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Funder: New faculty research seed money grant of Yonsei University College of Medicine for 2021 (2021-32-0049)., Two messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna are being rolled out. Despite the high volume of emerging evidence regarding adverse events (AEs) associated with the COVID-19 mRNA vaccines, previous studies have thus far been largely based on the comparison between vaccinated and unvaccinated control, possibly highlighting the AE risks with COVID-19 mRNA vaccination. Comparing the safety profile of mRNA vaccinated individuals with otherwise vaccinated individuals would enable a more relevant assessment for the safety of mRNA vaccination. We designed a comparative safety study between 18 755 and 27 895 individuals who reported to VigiBase for adverse events following immunization (AEFI) with mRNA COVID-19 and influenza vaccines, respectively, from January 1, 2020, to January 17, 2021. We employed disproportionality analysis to rapidly detect relevant safety signals and compared comparative risks of a diverse span of AEFIs for the vaccines. The safety profile of novel mRNA vaccines was divergent from that of influenza vaccines. The overall pattern suggested that systematic reactions like chill, myalgia, fatigue were more noticeable with the mRNA COVID-19 vaccine, while injection site reactogenicity events were more prevalent with the influenza vaccine. Compared to the influenza vaccine, mRNA COVID-19 vaccines demonstrated a significantly higher risk for a few manageable cardiovascular complications, such as hypertensive crisis (adjusted reporting odds ratio [ROR], 12.72; 95% confidence interval [CI], 2.47-65.54), and supraventricular tachycardia (adjusted ROR, 7.94; 95% CI, 2.62-24.00), but lower risk of neurological complications such as syncope, neuralgia, loss of consciousness, Guillain-Barre syndrome, gait disturbance, visual impairment, and dyskinesia. This study has not identified significant safety concerns regarding mRNA vaccination in real-world settings. The overall safety profile patterned a lower risk of serious AEFI following mRNA vaccines compared to influenza vaccines.

IgA vasculitis, formerly known as Henoch-Schönlein purpura, is a systemic IgA-mediated vasculitis of the small vessels commonly seen in children. The natural history of IgA vasculitis is generally self-limiting; however, one-third of patients experience symptom recurrence and a refractory course. This systematic review examined the use of dapsone in refractory IgA vasculitis cases. A literature search of PubMed databases retrieved 13 articles published until June 14, 2018. The most common clinical feature was a palpable rash (100% of patients), followed by joint pain (69.2%). Treatment response within 1–2 days was observed in 6 of 26 patients (23.1%) versus within 3–7 days in 17 patients (65.4%). Relapse after treatment discontinuation was reported in 17 patients (65.4%) but not in 3 patients (11.5 %). Four of the 26 patients (15.4%) reported adverse effects of dapsone including arthralgia (7.7%), rash (7.7%), and dapsone hypersensitivity syndrome (3.8%). Our findings suggest that dapsone may affect refractory IgA vasculitis. Multicenter randomized placebo-controlled trials are necessary to determine the standard dosage of dapsone at initial or tapering of treatment in IgA vasculitis patients and evaluate whether dapsone has a significant benefit versus steroids or other medications.

