Trans-Nasal Endoscopic Repair of CSF Rhinorrhea: An Institutional Experience.

Introduction: Cerebrospinal Fluid (CSF) rhinorrhea results from breakdown in the integrity of structures separating the subarachnoid space and nasal cavity, namely subarachnoid space and dura mater, the bony skull base and periostea alongside the upper aerodigestive tract mucosa. Endoscopic repair is considered the treatment of choice for CSF rhinorrhea. Our aim of study was to analyze the etiopathogenesis and outcomes of treatment. Material and Methods: A retrospective study review of patients treated with endoscopic repair of CSF rhinorrhea at tertiary care hospital in ENT Department Benazir Bhutto hospital Rawalpindi from august 2013 to September 2017 identified 25 patients. Majority of them were male. The defects were closed in three layers using fat, fascia lata and nasal mucosa along with fibrin sealant in majority of patients. Pre operatively subarachnoid drain was placed in all patients. Patients were followed up to 3 months. Results: Forty-four patients underwent endoscopic repair of CSF rhinorrhea. The age group ranged from 16 to 55 years. Of the total of 44 patients 26 (59%) were males and 18(41%) females. The mean age of the patients in our study was 32.8 ± 9.7. Post trauma CSF leak was seen up to 52.3% of the patients. The most common site of leakage was identified Cribriform plate area. Our success rate of endoscopic repair was 88.6%. The most commonly observed complication was meningitis that was observed in 2 (4.5%) of the patients that too were managed conservatively. Conclusion: Accurate localization of site of leakage appears to be essential for successful endoscopic repair of CSF rhinorrhea. In our study cribriform plate area was commonly observed area of CSF leak. In our study, the success rate was 88.6% and low complication rate 4.5%.

Neuroprotective effects of alpha-pinene against behavioral deficits in ketamine-induced mice model of schizophrenia: Focusing on oxidative stress status.

Schizophrenia (SCZ) is a profound neurological disorder that affects approximately 1% of the global population. Alpha-pinene (α-pinene) is a natural and active monoterpene found in coniferous tree oil, primarily pine, with diverse pharmacological characteristics, including antioxidative, anxiolytic, and antidepressant properties. This research study delves into the neuroprotective effects of α-pinene on oxidative stress, memory deficits, and depressive and anxiety-like behaviors in a ketamine-induced mice model of SCZ using male mice. The mice were randomly divided into six groups: vehicle, control, positive control, ketamine, α-pinene at 50 mg/kg, and α-pinene at 100 mg/kg. Treatment of the ketamine-induced mice model of SCZ with α-pinene yielded significant improvements in depressive and anxiety-like behaviors and cognitive impairments. Furthermore, it significantly elevated glutathione (GSH) levels, total antioxidant capacity (TAC), dopamine levels, catalase (CAT), and superoxide dismutase (SOD) activities while markedly reducing malondialdehyde (MDA) levels. The current study establishes that α-pinene treatment effectively mitigates oxidative damage, cognitive deficits, and depressive and anxiogenic-like behaviors in the brains of ketamine-treated mice. Therefore, α-pinene treatment is an efficacious approach to forestall the neurobehavioral and neurobiochemical adverse effects of the ketamine-induced SCZ model of mice.

Severe disease during both primary and secondary dengue virus infections in pediatric populations.

Dengue is a global epidemic causing over 100 million cases annually. The clinical symptoms range from mild fever to severe hemorrhage and shock, including some fatalities. The current paradigm is that these severe dengue cases occur mostly during secondary infections due to antibody-dependent enhancement after infection with a different dengue virus serotype. India has the highest dengue burden worldwide, but little is known about disease severity and its association with primary and secondary dengue infections. To address this issue, we examined 619 children with febrile dengue-confirmed infection from three hospitals in different regions of India. We classified primary and secondary infections based on IgM:IgG ratios using a dengue-specific enzyme-linked immunosorbent assay according to the World Health Organization guidelines. We found that primary dengue infections accounted for more than half of total clinical cases (344 of 619), severe dengue cases (112 of 202) and fatalities (5 of 7). Consistent with the classification based on binding antibody data, dengue neutralizing antibody titers were also significantly lower in primary infections compared to secondary infections (P ≤ 0.0001). Our findings question the currently widely held belief that severe dengue is associated predominantly with secondary infections and emphasizes the importance of developing vaccines or treatments to protect dengue-naive populations.

