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Background: This study aimed to investigate whether persistent human papillomavirus integration at the same loci (PHISL) before and after treatment can predict recurrent/residual disease in women with CIN2-3. Methods: A total of 151 CIN2-3 women treated with conization between August 2020 and September 2021 were included. To investigate the precision of HPV integration, we further analyzed HPV integration-positive patients. Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), and the Youden index for predicting recurrence/residual disease were calculated. Results: Among the 151 enrolled CIN2-3 women, 56 were HPV integration-positive and 95 had HPV integration-negative results. Six (10.7%) experienced recurrence among 56 HPV integration-positive patients, which was more than those in HPV integration-negative patients (one patient, 1.1%). In the 56 HPV integration-positive patients, 12 had positive HPV results after treatment, seven had PHISL, and two had positive cone margin. Among the seven patients who tested with PHISL, six (85.7%) had residual/recurrent disease. PHISL was a prominent predictor of persistent/recurrent disease. The HPV test, the HPV integration test, and PHISL all had a sensitivity of 100% and a NPV of 100% for residual/recurrent disease. PHISL showed better specificity (98.0% vs. 82.0%, p = 0.005) and PPV (85.7% vs. 40.0%, p = 0.001) than the HPV test for predicting recurrence. Conclusions: The HPV-integration-positive CIN2-3 women had much higher relapse rates than HPV-integration-negative CIN2-3 women. The findings indicate that PHISL derived from preoperative and postoperative HPV integration tests may be a precise biomarker for the identification of residual/recurrent CIN 2/3. [ABSTRACT FROM AUTHOR]

The discovery of interferon in the 1950s represents much more than the identification of the first cytokine and the key mediator of antiviral host defense. Defining the molecular nature and complexity of the type I interferon family, as well as its inducers and molecular mechanisms of action, was the work of investigators working at the highest level and producing insights of great consequence. Current knowledge of receptor–ligand interactions, cell signaling, and transcriptional regulation derives from studies of type I interferon. It is on the shoulders of the giants who produced that knowledge that others stand and have revealed critical mechanisms of the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. The design of novel therapeutics is informed by the advances in investigation of type I interferon, with the potential for important impact on patient management. [ABSTRACT FROM AUTHOR]

Background There are limited data on the viral dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children. Understanding viral load changes over the course of illness and duration of viral shedding may provide insight into transmission dynamics to inform public health and infection-control decisions. Methods We conducted a prospective cohort study of children aged 18 years and younger with polymerase chain reaction–confirmed SARS-CoV-2 between 1 February 2022 and 14 March 2022. SARS-CoV-2 testing occurred on daily samples for 10 days; a subset of participants completed daily rapid antigen tests (RATs). Viral RNA trajectories were described in relation to symptom onset and resolution. The associations between both time since symptom onset/resolution and non-infectious viral load were evaluated using a Cox proportional hazards model. Results Among 101 children aged 2 to 17 years, the median time to study-defined non-infectious viral load was 5 days post–symptom onset, with 75% meeting this threshold by 7 days and 90% by 10 days. On the day of and day after symptom resolution, 43 (49%) and 52 (60%) of 87 had met the non-infectious thresholds, respectively. Of the 50 participants completing a RAT, positivity at symptom onset and on the day after symptom onset was 67% (16/24) and 75% (14/20). On the first day where the non-infectious threshold was met, 61% (n = 27/44) of participant RAT results were positive. Conclusions Children often met the study-defined non-infectiousness threshold on the day after symptom resolution. The RATs were often negative early in the course of illness and should not be relied on to exclude infection. Clinical Trials Registration. clinicaltrials.org; NCT05240183. [ABSTRACT FROM AUTHOR]

Purpose: Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect. Methods: This retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥ 106 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥ 106 copies/ml. Therapeutic strategies and risk groups were compared using odds ratios and Fisher's tests or Kaplan−Meier analysis and long-rank tests. Multivariable regression analysis was performed. Results: 144 patients were included with a median duration of SARS-CoV-2 viral load ≥ 106 copies/ml of 8.0 days (IQR 6.0–15.3). Underlying haematological malignancies (HM) (p = 0.03) and treatment initiation later than five days after diagnosis (p < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% (n = 21/144), particularly in patients with underlying HM (OR 3.5; 95% CI 1.2–9.9; p = 0.02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially related to combination treatment. Conclusion: Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients. [ABSTRACT FROM AUTHOR]

Background The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus disease (EVD) caused by Zaire ebolavirus in individuals 12 months of age and older. Methods The Partnership for Research on Ebola VACcination (PREVAC) is a multicenter, phase 2, randomized, double-blind, placebo-controlled trial of 3 vaccine strategies in healthy children (ages 1–17) and adults, with projected 5 years of follow-up (NCT02876328). Using validated assays (GP-ELISA and PRNT), we measured antibody responses after 1-dose rVSVΔG-ZEBOV-GP, 2-dose rVSVΔG-ZEBOV-GP (given on Day 0 and Day 56), or placebo. Furthermore, we quantified vaccine virus shedding in a subset of children's saliva using RT-PCR. Results In total, 819 children and 783 adults were randomized to receive rVSVΔG-ZEBOV-GP (1 or 2 doses) or placebo. A single dose of rVSVΔG-ZEBOV-GP increased antibody responses by Day 28 that were sustained through Month 12. A second dose of rVSVΔG-ZEBOV-GP given on Day 56 transiently boosted antibody concentrations. In vaccinated children, GP-ELISA titers were superior to placebo and non-inferior to vaccinated adults. Vaccine virus shedding was observed in 31.7% of children, peaking by Day 7, with no shedding observed after Day 28 post-dose 1 or any time post-dose 2. Conclusions A single dose of rVSVΔG-ZEBOV-GP induced robust antibody responses in children that was non-inferior to the responses induced in vaccinated adults. Vaccine virus shedding in children was time-limited and only observed after the first dose. Overall, these data support the use of rVSVΔG-ZEBOV-GP for the prevention of EVD in at-risk children. Clinical Trials Registration. The study is registered at ClinicalTrials.gov (NCT02876328), the Pan African Clinical Trials Registry (PACTR201712002760250), and the European Clinical Trials Register (EudraCT number: 2017-001798-18). [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate how long hospitalized patients stayed positive to the nasopharyngeal swab, and what demographic and clinical factors influence the time-to-negative swab. Methods: We enrolled in a multicenter, observational, retrospective study involving 17 COVID-19 units in eight cities of the Campania, southern Italy all patients hospitalized from March 2020 to May 2021 diagnosed with Severe Acute Respiratory Distress Syndrome-Coronavirus-2 (SARS-CoV-2) infection for whom time-to-negative swab was available. Results: 963 patients were enrolled. We defined three groups considering time-to-negative swab: the first including patients with time-to-negative swab before the 26th day, the second including patients with time-to-negative swab from day 26 to day 39, and the third including patients with time-to-negative swab > 39 days. 721 (74.9%) patients belonged to the first group, 194 (20.1%) to the second, and 52 (5.4%) belonged to the third group. Belonging to group 2 and 3 seemed to be influenced by age (p value < 0.001), Charlson comorbidity index (p = 0.009), arterial hypertension (p = 0.02), cardiovascular disease (p = 0.017), or chronic kidney disease (CKD) (p = 0.001). The multivariable analysis confers a leading role to CKD, with an odds ratio of 2.3 as factor influencing belonging to the groups showing a longer time-to-negative swab. Patients with CKD and diabetes were more frequently in the third group. Discussion: Our analysis showed that CKD is a factor related to longer time-to-negative swab, probably because of immunosuppression related to this condition. [ABSTRACT FROM AUTHOR]