Background\ud Every year, at least one million children become ill with tuberculosis and around 200,000 children die. Xpert MTB/RIF and Xpert Ultra are World Health Organization (WHO)‐recommended rapid molecular tests that simultaneously detect tuberculosis and rifampicin resistance in adults and children with signs and symptoms of tuberculosis, at lower health system levels. To inform updated WHO guidelines on molecular assays, we performed a systematic review on the diagnostic accuracy of these tests in children presumed to have active tuberculosis.\ud \ud Objectives\ud Primary objectives\ud \ud • To determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for (a) pulmonary tuberculosis in children presumed to have tuberculosis; (b) tuberculous meningitis in children presumed to have tuberculosis; (c) lymph node tuberculosis in children presumed to have tuberculosis; and (d) rifampicin resistance in children presumed to have tuberculosis\ud \ud ‐ For tuberculosis detection, index tests were used as the initial test, replacing standard practice (i.e. smear microscopy or culture)\ud \ud ‐ For detection of rifampicin resistance, index tests replaced culture‐based drug susceptibility testing as the initial test\ud \ud Secondary objectives\ud \ud • To compare the accuracy of Xpert MTB/RIF and Xpert Ultra for each of the four target conditions\ud \ud • To investigate potential sources of heterogeneity in accuracy estimates\ud \ud ‐ For tuberculosis detection, we considered age, disease severity, smear‐test status, HIV status, clinical setting, specimen type, high tuberculosis burden, and high tuberculosis/HIV burden\ud \ud ‐ For detection of rifampicin resistance, we considered multi‐drug‐resistant tuberculosis burden\ud \ud • To compare multiple Xpert MTB/RIF or Xpert Ultra results (repeated testing) with the initial Xpert MTB/RIF or Xpert Ultra result\ud \ud Search methods\ud We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number (ISRCTN) Registry up to 29 April 2019, without language restrictions.\ud \ud Selection criteria\ud Randomized trials, cross‐sectional trials, and cohort studies evaluating Xpert MTB/RIF or Xpert Ultra in HIV‐positive and HIV‐negative children younger than 15 years. Reference standards comprised culture or a composite reference standard for tuberculosis and drug susceptibility testing or MTBDRplus (molecular assay for detection of Mycobacterium tuberculosis and drug resistance) for rifampicin resistance. We included studies evaluating sputum, gastric aspirate, stool, nasopharyngeal or bronchial lavage specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), fine needle aspirates, or surgical biopsy tissue (lymph node tuberculosis).\ud \ud Data collection and analysis\ud Two review authors independently extracted data and assessed study quality using the Quality Assessment of Studies of Diagnostic Accuracy ‐ Revised (QUADAS‐2). For each target condition, we used the bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We assessed certainty of evidence using the GRADE approach.\ud \ud Main results\ud For pulmonary tuberculosis, 299 data sets (68,544 participants) were available for analysis; for tuberculous meningitis, 10 data sets (423 participants) were available; for lymph node tuberculosis, 10 data sets (318 participants) were available; and for rifampicin resistance, 14 data sets (326 participants) were available. Thirty‐nine studies (80%) took place in countries with high tuberculosis burden. Risk of bias was low except for the reference standard domain, for which risk of bias was unclear because many studies collected only one specimen for culture.\ud \ud Detection of pulmonary tuberculosis\ud \ud For sputum specimens, Xpert MTB/RIF pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 64.6% (55.3% to 72.9%) (23 studies, 493 participants; moderate‐certainty evidence) and 99.0% (98.1% to 99.5%) (23 studies, 6119 participants; moderate‐certainty evidence). For other specimen types (nasopharyngeal aspirate, 4 studies; gastric aspirate, 14 studies; stool, 11 studies), Xpert MTB/RIF pooled sensitivity ranged between 45.7% and 73.0%, and pooled specificity ranged between 98.1% and 99.6%.\ud \ud For sputum specimens, Xpert Ultra pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 72.8% (64.7% to 79.6%) (3 studies, 136 participants; low‐certainty evidence) and 97.5% (95.8% to 98.5%) (3 studies, 551 participants; high‐certainty evidence). For nasopharyngeal specimens, Xpert Ultra sensitivity (95% CI) and specificity (95% CI) were 45.7% (28.9% to 63.3%) and 97.5% (93.7% to 99.3%) (1 study, 195 participants).\ud \ud For all specimen types, Xpert MTB/RIF and Xpert Ultra sensitivity were lower against a composite reference standard than against culture.\ud \ud Detection of tuberculous meningitis\ud \ud For cerebrospinal fluid, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 54.0% (95% CI 27.8% to 78.2%) (6 studies, 28 participants; very low‐certainty evidence) and 93.8% (95% CI 84.5% to 97.6%) (6 studies, 213 participants; low‐certainty evidence).\ud \ud Detection of lymph node tuberculosis\ud \ud For lymph node aspirates or biopsies, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 90.4% (95% CI 55.7% to 98.6%) (6 studies, 68 participants; very low‐certainty evidence) and 89.8% (95% CI 71.5% to 96.8%) (6 studies, 142 participants; low‐certainty evidence).\ud \ud Detection of rifampicin resistance\ud \ud Xpert MTB/RIF pooled sensitivity and specificity were 90.0% (67.6% to 97.5%) (6 studies, 20 participants; low‐certainty evidence) and 98.3% (87.7% to 99.8%) (6 studies, 203 participants; moderate‐certainty evidence).\ud \ud Authors' conclusions\ud We found Xpert MTB/RIF sensitivity to vary by specimen type, with gastric aspirate specimens having the highest sensitivity followed by sputum and stool, and nasopharyngeal specimens the lowest; specificity in all specimens was > 98%. Compared with Xpert MTB/RIF, Xpert Ultra sensitivity in sputum was higher and specificity slightly lower. Xpert MTB/RIF was accurate for detection of rifampicin resistance. Xpert MTB/RIF was sensitive for diagnosing lymph node tuberculosis. For children with presumed tuberculous meningitis, treatment decisions should be based on the entirety of clinical information and treatment should not be withheld based solely on an Xpert MTB/RIF result. The small numbers of studies and participants, particularly for Xpert Ultra, limits our confidence in the precision of these estimates.

