The Role of Predeployment Retraction in Biopsy Marker Migration During Stereotactic Breast Biopsies: A Randomized Controlled Trial.

OBJECTIVE: Inaccurate breast biopsy marker placement and marker migration during stereotactic biopsy procedures compromise their reliability for lesion localization and precise surgical excision. This trial evaluated the impact of 5-mm predeployment retraction of the marker introducer on marker migration, investigating other potential factors that influence the outcome. METHODS: This parallel, randomized controlled trial enrolled women aged ≥18 years undergoing stereotactic breast biopsy at a single institution from May 2020 through August 2022. The study was approved by the institutional review board at the University of Alabama at Birmingham (UAB). Patients were randomized to intervention (5-mm introducer retraction before marker deployment) or control (standard marker placement) by drawing a labeled paper. The primary outcome was the distance of marker migration on immediate postprocedure mammogram. RESULTS: Of 251 patients enrolled, 223 were analyzed; 104 received the intervention, and 119 received control. Mean (SD) marker migration was 12.1 (14.9) mm in the intervention group vs 9.8 (14.9) mm, with differences between groups estimated at 2.3 mm (SE = 1.9, P = .2312) (d = 0.16; 95% CI, 1.5-6.0). Effects of age, breast density, thickness, and biopsy approach showed no statistical significance. In exploratory models, central lesions exhibited 5.7 mm less migration than proximal lesions (95% CI, 0.7-10.6; P = .025), and each body mass index (BMI) unit increase was associated with 0.3 mm greater migration (95% CI, 0-0.6; P = .044). CONCLUSION: Retracting the marker introducer 5 mm before deployment did not reduce migration. Higher BMI and certain lesion locations were all associated with marker migration, highlighting the need to investigate biomechanical factors and techniques to optimize breast marker placement.Clinical Trials Registration: NCT04398537.

Cognitive Intraindividual variability in injection drug use among Hispanic residents of Puerto Rico.

Despite a high prevalence of injection drug use (IDU) in Puerto Rico, little is known about how it affects neuropsychological functioning in this population. Investigations of intra-individual variability (IIV) have alluded to its utility as a potential indicator of neural decline. The purpose of this study was to characterize IIV among Hispanic residents of Puerto Rico who engage in IDU. Injectors and non-injectors completed the Neuropsí Atención y Memoria battery. Measures of IIV were calculated for the overall test battery (OTB), the three battery indices, and three domains of attention, memory, and executive functioning. The injector group showed significantly greater IIV than the non-injector group on all measures (OTB, indices, and individual domains). Additionally, injectors showed significantly higher IIV in the domain of executive functioning compared to other cognitive domains and battery indices. In contrast, non-injectors did not show any significant within-group differences on any IIV measures. The higher performance variability observed in the IDU group suggests a negative influence of IDU on cognition, with executive functioning being more susceptible to these effects. These findings support the need for continued investigations into the clinical application of IIV for diagnostic and prognostic purposes in the Hispanic IDU population.

Increased metamemory accuracy with practice does not require practice with metamemory.

Given that learners do not always predict their future memory performance accurately, there is a need to better understand how metamemory accuracy can be improved. Prior research suggests that one way to improve is practice-participants tend to become better at predicting their future memory performance over the course of multi-trial learning experiments. However, it is currently unclear whether such improvements result from participants having practised making metamemory judgements or whether comparable improvements occur even in their absence. This issue was investigated in three multi-trial, cued recall experiments wherein participants either did or did not receive practice making judgements of learning. Metamemory accuracy increased across study blocks but did so equally for the two groups. These results indicate that increased metamemory accuracy with practice is not due to participants having practised explicit metamemory monitoring but instead due to other factors associated with multi-trial learning such as retrieval practice and the availability of prior test performance as a metamemory cue.

Limited HIV-associated neuropathologies and lack of immune activation in sub-saharan African individuals with late-stage subtype C HIV-1 infection.