Anterolateral advancement pharyngoplasty versus barbed reposition pharyngoplasty in patients with obstructive sleep apnea.

OBJECTIVES: To compare functional outcomes and complication rates of anterolateral advancement pharyngoplasty (ALA) versus barbed reposition pharyngoplasty (BRP) in the treatment of obstructive sleep apnea patients with palatal and lateral pharyngeal wall collapse. STUDY DESIGN: Prospective study. SETTING: University hospitals. SUBJECTS AND METHODS: Forty-six patients were included in this study. Patients were divided into two groups randomly, group 1 (23 cases) underwent anterolateral advancement pharyngoplasty and group 2 (23 cases) underwent barbed relocation pharyngoplasty. According to the following criteria: both sex, age between 18 and 65 years, body mass index ≤ 32 kg/m2, Friedman stage II or III, type I Fujita, nocturnal polysomnography study diagnostic for OSA, retropalatal and lateral pharyngeal wall collapse, diagnosis with flexible nasoendoscopy during a Muller's maneuver based on a 5-point scale and drug-induced sleep endoscopy. Patients who suffered from retroglossal airway collapse were rolled out. RESULTS: Apnea-hypopnea index decreased from 27.50 ± 11.56 to 11.22 ± 7.63 (P ≤ .001) in group 1 and from 33.18 ± 10.94 to 12.38 ± 6.77 (P ≤ .001) in group 2. Retropalatal posterior airway space increased from 9.84 ± 1.29 mm to 21.48 ± 2.8 mm (P ≤ .001) in group 1 and increased from 10.26 ± 1.2 mm to 22.86 ± 2.62 mm (P ≤ .001) in group 2. Retropalatal space volume increased from 1.9 ± 0.68 cm3 to 2.75 ± 0.7 cm3 (P ≤ .001) in group 1 and increased from 1.96 ± 0.88 cm3 to 2.82 ± 0.83 cm3 (P ≤ .001) in group 2. Surgical success was 86.95% in group 1 compared to 82.6% in group 2. CONCLUSIONS: Both techniques appear to be effective with a high surgical success rate in the treatment of OSA patients with retropalatal and lateral pharyngeal wall collapse.

Prevention of respiratory virus transmission by resident memory CD8+ T cells.

An ideal vaccine both attenuates virus growth and disease in infected individuals and reduces the spread of infections in the population, thereby generating herd immunity. Although this strategy has proved successful by generating humoral immunity to measles, yellow fever and polio, many respiratory viruses evolve to evade pre-existing antibodies1. One approach for improving the breadth of antiviral immunity against escape variants is through the generation of memory T cells in the respiratory tract, which are positioned to respond rapidly to respiratory virus infections2-6. However, it is unknown whether memory T cells alone can effectively surveil the respiratory tract to the extent that they eliminate or greatly reduce viral transmission following exposure of an individual to infection. Here we use a mouse model of natural parainfluenza virus transmission to quantify the extent to which memory CD8+ T cells resident in the respiratory tract can provide herd immunity by reducing both the susceptibility of acquiring infection and the extent of transmission, even in the absence of virus-specific antibodies. We demonstrate that protection by resident memory CD8+ T cells requires the antiviral cytokine interferon-γ (IFNγ) and leads to altered transcriptional programming of epithelial cells within the respiratory tract. These results suggest that tissue-resident CD8+ T cells in the respiratory tract can have important roles in protecting the host against viral disease and limiting viral spread throughout the population.

Effectiveness of Journal Club Presentation as a Learning Modality in the Endocrinology and Endocrine Surgery Module in an Integrative Undergraduate Medical Curriculum.

