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Abstract Background Seasonal influenza imposes a substantial personal morbidity and societal cost burden. Vaccination is the major strategy for influenza prevention; however, because antigenically drifted influenza A and B viruses circulate annually, influenza vaccines must be updated to provide protection against the predicted prevalent strains for the next influenza season. The aim of this study was to assess the efficacy, safety, reactogenicity, and immunogenicity of a trivalent inactivated split virion influenza vaccine (TIV) in healthy adults over two influenza seasons in the US. Methods The primary endpoint of this double-blind, randomized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched, culture-confirmed influenza (VMCCI) across the 2005-2006 and 2006-2007 influenza seasons. Secondary endpoints included the prevention of laboratory-confirmed (defined by culture and/or serology) influenza, as well as safety, reactogenicity, immunogenicity, and consistency between three consecutive vaccine lots. Participants were assessed actively during both influenza seasons, and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness. Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season's surveillance period. Results Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2% (97.5% confidence interval [CI] lower bound of 48.2%), the point estimate for the primary endpoint, efficacy of TIV against VMCCI across both influenza seasons, was 46.3% with a 97.5% CI lower bound of 9.8%. This did not satisfy the pre-specified success criterion of a one-sided 97.5% CI lower bound of >35% for vaccine efficacy. The VMCCI attack rates were very low overall at 0.6% and 1.2% in the TIV and placebo groups, respectively. Apart from a mismatch for influenza B virus lineage in 2005-2006, there was a good match between TIV and the circulating strains. TIV was highly immunogenic, and immune responses were consistent between three different TIV lots. The most common reactogenicity events and spontaneous adverse events were associated with the injection site, and were mild in severity. Conclusions Despite a good immune response, and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2%, the pre-specified target (lower one-sided 97.5% confidence bound for efficacy > 35%) for the primary efficacy endpoint, the prevention of VMCCI, was not met. However, the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005-2006 and 2006-2007, which corresponded to relatively mild influenza seasons in the US. Overall, the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk. Trial registration NCT00216242

Immigrants and refugees seeking admission to the United States must first undergo an overseas medical exam, overseen by the US Centers for Disease Control and Prevention (CDC), during which all persons ≥15 years old receive a chest x-ray to look for signs of tuberculosis. Although individual screening sites often implement quality control (QC) programs to ensure radiographs are interpreted correctly, the CDC does not currently have a method for conducting similar QC reviews at scale. We obtained digitized chest radiographs collected as part of the overseas immigration medical exam. Using radiographs from applicants 15 years old and older, we trained deep learning models to perform three tasks: identifying abnormal radiographs; identifying abnormal radiographs suggestive of tuberculosis; and identifying the specific findings (e.g., cavities or infiltrates) in abnormal radiographs. We then evaluated the models on both internal and external testing datasets, focusing on two classes of performance metrics: individual-level metrics, like sensitivity and specificity, and sample-level metrics, like accuracy in predicting the prevalence of abnormal radiographs. A total of 152,012 images (one image per applicant; mean applicant age 39 years) were used for model training. On our internal test dataset, our models performed well both in identifying abnormalities suggestive of TB (area under the curve [AUC] of 0.97; 95% confidence interval [CI]: 0.95, 0.98) and in estimating sample-level counts of the same (-2% absolute percentage error; 95% CIC: -8%, 6%). On the external test datasets, our models performed similarly well in identifying both generic abnormalities (AUCs ranging from 0.89 to 0.92) and those suggestive of TB (AUCs from 0.94 to 0.99). This performance was consistent across metrics, including those based on thresholded class predictions, like sensitivity, specificity, and F1 score. Strong performance relative to high-quality radiological reference standards across a variety of datasets suggests our models may make reliable tools for supporting chest radiography QC activities at CDC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The first author is a left-handed, 51-year-old nephrologist who experienced a neurologic event. She underwent neurosurgery complicated by hemorrhage. Postoperatively, she developed persistent vertigo and unilateral tongue pain which persisted for over 5 years. Early neuroimaging revealed expected encephalomalacia but no neuroanatomical basis for her symptoms. A functional neurological disorder was suspected, and she was seen by several psychiatrists and psychotherapists. However, she suspected a neuroanatomical lesion would better explain her unrelenting symptoms. After seeing many neurologists, a neuroanatomical diagnosis was finally made. The theory and practice of medicine mandate that subjective complaint guides the modality and interpretation of objective evidence. The final neurologist knew where on neuroimaging to look because she was guided by the patient's complaints - vertigo and unilateral tongue pain. In this case, detailed scrutiny of neuroimaging by a neurologist, after encephalomalacia and gliosis were fully completed, gave a more accurate neuroanatomical diagnosis and a more realistic prognosis., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Abstract: One in 3 patients with lumbar spinal stenosis undergoing decompressive laminectomy (DL) to alleviate neurogenic claudication do not experience substantial improvement. This prospective cohort study conducted in 193 Veterans aimed to identify key spinal and extraspinal factors that may contribute to a favorable DL outcome. Biopsychosocial factors evaluated pre-DL and 1 year post-DL were hip osteoarthritis, imaging-rated severity of spinal stenosis, scoliosis/kyphosis, leg length discrepancy, comorbidity, fibromyalgia, depression, anxiety, pain coping, social support, pain self-efficacy, sleep, opioid and nonopioid pain medications, smoking, and other substance use. The Brigham Spinal Stenosis (BSS) questionnaire was the main outcome. Brigham Spinal Stenosis scales (symptom severity, physical function [PF], and satisfaction [SAT]) were dichotomized as SAT < 2.42, symptom severity improvement ≥ 0.46, and PF improvement ≥ 0.42, and analyzed using logistic regression. Sixty-two percent improved in 2 of 3 BSS scales (ie, success). Baseline characteristics associated with an increased odds of success were-worse BSS PF (odds ratio [OR] 1.24 [1.08-1.42]), greater self-efficacy for PF (OR 1.30 [1.08-1.58]), lower self-efficacy for pain management (OR 0.80 [0.68-0.94]), less apparent leg length discrepancy (OR 0.71 [0.56-0.91]), greater self-reported alcohol problems (OR 1.53 [1.07-2.18]), greater treatment credibility (OR 1.31 [1.07-1.59]), and moderate or severe magnetic resonance imaging-identified central canal stenosis (OR 3.52 [1.06-11.6]) moderate, OR 5.76 [1.83-18.1] severe). Using opioids was associated with lower odds of significant functional improvement (OR 0.46 [0.23-0.93]). All P < 0.05. Key modifiable factors associated with DL success-self-efficacy, apparent leg length inequality, and opioids-require further investigation and evaluation of the impact of their treatment on DL outcomes., (Copyright © 2020 International Association for the Study of Pain.)