Although previous studies have suggested that subtype B HIV-1 proviruses in the brain are associated with physiological changes and immune activation accompanied with microgliosis and astrogliosis, and indicated that both HIV-1 subtype variation and geographical location might influence the neuropathogenicity of HIV-1 in the brain. The natural course of neuropathogenesis of the most widespread subtype C HIV-1 has not been adequately investigated, especially for people living with HIV (PLWH) in sub-Saharan Africa. To characterize the natural neuropathology of subtype C HIV-1, postmortem frontal lobe and basal ganglia tissues were collected from nine ART-naïve individuals who died of late-stage AIDS with subtype C HIV-1 infection, and eight uninfected deceased individuals as controls. Histological staining was performed on all brain tissues to assess brain pathologies. Immunohistochemistry (IHC) against CD4, p24, Iba-1, GFAP, and CD8 in all brain tissues was conducted to evaluate potential viral production and immune activation. Histological results showed mild perivascular cuffs of lymphocytes only in a minority of the infected individuals. Viral capsid p24 protein was only detected in circulating immune cells of one infected individual, suggesting a lack of productive HIV-1 infection of the brain even at the late-stage of AIDS. Notably, similar levels of Iba-1 or GFAP between HIV + and HIV- brain tissues indicated a lack of microgliosis and astrogliosis, respectively. Similar levels of CD8 + cytotoxic T lymphocyte (CTL) infiltration between HIV + and HIV- brain tissues indicated CTL were not likely to be involved within subtype C HIV-1 infected participants of this cohort. Results from this subtype C HIV-1 study suggest that there is a lack of productive infection and limited neuropathogenesis by subtype C HIV-1 even at late-stage disease, which is in contrast to what was reported for subtype B HIV-1 by other investigators.

Viral Epitope Scanning Reveals Correlation between Seasonal HCoVs and SARS-CoV-2 Antibody Responses among Cancer and Non-Cancer Patients.

Seasonal coronaviruses (HCoVs) are known to contribute to cross-reactive antibody (Ab) responses against SARS-CoV-2. While these responses are predictable due to the high homology between SARS-CoV-2 and other CoVs, the impact of these responses on susceptibility to SARS-CoV-2 infection in cancer patients is unclear. To investigate the influence of prior HCoV infection on anti-SARS-CoV-2 Ab responses among COVID-19 asymptomatic individuals with cancer and controls without cancers, we utilized the VirScan technology in which phage immunoprecipitation and sequencing (PhIP-seq) of longitudinal plasma samples was performed to investigate high-resolution (i.e., epitope level) humoral CoV responses. Despite testing positive for anti-SARS-CoV-2 Ab in the plasma, a majority of the participants were asymptomatic for COVID-19 with no prior history of COVID-19 diagnosis. Although the magnitudes of the anti-SARS-CoV-2 Ab responses were lower in individuals with Kaposi sarcoma (KS) compared to non-KS cancer individuals and those without cancer, the HCoV Ab repertoire was similar between individuals with and without cancer independent of age, sex, HIV status, and chemotherapy. The magnitudes of the anti-spike HCoV responses showed a strong positive association with those of the anti-SARS-CoV-2 spike in cancer patients, and only a weak association in non-cancer patients, suggesting that prior infection with HCoVs might play a role in limiting SARS-CoV-2 infection and COVID-19 disease severity.

Anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation in patients with high-risk CD30+ lymphoma: a phase 1 study.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30+ lymphoma at high risk of relapse. METHODS: This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30+ disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 107 CAR T cells per m2, 1 × 108 CAR T cells per m2, or 2 × 108 CAR T cells per m2) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per µL for 3 days, platelet count ≥25 × 109 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete. FINDINGS: Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 108 CAR T cells per m2, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. INTERPRETATION: Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. FUNDING: National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.

Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target.

Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.

Antibody profiling and predictive modeling discriminate between Kaposi sarcoma and asymptomatic KSHV infection.