In this article, we argue that in a supply-deficient situation, a vaccination strategy that makes use of an analysis of the different stages of the COVID waves and the pattern of their geographical spread can prove to be far more effective than the current non-transparent mechanism of inter-state allocation of the vaccines. We divide the spread of the COVID waves into three stages: (a) seeding stage, (b) explosion stage and (c) subsiding and diffusion stages. In the seeding stage, two critical determinants of seeding the virus into the population are (a) the inter-state pattern of arrival of international passengers and (b) the inter-state pattern of the continuing active COVID-affected population from the previous wave. The explosion stage induces a policy response in the form of lockdowns which is followed by the wave starting to subside. But the lockdown also results in the migration of labour out of the state into the rural and less populated areas, leading to the diffusion stage. We advocate a vaccination strategy targeting universal coverage with strategic sequencing in which prioritisation is given to 'saturation vaccination' of high-density and high COVID-intensity urban areas. This would not only minimise the economic costs in terms of duration and spread of lockdowns but also the pressures on the inadequate health infrastructure in terms of availability of hospital beds, ambulances, oxygen and drugs. This strategy may be implemented in curbing the COVID's subsequent waves which may hit India while its population is still only partially vaccinated. [ABSTRACT FROM AUTHOR]

Aim: This study evaluated pediatric patient clinical and epidemiological features to identify factors associated with prolonged severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR) positivity in children. Methods: This retrospective cohort study consecutively enrolled SARS-CoV-2-positive cases admitted to the University of Health Sciences Turkey, Istanbul Haseki Training and Research Hospital between March 31 and July 1, 2020. Their PCR results were retrieved from the system, and the time to a negative PCR result was calculated. Demographics, clinical disease severity, and laboratory and radiologic findings of patients with a SARS-CoV-2 PCR negative result within the first 14 days (Group 1) and after 14 days (Group 2) were compared. Results: We evaluated 258 patients with a median age of 132.6 months, of whom 134 were female. The median C-reactive protein (CRP) level was significantly higher in group 1 than in group 2. A multivariate logistic regression model including age, sex, fever complaints, D-dimer value >0.55 mg/L, high CRP, and lymphocyte <1500/uL at admission showed that lymphopenia was an independent predictor of prolonged SARS-CoV-2 PCR test positivity. Conclusion: Our findings indicate that children with fever, high CRP levels, and lymphopenia are particularly associated with prolonged SARS-CoV-2 PCR positivity. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV-1) is the primary epidemic strain in China. Its genome contains two regulatory genes (tat and rev), three structural genes (gag, pol, and env), and four accessory genes (nef, vpr, vpu, and vif). Long terminal repeats (LTRs) in thegenome regulate integration, duplication, and expression of viral gene. The permissibility of HIV-1 infection hinges on the host cell cycle status. HIV-1 replicates by exploiting various cellular processes via upregulation or downregulation of specific cellular proteins that also control viral pathogenesis. For example, HIV-1 regulates the life cycle of p53, which in turn contributes significantly to HIV-1 pathogenesis. In this article, we review the interaction between HIV-1-associated factors and p53, providing information on their regulatory and molecular mechanisms, hinting possible directions for further research. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prone positioning and neuromuscular blocking agents (NMBAs) are frequently used to treat severe respiratory failure from COVID-19 pneumonia. Prone positioning has shown to improve mortality, whereas NMBAs are used to prevent ventilator asynchrony and reduce patient self-inflicted lung injury. However, despite the use of lung-protective strategies, high death rates in this patient population have been reported. METHODS: We retrospectively examined the factors affecting prolonged mechanical ventilation in subjects receiving prone positioning plus muscle relaxants. The medical records of 170 patients were reviewed. Subjects were divided into 2 groups according to ventilator-free days (VFDs) at day 28. Whereas subjects with VFDs < 18 d were defined as prolonged mechanical ventilation, subjects with VFDs 618 d were defined as short-term mechanical ventilation. Subjects' baseline status, status at ICU admission, therapy before ICU admission, and treatment in the ICU were studied. RESULTS: Under the proning protocol for COVID-19, the mortality rate in our facility was 11.2%. The prognosis may be improved by avoiding lung injury in the early stages of mechanical ventilation. According to multifactorial logistic regression analysis, persistent SARS-CoV-2 viral shedding in blood (P = .03), higher daily corticosteroid use before ICU admission (P = .007), delayed recovery of lymphocyte count (P < .001), and higher maximal fibrinogen degradation products (P = .039) were associated with prolonged mechanical ventilation. A significant relationship was found between daily corticosteroid use before admission and VFDs by squared regression analysis (y = -0.00008522x² + 0.01338x + 12.8; x: daily corticosteroids dosage before admission [prednisolone mg/d]; y: VFDs/28 d, R² 5 0.047, P 5 .02). The peak point of the regression curve was 13.4 d at 78.5 mg/d of the equivalent prednisolone dose, which corresponded to the longest VFDs. CONCLUSIONS: Persistent SARS-CoV-2 viral shedding in blood, high corticosteroid dose from the onset of symptoms to ICU admission, slow recovery of lymphocyte counts, and high levels of fibrinogen degradation products after admission were associated with prolonged mechanical ventilation in subjects with severe COVID-19 pneumonia. Key words: COVID-19; invasive mechanical [ABSTRACT FROM AUTHOR]

The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which can lead to liver cancer—the progressive liver damage results from the host's immune response to the unresolved infection. The HCV replication process, including the entry, replication, assembly, and release stages, while the virus circulates in the bloodstream, it is intricately linked to the host's lipid metabolism, including the dynamic of the cytosolic lipid droplets (cLDs). This review article depicts how this interaction regulates viral cell tropism and aids immune evasion by coining viral particle characteristics. cLDs are intracellular organelles that store most of the cytoplasmic components of neutral lipids and are assumed to play an increasingly important role in the pathophysiology of lipid metabolism and host-virus interactions. cLDs are involved in the replication of several clinically significant viruses, where viruses alter the lipidomic profiles of host cells to improve viral life cycles. cLDs are involved in almost every phase of the HCV life cycle. Indeed, pharmacological modulators of cholesterol synthesis and intracellular trafficking, lipoprotein maturation, and lipid signaling molecules inhibit the assembly of HCV virions. Likewise, small-molecule inhibitors of cLD-regulating proteins inhibit HCV replication. Thus, addressing the molecular architecture of HCV replication will aid in elucidating its pathogenesis and devising preventive interventions that impede persistent infection and prevent disease progression. This is possible via repurposing the available therapeutic agents that alter cLDs metabolism. This review highlights the role of cLD in HCV replication. [ABSTRACT FROM AUTHOR]