Background: Children are susceptible to severe influenza infections and facilitate community transmission. One potential strategy to improve vaccine immunogenicity in children against seasonal influenza involves a trivalent hemagglutinin DNA prime-trivalent inactivated influenza vaccine (IIV3) boost regimen., Methods: Sites enrolled adolescents, followed by younger children, to receive DNA prime (1 mg or 4 mg) intramuscularly by needle-free jet injector (Biojector), followed by split virus 2012/13 seasonal IIV3 boost by needle and syringe approximately 18 weeks later. A comparator group received IIV3 prime and boost at similar intervals. Primary study objectives included evaluation of the safety and tolerability of the vaccine regimens, with secondary objectives of measuring antibody responses at four weeks post boost by hemagglutination inhibition (HAI) and neutralization assays., Results: Seventy-five children ≥6 to ≤17 years old enrolled. Local reactogenicity was higher after DNA prime compared to IIV3 prime (p<0.001 for pain/tenderness, redness, or swelling), but symptoms were mild to moderate in severity. Systemic reactogenicity was similar between vaccines. Overall, antibody responses were similar among groups, although HAI antibodies revealed a trend towards higher responses following 4 mg DNA-IIV3 compared to IIV3-IIV3. The fold increase of HAI antibodies to A/California/07/2009 [A(H1N1)pdm09] was significantly greater following 4 mg DNA-IIV3 (10.12 fold, 5.60-18.27 95%CI) compared to IIV3-IIV3 (3.86 fold, 2.32-6.44 95%CI). Similar neutralizing titers were observed between regimens, with a trend towards increased response frequencies in 4 mg DNA-IIV3. However, significant differences in fold increase, reported as geometric mean fold ratios, were detected against the H1N1 viruses within the neutralization panel: A/New Caledonia/20/1999 (1.41 fold, 1.10-1.81 95%CI) and A/South Carolina/1/1918 (1.55 fold, 1.27-1.89 95%CI)., Conclusions: In this first pediatric DNA vaccine study conducted in the U.S., the DNA prime-IIV3 boost regimen was safe and well tolerated. In children, the 4 mg DNA-IIV3 regimen resulted in antibody responses comparable to the IIV3-IIV3 regimen., Competing Interests: I have read the journal's policy and the authors of the manuscript have the following competing interests: this clinical study was conducted with funding and support by the National Institute of Allergy and Infectious Diseases (NIAID) Intramural Research program, using resources provided by the American Recovery and Reinvestment Act of 2009 (Recovery Act), and contract #HHSN272201000049I awarded to the EMMES Corporation (AB, JM, EA, DB, BC, HK, PS, PW). AB and JM are salaried employees of the EMMES Corporation. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Background: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration., Methods: 524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×10(7) TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination., Results: Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P=0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P=0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months. After second vaccination Day (42-208), geometric mean of peak neutralization titers were 87.8, 49.5 and 59.5 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders based on peak titer in each group was 142/145 (97.9%), 142/149 (95.3%) and 138/146 (94.5%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group., Conclusions: Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Children 6 through 35 months of age are recommended to receive half the dose of influenza vaccine compared with older children and adults., Methods: This was a 6-site, randomized 2:1, double-blind study comparing full-dose (0.5 mL) trivalent inactivated influenza vaccine (TIV) with half-dose (0.25 mL) TIV in children 6 through 35 months of age. Children previously immunized with influenza vaccine (primed cohort) received 1 dose, and those with no previous influenza immunizations (naive cohort) received 2 doses of TIV. Local and systemic adverse events were recorded. Sera were collected before immunization and 1 month after last dose of TIV. Hemagglutination inhibition antibody testing was performed., Results: Of the 243 subjects enrolled (32 primed, 211 naive), data for 232 were available for complete analysis. No significant differences in local or systemic reactions were observed. Few significant differences in immunogenicity to the 3 vaccine antigens were noted. The immune response to H1N1 was significantly higher in the full-dose group among primed subjects. In the naive cohort, the geometric mean titer for all 3 antigens after 2 doses of TIV were significantly higher in the 12 through 35 months compared with the 6 through 11 months age group., Conclusions: Our study confirms the safety of full-dose TIV given to children 6 through 35 months of age. An increase in antibody responses after full- versus half-dose TIV was not observed, except for H1N1 in the primed group. Larger studies are needed to clarify the potential for improved immunogenicity with higher vaccine doses. Recommending the same dose could simplify the production, storage, and administration of influenza vaccines.