Introduction: The journal club is widely used in most postgraduate programs of medical institutes; however, the use of journal clubs in undergraduate medical programs is nearly absent or very rare. Aim: The aim of this work is to document the insertion of the journal club as a method for learning in the undergraduate starting with the endocrinology/endocrine surgery module to be fully implemented in all modules of the MBBS of FMBU. In addition, the study aimed to outline the steps of designing a journal club by following specific procedures and Identification of students' and faculty satisfaction through 5-years implementation of the journal club. Material and Methods: A total of 453 students representing the five consecutive batches of medical students from 2019 to 2023 who studied the endocrinology/endocrine surgery module were entered into the study. Following guidelines for implementation of the journal clubs that were adopted by the quality and accreditation committee, the faculty select the types of papers from the articles chosen by students. The papers discussed were case reports, original research, and review articles. The students were asked to formulate critical appraisal topics, PICO, for each paper. A 20-question test was applied to all participants. The students' attendance, scores, and students/faculty satisfaction were estimated. Results: A total of 50 papers were discussed in the 5-year journal club 15 case reports (30%), 26 original research (52%), and 9 review articles (18%). The student's attendance ranged from 72.53±3.74 to 98.07±3.15. The students and faculty's satisfaction were 3.52 and 3.82 respectively. The mean Students' score in A 20-question test in a 5-year journal club was 76.93 ± 9.78 and the lowest score was in the 2nd batch (online batch). Conclusion: The insertion of a well-structured journal club in the undergraduate medical program is necessary to improve the knowledge including knowledge among students. In addition, journal clubs inspire students to be lifelong learners.

When does humoral memory enhance infection?

Antibodies and humoral memory are key components of the adaptive immune system. We consider and computationally model mechanisms by which humoral memory present at baseline might increase rather than decrease infection load; we refer to this effect as EI-HM (enhancement of infection by humoral memory). We first consider antibody dependent enhancement (ADE) in which antibody enhances the growth of the pathogen, typically a virus, and typically at intermediate 'Goldilocks' levels of antibody. Our ADE model reproduces ADE in vitro and enhancement of infection in vivo from passive antibody transfer. But notably the simplest implementation of our ADE model never results in EI-HM. Adding complexity, by making the cross-reactive antibody much less neutralizing than the de novo generated antibody or by including a sufficiently strong non-antibody immune response, allows for ADE-mediated EI-HM. We next consider the possibility that cross-reactive memory causes EI-HM by crowding out a possibly superior de novo immune response. We show that, even without ADE, EI-HM can occur when the cross-reactive response is both less potent and 'directly' (i.e. independently of infection load) suppressive with regard to the de novo response. In this case adding a non-antibody immune response to our computational model greatly reduces or completely eliminates EI-HM, which suggests that 'crowding out' is unlikely to cause substantial EI-HM. Hence, our results provide examples in which simple models give qualitatively opposite results compared to models with plausible complexity. Our results may be helpful in interpreting and reconciling disparate experimental findings, especially from dengue, and for vaccination.

Competing Heterogeneities in Vaccine Effectiveness Estimation.

Understanding the waning of vaccine-induced protection is important for both immunology and public health. Population heterogeneities in underlying (pre-vaccination) susceptibility and vaccine response can cause measured vaccine effectiveness (mVE) to change over time, even in the absence of pathogen evolution and any actual waning of immune responses. We use multi-scale agent-based models parameterized using epidemiological and immunological data, to investigate the effect of these heterogeneities on mVE as measured by the hazard ratio. Based on our previous work, we consider the waning of antibodies according to a power law and link it to protection in two ways: (1) motivated by correlates of risk data and (2) using a within-host model of stochastic viral extinction. The effect of the heterogeneities is given by concise and understandable formulas, one of which is essentially a generalization of Fisher's fundamental theorem of natural selection to include higher derivatives. Heterogeneity in underlying susceptibility accelerates apparent waning, whereas heterogeneity in vaccine response slows down apparent waning. Our models suggest that heterogeneity in underlying susceptibility is likely to dominate. However, heterogeneity in vaccine response offsets <10% to >100% (median of 29%) of this effect in our simulations. Our study suggests heterogeneity is more likely to 'bias' mVE downwards towards the faster waning of immunity but a subtle bias in the opposite direction is also plausible.

Poor immunogenicity upon SARS-CoV-2 mRNA vaccinations in autoimmune SLE patients is associated with pronounced EF-mediated responses and anti-BAFF/Belimumab treatment.

