Miracle-dz/UniFAR-FTUs huggingface dataset:
Enhanced Cross-Reactive and Polyfunctional Effector-Memory T Cell Responses by ICVAX—a Human PD1-Based Bivalent HIV-1 Gag-p41 Mosaic DNA Vaccine

This study presents that ICVAX, a PD1-based DNA vaccine against HIV-1, could induce broad and polyfunctional T cell responses against different HIV-1 subtypes. ICVAX encodes a recombinant antigen consisting of the human soluble PD1 domain fused with two mosaic Gag-p41 antigens. ABSTRACT Vaccine-induced protective T cell immunity is necessary for HIV-1 functional cure. We previously reported that rhesus PD1-Gag-based DNA vaccination sustained simian-human immunodeficiency virus (SHIV) suppression by inducing effector-memory CD8+ T cells. Here, we investigated a human PD1-Gag-based DNA vaccine, namely, ICVAX, for clinical translation. PD1-based dendritic cell targeting and mosaic antigenic designs were combined to generate the ICVAX by fusing the human soluble PD1 domain with a bivalent HIV-1 Gag-p41 mosaic antigen. The mosaic antigen was cross-reactive with patients infected with B, CRF07/08_BC, and CRF01_AE variants. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses than mosaic Gag-p41 alone, and suppressed EcoHIV infection more efficiently. In macaques, ICVAX elicited polyfunctional effector-memory T cell responses that targeted multiple nonoverlapping epitopes of the Gag-p41 antigen. Furthermore, ICVAX manufactured following good manufacturing practices proved potent immunogenicity in macaques after biannual homologous vaccination, warranting clinical evaluation of ICVAX as an immunotherapy against HIV-1. IMPORTANCE This study presents that ICVAX, a PD1-based DNA vaccine against HIV-1, could induce broad and polyfunctional T cell responses against different HIV-1 subtypes. ICVAX encodes a recombinant antigen consisting of the human soluble PD1 domain fused with two mosaic Gag-p41 antigens. The mosaic antigens cover more than 500 HIV-1 strains circulating in China including the subtypes B/B’, CRF01_AE, and CRF07/08_BC. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses, with better EcoHIV suppression than the nontargeting mosaic Gag-p41 DNA vaccine. Moreover, both lab-generated and GMP-grade ICVAX also elicited strong polyfunctional effector-memory T cell responses in rhesus macaques with good immunogenicity against multiple nonoverlapping epitopes of the Gag-p41 antigen. This study therefore highlights the great potential to translate the PD1-based DNA vaccine approach into clinical use, and opens up new avenues for alternative HIV-1 vaccine design for HIV-1 preventive and functional cure.
Interventions for cancer screening among Chinese Americans: A systematic review and meta-analysis

Background Cancer is the leading cause of death among Chinese Americans (CAs). Although death rates of cancers can be significantly reduced by screening cancers at an early stage, cancer screening (CS) rates are low among CAs. Interventions on CS may increase the uptake rates of CS and help to decrease the death rates of cancers in CAs. Objectives This study aims to summarize the intervention methods on CS among CAs and compare effects of various intervention methods on the outcomes of CS, including knowledge levels of CS, intentions to complete CS, and actual completions of CS. Methods A systematic review and meta-analysis design was used. Keyword searching was conducted on PubMed, Google Scholar, PsycINFO, and CINAHL. Inclusion and exclusion criteria were applied. The PEDro scale was used to evaluate the quality of the studies. Data was analyzed using Review Manager Version 5.4 software. Random effect model and subgroup analyses were conducted. Results The search yielded 13 eligible studies. All of the reviewed interventions were culturally tailored. Systematic review results were categorized by intervention delivery objects, intervention led, intervention contact, intervention types, and intervention focus according to group consensus. Meta-analysis results showed that the interventions on CS had a positive effect on all outcomes, including a 1.58 (95% CI, 1.17–2.14; P = 0.003), 1.78 (95% CI, 1.27–2.48; P = 0.0007), and 1.72 (95% CI, 1.22–2.42; P = 0.002) effect on knowledge of CS, intentions to complete CS, and completions of CS, respectively, compared to the control group. The subgroup analysis suggested that physician-led, individual-based, face-to-face client-focused interventions with multiple components increased CS among CAs, with the OR ranging from 1.60 (95% CI, 1.08–2.39; P = 0.02) to 3.11 (95%CI, 1.02–9.49; P = 0.05). Discussion Interventions on CS significantly increased CAs’ knowledge of CS, intentions to complete CS, and completions of CS. Physician-led, individual-based, face-to-face client-focused interventions with multiple components should be utilized for CAs.
Fast and slow feedforward inhibitory circuits for cortical odor processing