Background: In COVID 19 related lung disease, which is a leading cause of death from this disease, cytokines like tumor necrosis factor-alpha (TNF alpha) may be pivotal in the pathogenesis. TNF alpha reduces fluid absorption due to impairment of sodium and chloride transport required for building an osmotic gradient across epithelial cells, which in the airways maintains airway surface liquid helping to keep airways open and enabling bacterial clearance and aids water absorption from the alveolar spaces. TNF alpha can, through Rho-kinase, disintegrate the endothelial and epithelial cytoskeleton, and thus break up intercellular tight junctional proteins, breaching the intercellular barrier, which prevents flooding of the interstitial and alveolar spaces with fluid. Hypotheses: (1) Preservation and restoration of airway and alveolar epithelial sodium and chloride transport and the cytoskeleton dependent integrity of the cell barriers within the lung can prevent and treat COVID 19 lung disease. (2) TNF alpha is the key mediator of pulmonary edema in COVID 19 lung disease. Confirmation of hypothesis and implications: The role of a reduction in the function of epithelial sodium and chloride transport could with regards to chloride transport be tested by analysis of chloride levels in exhaled breath condensate and levels correlated with TNF alpha concentrations. Reduced levels would indicate a reduction of the function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and a correlation with TNF alpha levels indicative of its involvement. Anti-TNF alpha treatment with antibodies is already available and needs to be tested in randomized controlled trials of COVID 19 lung disease. TNF alpha levels could also be reduced by statins, aspirin, and curcumin. Chloride transport could be facilitated by CFTR activators, including curcumin and phosphodiesterase-5 inhibitors. Sodium and chloride transport could be further regulated to prevent accumulation of alveolar fluid by use of Na(+)/K(+)/2Cl(−) cotransporter type 1 inhibitors, which have been associated with improved outcome in adults ventilated for acute respiratory distress syndrome (ARDS) in randomized controlled trials. Primary prevention of coronavirus infection and TNF alpha release in response to it could be improved by induction of antimicrobial peptides LL-37 and human beta defensin-2 and reduction of TNF alpha production by vitamin D prophylaxis for the population as a whole.

Now COVID-19 is causing a severe public health emergency and the mortality is rapidly increasing all over the world. In the current pandemic era, although there have been many efforts to diagnose a number of patients with symptoms or close contacts, there is no definite guideline for the initial therapeutic approach for them and therefore, many patients have been dying due to a hyperinflammatory immunological reaction labeled as "cytokine storm". Severe patients are hospitalized and the treatment is done, though they have not been established yet. Currently, however, no treatment is provided for those who are isolated at home or shelter until they get severe symptoms, which will increase the harms to the patients. In this review, we discuss some important points dedicated to the management of patients with COVID-19, which should help reducing morbidity and mortality. In this era, we suggest 7 recommendations to rescue the patients and to reduce the morbidity and mortality due to COVID-19 based on the immunological point of view.