Background Aerosol inhalation is recognized as the dominant mode of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Three highly transmissible lineages evolved during the pandemic. One hypothesis to explain increased transmissibility is that natural selection favors variants with higher rates of viral aerosol shedding. However, the extent of aerosol shedding of successive SARS-CoV-2 variants is unknown. We aimed to measure the infectivity and rate of SARS-CoV-2 shedding into exhaled breath aerosol (EBA) by individuals during the Delta and Omicron waves and compared those rates with those of prior SARS-CoV-2 variants from our previously published work. Methods Individuals with coronavirus disease 2019 (COVID-19) (n = 93; 32 vaccinated and 20 boosted) were recruited to give samples, including 30-minute breath samples into a Gesundheit-II EBA sampler. Samples were quantified for viral RNA using reverse-transcription polymerase chain reaction and cultured for virus. Results Alpha (n = 4), Delta (n = 3), and Omicron (n = 29) cases shed significantly more viral RNA copies into EBAs than cases infected with ancestral strains and variants not associated with increased transmissibility (n = 57). All Delta and Omicron cases were fully vaccinated and most Omicron cases were boosted. We cultured virus from the EBA of 1 boosted and 3 fully vaccinated cases. Conclusions Alpha, Delta, and Omicron independently evolved high viral aerosol shedding phenotypes, demonstrating convergent evolution. Vaccinated and boosted cases can shed infectious SARS-CoV-2 via EBA. These findings support a dominant role of infectious aerosols in transmission of SARS-CoV-2. Monitoring aerosol shedding from new variants and emerging pathogens can be an important component of future threat assessments and guide interventions to prevent transmission. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the oral shedding of herpes viruses in patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) and investigate its relationship with clinical outcomes. Materials and Methods: Polymerase chain reaction and enzymatic digestion were performed to identify the oral shedding of the members of the Herpesviridae family in 31 patients. The samples were collected from the oral cavity at five timestamps. Results: The presence of each herpesvirus in the oral cavity was observed in 3.2%, 12.9%, 19.3%, 32.2%, 54.8% and 93.5% patients for human herpesvirus (HHV)‐6A, herpes simplex virus‐1, HHV‐6B, cytomegalovirus (CMV), Epstein–Barr virus (EBV) and HHV‐7, respectively. Oral shedding of herpes virus was not uncommon after alloHSCT. There was a statistically significant association between the EBV and CMV oral shedding at C1 and the cumulative incidence of acute graft‐versus‐host disease (aGVHD). The results suggested that the presence of HSV‐1 at C2 was related to a relapse. The HHV‐7 oral shedding at C2 suggests a possible link between relapse, progression‐free survival and overall survival of the patients. Conclusions: Patients who developed aGVHD showed higher CMV and EBV shedding in the oral cavity at aplasia, suggesting modifications to the pattern of immune cell response and inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

Background Acceleration of negative respiratory conversion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19) might reduce viral transmission. Nirmatrelvir/ritonavir is a new antiviral agent recently approved for treatment of COVID-19 that has the potential to facilitate negative conversion. Methods A cohort of hospitalized adult patients with mild-to-moderate COVID-19 who had a high risk for progression to severe disease were studied. These patients presented with COVID-19 symptoms between 5 March and 5 April 2022. The time from positive to negative upper respiratory reverse transcription-polymerase chain reaction (RT-PCR) conversion was assessed by Kaplan-Meier plots and Cox proportional hazards regression with the adjustment for patients' baseline demographic and clinical characteristics. Results There were 258 patients treated with nirmatrelvir/ritonavir and 224 nontreated patients who had mild-to-moderate COVID-19. The median (interquartile range) time for patients who converted from positive to negative RT-PCR was 10 days (7–12 days) in patients treated ≤5 days after symptom onset and 17 days (12–21 days) in nontreated patients. The proportions of patients with a negative conversion at day 15 were 89.7% and 42.0% in treated patients and nontreated patients, corresponding to a hazard ratio of 4.33 (95% confidence interval, 3.31–5.65). Adjustment for baseline differences between the groups had little effect on the association. Subgroup analysis on treated patients suggests that time to negative conversion did not vary with the patients' baseline characteristics. Conclusions This cohort study of high-risk patients with mild-to-moderate COVID-19 found an association between nirmatrelvir/ritonavir treatment and accelerated negative RT-PCR respiratory SARS-CoV-2 conversion that might reduce the risk of viral shedding and disease transmission. [ABSTRACT FROM AUTHOR]

Background Patterns of shedding replication-competent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in severe or critical COVID-19 are not well characterized. We investigated the duration of replication-competent SARS-CoV-2 shedding in upper and lower airway specimens from patients with severe or critical coronavirus disease 2019 (COVID-19). Methods We enrolled patients with active or recent severe or critical COVID-19 who were admitted to a tertiary care hospital intensive care unit (ICU) or long-term acute care hospital (LTACH) because of COVID-19. Respiratory specimens were collected at predefined intervals and tested for SARS-CoV-2 using viral culture and reverse transcription–quantitative polymerase chain reaction (RT-qPCR). Clinical and epidemiologic metadata were reviewed. Results We collected 529 respiratory specimens from 78 patients. Replication-competent virus was detected in 4 of 11 (36.3%) immunocompromised patients up to 45 days after symptom onset and in 1 of 67 (1.5%) immunocompetent patients 10 days after symptom onset (P =.001). All culture-positive patients were in the ICU cohort and had persistent or recurrent symptoms of COVID-19. Median time from symptom onset to first specimen collection was 15 days (range, 6–45) for ICU patients and 58.5 days (range, 34–139) for LTACH patients. SARS-CoV-2 RNA was detected in 40 of 50 (80%) ICU patients and 7 of 28 (25%) LTACH patients. Conclusions Immunocompromise and persistent or recurrent symptoms were associated with shedding of replication-competent SARS-CoV-2, supporting the need for improving respiratory symptoms in addition to time as criteria for discontinuation of transmission-based precautions. Our results suggest that the period of potential infectiousness among immunocompetent patients with severe or critical COVID-19 may be similar to that reported for patients with milder disease. [ABSTRACT FROM AUTHOR]

Introduction: Acute bronchiolitis is a defined as inflammatory injury of the bronchioles, caused by droplet inhalation of viruses. The most common causative agent is the Respiratory Syncytial Virus (RSV), responsible for the most severe infection. Recently, Chest Ultrasound has been introduced as a diagnostic tool in many of the pediatric and neonatal respiratory diseases. The main advantages of chest ultrasound are the low risk of irradiation, the feasibility of a bedside evaluation, and the short time needed for the examination. Objective: The purpose of this study was to differentiate between simple and complicated cases of bronchiolitis. Method: We carried out a prospective observational study on 65 cases of bronchiolitis. Chest X ray and Chest Ultrasound were done for all cases, findings of both were compared. Results: There was statistically difference between Chest X ray and Chest Ultrasound in detection of complicated bronchiolitis. Conclusion: Chest Ultrasound is more accurate, sensitive and specific than Chest X ray in detection of complicated bronchiolitis. [ABSTRACT FROM AUTHOR]