Feedforward inhibitory circuits are key contributors to the complex interplay between excitation and inhibition in the brain. Little is known about the function of feedforward inhibition in the primary olfactory (piriform) cortex. Using in vivo two-photon-targeted patch clamping and calcium imaging in mice, we find that odors evoke strong excitation in two classes of interneurons – neurogliaform (NG) cells and horizontal (HZ) cells – that provide feedforward inhibition in layer 1 of the piriform cortex. NG cells fire much earlier than HZ cells following odor onset, a difference that can be attributed to the faster odor-driven excitatory synaptic drive that NG cells receive from the olfactory bulb. As a result, NG cells strongly but transiently inhibit odor-evoked excitation in layer 2 principal cells, whereas HZ cells provide more diffuse and prolonged feedforward inhibition. Our findings reveal unexpected complexity in the operation of inhibition in the piriform cortex.
Methodological aspects of a randomized within-patient concurrent controlled design for clinical trials in spine surgery

Introduction: Randomized controlled trials are considered the highest level of evidence, but their feasibility in the surgical field is severely hampered by methodological and practical issues. Concurrent comparison between the experimental and control conditions within the same patient can be an effective strategy to mitigate some of these challenges and improve generalizability, mainly by the elimination of between-patient variability and reduction of the required sample size. This article aims (1) to describe the methodological aspects of a randomized within-patient controlled trial and (2) to quantify the added value of this design, based on a recently completed randomized within-patient controlled trial on bone grafts in instrumented lumbar posterolateral spinal fusion. Methods: Boundary conditions for the application of the randomized within-patient controlled trial design were identified. Between-patient variability was quantified by the intraclass correlation coefficient and concordance in the primary fusion outcome. Sample size, study duration and costs were compared with a classic randomized controlled trial design. Results: Boundary conditions include the concurrent application of the experimental and control conditions to identical but physically separated sites. Moreover, the outcome of interest should be local, uncorrelated and independently assessable. The spinal fusion outcomes within a patient were found to be more similar than between different patients (intraclass correlation coefficient 32% and concordance 64%), demonstrating a clear effect of patient-related factors. The randomized within-patient controlled trial design allowed a reduction of the sample size to one-third of a parallel-group randomized controlled trial, thereby halving the trial duration and costs. Conclusion: When suitable, the randomized within-patient controlled trial is an efficient design that provides a solution to some of the considerable challenges of a classic randomized controlled trial in (spine) surgery. This design holds specific promise for efficacy studies of non-active bone grafts in instrumented posterolateral fusion surgery.
The respiratory depressant effects of mitragynine are limited by its conversion to 7‐OH mitragynine

Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A‐dependent oxidation of mitragynine yields the metabolite 7‐OH mitragynine, a more efficacious μ receptor agonist. While both mitragynine and 7‐OH mitragynine can induce anti‐nociception in mice, recent evidence suggests that 7‐OH mitragynine formed as a metabolite is sufficient to explain the anti‐nociceptive effects of mitragynine. However, the ability of 7‐OH mitragynine to induce μ receptor‐dependent respiratory depression has not yet been studied.
Increased risk of genital warts in inflammatory bowel disease: A Danish registry‐based cohort study (1996–2018)