BackgroundAntibodies to blood stages protective against complications of Plasmodium falciparum infection were found to be of immunoglobulin G 1 (IgG1) and IgG3 subclasses and of high affinity to the target epitopes. These target epitopes cannot be characterized using recombinant antigens because of a lack of appropriate glycosylation, phosphorylation, methylation, and bisulfide bond formation, which determine the structure of conformational and nonlinear epitopes within the tertiary and quaternary structures of native P. falciparum antigens.ObjectiveThis study aims to develop a method for the comprehensive detection of all P. falciparum schizont antigens, eliciting a protective immune response.MethodsPurified parasitophorous vacuole membrane–enclosed merozoite structures (PEMSs) containing native schizont antigens are initially generated, separated by two-dimensional (2D) gel electrophoresis and blotted onto nitrocellulose. Antigens eliciting a protective antibody response are visualized by incubation with sera from patients with clinical immunity. This is followed by the elution of low-affinity antibodies with urea and detection of protective antibody responses by incubation with anti-IgG1 and anti-IgG3 antibodies, which were conjugated to horseradish peroxidase. This is followed by visualization with a color reaction. Blot signals are normalized by relating to the intensity of blot staining with a reference antibody and housekeeping antigens. Results are corrected for intensity of exposure by the relation of antibody responses to global P. falciparum antibody titers. Antigens eliciting the protective responses are identified as immunorelevant from the comparison of spot positions, indicating high-affinity IgG1 or IgG3 responses on the western blot, which is unique to or consistently more intensive in clinically immune individuals compared with nonimmune individuals. The results obtained are validated by using affinity chromatography.ResultsAnother group previously applied 2D western blotting to analyze antibody responses to P. falciparum. The sera of patients allowed the detection of 42 antigenic spots on the 2D immunoblot. The spots detected were excised and subjected to mass spectrometry for identification. A total of 19 protein spots were successfully identified and corresponded to 13 distinct proteins. Another group used immunoaffinity chromatography to identify antigens bound by IgGs produced by mice with enhanced immunity to Plasmodium yoelii. Immunorelevant antigens were isolated and identified by immobilizing immunoglobulin from immune mice to a Sephadex column and then passing a blood-stage antigen mixture through the column followed by the elution of specific bound antigens with sodium deoxycholate and the identification of those antigens by western blotting with specific antibodies.Conclusions2D western blotting using native antigens has the potential to identify antibody responses selective for specific defined isomeric forms of the same protein, including isoforms (protein species) generated by posttranscriptional modifications such as phosphorylation, glycosylation, and methylation. The process involved in 2D western blotting enables highly sensitive detection, high resolution, and preservation of antibody responses during blotting. Validation by immunoaffinity chromatography can compensate for the antigen loss associated with the blotting process. It has the potential for indirect quantification of protective antibody responses by enabling quantification of the amount of eluted antibody bound antigens through mass spectrometry.International Registered Report Identifier (IRRID)PRR1-10.2196/15690

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. Objectives: In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. Methods: We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. Results: A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). Conclusions: We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.

Background: Cancer risk has been associated with certain gene variations in microRNA (miRNA), but conflicting evidence warrants re-assessing of significant results in meta-analyses. We summarized published meta-analyses that assess the associations between miRNA polymorphism and cancers to show the validity of the findings. Method: We searched PubMed and investigated the results of meta-analyses published through November 2018. We re-assessed the results based on false-positive report probability (FPRP) to test the noteworthiness of the associations. Results: Sixty-eight miRNA polymorphisms in 45 meta-analyses associated with cancer were included. Four (7.4%) and sixteen (25.0%) single nucleotide polymorphisms (SNPs) were noteworthy (FPRP