Novel mRNA vaccines have resulted in a reduced number of SARS-CoV-2 infections and hospitalizations. Yet, there is a paucity of studies regarding their effectiveness on immunocompromised autoimmune subjects. In this study, we enrolled subjects naïve to SARS-CoV-2 infections from two cohorts of healthy donors (HD, n=56) and systemic lupus erythematosus (SLE, n=69). Serological assessments of their circulating antibodies revealed a significant reduction of potency and breadth of neutralization in the SLE group, only partially rescued by a 3rd booster dose. Immunological memory responses in the SLE cohort were characterized by a reduced magnitude of spike-reactive B and T cell responses that were strongly associated with poor seroconversion. Vaccinated SLE subjects were defined by a distinct expansion and persistence of a DN2 spike-reactive memory B cell pool and a contraction of spike-specific memory cTfh cells, contrasting with the sustained germinal center (GC)-driven activity mediated by mRNA vaccination in the healthy population. Among the SLE-associated factors that dampened the vaccine responses, treatment with the monoclonal antibody anti-BAFF/Belimumab (a lupus FDA-approved B cell targeting agent) profoundly affected the vaccine responsiveness by restricting the de novo B cell responses and promoting stronger extra-follicular (EF)-mediated responses that were associated with poor immunogenicity and impaired immunological memory. In summary, this study interrogates antigen-specific responses and characterized the immune cell landscape associated with mRNA vaccination in SLE. The identification of factors associated with reduced vaccine efficacy illustrates the impact of SLE B cell biology on mRNA vaccine responses and provides guidance for the management of boosters and recall vaccinations in SLE patients according to their disease endotype and modality of treatment.

Clinical and economic evaluations of natalizumab, rituximab, and ocrelizumab for the management of relapsing-remitting multiple sclerosis in Saudi Arabia.

INTRODUCTION: The advent of new disease-modifying therapies (DMTs), such as monoclonal antibodies (mAbs), resulted in significant changes in the treatment guidelines for Multiple sclerosis (MS) and improvement in the clinical outcomes. However, mAbs, such as rituximab, natalizumab, and ocrelizumab, are expensive with variable effectiveness rates. Thus, the present study aimed to compare the direct medical cost and consequences (e.g., clinical relapse, disability progression, and new MRI lesions) between rituximab and natalizumab in managing relapsing-remitting multiple sclerosis (RRMS) in Saudi Arabia. Also, the study aimed to explore the cost and consequence of ocrelizumab in managing RRMS as a second-choice treatment. METHODS: The electronic medical records (EMRs) of patients with RRMS were retrospectively reviewed to retrieve the patients' baseline characteristics and disease progression from two tertiary care centers in Riyadh, Saudi Arabia. Biologic-naïve patients treated with rituximab or natalizumab or those switched to ocrelizumab and treated for at least six months were included in the study. The effectiveness rate was defined as no evidence of disease activity (NEDA-3) (i.e., absence of new T2 or T1 gadolinium (Gd) lesions as demonstrated by the Magnetic Resonance Imaging (MRI), disability progression, and clinical relapses), while the direct medical costs were estimated based on the utilization of healthcare resources. In addition, bootstrapping with 10,000 replications and inverse probability weighting based on propensity score were conducted. RESULTS: Ninety-three patients met the inclusion criteria and were included in the analysis (natalizumab (n = 50), rituximab (n = 26), ocrelizumab (n = 17)). Most of the patients were otherwise healthy (81.72%), under 35 years of age (76.34%), females (61.29%), and on the same mAb for more than one year (83.87%). The mean effectiveness rates for natalizumab, rituximab, and ocrelizumab were 72.00%, 76.92%, and 58.83%, respectively. Natalizumab mean incremental cost compared to rituximab was $35,383 (95% CI: $25,401.09- $49,717.92), and its mean effectiveness rate was 4.92% lower than rituximab (95% CI: -30-27.5) with 59.41% confidence level that rituximab will be dominant. CONCLUSIONS: Rituximab seems to be more effective and is less costly than natalizumab in the management of RRMS. Ocrelizumab does not seem to slow the rates of disease progression among patients previously treated with natalizumab.

Competing Heterogeneities in Vaccine Effectiveness Estimation.

Understanding waning of vaccine-induced protection is important for both immunology and public health. Population heterogeneities in underlying (pre-vaccination) susceptibility and vaccine response can cause measured vaccine effectiveness (mVE) to change over time even in the absence of pathogen evolution and any actual waning of immune responses. We use a multi-scale agent-based models parameterized using epidemiological and immunological data, to investigate the effect of these heterogeneities on mVE as measured by the hazard ratio. Based on our previous work, we consider waning of antibodies according to a power law and link it to protection in two ways: 1) motivated by correlates of risk data and 2) using a within-host model of stochastic viral extinction. The effect of the heterogeneities is given by concise and understandable formulas, one of which is essentially a generalization of Fisher's fundamental theorem of natural selection to include higher derivatives. Heterogeneity in underlying susceptibility accelerates apparent waning, whereas heterogeneity in vaccine response slows down apparent waning. Our models suggest that heterogeneity in underlying susceptibility is likely to dominate. However, heterogeneity in vaccine response offsets <10% to >100% (median of 29%) of this effect in our simulations. Our methodology and results may be helpful in understanding competing heterogeneities and waning of immunity and vaccine-induced protection. Our study suggests heterogeneity is more likely to 'bias' mVE downwards towards faster waning of immunity but a subtle bias in the opposite direction is also plausible.