Protein-level immunodominance patterns against Kaposi sarcoma-associated herpesvirus (KSHV), the aetiologic agent of Kaposi sarcoma (KS), have been revealed from serological probing of whole protein arrays, however, the epitopes that underlie these patterns have not been defined. We recently demonstrated the utility of phage display in high-resolution linear epitope mapping of the KSHV latency-associated nuclear antigen (LANA/ORF73). Here, a VirScan phage immunoprecipitation and sequencing approach, employing a library of 1,988 KSHV proteome-derived peptides, was used to quantify the breadth and magnitude of responses of 59 sub-Saharan African KS patients and 22 KSHV-infected asymptomatic individuals (ASY), and ultimately to support an application of machine-learning-based predictive modeling using the peptide-level responses. Comparing anti-KSHV antibody repertoire revealed that magnitude, not breadth, increased in KS. The most targeted epitopes in both KS and ASY were in the immunodominant proteins, notably, K8.129-56 and ORF65140-168, in addition to LANA. Finally, using unbiased machine-learning-based predictive models, reactivity to a subset of 25 discriminative peptides was demonstrated to successfully classify KS patients from asymptomatic individuals. Our study provides the highest resolution mapping of antigenicity across the entire KSHV proteome to date, which is vital to discern mechanisms of viral pathogenesis, to define prognostic biomarkers, and to design effective vaccine and therapeutic strategies. Future studies will investigate the diagnostic, prognostic, and therapeutic potential of the 25 discriminative peptides.

Cannabis Use Associates With Reduced Proviral Burden and Inflammatory Cytokine in Tissues From Men With Clade C HIV-1 on Suppressive Antiretroviral Therapy.

BACKGROUND: Human immunodeficiency virus 1 (HIV-1) tissue reservoirs remain the main obstacle against an HIV cure. Limited information exists regarding cannabis's effects on HIV-1 infections in vivo, and the impact of cannabis use on HIV-1 parenchymal tissue reservoirs is unexplored. METHODS: To investigate whether cannabis use alters HIV-1 tissue reservoirs, we systematically collected 21 postmortem brain and peripheral tissues from 20 men with subtype C HIV-1 and with suppressed viral load enrolled in Zambia, 10 of whom tested positive for cannabis use. The tissue distribution and copies of subtype C HIV-1 LTR, gag, env DNA and RNA, and the relative mRNA levels of cytokines IL-1ß, IL-6, IL-10, and TGF-ß1 were quantified using PCR-based approaches. Utilizing generalized linear mixed models we compared persons with HIV-1 and suppressed viral load, with and without cannabis use. RESULTS: The odds of tissues harboring HIV-1 DNA and the viral DNA copies in those tissues were significantly lower in persons using cannabis. Moreover, the transcription levels of proinflammatory cytokines IL-1ß and IL-6 in lymphoid tissues of persons using cannabis were also significantly lower. CONCLUSIONS: Our findings suggested that cannabis use is associated with reduced sizes and inflammatory cytokine expression of subtype C HIV-1 reservoirs in men with suppressed viral load.

Co-infection and co-localization of Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus in HIV-associated Kaposi sarcoma: a case report.

Kaposi sarcoma (KS), a multifocal vascular neoplasm frequently observed in HIV-positive individuals, primarily affects the skin, mucous membranes, visceral organs, and lymph nodes. KS is associated primarily with Kaposi sarcoma-associated herpesvirus (KSHV) infection. In this case report, we present a rare occurrence of co-infection and co-localization of KSHV and Epstein-Barr virus (EBV) in KS arising from the conjunctiva, which, to our knowledge, has not been reported previously. Immunohistochemistry (IHC), DNA polymerase chain reaction (PCR), and EBV-encoded RNA in situ hybridization (EBER-ISH) were utilized to demonstrate the presence of KSHV and EBV infection in the ocular KS lesion. Nearly all KSHV-positive cells displayed co-infection with EBV. In addition, the KS lesion revealed co-localization of KSHV Latency-Associated Nuclear Antigen (LANA) and EBV Epstein Barr virus Nuclear Antigen-1 (EBNA1) by multi-colored immunofluorescence staining with different anti-EBNA1 antibodies, indicating the possibility of interactions between these two gamma herpesviruses within the same lesion. Additional study is needed to determine whether EBV co-infection in KS is a common or an opportunistic event that might contribute to KS development and progression.

