Natural IgG protects against early dissemination of vesicular stomatitis virus.

Neonatal Fc receptor (FcRn) recycles immunoglobulin G, and inhibition of FcRn is used clinically for treatment of autoimmune diseases. In this work, using the vesicular stomatitis virus (VSV) mouse infection model system, we determined the role of FcRn during virus infection. While induction of neutralizing antibodies and long-term protection of these antibodies was hardly affected in FcRn deficient mice, FcRn deficiency limited the amount of natural IgG (VSV-specific) antibodies. Lack of natural antibodies (nAbs) limited early control of VSV in macrophages, accelerated propagation of virus in several organs, led to the spread of VSV to the neural tissue resulting in fatal outcomes. Adoptive transfer of natural IgG into FcRn deficient mice limited early propagation of VSV in FcRn deficient mice and enhanced survival of FcRn knockout mice. In line with this, vaccination of FcRn mice with very low dose of VSV prior to infection similarly prevented death after infection. In conclusion we determined the importance of nAbs during VSV infection. Lack of FcRn limited nAbs and thereby enhanced the susceptibility to virus infection.

Feasibility of diffusion-weighted magnetic resonance imaging in evaluation of early therapeutic response after CT-guided microwave ablation of inoperable lung neoplasms.

OBJECTIVE: To determine the early treatment response after microwave ablation (MWA) of inoperable lung neoplasms using the apparent diffusion coefficient (ADC) value calculated 24 h after the ablation. MATERIALS AND METHODS: This retrospective study included 47 patients with 68 lung lesions, who underwent percutaneous MWA from January 2008 to December 2017. Evaluation of the lesions was done using MRI including DWI sequence with ADC value calculation pre-ablation and 24 h post-ablation. DWI-MR was performed with b values (50, 400, 800 mm2/s). The post-ablation follow-up was performed using chest CT and/or MRI within 24 h following the procedure; after 3, 6, 9, and 12 months; and every 6 months onwards to determine the local tumor response. The post-ablation ADC value changes were compared to the end response of the lesions. RESULTS: Forty-seven patients (mean age: 63.8 ± 14.2 years, 25 women) with 68 lesions having a mean tumor size of 1.5 ± 0.9 cm (range: 0.7-5 cm) were evaluated. Sixty-one lesions (89.7%) showed a complete treatment response, and the remaining 7 lesions (10.3%) showed a local progression (residual activity). There was a statistically significant difference regarding the ADC value measured 24 h after the ablation between the responding (1.7 ± 0.3 × 10-3 mm2/s) and non-responding groups (1.4 ± 0.3 × 10-3 mm2/s) with significantly higher values in the responding group (p = 0.001). A suggested ADC cut-off value of 1.42 could be used as a reference point for the post-ablation response prediction (sensitivity: 66.67%, specificity: 84.21%, PPV: 66.7%, and NPV: 84.2%). No significant difference was reported regarding the ADC value performed before the ablation as a factor for the prognosis of treatment response (p = 0.86). CONCLUSION: ADC value assessment following ablation may allow the early prediction of treatment efficacy after MWA of inoperable lung neoplasms. KEY POINTS: • ADC value calculated 24 h post-treatment may allow the early prediction of MWA efficacy as a treatment of pulmonary tumors and can be used in the early immediate post-ablation imaging follow-up. • The pre-treatment ADC value of lung neoplasms is not different between the responding and non-responding tumors.

Validity and Reproducibility of the ADNEX MR Scoring System in the Diagnosis of Sonographically Indeterminate Adnexal Masses.

BACKGROUND: The diagnosis of sonographically indeterminate adnexal masses (AM) signifies a major challenge in clinical practice. Early detection and characterization have increased the need for accurate imaging evaluation before treatment. PURPOSE: To assess the validity and reproducibility of the ADNEX MR Scoring system in the diagnosis of sonographically indeterminate AM. STUDY TYPE: A prospective multicenter study. POPULATION: In all, 531 women (mean age, 44 ± 11.2 years; range, 21-79 years) with 572 sonographically indeterminate AM. FIELD STRENGTH/SEQUENCE: 1.5T/precontrast T1 -weighted imaging (WI) fast spin echo (FSE) (in-phase and out-of-phase, with and without fat suppression); T2 -WI FSE; diffusion-WI single-shot echo planner with b-values of 0 and 1000 s/mm2 ; and dynamic contrast-enhanced perfusion T1 -WI liver acquisition with volume acceleration (LAVA). ASSESSMENT: All MRI examinations were evaluated by three radiologists, and the AM were categorized into five scores based on the ADNEX MR Scoring system. Score 1: no AM; 2: benign AM; 3: probably benign AM; 4: indeterminate AM; 5: probably malignant AM. Histopathology and imaging follow-up were used as the standard references for evaluating the validity of the ADNEX MR Scoring system for detecting ovarian malignancy. STATISTICAL TESTS: Four-fold table test, kappa statistics (κ), and receiver operating characteristic (ROC) curve. RESULTS: In all, 136 (23.8%) AM were malignant, and 436 (76.2%) were benign. Of the 350 AM classified as score 2, one (0.3%) was malignant; of the 62 AM classified as score 3, six (9.7%) were malignant; of the 73 AM classified as score 4, 43 (58.9%) were malignant; and of the 87 AM categorized as score 5, 86 (98.9%) were malignant. The best cutoff value for predicting malignant AM was score >3 with sensitivity and specificity of 92.9% and 94.9%, respectively. The interreader agreement of the ADNEX MR Scoring was very good (κ = 0.861). DATA CONCLUSION: The current study supports the high validity and reproducibility of the ADNEX MR Scoring system for the diagnosis of sonographically indeterminate AM. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Association of estrogen receptor ß and estrogen-related receptor α gene polymorphisms with bone mineral density in postmenopausal women.