Importance: Herpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries.Objective: To inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized.Design, Setting, and Participants: Prospective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment.Exposures: First-episode genital HSV-1 infection.Main Outcomes and Measures: Genital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Participants self-collected oral and genital swabs for HSV polymerase chain reaction testing for 30 days at 2 and 11 months and up to 2 years after diagnosis of genital HSV-1. Blood samples were collected at serial time points to assess immune responses to HSV-1. Primary HSV-1 infection was defined as absent HSV antibody at baseline or evolving antibody profile using the University of Washington HSV Western Blot. HSV-specific T-cell responses were detected using interferon γ enzyme-linked immunospot.Results: Among the 82 participants, the median (range) age was 26 (16-64) years, 54 (65.9%) were women, and 42 (51.2%) had primary HSV-1 infection. At 2 months, HSV-1 was detected from the genital tract in 53 participants (64.6%) and in the mouth in 24 participants (29.3%). Genital HSV-1 shedding was detected on 275 of 2264 days (12.1%) at 2 months and declined significantly to 122 of 1719 days (7.1%) at 11 months (model-predicted rate, 6.2% [95% CI, 4.3%-8.9%] at 2 months vs 3.2% [95% CI, 1.8%-5.7%] at 11 months; relative risk, 0.52 [95% CI, 0.29-0.93]). Genital lesions were rare, reported on 65 of 2497 days (2.6%) at 2 months and 72 of 1872 days (3.8%) at 11 months. Oral HSV-1 shedding was detected on 88 of 2247 days (3.9%) at 2 months. Persons with primary HSV-1 infection had a higher risk of genital shedding compared with those with nonprimary infection (model-predicted rate, 7.9% [95% CI, 5.4%-11.7%] vs 2.9% [95% CI, 1.7%-5.0%]; relative risk, 2.75 [95% CI, 1.40-5.44]). Polyfunctional HSV-specific CD4+ and CD8+ T-cell responses were maintained during the follow-up period.Conclusions and Relevance: Genital HSV-1 shedding was frequent after first-episode genital HSV-1, particularly among those with primary infection, and declined rapidly during the first year after infection. [ABSTRACT FROM AUTHOR]

Simple Summary: Viruses are well known causes of several human malignancies. Oral squamous cell carcinoma (OSCC) is rising in patients with limited exposure to traditional risk factors, including smoking. As a causative factor of OSCC is yet to be found, our study aimed to identify a virus that may drive this cancer. First, we examined whole genome sequencing data from 28 patients under the age of 50 with limited exposure to carcinogens for viruses. Using viral detection software that screens for >700,000 viruses, we identified one 49 year old male patient with human papillomavirus (HPV). We further validated our findings in 657 patients, using immunohistochemistry and RNA in situ hybridization specific for HPV, and identified 8 (1.2%) male patients with HPV integration. Through a comprehensive search for viruses and evaluation in a large patient OSCC cohort, we demonstrate that viral integration occurs in a minority of male OSCC patients. Viruses are well known drivers of several human malignancies. A causative factor for oral cavity squamous cell carcinoma (OSCC) in patients with limited exposure to traditional risk factors, including tobacco use, is yet to be identified. Our study aimed to comprehensively evaluate the role of viral drivers in OSCC patients with low cumulative exposure to traditional risk factors. Patients under 50 years of age with OSCC, defined using strict anatomic criteria were selected for WGS. The WGS data was interrogated using viral detection tools (Kraken 2 and BLASTN), together examining >700,000 viruses. The findings were further verified using tissue microarrays of OSCC samples using both immunohistochemistry and RNA in situ hybridisation (ISH). 28 patients underwent WGS and comprehensive viral profiling. One 49-year-old male patient with OSCC of the hard palate demonstrated HPV35 integration. 657 cases of OSCC were then evaluated for the presence of HPV integration through immunohistochemistry for p16 and HPV RNA ISH. HPV integration was seen in 8 (1.2%) patients, all middle-aged men with predominant floor of mouth involvement. In summary, a wide-ranging interrogation of >700,000 viruses using OSCC WGS data showed HPV integration in a minority of male OSCC patients and did not carry any prognostic significance. [ABSTRACT FROM AUTHOR]

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron variant has been hypothesized to exhibit faster clearance (time from peak viral concentration to clearance of acute infection), decreased sensitivity of antigen tests, and increased immune escape (the ability of the variant to evade immunity conferred by past infection or vaccination) compared to prior variants. These factors necessitate reevaluation of prevention and control strategies, particularly in high-risk, congregate settings like nursing homes that have been heavily impacted by other coronavirus disease 2019 (COVID-19) variants. We used a simple model representing individual-level viral shedding dynamics to estimate the optimal strategy for testing nursing home healthcare personnel and quantify potential reduction in transmission of COVID-19. This provides a framework for prospectively evaluating testing strategies in emerging variant scenarios when data are limited. We find that case-initiated testing prevents 38% of transmission within a facility if implemented within a day of an index case testing positive, and screening testing strategies could prevent 30% to 78% of transmission within a facility if implemented daily, depending on test sensitivity. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes congenital defects. Sexual transmission of ZIKV was confirmed in a recent epidemic; however, mechanisms behind ZIKV infection and persistence in the male reproductive tract (MRT) are unknown. Previously, we found that approximately 33% of men with symptomatic ZIKV infections shed ZIKV RNA in semen, and some men shed ZIKV RNA for >3 months. Here, we evaluated the semen of 49 ZIKV-infected men to identify immune factors correlating with long-term ZIKV shedding in semen and ZIKV-infected cell types in semen. We found that prolonged ZIKV RNA shedding in semen was associated with MRT inflammation, indicated by higher leukocyte counts and inflammatory cytokine concentrations in semen of long-term versus short-term shedders. In addition, we found ZIKV RNA in seminal leukocytes and epithelial cells. This study of human semen from ZIKV-infected men provides critical insights into the effects of ZIKV on MRT health. [ABSTRACT FROM AUTHOR]

Purpose: Duodenal involvement in COVID-19 is poorly studied. Aim was to describe clinical and histopathological characteristics of critically ill COVID-19 patients suffering from severe duodenitis that causes a significant bleeding and/or gastrointestinal dysmotility. Methods: In 51 critically ill patients suffering from SARS-CoV-2 pneumonia, severe upper intestinal bleeding and/or gastric feeding intolerance were indications for upper gastrointestinal endoscopy. Duodenitis was diagnosed according to macroscopic signs and mucosal biopsies. Immunohistochemistry was performed to detect viral specific protein and ACE2. In situ hybridization was applied to confirm viral replication. Results: Nine of 51 critically ill patients (18%) suffering from SARS-CoV-2 pneumonia had developed upper GI bleeding complications and/or high gastric reflux. Five of them presented with minor and four (44%) with severe duodenitis. In two patients, erosions had caused severe gastrointestinal bleeding requiring PRBC transfusions. Immunohistochemical staining for SARS-CoV-2 spike protein was positive inside duodenal enterocytes in three of four patients suffering from severe duodenitis. Viral replication could be confirmed by in situ hybridization. Conclusion: Our data suggest that about 8% of critically ill COVID-19 patients may develop a severe duodenitis presumably associated with a direct infection of the duodenal enterocytes by SARS-CoV-2. Clinical consequences from severe bleeding and/or upper gastrointestinal dysmotility seem to be underestimated. [ABSTRACT FROM AUTHOR]

Updated guidelines on cognitive rehabilitation... Cognition performance may influence viral shedding, symptom severity... Voice recognition may rely on visual memory... QI strategies reduce racial disparities in BP control... Social media, rewards, and punishments... [ABSTRACT FROM AUTHOR]

Background Influenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. Methods Using the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018–19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. Results The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th–97.5th percentiles, 1.68–1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs' age category, virus type, and month of onset revealed similar trends favoring BXM. Conclusions BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment. [ABSTRACT FROM AUTHOR]