The epidemiological pattern of seasonal influenza in four sentinel sites in Iraq.

Introduction: Influenza is an acute viral infection with significant morbidity and mortality. It occurs annually each winter, which is called seasonal influenza, and is preventable through safe vaccine. Aim: The aim of this work is to know the epidemiological pattern of patients with seasonal influenza in Iraqi sentinel sites. Methods: A cross-sectional study was carried out on records of patients who attended four sentinel sites and registered to have influenza-like illness (ILI) or severe acute respiratory infection (SARI), and laboratory investigated. Results: The total number of cases was 1124; 36.2% of them aged 19-39 years; 53.9% were female; 74.9% lived in urban areas; 64.3% diagnosed as ILI; and 35.7% as SARI; 15.9% had diabetes, 12.7% had heart disease, 4.8% had asthma, 3% had a chronic lung disease, and 2% had hematological disease; 94.6% did not get influenza vaccine. About COVID-19 vaccine, 69.4% were not vaccinated, 3.5% got only one dose, and 27.1% completed two doses. Only the SARI cases needed admission; among them, 95.7% were cured. 6.5% were diagnosed with influenza-A virus, 26.1% had COVID-19, and 67.5% were negative. Among those with influenza, 97.3% had H3N2 subtype and 2.7% had H1N1 pdm09. Conclusions: The percentage of influenza virus in Iraq is relatively small. The age, classification of case (ILI or SARI), having diabetes, heart disease, or immunological disease, and taking COVID-19 vaccine have a significant association with influenza. Recommendations: It is needed for similar sentinel sites in other health directorates and for rising health education about seasonal influenza and its vaccine.

Magnetic Resonance Left Ventricle Mass-Index/Fibrosis: Long-Term Predictors for Ventricular Arrhythmia in Hypertrophic Cardiomyopathy-A Retrospective Registry.

Objective: We aimed to study the long-term association of LV mass index (LVMI) and myocardial fibrosis with ventricular arrhythmia (VA) in a population of patients with confirmed hypertrophic cardiomyopathy (HCM) using cardiac magnetic resonance imaging (CMR). Methods: We retrospectively analyzed the data in consecutive HCM patients confirmed on CMR referred to an HCM clinic between January 2008 and October 2018. Patients were followed up yearly following diagnosis. Baseline demographics, risk factors and clinical outcomes from cardiac monitoring and an implanted cardioverter defibrillator (ICD) were analyzed for association of LVMI and LV late gadolinium enhancement (LVLGE) with VA. Patients were then allocated to one of two groups according to the presence of VA (Group A) or absence of VA (Group B) during the follow-up period. The transthoracic echocardiogram (TTE) and CMR parameters were compared between the two groups. Results: A total of 247 patients with confirmed HCM (age 56.2 ± 16.6, male = 71%) were studied over the follow-up period of 7 ± 3.3 years (95% CI = 6.6-7.4 years). LVMI derived from CMR was higher in Group A (91.1 ± 28.1 g/m2 vs. 78.8 ± 28.3 g/m2, p = 0.003) when compared to Group B. LVLGE was higher in Group A (7.3 ± 6.3% vs. 4.7 ± 4.3%, p = 0.001) when compared to Group B. Multivariable Cox regression analysis showed LVMI (hazard ratio (HR) = 1.02, 95% CI = 1.001-1.03, p = 0.03) and LVLGE (HR = 1.04, 95% CI = 1.001-1.08, p = 0.04) to be independent predictors for VA. Receiver operative curves showed higher LVMI and LVLGE with a cut-off of 85 g/m2 and 6%, respectively, to be associated with VA. Conclusions: LVMI and LVLGE are strongly associated with VA over long-term follow-up. LVMI requires more thorough studies to consider it as a risk stratification tool in patients with HCM.

Estimating Waning of Vaccine Effectiveness: A Simulation Study.