The aim of the study was to investigate the possible association of AluI and RsaI polymorphisms of estrogen receptor ß (ER-ß) gene and 23-bp nucleotide repeat polymorphism of estrogen-related receptor α (ERRα) gene with bone mineral density (BMD) in postmenopausal Egyptian women. Two-hundred postmenopausal osteoporotic women as cases and 180 healthy age-matched postmenopausal women as controls were genotyped by PCR fragment length polymorphism for AluI, allele-specific PCR for RsaI, and by sizing of PCR products on agarose gels for ERRα repeats. sRANKL levels were estimated by ELISA. BMD measurements for spine and femoral neck were performed by dual energy X-ray absorptiometry. A significant difference between women with osteoporosis and controls regarding allele and genotype distributions of AluI G/A (OR 2.37, 95 % CI 1.77-3.18 and p < 0.001 for A allele) and ERRα polymorphisms (for the two repeats allele OR 2.08, 95 % CI 1.09-4.00, and p = 0.02). Osteoporotic women with the AluI AA + GA genotype or with the EERα 2,2 genotype had significantly lower BMD than did women with the other genotypes. Moreover, there was a significant increase of the mean values of sRANKL in carriers of AluI A, RsaI A alleles and in patients having 2,2 genotypes of ERRα (p < 0.001, p < 0.001, p = 0.02, respectively). We demonstrated an association of ER-ß AluI G/A and ERRα 23-repeats polymorphisms with BMD in postmenopausal Egyptian women. A possible effect of ER-ß and ERRα polymorphisms on the levels of sRANKL was estimated.

Stroke and myocardial infarction induce neutrophil extracellular trap release disrupting lymphoid organ structure and immunoglobulin secretion.

Post-injury dysfunction of humoral immunity accounts for infections and poor outcomes in cardiovascular diseases. Among immunoglobulins (Ig), IgA, the most abundant mucosal antibody, is produced by plasma B cells in intestinal Peyer's patches (PP) and lamina propria. Here we show that patients with stroke and myocardial ischemia (MI) had strongly reduced IgA blood levels. This was phenocopied in experimental mouse models where decreased plasma and fecal IgA were accompanied by rapid loss of IgA-producing plasma cells in PP and lamina propria. Reduced plasma IgG was detectable in patients and experimental mice 3-10 d after injury. Stroke/MI triggered the release of neutrophil extracellular traps (NETs). Depletion of neutrophils, NET degradation or blockade of NET release inhibited the loss of IgA+ cells and circulating IgA in experimental stroke and MI and in patients with stroke. Our results unveil how tissue-injury-triggered systemic NET release disrupts physiological Ig secretion and how this can be inhibited in patients.

Performance of the Cue COVID-19 point-of-care molecular test: insights from a multi-site clinic service model.

The COVID-19 pandemic highlighted the critical need for rapid and accurate molecular diagnostic testing. The Cue COVID-19 Point-of-Care Test (Cue POCT) is a nucleic acid amplification test (NAAT), authorized by Health Canada and FDA as a POCT for SARS-CoV-2 detection. Cue POCT was deployed at a network of clinics in Ontario, Canada with n = 13,848 patrons tested between 17 July 2021 and 31 January 2022. The clinical performance and operational experience with Cue POCT were examined for this testing population composed mostly of asymptomatic individuals (93.7%). A head-to-head prospective clinical verification was performed between 17 July and 4 October for all POCT service clients (n = 3,037) with paired COVID-19 testing by Cue and RT-PCR. Prospective verification demonstrated a clinical sensitivity of 100% and clinical specificity of 99.4% for Cue COVID-19 POCT. The lack of false negatives and low false positive rate (0.64%), underscores the high accuracy (99.4%) of Cue POCT to provide rapid PCR quality results. Low error rates (cancellation rate of 0% and invalid rate of 0.63%) with the current software version were additionally noted. Taken together, these findings highlight the value of accurate molecular COVID-19 POCT in a distributed service delivery model to rapidly detect cases in the community with the potential to curb transmission in high-exposure settings (i.e., in-flight, congregate workplace, and social events). The insights gleaned from this operational implementation are readily transferable to future POCT diagnostic services. IMPORTANCE This manuscript reports on the findings of a large asymptomatic population who underwent surveillance COVID testing on the Cue COVID-19 Point-of-Care Test (POCT). Review of test performance of this rapid molecular POCT, as compared to gold standard RT-PCR, is valuable to many audiences, including public health, emergency testing services, employers, and the general population of consumers who are seeking a user-friendly, accurate, cost-effective, and sustainable testing model for COVID screening. The findings from this operational experience also inform future models of POCT services beyond COVID.