Background We assessed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding duration and magnitude among persons living with human immunodeficiency virus (HIV, PLHIV). Methods From May through December 2020, we conducted a prospective cohort study at 20 hospitals in South Africa. Adults hospitalized with symptomatic coronavirus disease 2019 (COVID-19) were enrolled and followed every 2 days with nasopharyngeal/oropharyngeal (NP/OP) swabs until documentation of cessation of SARS-CoV-2 shedding (2 consecutive negative NP/OP swabs). Real-time reverse transcription-polymerase chain reaction testing for SARS-CoV-2 was performed, and cycle-threshold (Ct) values < 30 were considered a proxy for high SARS-CoV-2 viral load. Factors associated with prolonged shedding were assessed using accelerated time-failure Weibull regression models. Results Of 2175 COVID-19 patients screened, 300 were enrolled, and 257 individuals (155 HIV-uninfected and 102 PLHIV) had > 1 swabbing visit (median 5 visits [range 2–21]). Median time to cessation of shedding was 13 days (interquartile range [IQR] 6–25) and did not differ significantly by HIV infection. Among a subset of 94 patients (41 PLHIV and 53 HIV-uninfected) with initial respiratory sample Ct-value < 30, median time of shedding at high SARS-CoV-2 viral load was 8 days (IQR 4–17). This was significantly longer in PLHIV with CD4 count < 200 cells/µL, compared to HIV-uninfected persons (median 27 days [IQR 8–43] vs 7 days [IQR 4–13]; adjusted hazard ratio [aHR] 0.14, 95% confidence interval [CI].07–.28, P  < .001), as well as in unsuppressed-HIV versus HIV-uninfected persons. Conclusions Although SARS-CoV-2 shedding duration did not differ significantly by HIV infection, among a subset with high initial SARS-CoV-2 viral loads, immunocompromised PLHIV shed SARS-CoV-2 at high viral loads for longer than HIV-uninfected persons. Better HIV control may potentially decrease transmission time of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Background The impact of SARS-CoV-2 variants of concern (VOCs) on disease severity is unclear. In this retrospective study, we compared the outcomes of patients infected with B.1.1.7, B.1.351, and B.1.617.2 with wild-type strains from early 2020. Methods National surveillance data from January to May 2021 were obtained and outcomes in relation to VOCs were explored. Detailed patient-level data from all patients with VOC infection admitted to our center between December 2020 and May 2021 were analyzed. Clinical outcomes were compared with a cohort of 846 patients admitted from January to April 2020. Results A total of 829 patients in Singapore in the study period were infected with these 3 VOCs. After adjusting for age and sex, B.1.617.2 was associated with higher odds of oxygen requirement, intensive care unit admission, or death (adjusted odds ratio [aOR], 4.90; 95% confidence interval [CI]: 1.43-30.78). Of these patients, 157 were admitted to our center. After adjusting for age, sex, comorbidities, and vaccination, the aOR for pneumonia with B.1.617.2 was 1.88 (95% CI:.95-3.76) compared with wild-type. These differences were not seen with B.1.1.7 and B.1.351. Vaccination status was associated with decreased severity. B.1.617.2 was associated with significantly lower polymerase chain reaction cycle threshold (Ct) values and longer duration of Ct value ≤30 (median duration 18 days for B.1.617.2, 13 days for wild-type). Conclusions B.1.617.2 was associated with increased severity of illness, and with lower Ct values and longer viral shedding. These findings provide impetus for the rapid implementation of vaccination programs. [ABSTRACT FROM AUTHOR]

Viruses often use ion channel proteins to initialise host infections. Defects in ion channel proteins are also linked to several metabolic disorders in humans. In that instance, modulation of ion channel activities becomes central to development of antiviral therapies and drug design. Kesv, a potassium-selective ion channel protein expressed by Ectocarpus siliculosus virus (EsV), possesses remarkable properties which can help to characterise the molecular basis of the functional processes relevant to virus biology and human physiology. The small structural features of this ion channel could serve as a fundamental primer to study more complex ion channels from humans. Therefore, in spite of their evolutionary distance, the potential link between viral and human ion channel proteins could provide opportunities for therapeutic and biotechnological applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the expression of the receptor protein ACE-2 alongside the urinary tract, urinary shedding and urinary stability of SARS-CoV-2 RNA. Methods: Immunohistochemical staining was performed on tissue from urological surgery of 10 patients. Further, patients treated for coronavirus disease (COVID-19) at specialized care-units of a university hospital were assessed for detection of SARS-CoV-2 RNA in urinary samples via PCR, disease severity (WHO score), inflammatory response of patients. Finally, the stability of SARS-CoV-2 RNA in urine was analyzed. Results: High ACE-2 expression (3/3) was observed in the tubules of the kidney and prostate glands, moderate expression in urothelial cells of the bladder (0–2/3) and no expression in kidney glomeruli, muscularis of the bladder and stroma of the prostate (0/3). SARS-CoV-2 RNA was detected in 5/199 urine samples from 64 patients. Viral RNA was detected in the first urinary sample of sequential samples. Viral RNA load from other specimen as nasopharyngeal swabs (NPS) or endotracheal aspirates revealed higher levels than from urine. Detection of SARS-CoV-2 RNA in urine was not associated with impaired WHO score (median 5, range 3–8 vs median 4, range 1–8, p = 0.314), peak white blood cell count (median 24.1 × 1000/ml, range 5.19–48.1 versus median 11.9 × 1000/ml, range 2.9–60.3, p = 0.307), peak CRP (median 20.7 mg/dl, 4.2–40.2 versus median 11.9 mg/dl, range 0.1–51.9, p = 0.316) or peak IL-6 levels (median: 1442 ng/ml, range 26.7–3918 versus median 140 ng/ml, range 3.0–11,041, p = 0.099). SARS-CoV-2 RNA was stable under different storage conditions and after freeze–thaw cycles. Conclusions: SARS-CoV-2 RNA in the urine of COVID-19 patients occurs infrequently. The viral RNA load and dynamics of SARS-CoV-2 RNA shedding suggest no relevant route of transmission through the urinary tract. [ABSTRACT FROM AUTHOR]

Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with bromodomain (BD) and extraterminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single-cell RNA-Seq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bD-selective BET, or selective BET isoform targeting in CD4+ T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA, but lesser induction of fully elongated and tat-rev RNA compared with T cell activation-positive controls. IAPi+BETi resulted in HIV protein induction in bulk cultures of CD4+ T cells using an ultrasensitive p24 assay, but did not result in enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. This study defines HIV transcriptional elongation and splicing as important barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their BDs in HIV latency, and provides a rationale for exploration of IAPi+BETi in animal models of HIV latency. [ABSTRACT FROM AUTHOR]

Little is known about severe acute respiratory syndrome coronavirus 2 "vaccine-breakthrough" infections (VBIs). Here we characterize 24 VBIs in predominantly young healthy persons. While none required hospitalization, a proportion endorsed severe symptoms and shed live virus as high as 4.13 × 103 plaque-forming units/mL. Infecting genotypes included both variant-of-concern (VOC) and non-VOC strains. [ABSTRACT FROM AUTHOR]

We tested the combination of a broadly neutralizing HIV antibody with the latency reversal agent vorinostat (VOR). Eight participants received 2 month-long cycles of VRC07-523LS with VOR. Low-level viremia, resting CD4+ T-cell-associated HIV RNA (rca-RNA) was measured, and intact proviral DNA assay (IPDA) and quantitative viral outgrowth assay (QVOA) were performed at baseline and posttreatment. In 3 participants, IPDA and QVOA declines were accompanied by significant declines of rca-RNA. However, no IPDA or QVOA declines clearly exceeded assay variance or natural decay. Increased resistance to VRC07-523LS was not observed. This combination therapy did not reduce viremia or the HIV reservoir. Clinical Trials Registration. NCT03803605. [ABSTRACT FROM AUTHOR]