Noninvasive Assessment of Impaired Gas Exchange with the Alveolar Gas Monitor Predicts Clinical Deterioration in COVID-19 Patients.

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic magnified the importance of gas exchange abnormalities in early respiratory failure. Pulse oximetry (SpO2) has not been universally effective for clinical decision-making, possibly because of limitations. The alveolar gas monitor (AGM100) adds exhaled gas tensions to SpO2 to calculate the oxygen deficit (OD). The OD parallels the alveolar-to-arterial oxygen difference (AaDO2) in outpatients with cardiopulmonary disease. We hypothesized that the OD would discriminate between COVID-19 patients who require hospital admission and those who are discharged home, as well as predict need for supplemental oxygen during the index hospitalization. METHODS: Patients presenting with dyspnea and COVID-19 were enrolled with informed consent and had OD measured using the AGM100. The OD was then compared between admitted and discharged patients and between patients who required supplemental oxygen and those who did not. The OD was also compared to SpO2 for each of these outcomes using receiver operating characteristic (ROC) curves. RESULTS: Thirty patients were COVID-19 positive and had complete AGM100 data. The mean OD was significantly (p = 0.025) higher among those admitted 50.0 ± 20.6 (mean ± SD) vs. discharged 27.0 ± 14.3 (mean ± SD). The OD was also significantly (p < 0.0001) higher among those requiring supplemental oxygen 60.1 ± 12.9 (mean ± SD) vs. those remaining on room air 25.2 ± 11.9 (mean ± SD). ROC curves for the OD demonstrated very good and excellent sensitivity for predicting hospital admission and supplemental oxygen administration, respectively. The OD performed better than an SpO2 threshold of <94%. CONCLUSIONS: The AGM100 is a novel, noninvasive way of measuring impaired gas exchange for clinically important endpoints in COVID-19.

Detection of sensitivity and vestigiality of presumptive tests for swabbed blood stains.

It is a common practice in forensic casework to use presumptive tests for blood stains before DNA extraction and testing. Stains are usually swabbed and then the swabs are sent for analysis. The Kastle-Meyer (KM) and Leucomalachite green (LMG) presumptive tests for blood are widely used, and their sensitivities have been thoroughly tested in the literature in solution and directly on stains, but not on swabbed stains to mimic casework. In this study, the sensitivity of the KM and LMG tests was tested on eight blood dilutions on cotton fabric and ceramic tile that were stained and subsequently swabbed. Both tests showed sensitivity up to 1:5000, which is slightly lower than reported values in solution or directly on stain but still highly effective in most cases. Stains were also cleaned with common agents, then swabbed and re-tested. Stained ceramic tiles cleaned with soap/water or bleach gave mixed positive and negative results for the 1:10 dilution, presumably due to variance in how thoroughly each investigator cleaned the stain, and other dilutions were undetectable after cleaning. The LMG test gave false positives for bleach cleaned stains, due to reagent reactivity with bleach. Surprisingly, blood was detectible up to the 1:100 dilution with both tests on stained cotton fabric that was cleaned in a washing machine with detergent and dried. Ultimately the KM and LMG presumptive tests remain effective tools for swabbed blood stains, and their practicality for cleaned stains is dependent on material containing the stain, cleaning agent and processing.

PRIME score for prediction of permanent pacemaker implantation after transcatheter aortic valve replacement.