Abstract Background Patients with inflammatory bowel disease (IBD) are at increased risk of human papillomavirus (HPV) related cancers such as anal squamous cell carcinoma. However, risk of non‐malignant HPV infection has never been systematically studied in IBD. This study aims to assess the risk of genital warts (GW) in IBD patients. Methods Using the Danish nationwide registries, we identified 49,163 patients with IBD between 1996 and 2018 and matched them to 491,665 individuals from the general population by age, sex, and HPV immunisation. Cumulative incidence rates for GW in IBD and non‐IBD patients were calculated by age. Cox proportional regression analysis was used to calculate hazard ratios (HR) for GW in IBD compared to matched population and in Crohn's disease (CD) compared to ulcerative colitis (UC). We undertook subgroup analysis for risk of GW by sex, year of IBD diagnosis, contraceptive exposure and IBD treatment exposure. Results The fully adjusted HR for GW in IBD patients compared to the matched non‐IBD population was 1.33 (95% CI: 1.19–1.49) and 1.13 (95% CI: 1.01, 1.27) in CD as compared to UC. This increased risk was particularly observed in female (HR: 1.54, 95% CI: 1.33–1.79) over male (HR: 1.14, 95% CI: 0.97–1.34) IBD patients, but was also found across all periods of diagnosis with IBD, regardless of contraceptive treatment exposure, and also seen in IBD patients who had never been exposed to immunosuppressive treatment (HR: 1.33, 95% CI: 1.19–1.49). Conclusion In this nationwide, population‐representative cohort study, we observed a 33% increased risk of GW in patients with IBD compared to the matched population and a 13% increased risk of GW in CD compared with UC. This risk was particularly increased in female over male IBD patients and seen independent of IBD treatment exposure.
Occupational performance issues in a longitudinal perspective in people with depression and/or anxiety on sick leave, returning to work or working

Abstract Background People with depression and anxiety disorder may experience occupational performance issues (OPIs). Further knowledge about these issues longitudinally and about potential differences between people is valuable. Aim To explore experienced OPIs longitudinally in a sample living with depression and/or anxiety disorder participating in occupational therapy and varying in terms of their work situation. Material and methods The Canadian occupational performance measure (COPM) was completed by 54 participants with depression and/or anxiety at four measure-points from baseline to one-year after participation in occupational therapy. The participants constituted three groups: continuously on sick leave (SL), returned to work within a year and continuing working. Descriptive and non-parametric analysis was used. Results Participants in all groups identified OPIs in all occupational areas in the COPM. All groups increased their occupational performance and satisfaction with their occupational performance in the area socialisation. Each group also made improvements in relation to other occupational areas, varying between the groups. Conclusions OPIs and improvements were identified among the participants regardless of them being on SL, returning to work or working. Significance The diverse nature of OPIs and improvements in the clients indicate the relevance of occupational therapy.
Infant immune response to hepatitis B vaccine after fetal exposure to telbivudine

ABSTRACT Whether telbivudine (LdT) treatment to pregnant women with hepatitis B surface antigen (HBsAg) affects infant immune response to hepatitis B vaccine (HepB) has not been investigated. A total of 127 HBsAg positive mothers and their neonates were enrolled and followed up at 11–13 months. Mothers took LdT (LdT group) or did not receive antiviral therapy (control group). Infant anti-HBs, immune cells and cytokines were measured after HepB was administered according to 0-1-6 procedure. We performed a 1:3 propensity score matching (PSM). Immune indexes in the two groups were compared. Baseline characteristics of mother-baby pairs were comparable in LdT group and control group. Infant anti-HBs geometric mean concentration (GMC) did not differ significantly between the two groups [767.70 (745.35) vs. 711.90 (819.60), P = . 599]. There was no difference between the two groups in infant positive rate of anti-HBs [97.8% (91/93) vs. 97.1% (33/34), P = . 999] and strong positive rate of anti-HBs [40.9% (38/93) vs. 44.1% (15/34), P = . 742]. Infants with negative, low, medium, and high anti-HBs levels were similarly distributed between the two groups (P = .511). No differences in proportion of helper T cells, cytotoxic T cells, B cells, myeloid dendritic cells, and plasmacytoid dendritic cells of infants (P > .05) were detected between the two groups. Children in the LdT and control group had comparable levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, interleukin-12, interferon-α, interferon-γ and tumor necrosis factor-α (P > .05). Intrauterine exposure to LdT was safe to infant immune response to HepB after birth.
TNFRSF1B and TNF Variants Are Associated With Differences in Levels of Soluble Tumor Necrosis Factor Receptors in Patients With Severe COVID-19