Background: The duration of virus shedding is necessary for determining the infectious period. But there were few quantitative studies on the changes of viral load and the law of the viral shedding in hand foot and mouth disease (HFMD) patients has not yet been clarified.Methods: This study will prospectively recruit coxsackievirus A10 (CV-A10), coxsackievirus A16 (CV-A16) and coxsackievirus A6 (CV-A6) infected inpatients from January 2022 to December 2022. A series of samples and questionnaire information will be collected regularly to establish the dynamic function relationship between time and viral load changes and a Bayesian multilevel model will be constructed to clarify the evolvement rules which reflect the dynamic changes of viral load and the duration of viral shedding in patients with HFMD.Discussion: The results of this study is expected to further clarify the evolvement rules which reflect the dynamic changes of viral load and the duration of viral shedding in HFMD patients under the influence of related factors. It can also provide important evidence for the scientific definition of the infectious period and isolation period of HFMD in China. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) treatment for the coronavirus disease 2019 (COVID-19) can improve clinical symptoms, but it is not clear whether it can shorten viral shedding. This is an observational study including 97 patients with COVID-19 who were consecutively admitted to the Jiangxia Fangcang hospital in Wuhan (Hubei, China) from January 15, 2020, to March 10, 2020. All patients were treated with TCM, and we assessed the patients daily and collected clinical information via a diary card. The primary endpoint was the time to achieve a negative result for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) RT-PCR. The final analysis included 92 patients. The median time to negative oropharyngeal swab for all the participants was 22 days (IQR 15–30). The participants were divided into three groups according to time from symptom onset to start of TCM treatment: within 7 days group (early treatment group), 8–14 days group (middle treatment group), and over 14 days group (late treatment group). The median time to negative oropharyngeal swab for the early treatment group was 14 days (IQR 12–17) and for the middle and late treatment groups was statistically shorter than 20 days (IQR 18–22) and 30 days (IQR 25–34), respectively. In univariate Cox proportional hazards regression analysis, the incidence of negative oropharyngeal swab for the early and middle treatment groups was 7.674 times and 3.609 times statistically higher than the late treatment group, respectively; whereas in multivariate Cox proportional hazards regression analysis, the incidence for the early and middle treatment groups was 18.093 times and 5.804 times statistically higher than the late treatment group, respectively. In patients with moderate COVID-19, those who had no cough, no dyspnea, and those who received TCM treatment earlier could achieve nucleic acid negative sooner by shortening viral shedding. [ABSTRACT FROM AUTHOR]

COVID-19 is a pandemic that has been affecting the entire world and has caused the death of approximately 2.8 million people. Although the duration of viral shedding varies, an average of 7-10 days is accepted. It is still unclear whether prolonged viral shedding means prolonged contagious period and whether COVID-19 will become chronic or not. This article presents a case with hematological malignancy (lymphoma) with the longest polymerase chain reaction positivity that we could find in the literature (110 days in total). [ABSTRACT FROM AUTHOR]

Background: Whether acute respiratory illnesses (ARIs), often associated with virus detection, are associated with lower risk for subsequent ARI remains unclear. We assessed the association between symptomatic ARI and subsequent ARI in young children.Methods: In a prospective cohort of Peruvian children <3 years, we examined the impact of index ARI on subsequent ARI risk. Index ARI were matched with ≤3 asymptomatic observations and followed over 28 days. We compared risk of subsequent ARI between groups using conditional logistic regression adjusting for several covariates, accounting for repeat observations from individual children.Results: Among 983 index ARI, 339 (34%) had an ARI event during follow-up, compared with 876/2826 (31%) matched asymptomatic observations. We found no significant association of index ARI and subsequent ARI risk during follow-up overall (adjusted odds ratio [aOR], 1.10; 95% confidence interval [CI], .98-1.23) or when limited to index ARI with respiratory viruses detected (aOR, 1.03; 95% CI, .86-1.24). Similarly, when the outcome was limited to ARI in which viruses were detected, no significant association was seen (aOR, 1.05; 95% CI, .87-1.27).Conclusions: ARIs were not associated with short-term protection against subsequent ARI in these children. Additional longitudinal studies are needed to understand drivers of recurrent ARI in young children. [ABSTRACT FROM AUTHOR]

Background Recurrent reports of suboptimal influenza vaccine effectiveness have renewed calls to develop improved, broadly cross-protective influenza vaccines. Here, we evaluated the safety and immunogenicity of a novel, saponin (Matrix-M)–adjuvanted, recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV). Methods We conducted a randomized, observer-blind, comparator-controlled (trivalent high-dose inactivated influenza vaccine [IIV3-HD] or quadrivalent recombinant influenza vaccine [RIV4]), safety and immunogenicity trial of qNIV (5 doses/formulations) in healthy adults ≥65 years. Vaccine immunogenicity was measured by hemagglutination-inhibition assays using reagents that express wild-type hemagglutination inhibition (wt-HAI) sequences and cell-mediated immune responses. Results A total of 1375 participants were randomized, immunized, and followed for safety and immunogenicity. Matrix-M–adjuvanted qNIV induced superior wt-HAI antibody responses against 5 of 6 homologous or drifted strains compared with unadjuvanted qNIV. Adjuvanted qNIV induced post-vaccination wt-HAI antibody responses at day 28 that were statistically higher than IIV3-HD against a panel of homologous or drifted A/H3N2 strains, similar to IIV3-HD against homologous A/H1N1 and B (Victoria) strains and similar to RIV4 against all homologous and drifted strains evaluated. The qNIV formulation with 75 µg Matrix-M adjuvant induced substantially higher post-vaccination geometric mean fold increases of influenza HA-specific polyfunctional CD4+ T cells compared with IIV3-HD or RIV4. Overall, similar frequencies of solicited and unsolicited adverse events were reported in all treatment groups. Conclusions qNIV with 75 µg Matrix-M adjuvant was well tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses. Further investigation in a pivotal phase 3 trial is underway. Clinical Trials Registration NCT03658629. [ABSTRACT FROM AUTHOR]