OBJECTIVES: We sought to produce a simple scoring system that can be applied at clinical visits before transcatheter aortic valve replacement (TAVR) to stratify the risk of permanent pacemaker (PPM) after the procedure. BACKGROUND: Atrioventricular block is a known complication of TAVR. Current models for predicting the risk of PPM after TAVR are not designed to be applied clinically to assist with preprocedural planning. METHODS: Patients undergoing TAVR at the University of Colorado were split into a training cohort for the development of a predictive model, and a testing cohort for model validation. Stepwise and binary logistic regressions were performed on the training cohort to produce a predictive model. Beta coefficients from the binary logistic regression were used to create a simple scoring system for predicting the need for PPM implantation. Scores were then applied to the validation cohort to assess predictive accuracy. RESULTS: Patients undergoing TAVR from 2013 to 2019 were analyzed: with 483 included in the training cohort and 123 included in the validation cohort. The need for a pacemaker was associated with five preprocedure variables in the training cohort: PR interval > 200 ms, Right bundle branch block, valve-In-valve procedure, prior Myocardial infarction, and self-Expandable valve. The PRIME score was developed using these clinical features, and was highly accurate for predicting PPM in both the training and model validation cohorts (area under the curve 0.804 and 0.830 in the model training and validation cohorts, respectively). CONCLUSIONS: The PRIME score is a simple and accurate preprocedural tool for predicting the need for PPM implantation after TAVR.

Comparative polar and lipid plasma metabolomics differentiate KSHV infection and disease states.

BACKGROUND: Kaposi sarcoma (KS) is a neoplastic disease etiologically associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV). KS manifests primarily as cutaneous lesions in individuals due to either age (classical KS), HIV infection (epidemic KS), or tissue rejection preventatives in transplantation (iatrogenic KS) but can also occur in individuals, predominantly in sub-Saharan Africa (SSA), lacking any obvious immune suppression (endemic KS). The high endemicity of KSHV and human immunodeficiency virus-1 (HIV) co-infection in Africa results in KS being one of the top 5 cancers there. As with most viral cancers, infection with KSHV alone is insufficient to induce tumorigenesis. Indeed, KSHV infection of primary human endothelial cell cultures, even at high levels, is rarely associated with long-term culture, transformation, or growth deregulation, yet infection in vivo is sustained for life. Investigations of immune mediators that distinguish KSHV infection, KSHV/HIV co-infection, and symptomatic KS disease have yet to reveal consistent correlates of protection against or progression to KS. In addition to viral infection, it is plausible that pathogenesis also requires an immunological and metabolic environment permissive to the abnormal endothelial cell growth evident in KS tumors. In this study, we explored whether plasma metabolomes could differentiate asymptomatic KSHV-infected individuals with or without HIV co-infection and symptomatic KS from each other. METHODS: To investigate how metabolic changes may correlate with co-infections and tumorigenesis, plasma samples derived from KSHV seropositive sub-Saharan African subjects in three groups, (A) asymptomatic (lacking neoplastic disease) with KSHV infection only, (B) asymptomatic co-infected with KSHV and HIV, and (C) symptomatic with clinically diagnosed KS, were subjected to analysis of lipid and polar metabolite profiles RESULTS: Polar and nonpolar plasma metabolic differentials were evident in both comparisons. Integration of the metabolic findings with our previously reported KS transcriptomics data suggests dysregulation of amino acid/urea cycle and purine metabolic pathways, in concert with viral infection in KS disease progression. CONCLUSIONS: This study is, to our knowledge, the first to report human plasma metabolic differentials between in vivo KSHV infection and co-infection with HIV, as well as differentials between co-infection and epidemic KS.

Yes-associated protein-1 overexpression in ocular surface squamous neoplasia; a potential diagnostic marker and therapeutic target.