The aim of this study is to provide an overview and understand the strength of evidence and the extent of potential biases and the validity of claimed associations between the use of statins and cancer mortality or survival. We performed a comprehensive umbrella review of meta-analyses and systematically appraised the relevant meta-analyses of observational studies on the associations between statin use and cancer mortality or survival in various kinds of cancer. We searched the PubMed database and screened the reference list of relevant articles. We obtained the summary effect, 95% confidence interval, heterogeneity, and also examined small study effects and 95% prediction intervals for effect sizes, and the level of evidence was determined from the criteria. Regarding cancer mortality, statin use showed convincing evidence for an association with a reduced cancer-specific mortality rate for colorectal cancer. Four associations with reduced all-cause mortality (for breast cancer, colorectal cancer, endocrine-related gynecological cancer, and ovarian cancer) had a suggestive evidence. Moreover, analyses in nine cancers showed a weak level of evidence, while the remaining 15 did not indicate significant changes in either direction. Although there was a preventive effect of statin on cancer mortality in some cancer types, the evidence supporting the use of statins to reduce cancer mortality or survival was low.

Highlights • The estimation of the coronavirus disease 2019 (COVID-19) pandemic’s case fatality rate (CFR) has been the focus and interest of many stakeholders as it plays a key role in understanding this pandemic and guides appropriate responses and efficient mitigation strategies. • The traditional cumulative CFR estimation is static; however, it is rather a dynamic value. Moreover, the estimation of the global CFR of COVID-19 according to the calendar date and days since the outbreak of the first confirmed case is different. • We propose that the estimated kinetics of CFR according to days since the outbreak of the first confirmed case could be a useful predictor to design COVID-19 mitigation strategies., Objective Since the outbreak of the coronavirus disease 2019 (COVID-19) in December of 2019 in China, the estimation of the pandemic’s case fatality rate (CFR) has been the focus and interest of many stakeholders. In this manuscript, we prove that the method of using the cumulative CFR is static and does not reflect the trend according to the daily change per unit of time. Methods A proportion meta-analysis was carried out on CFR in every country reporting COVID-19 cases. Based on the results, we performed a meta-analysis for global COVID-19 CFR. Each analysis was performed on two different calculations of CFR: according to calendar date and according to days since the outbreak of the first confirmed case. We thus explored an innovative and original calculation of CFR concurrently based on the date of the first confirmed case as well as on a daily basis. Results For the first time, we showed that using meta-analyses, according to calendar date and days since the outbreak of the first confirmed case were different. Conclusion We propose that CFR according to days since the outbreak of the first confirmed case might be a better predictor of the current CFR of COVID-19 and its kinetics.

This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk, however, genuine associations should be carefully verified and understood.

Multiple studies have suggested that ω-3 fatty acid intake may have a protective effect on cancer risk; however, its true association with cancer risk remains controversial. We performed an umbrella review of meta-analyses to summarize and evaluate the evidence for the association between ω-3 fatty acid intake and cancer outcomes. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews from inception to December 1, 2018. We included meta-analyses of observational studies that examined associations between intake of fish or ω-3 fatty acid and cancer risk (gastrointestinal, liver, breast, gynecologic, prostate, brain, lung, and skin) and determined the level of evidence of associations. In addition, we appraised the quality of the evidence of significant meta-analyses by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We initially screened 598 articles, and 15 articles, including 57 meta-analyses, were eligible. Among 57 meta-analyses, 15 reported statistically significant results. We found that 12 meta-analyses showed weak evidence of an association between ω-3 fatty acid intake and risk of the following types of cancer: liver cancer (n = 4 of 6), breast cancer (n = 3 of 14), prostate cancer (n = 3 of 11), and brain tumor (n = 2 of 2). In the other 3 meta-analyses, studies of endometrial cancer and skin cancer, there were no assessable data for determining the evidence levels. No meta-analysis showed convincing, highly suggestive, or suggestive evidence of an association. In the sensitivity analysis of meta-analyses by study design, we found weak associations between ω-3 fatty acid intake and breast cancer risk in cohort studies, but no statistically significant association in case-control studies. However, the opposite results were found in case of brain tumor risk. Although ω-3 fatty acids have been studied in several meta-analyses with regard to a wide range of cancer outcomes, only weak associations were identified in some cancer types, with several limitations. Considering the nonsignificant or weak evidence level, clinicians and researchers should cautiously interpret reported associations between ω-3 fatty acid consumption and cancer risks. Copyright © 2020 The Author(s) on behalf of the American Society for Nutrition.