BACKGROUND: Developing accurate and reliable methods to estimate vaccine protection is a key goal in immunology and public health. While several statistical methods have been proposed, their potential inaccuracy in capturing fast intraseasonal waning of vaccine-induced protection needs to be rigorously investigated. METHODS: To compare statistical methods for estimating vaccine effectiveness (VE), we generated simulated data using a multiscale, agent-based model of an epidemic with an acute viral infection and differing extents of VE waning. We apply a previously proposed framework for VE measures based on the observational data richness to assess changes of vaccine-induced protection over time. RESULTS: While VE measures based on hard-to-collect information (eg, the exact timing of exposures) were accurate, usually VE studies rely on time-to-infection data and the Cox proportional hazards model. We found that its extension using scaled Schoenfeld residuals, previously proposed for capturing VE waning, was unreliable in capturing both the degree of waning and its functional form and identified the mathematical factors contributing to this unreliability. We showed that partitioning time and including a time-vaccine interaction term in the Cox model significantly improved estimation of VE waning, even in the case of dramatic, rapid waning. We also proposed how to optimize the partitioning scheme. CONCLUSIONS: While appropriate for rejecting the null hypothesis of no waning, scaled Schoenfeld residuals are unreliable for estimating the degree of waning. We propose a Cox-model-based method with a time-vaccine interaction term and further optimization of partitioning time. These findings may guide future analysis of VE waning data.

Risk Factors for Major Adverse Cardiac Events Outcomes in Post Percutaneous Coronary Intervention during Index Admission

@#Introduction: Patients with ST-segment elevation myocardial infarction (STEMI) often undergo percutaneous coronary intervention (PCI) procedures during their index hospitalisation. However, some factors may increase the risk of major adverse cardiac event (MACE) outcomes after delaying PCI. We aimed to determine the risk factors for MACE outcomes in acute STEMI patients who had PCI during their index admission. Methods: In this retrospective single-center study, the medical records of STEMI patients who had PCI during their index hospitalisation in our facility were retrieved. At 30 days and six months post-PCI, demographic characteristics, clinical presentation, coronary risk factors, and the rate of MACE outcome were recorded and analysed. Results: This study included 91 STEMI patients. At 30 days and six months post-PCI, the rate of MACE was 10.5% and 8.0% respectively. At 30 days post-PCI, gender (p = 0.025), systolic blood pressure (p = 0.005) and heart rate (p = 0.003) were all associated with MACE outcomes. At six months, systolic blood pressure (p = 0.017), heart rate (p = 0.003), and previous coronary artery disease (CAD) (p = 0.014) were all associated with MACE. Conclusion: In acute STEMI patients, female gender, systolic blood pressure, heart rate, and a history of CAD are the risk factors for MACE outcomes after the PCI during the index admission. However, this is only single center study with short follow up period. Therefore, multi centers study and longer follow up period could provide better understanding on the factors associated with delayed PCI.

Vaccine models predict rules for updating vaccines against evolving pathogens such as SARS-CoV-2 and influenza in the context of pre-existing immunity.

Currently, vaccines for SARS-CoV-2 and influenza viruses are updated if the new vaccine induces higher antibody-titers to circulating variants than current vaccines. This approach does not account for complex dynamics of how prior immunity skews recall responses to the updated vaccine. We: (i) use computational models to mechanistically dissect how prior immunity influences recall responses; (ii) explore how this affects the rules for evaluating and deploying updated vaccines; and (iii) apply this to SARS-CoV-2. Our analysis of existing data suggests that there is a strong benefit to updating the current SARS-CoV-2 vaccines to match the currently circulating variants. We propose a general two-dose strategy for determining if vaccines need updating as well as for vaccinating high-risk individuals. Finally, we directly validate our model by reanalysis of earlier human H5N1 influenza vaccine studies.

PD-1 blockade following ART interruption enhances control of pathogenic SIV in rhesus macaques.

Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after anti-retrovial therapy (ART) interruption (ATI) by treating SIV-infected and ART-suppressed macaques with either an anti-PD-1 antibody (n = 7) or saline (n = 4) at 4 wk after ATI. Following ATI, the plasma viremia increased rapidly in all animals, and the frequency of SIV-specific CD8 T cells also increased in some animals. PD-1 blockade post ATI resulted in higher proliferation of total memory CD8 and CD4 T cells and natural killer cells. PD-1 blockade also resulted in higher proliferation of SIV-specific CD8 T cells and promoted their differentiation toward better functional quality. Importantly, four out of the seven anti-PD-1 antibody-treated animals showed a rapid decline in plasma viremia by 100- to 2300-fold and this was observed only in animals that showed measurable SIV-specific CD8 T cells post PD-1 blockade. These results demonstrate that PD-1 blockade following ATI can significantly improve the function of anti-viral CD8 T cells and enhance viral control and strongly suggests its potential synergy with other immunotherapies that induce functional CD8 T-cell response under ART. These results have important implications for HIV cure research.

Modeling suggests that multiple immunizations or infections will reveal the benefits of updating SARS-CoV-2 vaccines.

When should vaccines to evolving pathogens such as SARS-CoV-2 be updated? Our computational models address this focusing on updating SARS-CoV-2 vaccines to the currently circulating Omicron variant. Current studies typically compare the antibody titers to the new variant following a single dose of the original-vaccine versus the updated-vaccine in previously immunized individuals. These studies find that the updated-vaccine does not induce higher titers to the vaccine-variant compared with the original-vaccine, suggesting that updating may not be needed. Our models recapitulate this observation but suggest that vaccination with the updated-vaccine generates qualitatively different humoral immunity, a small fraction of which is specific for unique epitopes to the new variant. Our simulations suggest that these new variant-specific responses could dominate following subsequent vaccination or infection with either the currently circulating or future variants. We suggest a two-dose strategy for determining if the vaccine needs updating and for vaccinating high-risk individuals.

Antibody Response to COVID-19 mRNA Vaccine in Patients With Lung Cancer After Primary Immunization and Booster: Reactivity to the SARS-CoV-2 WT Virus and Omicron Variant.

PURPOSE: To examine COVID-19 mRNA vaccine-induced binding and neutralizing antibody responses in patients with non-small-cell lung cancer (NSCLC) to SARS-CoV-2 614D (wild type [WT]) strain and variants of concern after the primary 2-dose and booster vaccination. METHODS: Eighty-two patients with NSCLC and 53 healthy volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2-specific binding and neutralizing antibody responses were evaluated by Meso Scale Discovery assay and live virus Focus Reduction Neutralization Assay, respectively. RESULTS: A majority of patients with NSCLC generated binding and neutralizing antibody titers comparable with the healthy vaccinees after mRNA vaccination, but a subset of patients with NSCLC (25%) made poor responses, resulting in overall lower (six- to seven-fold) titers compared with the healthy cohort (P = < .0001). Although patients age > 70 years had lower immunoglobulin G titers (P = < .01), patients receiving programmed death-1 monotherapy, chemotherapy, or a combination of both did not have a significant impact on the antibody response. Neutralizing antibody titers to the B.1.617.2 (Delta), B.1.351 (Beta), and in particular, B.1.1.529 (Omicron) variants were significantly lower (P = < .0001) compared with the 614D (WT) strain. Booster vaccination led to a significant increase (P = .0001) in the binding and neutralizing antibody titers to the WT and Omicron variant. However, 2-4 months after the booster, we observed a five- to seven-fold decrease in neutralizing titers to WT and Omicron viruses. CONCLUSION: A subset of patients with NSCLC responded poorly to the SARS-CoV-2 mRNA vaccination and had low neutralizing antibodies to the B.1.1.529 Omicron variant. Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant.

Cleanup Sketched Drawings: Deep Learning-Based Model.

Rough drawings provide artists with a simple and efficient way to express shapes and ideas. Artists frequently use sketches to highlight their envisioned curves, using several groups' raw strokes. These rough sketches need enhancement to remove some subtle impurities and completely simplify curves over the sketched images. This research paper proposes using a fully convolutional network (FCNN) model to simplify rough raster drawings using deep learning. As input, the FCNN takes a sketch image of any size and automatically generates a high-quality simplified sketch image as output. Our model intuitively addresses the shortcomings in the rough sketch image, such as noises and unwanted background, as well as the low resolution of the rough sketch image. The FCNN model is trained by three raster image datasets, which are publicly available online. This paper demonstrates the efficiency and effectiveness of using deep learning in cleaning and improving the roughly drawn image in an automatic way. For evaluating the results, the mean squared error (MSE) metric was used. From experimental results, it was observed that an enhanced FCNN model reported better accuracy, reducing the prediction error by 0.08 percent for simplifying the rough sketch compared to the existing methods.