Background We aimed to evaluate the efficacy and safety of leflunomide, an approved dihydroorotate dehydrogenase inhibitor, to treat coronavirus disease 2019 (COVID-19) patients with prolonged postsymptomatic viral shedding. Methods We conducted a prospective, randomized controlled, open-label trial involving hospitalized adult COVID-19 patients with prolonged polymerase chain reaction (PCR) positivity. Patients were randomly assigned to receive either leflunomide (50 mg every 12 hours, 3 consecutive times, orally; then 20 mg once daily for 8 days), in addition to nebulized interferon alpha 2a (IFN-α-2a, 3 million IU each time, twice daily for 10 days), or nebulized IFN-α-2a alone for 10 days. The primary endpoint was the duration of viral shedding. Results A total of 50 COVID-19 patients with prolonged PCR positivity were randomized into 2 groups: 26 were assigned to the leflunomide plus IFN-α-2a group, and 24 were assigned to the interferon-alone group. Treatment with leflunomide was not associated with a difference from the interferon-alone group in the duration of viral shedding (hazard ratio for negative reverse-transcription PCR, 0.70 [95% confidence interval,.391–1.256]; P  = .186). In addition, the patients given leflunomide did not have a substantially shorter length of hospital stay than patients treated with interferon alone, with median durations of 29.0 (interquartile range [IQR], 19.3–47.3) days and 33.0 (IQR, 29.3–42.8) days, respectively (P  = .170). Two leflunomide recipients were unable to complete the full 10-day course of administration due to adverse events. Conclusions In COVID-19 patients with prolonged PCR positivity, no benefit in terms of the duration of viral shedding was observed with the combined treatment of leflunomide and IFN-α-2a beyond IFN-α-2a alone. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection worldwide, but reports of temporal changes in the risk of transmission among close contacts has been scarce. This study aimed to examine an association between the viral load trajectory and transmission risk to develop a better control strategy for the disease spread. We conducted a household-based prospective cohort study in Biliran Province, the Philippines, and enrolled 451 participants to observe the development of acute respiratory infection. Including the cases found at the health-care facility, we analyzed the data of viral loads with symptom records obtained from 172 followed participants who had household member positive for RSV with a rapid test during an RSV outbreak in 2018–2019. We developed a model estimating a temporal change in the viral shedding from the infection and evaluated transmission dynamics. We found that most transmission events occurred within approximately 7 days of the household exposure, including potential presymptomatic transmissions. The inferred risk of infection among those younger than 5 years was 3.5 times higher than that of those older than 5 years. This finding suggested that the initial week after the household exposure is particularly important for preventing RSV spread. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate HIV-1 tropism in 1382 combined antiretroviral therapy (cART)-experienced patients failing therapy to characterize those with exhausted therapeutic options.Methods: HIV-1 genotypic tropism was inferred through Geno2Pheno by estimating the false-positive-rate (FPR) values. Cumulative resistance and drug activity were evaluated by Stanford algorithm.Results: Overall, median (IQR) CD4 count (cells/mm3) nadir and at last genotypic resistance test (GRT) available were 98 (33-211) and 312 (155-517), respectively. Considering HIV-1 tropism, 30.5% had X4/dual-mixed strains (FPR ≤5%: 22.2%; FPR 5%-10%: 8.3%). By stratifying according to tropism, by decreasing FPR, a significant decrease of CD4 nadir and at last GRT was observed. The proportion of individuals with CD4 count <200 cells/mm3, who were perinatally infected and with a long treatment history significantly increased as FPR levels decreased. Regarding resistance, 933 (67.5%) individuals accumulated at least one class resistance, with 52.7%, 48.2%, 23.5% and 13.2% of individuals showing resistance to NRTIs, NNRTIs, PIs and INIs; while 23.2%, 27.2%, 14.3% and 2.8% harboured resistance to 1, 2, 3 and 4 classes, respectively. Individuals with FPR ≤5% showed a significantly higher level of resistance to PIs, NRTIs and INIs compared with others. The proportion of individuals harbouring strains susceptible to ≤2 active drugs was only about 2%; nonetheless, this proportion doubled (4.6%) in patients infected with FPR ≤5%.Conclusions: Our findings showed that a small proportion of cART failing individuals have limited therapeutic options. However, tropism determination might help to identify people who have accumulated a high level of resistance and have a greater risk of advanced disease. [ABSTRACT FROM AUTHOR]

Background Key knowledge gaps remain in the understanding of viral dynamics and immune response of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Methods We evaluated these characteristics and established their association with clinical severity in a prospective observational cohort study of 100 patients with PCR-confirmed SARS-CoV-2 infection (mean age, 46 years; 56% male; 38% with comorbidities). Respiratory samples (n = 74) were collected for viral culture, serum samples for measurement of IgM/IgG levels (n = 30), and plasma samples for levels of inflammatory cytokines and chemokines (n = 81). Disease severity was correlated with results from viral culture, serologic testing, and immune markers. Results Fifty-seven (57%) patients developed viral pneumonia, of whom 20 (20%) required supplemental oxygen, including 12 (12%) with invasive mechanical ventilation. Viral culture from respiratory samples was positive for 19 of 74 patients (26%). No virus was isolated when the PCR cycle threshold (Ct) value was >30 or >14 days after symptom onset. Seroconversion occurred at a median (IQR) of 12.5 (9–18) days for IgM and 15.0 (12–20) days for IgG; 54/62 patients (87.1%) sampled at day 14 or later seroconverted. Severe infections were associated with earlier seroconversion and higher peak IgM and IgG levels. Levels of IP-10, HGF, IL-6, MCP-1, MIP-1α, IL-12p70, IL-18, VEGF-A, PDGF-BB, and IL-1RA significantly correlated with disease severity. Conclusions We found virus viability was associated with lower PCR Ct value in early illness. A stronger antibody response was associated with disease severity. The overactive proinflammatory immune signatures offer targets for host-directed immunotherapy, which should be evaluated in randomized controlled trials. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to describe the clinico-virological profile, treatment details, intensive care needs, and outcome of infants with acute viral bronchiolitis (AVB). Methodology: In this prospective observational study, 173 infants with AVB admitted to the pediatric emergency room and pediatric intensive care unit (PICU) of a tertiary care teaching hospital in North India during November 2019 to February 2020 were enrolled. The data collection included clinical features, viruses detected [respiratory syncytial virus (RSV), rhinovirus, influenza A virus, parainfluenza virus (PIV) 2 and 3, and human metapneumovirus (hMPV)], complications, intensive care needs, treatment, and outcomes. Multivariate analysis was performed to determine independent predictors for PICU admission. Results: Most common symptoms were rapid breathing (98.8%), cough (98.3%), and fever (74%). On examination, tachypnea (98.8%), chest retractions (93.6%), respiratory failure (84.4%), wheezing (49.7%), and crepitations (23.1%) were observed. RSV and rhinovirus were the predominant isolates. Complications were noted in 25% of cases as encephalopathy (17.3%), transaminitis (14.3%), shock (13.9%), acute kidney injury (AKI) (7.5%), myocarditis (6.4%), multiple organ dysfunction syndrome (MODS) (5.8%), and acute respiratory distress syndrome (ARDS) (4.6%). More than one-third of cases required PICU admission. The treatment details included nasal cannula oxygen (11%), continuous positive airway pressure (51.4%), high-flow nasal cannula (14.5%), mechanical ventilation (23.1%), nebulization (74%), antibiotics (35.9%), and vasoactive drugs (13.9%). The mortality was 8.1%. Underlying comorbidity, chest retractions, respiratory failure at admission, presence of shock, and need for mechanical ventilation were independent predictors of PICU admission. Isolation of virus or coinfection was not associated with disease severity, intensive care needs, and outcomes. Conclusion: Among infants with AVB, RSV and rhinovirus were predominant. One-third infants with AVB needed PICU admission. The presence of comorbidity, chest retractions, respiratory failure, shock, and need for mechanical ventilation independently predicted PICU admission. [ABSTRACT FROM AUTHOR]

Background We aimed to describe the epidemiological, virological, and serological features of coronavirus disease 2019 (COVID-19) cases in people living with human immunodeficiency virus (HIV; PLWH). Methods This population-based cohort study identified all COVID-19 cases among all PLWH in Wuhan, China, by 16 April 2020. The epidemiological, virological, and serological features were analyzed based on the demographic data, temporal profile of nucleic acid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the disease, and SARS-CoV-2–specific immunoglobin (Ig) M and G after recovery. Results From 1 January to 16 April 2020, 35 of 6001 PLWH experienced COVID-19, with a cumulative incidence of COVID-19 of 0.58% (95% confidence interval [CI],.42–.81%). Among the COVID-19 cases, 15 (42.86) had severe illness, with 2 deaths. The incidence, case-severity, and case-fatality rates of COVID-19 in PLWH were comparable to those in the entire population in Wuhan. There were 197 PLWH who had discontinued combination antiretroviral therapy (cART), 4 of whom experienced COVID-19. Risk factors for COVID-19 were age ≥50 years old and cART discontinuation. The median duration of SARS-CoV-2 viral shedding among confirmed COVID-19 cases in PLWH was 30 days (interquartile range, 20–46). Cases with high HIV viral loads (≥20 copies/mL) had lower IgM and IgG levels than those with low HIV viral loads (<20 copies/ml; median signal value divided by the cutoff value [S/CO] for IgM, 0.03 vs 0.11, respectively [ P  < .001]; median S/CO for IgG, 10.16 vs 17.04, respectively [ P  = .069]). Conclusions Efforts are needed to maintain the persistent supply of antiretroviral treatment to elderly PLWH aged 50 years or above during the COVID-19 epidemic. The coinfection of HIV and SARS-CoV-2 might change the progression and prognosis of COVID-19 patients in PLWH. [ABSTRACT FROM AUTHOR]