Yes-associated protein-1 (YAP-1) is a Hippo system transcription factor, which serves as an oncogene in squamous cell carcinoma, and several solid tumors when the Hippo pathway is dysregulated. Yet, the activity of YAP-1 in ocular surface squamous neoplasia (OSSN) has not been determined. Here, we investigate the relationship between YAP-1 overexpression and OSSN. Using a cross-sectional study design, we recruited 227 OSSN patients from the University Teaching Hospitals in Lusaka, Zambia. Immunohistochemistry was used to assess YAP-1 protein overexpression in tumor tissue relative to surrounding benign squamous epithelium. OSSN patient samples (preinvasive, n = 62, 27% and invasive, n = 165, 73%) were studied. One hundred forty-nine invasive tumors contained adjacent preinvasive tissue, bringing the total number of preinvasive lesions examined to 211 (62 + 149). There was adjacent benign squamous epithelium in 50.2% (114/227) of OSSN samples. Nuclear YAP- 1 was significantly overexpressed in preinvasive (Fisher's (F): p <.0001, Monte Carlo (MC): p <.0001) and invasive (F: p <.0001, MC: p <.0001) OSSN in comparison to adjacent benign squamous epithelium when analyzed for basal keratinocyte positive count, staining intensity, expression pattern, and Immunostaining intensity-distribution index. YAP-1 expression did not differ between preinvasive and invasive OSSN (p >.05), keratinizing and non- keratinizing cancer (p >.05), or between T1/T2 and T3/T4 stages in invasive tumors (p >.05). However, grade 2 and 3 tumors had significantly stronger nucleus YAP-1 overexpression intensity than grade 1 tumors (F: p = .0078, MC: p = .0489). By immunohistochemistry, we identified significant overexpression (upregulation of YAP-1 protein expression) in preinvasive and invasive OSSN lesions compared to neighboring benign squamous epithelium. YAP-1 expression was significantly higher in poorly and moderately differentiated invasive squamous cancer than in well-differentiated carcinomas. Overexpression of YAP-1 within the margin of preinvasive and invasive OSSN, but not in the neighboring normal epithelium, indicates that it plays a role in the development and progression of OSSN.

Memory and attention: A double dissociation between memory encoding and memory retrieval.

Research has found substantial negative effects of divided attention (DA) during encoding but less substantial effects when attention is divided during retrieval, an asymmetry which has been interpreted as indicating that different control processes or forms of attention are involved in encoding and retrieval (e.g., Chun & Johnson, 2011; Craik, Govoni, Naveh-Benjamin, & Anderson, 1996; Long, Kuhl, & Chun, 2018). The extant evidence, however, is not strong support for qualitative differences and might simply indicate differential sensitivity. The present experiments document a stronger, double dissociation by focusing on the Attentional Boost Effect (ABE) - a phenomenon in which the detection of targets in a secondary task enhances encoding of co-occurring stimuli. The dual-task interaction account proposes that the classical negative effects produced by dual-task interference are offset by a transient increase in externally-directed attention brought about by target detection. Since externally-directed attention is less valuable for retrieval processes, the ABE should result in a net negative effect when applied in the test phase because the dual-task interference would no longer be offset by the externally-directed boost occurring during target trials. Experiments 1, 2 and 4 confirmed the predictions by showing that test words paired with target stimuli were recognized significantly worse than test words paired with distractor stimuli. In contrast, Experiments 3 and 4 replicated the usual positive effects of the ABE with respect to encoding. We discuss these findings in light of recent theoretical proposals suggesting that encoding and retrieval processes are subserved by different forms of attention (external [perceptual] vs. internal [reflective]). Implications for the Transfer-Appropriate-Processing view of memory are also illustrated.

Origin of minicircular mitochondrial genomes in red algae.

Eukaryotic organelle genomes are generally of conserved size and gene content within phylogenetic groups. However, significant variation in genome structure may occur. Here, we report that the Stylonematophyceae red algae contain multipartite circular mitochondrial genomes (i.e., minicircles) which encode one or two genes bounded by a specific cassette and a conserved constant region. These minicircles are visualized using fluorescence microscope and scanning electron microscope, proving the circularity. Mitochondrial gene sets are reduced in these highly divergent mitogenomes. Newly generated chromosome-level nuclear genome assembly of Rhodosorus marinus reveals that most mitochondrial ribosomal subunit genes are transferred to the nuclear genome. Hetero-concatemers that resulted from recombination between minicircles and unique gene inventory that is responsible for mitochondrial genome stability may explain how the transition from typical mitochondrial genome to minicircles occurs. Our results offer inspiration on minicircular organelle genome formation and highlight an extreme case of mitochondrial gene inventory reduction.

Longitudinal Variations in Antibody Responses against SARS-CoV-2 Spike Epitopes upon Serial Vaccinations.