Background: Coronavirus Disease 2019 (COVID-19) caused by the novel virus named SARS-CoV-2 have been reported worldwide The outbreak of COVID-19 in South Korea

Systemic autoimmune diseases can affect various kinds of organs including the kidney, the skin, soft tissue and the bone. Among others, cardiovascular involvement in rheumatic diseases has been shown to affect myocardium, pericardium, cardiac vessels, conduction system and valves, eventually leading to increased mortality. In general, underlying chronic inflammation leads to premature atherosclerosis, but also other manifestations such as arrhythmia and heart failure may have a ‘silent’ progress. Traditional cardiovascular risk factors play a secondary role, while disease-specific factors (i.e. disease duration, severity, antibody positivity, persistent disease activity) can directly influence the cardiovascular system. Therefore, early diagnosis is critical to optimize management and to control inflammatory activity and recent data suggest that risk factors (i.e. hypercholesterolemia and hypertension) need intensive treatment as well. With the advent of immunosuppressive agents, most rheumatic diseases are well controlled on treatment, but information related to their cardioprotective efficacy is not well-defined. In this review, we focus on cardiovascular involvement in rheumatic diseases and highlight current evidence which should be of help for the treating physicians. Moreover, cardiotoxicity of immunosuppressive drugs is a rare issue and such potential adverse events will be briefly discussed.

The tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, toward the host cells is determined, at least in part, by the expression and distribution of its cell surface receptor, angiotensin-converting enzyme 2 (ACE2). The virus further exploits the host cellular machinery to gain access into the cells; its spike protein is cleaved by a host cell surface transmembrane serine protease 2 (TMPRSS2) shortly after binding ACE2, followed by its proteolytic activation at a furin cleavage site. The virus primarily targets the epithelium of the respiratory tract, which is covered by a tightly regulated airway surface liquid (ASL) layer that serves as a primary defense mechanism against respiratory pathogens. The volume and viscosity of this fluid layer is regulated and maintained by a coordinated function of different transport pathways in the respiratory epithelium. We argue that SARS-CoV-2 may potentially alter evolutionary conserved second-messenger signaling cascades via activation of G protein-coupled receptors (GPCRs) or by directly modulating G protein signaling. Such signaling may in turn adversely modulate transepithelial transport processes, especially those involving cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial Na

To provide an up-to-date summary of multiple sclerosis-susceptible gene variants and assess the noteworthiness in hopes of finding true associations, we investigated the results of 44 meta-analyses on gene variants and multiple sclerosis published through December 2016. Out of 70 statistically significant genotype associations, roughly a fifth (21%) of the comparisons showed noteworthy false-positive rate probability (FPRP) at a statistical power to detect an OR of 1.5 and at a prior probability of 10-6 assumed for a random single nucleotide polymorphism. These associations (IRF8/rs17445836, STAT3/rs744166, HLA/rs4959093, HLA/rs2647046, HLA/rs7382297, HLA/rs17421624, HLA/rs2517646, HLA/rs9261491, HLA/rs2857439, HLA/rs16896944, HLA/rs3132671, HLA/rs2857435, HLA/rs9261471, HLA/rs2523393, HLA-DRB1/rs3135388, RGS1/rs2760524, PTGER4/rs9292777) also showed a noteworthy Bayesian false discovery probability (BFDP) and one additional association (CD24 rs8734/rs52812045) was also noteworthy via BFDP computation. Herein, we have identified several noteworthy biomarkers of multiple sclerosis susceptibility. We hope these data are used to study multiple sclerosis genetics and inform future screening programs.