Background: Young, healthy children shedding cytomegalovirus (CMV) in urine and saliva appear to be the leading source of CMV in primary infection of pregnant women., Findings: We screened 48 children 6 months - 5 years old for CMV IgG and measured levels of CMV IgG, IgM and IgG avidity antibodies, frequency of CMV shedding, and viral loads in blood, urine, and saliva. Thirteen of the 48 children (27%) were CMV IgG positive, among whom 3 were also CMV IgM positive with evidence of recent primary infection. Nine of the 13 seropositive children (69%) were shedding 102-105 copies/ml of CMV DNA in one or more bodily fluid. Among seropositive children, low IgG antibody titer (1:20-1:80) was associated with the absence of shedding (p = 0.014), and enrollment in daycare was associated with the presence of CMV shedding (p = 0.037)., Conclusions: CMV antibody profiles correlated with CMV shedding. The presence of CMV IgM more often represents primary infection in children than in adults. Correlating antibodies with primary infection and viral shedding in healthy children adds to the understanding of CMV infection in children that can inform the prevention of CMV transmission to pregnant women.

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

Cohen's kappa coefficient, which was introduced in 1960, serves as the most widely employed coefficient to assess inter-observer agreement for categorical outcomes. However, the original kappa can only be applied to cross-sectional binary measurements and, therefore, cannot be applied in the practical situation when the observers evaluate the same subjects at repeated time intervals. This study summarizes six methods of assessing agreement of repeated binary outcomes under different assumptions and discusses under which condition we should use the most appropriate method in practice. These approaches are illustrated using data from the CDC anthrax vaccine adsorbed (AVA) human clinical trial comparing the agreement for two solicited adverse events after AVA between the 1-3 day in-clinic medical record and the patient's diary on the same day. We hope this article can inspire researchers to choose the most appropriate method to assess agreement for their own study with longitudinal binary data.

We evaluated whether coadministration of the yellow fever (YF) virus vaccine with human immunoglobulin (Ig) that contained YF virus-neutralizing antibodies would reduce post-vaccination viremia without compromising immunogenicity and thus, potentially mitigate YF vaccine-associated adverse events. We randomized 80 participants to receive either YF vaccine and Ig or YF vaccine and saline placebo. Participants were followed for 91 days for safety and assessments of viremia and immunogenicity. There were no differences found between the two groups in the proportion of vaccinated participants who developed viremia, seroconversion, cluster of differentiation (CD)-8(+) and CD4(+) T-cell responses, and cytokine responses. These results argue against one putative explanation for the increased reporting of YF vaccine side effects in recent years (i.e., a change in travel clinic practice after 1996 when hepatitis A prophylaxis with vaccine replaced routine use of pre-travel Ig, thus potentially removing an incidental YF vaccine-attenuating effect of anti-YF virus antibodies present in Ig).