Abstract Background The impact of genetic variants in the expression of tumor necrosis factor-α (TNF-α) and its receptors in coronavirus disease 2019 (COVID-19) severity has not been previously explored. We evaluated the association of TNF (rs1800629 and rs361525), TNFRSF1A (rs767455 and rs1800693), and TNFRSF1B (rs1061622 and rs3397) variants with COVID-19 severity, assessed as invasive mechanical ventilation (IMV) requirement, and the plasma levels of soluble TNF-α, TNFR1, and TNFR2 in patients with severe COVID-19. Methods The genetic study included 1353 patients. Taqman assays were used to assess the genetic variants. ELISA was used to determine soluble TNF-α, TNFR1, and TNFR2 in plasma samples from 334 patients. Results Patients carrying TT (TNFRSF1B rs3397) exhibited lower PaO2/FiO2 levels than those with CT + CC genotypes. Differences in plasma levels of TNFR1 and TNFR2 were observed according to the genotype of TNFRSF1B rs1061622, TNF rs1800629, and rs361525. According to the studied genetic variants, there were no differences in the soluble TNF-α levels. Higher soluble TNFR1 and TNFR2 levels were detected in patients with COVID-19 requiring IMV. Conclusions Genetic variants in TNF and TNFRSFB1 influence the plasma levels of soluble TNFR1 and TNFR2, implicated in COVID-19 severity.
Remote administration of BICAMS measures and the Trail-Making Test to assess cognitive impairment in multiple sclerosis

ABSTRACT Reliable remote cognitive testing could provide a safer assessment of cognitive impairment in multiple sclerosis (MS) during the COVID-19 pandemic and thereafter. Here we aimed to investigate the reliability and feasibility of administering Brief International Cognitive Assessment for MS (BICAMS) and the Trail-Making Test (TMT) to people with MS online. Between-group differences on BICAMS and the TMT were examined in a sample of 68 participants. Group 1 (N = 34) was tested in-person pre-pandemic. Group 2 was tested remotely. Within-group differences for in-person and virtual administrations were examined for Group 1. No significant differences between virtual and in-person administrations of the CVLT-II and SDMT were detected. BVMT-R scores were significantly higher for virtual administrations (M = 20.59, SD = 6.65) compared to in-person administrations (M = 16.35, SD = 6.05), possibly indicating inter-rater differences. Strong positive correlations were found for in-person and virtual scores within Group 1 on the CVLT-II (r = .84), SDMT (r = .85), TMT-A (r = .88), TMT-B (r = .76) and BVMT-R (r = .72). No significant differences between in-person and remote administrations of CVLT-II and SDMT in people living with MS were detected. Recommendations for future studies employing the TMT and BVMT-R online are provided.
Rates of Guideline-Concordant Surgery and Adjuvant Chemotherapy Among Patients With Early-Stage Lung Cancer in the US ALCHEMIST Study (Alliance A151216).

Importance Standard treatment for resectable non-small cell lung cancer (NSCLC) includes anatomic resection with adequate lymph node dissection and adjuvant chemotherapy for appropriate patients. Historically, many patients with early-stage NSCLC have not received such treatment, which may affect the interpretation of the results of adjuvant therapy trials. Objective To ascertain patterns of guideline-concordant treatment among patients enrolled in a US-wide screening protocol for adjuvant treatment trials for resected NSCLC. Design, Setting, and Participants This retrospective cohort study included 2833 patients with stage IB to IIIA NSCLC (per American Joint Committee on Cancer 7th edition criteria) who enrolled in the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) screening study (Alliance for Clinical Trials in Oncology A151216) from August 18, 2014, to April 1, 2019, and who did not enroll in a therapeutic adjuvant clinical trial; patients had tumors of at least 4 cm and/or with positive lymph nodes. Statistical analysis was conducted from June 1, 2020, through October 1, 2021. Exposures Care patterns were ascertained overall and by sociodemographic and clinical factors, including age, sex, race and ethnicity, educational level, marital status, geography, histologic characteristics, stage, genomic variant status, smoking history, and comorbidities. Main Outcomes and Measures Five outcomes are reported: whether patients (1) had anatomic surgical resection, (2) had adequate lymph node dissection (≥1 N1 nodal station plus ≥3 N2 nodal stations), (3) received any adjuvant chemotherapy, (4) received any cisplatin-based adjuvant chemotherapy, and (5) received at least 4 cycles of adjuvant chemotherapy. Results Of the 2833 patients (1505 women [53%]; mean [SD] age, 66.5 [9.2] years) included in this analysis, 2697 (95%) had anatomic surgical resection, 1513 (53%) had adequate lymph node dissection, 1617 (57%) received any adjuvant chemotherapy, 1237 (44%) received at least 4 cycles of adjuvant platinum-based chemotherapy, and 965 (34%) received any cisplatin-based adjuvant chemotherapy. Rates were similar across race and ethnicity. Conclusions and Relevance This cohort study found that among participants in a screening protocol for adjuvant clinical trials for resected early-stage NSCLC, just 53% underwent adequate lymph node dissection, and 57% received adjuvant chemotherapy, despite indications for such treatment. These results may affect the interpretation of adjuvant trials. Efforts are needed to optimize the use of proven therapies for early-stage NSCLC. Trial Registration ClinicalTrials.gov Identifier: NCT02194738.
Adhesion Promotes Allergic Rhinitis CD4+IL4+ T Cell Differentiation via ICAM1 and E-Selectin