Background: Evaluations of human immunodeficiency virus (HIV) curative interventions require reliable and efficient quantification of replication-competent latent reservoirs. The "classic" quantitative viral outgrowth assay (QVOA) has been regarded as the reference standard, although prohibitively resource and labor intensive. We compared 6 "next-generation" viral outgrowth assays, using polymerase chain reaction or ultrasensitive p24 to assess their suitability as scalable proxies for QVOA.Methods: Next-generation QVOAs were compared with classic QVOA using single leukapheresis-derived samples from 5 antiretroviral therapy-suppressed HIV-infected participants and 1 HIV-uninfected control; each laboratory tested blinded batches of 3 frozen and 1 fresh sample. Markov chain Monte Carlo methods estimated extra-Poisson variation at aliquot, batch, and laboratory levels. Models also estimated the effect of testing frozen versus fresh samples.Results: Next-generation QVOAs had similar estimates of variation to QVOA. Assays with ultrasensitive readout reported higher infectious units per million values than classic QVOA. Within-batch testing had 2.5-fold extra-Poisson variation (95% credible interval [CI], 2.1-3.5-fold) for next-generation assays. Between-laboratory variation increased extra-Poisson variation to 3.4-fold (95% CI, 2.6-5.4-fold). Frozen storage did not substantially alter infectious units per million values (-18%; 95% CI, -52% to 39%).Conclusions: The data offer cautious support for use of next-generation QVOAs as proxies for more laborious QVOA, while providing greater sensitivities and dynamic ranges. Measurement of latent reservoirs in eradication strategies would benefit from high throughput and scalable assays. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the oral shedding of herpesviruses in patients undergoing hematopoietic stem cell transplantation (HSCT) and correlate it with oral mucositis (OM). Methods: Saliva samples were collected before the HSCT and on day D + 8. Multiplex Polymerse Chain Reaction (PCR) was performed to detect herpes simplex virus (HSV)‐1 and HSV‐2, Epstein‐Barr virus (EBV), Cytomegalovirus (CMV), Variella‐zoster virus (VZV), and human herpesvirus (HHV)‐6, HHV‐7, and HHV‐8. OM was assessed according to WHO criteria. Results: Thirty one patients were enrolled, in which 20 of 31 (64.5%) were males; median age was 50 (21–70) years; 16 of 31 (51.6%) underwent allo‐HSCT; and 15 of 31 (48.4%) underwent auto‐HSCT. On D + 8, OM grades III and IV were observed in 8 of 31 (25.8%) patients. In the first salivary collection, EBV was found in 24 of 31 (77.4%), followed by HHV‐6 (7/31, 22.6%) and HHV‐7 (8/31 25.8%). In the second collection, EBV was found in 24 of 27(89%), followed by HSV‐1 (8/27, 30%) and CMV, HHV‐6, and HHV‐7 (5/27, 18.5%, each one). On D + 8, OM grades II and IV were associated with the presence of HSV‐1. HSV‐1 was also associated with worsening degrees of OM on D + 15. Conclusion: The presence of HSV‐1 and CMV in oral samples was more frequent on day D + 8 after HSCT. HSV‐1 detection was associated with severity and worsening of OM. HSV‐1 and CMV seem to be associated with oral dysbiosis due to HSCT. [ABSTRACT FROM AUTHOR]

What is known and objective: Therapeutic alternatives to simplify antiretroviral therapy (ART) in HIV‐infected children are needed. We report our experience with abacavir(ABC)/lamivudine(3TC) individualized dose compounded capsules (IDCC). Comment: We present a prospective case series of HIV‐infected children who did not weigh enough to receive the adult fixed‐dose combination including ABC/3TC 600mg/300mg, and were treated with weight‐adapted ABC/3TC IDCC in Barcelona, Spain. Thirteen patients (12 girls) received ABC/3TC IDCC for a median(IQR) time of 30(17‐54) months. No significant changes were observed in CD4 cell counts, weight or height z‐scores over time. Suppression of viral replication was maintained in 7 patients with undetectable viremia at baseline. Another 5 patients achieved viral suppression with ABC/3TC IDCC‐based ART, while one non‐adherent girl did not. No adverse events related to ABC/3TC IDCC were observed. What is new and conclusion: Despite small numbers, the long‐term use of ABC/3TC IDCC was feasible, safe, and effective in the treatment of HIV‐infected children. [ABSTRACT FROM AUTHOR]

Background: The human immunodeficiency virus (HIV)-1 latent reservoir (LR) in resting CD4+ T cells is a barrier to cure. LR measurements are commonly performed on blood samples and therefore may miss latently infected cells residing in tissues, including lymph nodes.Methods: We determined the frequency of intact HIV-1 proviruses and proviral inducibility in matched peripheral blood (PB) and lymph node (LN) samples from 10 HIV-1-infected patients on antiretroviral therapy (ART) using the intact proviral DNA assay and a novel quantitative viral induction assay. Prominent viral sequences from induced viral RNA were characterized using a next-generation sequencing assay.Results: The frequencies of CD4+ T cells with intact proviruses were not significantly different in PB versus LN (61/106 vs 104/106 CD4+ cells), and they were substantially lower than frequencies of CD4+ T cells with defective proviruses. The frequencies of CD4+ T cells induced to produce high levels of viral RNA were not significantly different in PB versus LN (4.3/106 vs 7.9/106), but they were 14-fold lower than the frequencies of cells with intact proviruses. Sequencing of HIV-1 RNA from induced proviruses revealed comparable sequences in paired PB and LN samples.Conclusions: These results further support the use of PB as an appropriate proxy for the HIV-1 LR in secondary lymphoid organs. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus (HPV) infection is associated with multiple types of cancer, but the evidence has not yet been fully elucidated in bladder cancer.Methods: Frozen tissue samples collected from 146 patients aged 32 to 89 years with bladder cancer pathological diagnosis between 2015 and 2019 were analyzed. HPV genotyping and integration status determination were performed by capture-based next generation sequencing. Statistical analysis of HPV type distributions was performed according to stage, grade, sex, and age group of patients.Results: Mean (SD) age of the 146 patients was 66.64 ± 10.06 years and 83.56% were men. Overall HPV infection rate was 28.77% (37.50% in women and 27.05% in men), with 11.90% HPV integration events. Among them, 17.12% single and 11.65% coinfections were observed. HPV18 (24.66%) was the most prevalent genotype, followed by HPV33, 16, and 39. All HPV were European lineage (A). HPV16 was more prevalent in women (P = .04).Conclusions: HPV infection may contribute to the etiology both in men and women with bladder cancer. HPV18, followed by HPV33, 16, and 39 genotypes, potentially represent the predominant oncogenic risk types for bladder carcinogenesis. [ABSTRACT FROM AUTHOR]