contributed to elevated risk of mental and physical health symptoms and decreased quality of life. The present investigation sought to examine if individual differences in anxiety sensitivity was associated with mental health, psychosomatic, and well-being among a sample of US adults during a 6-month period early in the COVID-19 pandemic. Employing longitudinal research methodology, we tested the hypothesis that the anxiety sensitivity global factor would be related to increased risk of anxiety, depression, fatigue, and lower well-being. Secondary analyses evaluated the lower order anxiety sensitivity factors for the same criterion variables. The sample consisted of 778 participants with an average age of 37.96 (SD = 11.81; range 18-73). Results indicated that, as hypothesized, anxiety sensitivity was associated with increased risk for more severe anxiety, depression, fatigue, and lesser well-being; the observed effects of anxiety sensitivity were relatively robust and evident in adjusted models that controlled for numerous theoretically and clinically relevant factors (e.g. perceived health status). Overall, these results suggest that pandemic functioning could likely be improved via interventions that target elevated anxiety sensitivity as a vulnerability factor for a broad range of aversive psychosomatic symptoms and personal well-being.

The Effects of Radiation Dose Heterogeneity on the Tumor Microenvironment and Anti-Tumor Immunity.

Radiotherapy elicits dose- and lineage-dependent effects on immune cell survival, migration, activation, and proliferation in targeted tumor microenvironments. Radiation also stimulates phenotypic changes that modulate the immune susceptibility of tumor cells. This has raised interest in using radiotherapy to promote greater response to immunotherapies. To clarify the potential of such combinations, it is critical to understand how best to administer radiation therapy to achieve activation of desired immunologic mechanisms. In considering the multifaceted process of priming and propagating anti-tumor immune response, radiation dose heterogeneity emerges as a potential means for simultaneously engaging diverse dose-dependent effects in a single tumor environment. Recent work in spatially fractionated external beam radiation therapy demonstrates the expansive immune responses achievable when a range of high to low dose radiation is delivered in a tumor. Brachytherapy and radiopharmaceutical therapies deliver inherently heterogeneous distributions of radiation that may contribute to immunogenicity. This review evaluates the interplay of radiation dose and anti-tumor immune response and explores emerging methodological approaches for investigating the effects of heterogeneous dose distribution on immune responses.

Rash and Fever in a Returned Traveler.

Case Presentation: A 21-year-old, otherwise healthy female presented to the emergency department with fever among other nonspecific symptoms after recently returning from Ghana. On physical exam, she had a characteristic upper extremity rash, and a tourniquet test revealed numerous petechiae. The diagnosis of dengue was suspected and subsequently confirmed. Discussion: Dengue is one of many viral illnesses that should be considered in returning travelers presenting with fever and other nonspecific symptoms. Emergency physicians must keep a broad differential when evaluating fever in returned travelers and prioritize history and physical exam findings to help narrow the diagnosis and provide appropriate management and supportive care while awaiting further confirmatory testing.

Multiattribute Decision-making in Macaques Relies on Direct Attribute Comparisons.

In value-based decisions, there are frequently multiple attributes, such as cost, quality, or quantity, that contribute to the overall goodness of an option. Because one option may not be better in all attributes at once, the decision process should include a means of weighing relevant attributes. Most decision-making models solve this problem by computing an integrated value, or utility, for each option from a weighted combination of attributes. However, behavioral anomalies in decision-making, such as context effects, indicate that other attribute-specific computations might be taking place. Here, we tested whether rhesus macaques show evidence of attribute-specific processing in a value-based decision-making task. Monkeys made a series of decisions involving choice options comprising a sweetness and probability attribute. Each attribute was represented by a separate bar with one of two mappings between bar size and the magnitude of the attribute (i.e., bigger = better or bigger = worse). We found that translating across different mappings produced selective impairments in decision-making. Choices were less accurate and preferences were more variable when like attributes differed in mapping, suggesting that preventing monkeys from easily making direct attribute comparisons resulted in less accurate choice behavior. This was not the case when mappings of unalike attributes within the same option were different. Likewise, gaze patterns favored transitions between like attributes over transitions between unalike attributes of the same option, so that like attributes were sampled sequentially to support within-attribute comparisons. Together, these data demonstrate that value-based decisions rely, at least in part, on directly comparing like attributes of multiattribute options.

An early case of successful peripheral nerve repair in 1880: Francis L. Parker, MD.

The modern technique of epineural suture repair, along with a detailed reporting of functional restoration, came from Carl Hueter in 1873. While there is extensive information on peripheral nerve surgery throughout recorded history leading up to the 1800s, little early American scientific literature is available. While Schwann, Nissl, and Waller were publishing their work on nerve anatomy and physiology, Francis LeJau Parker was born. The South Carolina native would go on to describe one of the first American cases of peripheral nerve repair with the restoration of function. Francis Parker was born in 1836 in Abbeville, South Carolina. He gained local notoriety as one of the first American surgeons to suture a severed nerve, resulting in restored function. The case dates back to 1880, when a patient presented to his clinic with severing of the posterior interosseous nerve. The details of this case come from the archives of the South Carolina Medical Association. The authors reviewed these records in detail and provide a case description of nerve repair not previously reported in the modern literature. The history, neurological examination, and details of the case provide insight into the adroit surgical skills of Dr. Parker.