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted healthcare, the workforce, and worldwide socioeconomics. Multi-dose mono- or bivalent mRNA vaccine regimens have shown high efficacy in protection against SARS-CoV-2 and its emerging variants with varying degrees of efficacy. Amino acid changes, primarily in the receptor-binding domain (RBD), result in selection for viral infectivity, disease severity, and immune evasion. Therefore, many studies have centered around neutralizing antibodies that target the RBD and their generation achieved through infection or vaccination. Here, we conducted a unique longitudinal study, analyzing the effects of a three-dose mRNA vaccine regimen exclusively using the monovalent BNT162b2 (Pfizer/BioNTech) vaccine, systematically administered to nine previously uninfected (naïve) individuals. We compare changes in humoral antibody responses across the entire SARS-CoV-2 spike glycoprotein (S) using a high-throughput phage display technique (VirScan). Our data demonstrate that two doses of vaccination alone can achieve the broadest and highest magnitudes of anti-S response. Moreover, we present evidence of novel highly boosted non-RBD epitopes that strongly correlate with neutralization and recapitulate independent findings. These vaccine-boosted epitopes could facilitate multi-valent vaccine development and drug discovery.

Immune profiling in Puerto Rican injection drug users with and without HIV-1 infection.

Antiretroviral therapy has been effective in suppressing HIV viral load and enabling people living with HIV to experience longer, more conventional lives. However, as people living with HIV are living longer, they are developing aging-related diseases prematurely and are more susceptible to comorbidities that have been linked to chronic inflammation. Coincident with HIV infection and aging, drug abuse has also been independently associated with gut dysbiosis, microbial translocation, and inflammation. Here, we hypothesized that injection drug use would exacerbate HIV-induced immune activation and inflammation, thereby intensifying immune dysfunction. We recruited 50 individuals not using injection drugs (36/50 HIV+) and 47 people who inject drugs (PWID, 12/47 HIV+). All but 3 of the HIV+ subjects were on antiretroviral therapy. Plasma immune profiles were characterized by immunoproteomics, and cellular immunophenotypes were assessed using mass cytometry. The immune profiles of HIV+/PWID-, HIV-/PWID+, and HIV+/PWID+ were each significantly different from controls; however, few differences between these groups were detected, and only 3 inflammatory mediators and 2 immune cell populations demonstrated a combinatorial effect of injection drug use and HIV infection. In conclusion, a comprehensive analysis of inflammatory mediators and cell immunophenotypes revealed remarkably similar patterns of immune dysfunction in HIV-infected individuals and in people who inject drugs with and without HIV-1 infection.

Evaluation of Quantitative Decision-Making for Rhythm Management of Atrial Fibrillation Using Tabular Q-Learning.

Background Rhythm management is a complex decision for patients with atrial fibrillation (AF). Although clinical trials have identified subsets of patients who might benefit from a given rhythm-management strategy, for individual patients it is not always clear which strategy is expected to have the greatest mortality benefit or durability. Methods and Results In this investigation 52 547 patients with a new atrial fibrillation diagnosis between 2010 and 2020 were retrospectively identified. We applied a type of artificial intelligence called tabular Q-learning to identify the optimal initial rhythm-management strategy, based on a composite outcome of mortality, change in treatment, and sustainability of the given treatment, termed the reward function. We first applied an unsupervised learning algorithm using a variational autoencoder with K-means clustering to cluster atrial fibrillation patients into 8 distinct phenotypes. We then fit a Q-learning algorithm to predict the best outcome for each cluster. Although rate-control strategy was most frequently selected by treating providers, the outcome was superior for rhythm-control strategies across all clusters. Subjects in whom provider-selected treatment matched the Q-table recommendation had fewer total deaths (4 [8.5%] versus 473 [22.4%], odds ratio=0.32, P=0.02) and a greater reward (P=4.8×10-6). We then demonstrated application of dynamic learning by updating the Q-table prospectively using batch gradient descent, in which the optimal strategy in some clusters changed from cardioversion to ablation. Conclusions Tabular Q-learning provides a dynamic and interpretable approach to apply artificial intelligence to clinical decision-making for atrial fibrillation. Further work is needed to examine application of Q-learning prospectively in clinical patients.