Background Neuroimmune communication plays an important role in allergic inflammation, but the neuroimmune regulation of allergic rhinitis remains unclear. Objective The goal of this study was to investigate the role of CD4-positive T lymphocyte (CD4+ T cells) adhesion to D-U87 neuron-like cells in mediating allergic rhinitis CD4+ T cell differentiation. Methods D-U87 neuron-like cells were derived from the human glioblastoma U87 cell line. CD4+ T cells were isolated from human peripheral blood using a magnetic separation technique. In vitro coculture of D-U87 neuron-like cells and CD4+ T cells was established. The number of adherent CD4+ T cells was counted using a fluorescence microscope. The percentages of CD4+IFNγ+ and CD4+IL4+ T cells and the levels of IFNγ and IL4 cytokines in the supernatant were measured by flow cytometry. Results The results showed that the number of adherent CD4+ T cells in patients with allergic rhinitis was significantly higher than that in healthy controls. In allergic rhinitis, the percentage of CD4+IL4+ T cells was significantly increased in the adherent group compared with that in the nonadherent group. Moreover, blocking ICAM1 and E-selectin decreased the number of adherent CD4+ T cells and the percentage of CD4+IL4+ T cells in allergic rhinitis. Conclusion Adhesion contributes to CD4+IL4+ T cell differentiation in the in vitro coculture system of D-U87 neuron-like cells and allergic rhinitis CD4+ T cells, which may provide new insights into therapeutic strategies for allergic rhinitis.
Prognostication in post-stroke aphasia: Perspectives of people with aphasia on receiving information about recovery

ABSTRACT Many people with aphasia (language impairment post-stroke) want to know their prognosis for recovery, yet current understanding of their experience of receiving prognoses is limited. Such insight is necessary to inform clinical practice in formulating and delivering aphasia prognoses, especially given the psycho-emotional distress and secondary adverse effects on recovery associated with conversations about prognosis. We sought an in-depth understanding of the perspectives of people with aphasia in relation to receiving prognoses post-stroke, with the aim of informing an evidence-based approach to aphasia prognostication in clinical practice. Semi-structured interviews, facilitated by communication support strategies, were conducted one-to-one with eight people with aphasia (ranging from mild to very severe) 3–12 months post-stroke. Reflexive thematic analysis was used to analyse the qualitative data, yielding two over-arching themes: (1) How would you know without knowing me? ; (2) I need to know, but I don’t want to know. Our findings illustrate issues of mistrust within the patient–clinician relationship, and complex emotions relating to hope and post-stroke adjustment. The present insight into the lived experience of receiving aphasia prognoses highlights the need for focused consideration of personal definitions of normalcy, measures for fostering trust, and the role of prognostic uncertainty.
Sharp Tuning of Head Direction and Angular Head Velocity Cells in the Somatosensory Cortex

Head direction (HD) cells form a fundamental component in the brain's spatial navigation system and are intricately linked to spatial memory and cognition. Although HD cells have been shown to act as an internal neuronal compass in various cortical and subcortical regions, the neural substrate of HD cells is incompletely understood. It is reported that HD cells in the somatosensory cortex comprise regular‐spiking (RS, putative excitatory) and fast‐spiking (FS, putative inhibitory) neurons. Surprisingly, somatosensory FS HD cells fire in bursts and display much sharper head‐directionality than RS HD cells. These FS HD cells are nonconjunctive, rarely theta rhythmic, sparsely connected and enriched in layer 5. Moreover, sharply tuned FS HD cells, in contrast with RS HD cells, maintain stable tuning in darkness; FS HD cells’ coexistence with RS HD cells and angular head velocity (AHV) cells in a layer‐specific fashion through the somatosensory cortex presents a previously unreported configuration of spatial representation in the neocortex. Together, these findings challenge the notion that FS interneurons are weakly tuned to sensory stimuli, and offer a local circuit organization relevant to the generation and transmission of HD signaling in the brain.