Usp22 Deficiency Leads to Downregulation of PD-L1 and Pathological Activation of CD8+ T Cells and Causes Immunopathology in Response to Acute LCMV Infection.

Ubiquitin-specific peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, including histone H2B and transcription factors. Recently, it was reported that Usp22 acts as a negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency in acute viral infection with lymphocytic choriomeningitis virus (LCMV). We found that the lack of Usp22 on bone marrow-derived cells (Usp22fl/fl Vav1-Cre mice) reduced the induction of type I and II interferons. A limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8+ T cells and rapid death of Usp22-deficient mice. CD8+ T cell depletion experiments revealed that accelerated CD8+ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8+ T cell response, which gave rise to severe disease in mice.

Study of serum hepcidin in hereditary hemolytic anemias.

The aim of this study was to assess the level of hepcidin in hereditary chronic hemolytic anemias and to correlate the serum hepcidin levels to the need for blood transfusions (frequency of blood transfusions and the serum ferritin level). Seventy pediatric patients with hereditary chronic hemolytic anemias, attending to hematology clinics of Cairo University and Misr University for Science and Technology (MUST) hospitals were the subjects of this study [53 patients with ß-thalassemia major (ß-TM), 10 patients with ß-thalassemia intermedia (ß-TI), four patients with congenital spherocytosis and three patients with sickle cell disease) (38 males and 32 females)]; their ages ranged from 1-14 years. Seventy normal children, age- and sex-matched, served as the control group. The results of this study revealed decreased hepcidin levels in patients (all types of congenital chronic hemolytic anemias) [mean ± SD (standard deviation) = 22.9 ± 6.0] compared to controls (mean ± SD = 132.4 ± 16.7) with highly significant statistical difference in between. Hepcidin levels were higher in ß-TM patients (mean ± SD = 23.7 ± 6.2) than in ß-TI patients (mean ± SD = 21.8 ± 4.0), the hepcidin to ferritin ratio was significantly less than one. In ß-TM patients, the mean ± SD was 0.03 ± 0.004, and in ß-TI patients the mean ± SD = 0.025 ± 0.002, with highly significant statistical difference with hepcidin-to-ferritin ratios in controls being mean ± SD = 2.3 ± 0.7. Hepcidin and hepcidin/ferritin ratios can be used as good markers of hemolytic anemia and iron overload as they have very high sensitivity (99.0 and 99.0%, respectively) and very high specificity (98.0 and 97.0%, respectively). Our findings highlight the potential usefulness of hepcidin measurement as a diagnostic tool. The use of hepcidin as an adjuvant therapy with iron chelators is important as it has a vital role in combating hemosidrosis.

Radiologic Relation of the Colon to the Trajectory of Percutaneous Nephrolithotomy Access in Prone Versus Flank-free Modified Supine Position: A Prospective Study of Intra and Interindividual Influencing Factors.

OBJECTIVE: To compare the distance between the colon and the trajectory of percutaneous nephrolithotomy (PCNL) access both in prone and flank-free modified supine (FFMS) positions as measured on computed tomography and to study the effect of age, gender, BMI, side, and previous renal surgery as influencing factors. PATIENTS AND METHODS: In this prospective study, we included 367 patients scheduled for PCNL. All patients underwent low dose abdominal computed tomography both in prone and FFMS positions. Patients <18 years and those with previous colonic surgery or renal congenital anomalies were excluded. The perpendicular distance between the imaginary line of the renal access and the colon was measured. Findings were correlated to different influencing factors. RESULTS: Two hundred nineteen patients were males, and 148 were females. BMI of <30 were reported in 158 patients whereas BMI >30 in 209 patients. Data analysis showed that the mean perpendicular distance between colon and the renal access in FFMS and prone positions were 35.92 ± 0.22 mm and 17.78 ± 0.09 mm, respectively. In prone position only obesity, age, and overall interaction effect were the significant factors on the studied distance. In FFMS position, in addition to the effect of the prior factors, previous renal surgery also significantly reduces this distance. CONCLUSION: The distance between the colon and assumed PCNL trajectory at a puncture on the posterior axillary line was influenced mainly by patient position. In FFMS position the colon appears to be farther than in prone position. BMI and age significantly influence this distance to a lesser extent.