Expression of high-risk HPV oncogenes results in a strong overexpression of cellular protein p16(INK4a). Immunohistochemical staining for p16(INK4a) is widely used as diagnostic marker. However, p16(INK4a) upregulation was also described as a biomarker of age. Here we analyzed p16(INK4a) expression in cervical smears to investigate if patient age may influence p16(INK4a)-based cervical cancer diagnosis. p14(ARF) was analyzed as a related supportive biomarker. Cervical scrapes were taken and stored in RNAlater. Total RNA was extracted, and cDNA was analyzed for expression of p16(INK4a) and p14(ARF) relative to β-actin, by real-time reverse transcriptase PCR SYBR-Green I assays. Patient-derived smears referred as HSIL (n=45) had 6.27-fold higher p16(INK4a) mRNA expression than smears of cytologically normal and HPV-negative persons (n=48). Expression of p14(ARF) was 4.87-fold higher. When women with normal diagnoses were stratified for age, a significantly enhanced p16(INK4a) (2.88-fold) and p14(ARF) (1.9-fold) expression was observed as a consequence of ageing. A significant age-dependent upregulation was also observed in older HSIL patients (2.54-fold). Our study revealed significantly enhanced expression of p16(INK4a)/p14(ARF) mRNA in cervical scrapes referred to as HSIL compared with normal women. An age-dependent bias has to be considered when quantifying these tumor suppressor genes, with respect to cervical cancer development.

Background: Host genetic characteristics and environmental factors may correlate with risk for cervical cancer development. Here we describe a retrospective screening study for single nucleotide polymorphisms (SNPs) in genetic markers TP53, MTHFR, CYP1A1, and CYP2E1 in 749 patients., Methods: A multiplex ligation-dependent polymerase chain reaction approach was applied. We used archived material from human papillomavirus tests and correlated SNP genotypes to the corresponding clinical data. Semantic integration was used to identify and evaluate the clinical status from electronic health records., Results: An association with cervical cancer and high-grade dysplasia was found for the rare homozygous CC genotype (rs4646903) in CYP1A1 (odds ratio [OR], 8.862). Odds ratios were also significantly elevated for heterozygous MTHFR CT genotype (rs1801133; OR, 1.457). No significant association was found in TP53 (rs1042522) and CYP2E1 (rs3813867). In addition, we found smokers at higher risk (OR, 2.688) and identified pregnancies as a significant risk factor (OR, 1.54)., Conclusions: Our protocol enables a feasible way for further retrospective large sample size evaluation of potential genetic markers. This study revealed genetic associations of a rare SNP genotype with cervical dysplasia in one of the largest patient sample to date that warrants further investigation.

Validation of PCR thermal cycler performance is crucial in order to obtain reliable results. In this study, high resolution melting curve (HRM) analysis is presented as a novel validation method for real-time PCR instruments. By applying HRM analysis using a defined PCR amplicon and EvaGreen dye, information about the temperature accuracy and thermal homogeneity of the heating block was obtained. This pilot study shows the potential of our technique for temperature validation of real-time quantitative PCR thermal cyclers. Our data correlated well with the temperature accuracy data obtained from the Mobile Temperature Acquisition System (MTAS; r2 = 0.93), which conforms to the National Institute of Standards and Technology criteria, and our method was reproducible in independent runs (r2 = 0.95). The advantages of this HRM-based method include: (i) temperature measurement under real world conditions in the reaction liquid in closed reaction tubes; (ii) temperature measurement of all wells; and (iii) applicability to all real-time PCR instruments capable of HRM analysis.

Limited sample size and low sensitivity of currently used functional assays challenge direct analysis of cytotoxic CD8+ T lymphocyte activity to quantify antigen-specific immunity after infection or vaccination. Our flow cytometry-based assay reproducibly detects at least three epitope-specific CD8+ T lymphocytes by their cytolytic function. As exemplified for viral epitopes restricted to the human leukocyte antigen (HLA)-A2, the HLA-A2+ human somatic cell hybrid T2 provided an about 10-fold more sensitive readout as compared to autologous B-lymphoblastoid cells or the human erythroleukemia cell line K562 transfected to express HLA-A2 when used as target cells. We named our assay VITAL-FR assay, referring to Hermans et al. (2004) and indicating the modification of using Far Red (FR) dye instead of CMTMR. Under optimal conditions the VITAL-FR assay proved 30 times more sensitive than the 51chromium-release assay to assess epitope-specific target cell lysis. The high overall sensitivity of the VITAL-FR assay basically depended on the negligible spectral overlap of the emission of a stable Far Red fluorescent reporter with the green tracer for target cell labelling. It also profited from long co-incubation of effector and target cells of up to 72, from prior in-vitro culture increasing the frequency of epitope-specific CD8+ T cells and from generic, easily accessible standardized target cells that were used with only 10(3) specific and 10(3) control target cells per individual experimental reaction. Our functional approach with the VITAL-FR assay therefore ideally suits for monitoring CD8+ T cell-mediated cytotoxicity in e.g. vaccination studies with known MHC-restricted immunogenic peptides in scientific and diagnostic applications., (2010 Elsevier B.V. All rights reserved.)