Henoch-Schonlein Purpura (HSP, IgA vasculitis) is an immunoglobulin A (IgA) mediated disorder characterized by systemic vasculitis with variable presentation, frequently affecting the skin, mucous membrane, joints, kidneys, and rarely lungs and the central nervous system. Interestingly, enhanced production of interleukin-8 (IL-8) levels are found during active disease and increased levels have been reported in supernatants from human umbilical venous endothelial cells after stimulation with sera from patients affected by HSP. While corticosteroid therapy is currently the recommended treatment for HSP, dapsone, an anti-leprosy agent, has also recently been suggested to have therapeutic efficacy due to its ability to suppress IL-8. Moreover, in addition to IL-8 suppression, dapsone has been reported to exert various anti-inflammatory effects by inhibiting the generation of toxic free radicals, myeloperoxidase mediated halogenation that converts H2O2 to HOCl, leukocyte chemotaxis, production of tumor necrosis factor, and other anti-inflammatory molecules. This review aims to provide a solid hypothesis for the pathogenesis of vasculitis in HSP. Moreover, we highlight potential mechanistic actions of dapsone in hopes that dapsone may be considered as an alternative viable treatment for patients affected by HSP.

68Ga-Glu-urea-Lys-(Ahx)-HBED-CC (68Ga-PSMA-11) represents a successful radiopharmaceutical for PET/CT imaging of prostate cancer. Further optimization of the tumor-to-background contrast might significantly enhance the sensitivity of PET/CT imaging and the probability of detecting recurrent prostate cancer at low PSA values. This study describes the advantage of histidine (H)/glutamic acid (E) and tryptophan (W)/glutamic acid (E) containing linkers on the pharmacokinetic properties of 68Ga-PSMA-11. The tracers were obtained by a combination of standard Fmoc-based solid-phase synthesis and copper(I)-catalyzed azide–alkyne cycloaddition. Their 68Ga complexes were compared to the clinical reference 68Ga-PSMA-11 with respect to cell binding, effective internalization, and tumor targeting properties in LNCaP-bearing balb/c nu/nu mice. The introduction of (HE)i (i = 1–3) or (WE)i (i = 1–3) into PSMA-11 resulted in a significantly changed biodistribution profile. The uptake values in kidneys, spleen, liver, and ...

Background: Various errors in the design, conduct, and analysis of medical and public health research studies can produce false results and waste valuable resources. While systematic reviews and meta-analyses are arguably considered the most dependable source of evidence-based medicine, increasing numbers of studies are indicating that, on the contrary to the public's belief, many of these investigations are redundant, erroneous, and even biased.Methods: Ninety-four meta-analyses on microRNA polymorphism and risk of cancer were extracted from Pubmed database on August 2016. Two investigators independently extracted data (i.e. number of studies, ethnicity, number of cases/controls, bias, etc.) from each meta-analysis. PROSPERO registration status and reference status were also recorded.Results: Among the 217 microRNA gene-variant cancer associations reported by 94 published meta-analyses, 37% had overlapping results and were extracted from the exact identical case-control studies. However, not one meta-analysis was registered into PROSPERO. Thirty-one percent of the overlapping associations referenced a previous meta-analysis investigating the same association; although only 36% of these overlapping associations referenced earlier meta-analysis that had the same overlapping results. Seventy-four percent of these references were limited to mere citations. Twenty-six percent of the overlapping associations from 16 meta-analyses showed discordant results, and of these, 87% of the genotype comparisons were found significant, contrary to the initial reports of being non-significant. However, no association was noteworthy in regards to false positive rate probability calculations at a given prior probability of 0.001 and 0.000001 and statistical power to detect an odds ratio (OR) of 1.1 and 1.5.Conclusions: Genetic association meta-analyses were by far more redundant, erroneous, and lacking references than initially expected. Careful search of similar studies, attention to small details, and inclination to reference previous works are needed. This paper proposes potential solutions for these problems in hopes of standardizing research efforts and in improving the quality of medical research.

Purpose Since the clinical introduction of 68Ga-PSMA-11 PET/CT, this imaging method has rapidly spread and is now regarded as a significant step forward in the diagnosis of recurrent prostate cancer (PCa). The aim of this study was to analyse the influence of several variables with possible influence on PSMA ligand uptake in a large cohort. Methods We performed a retrospective analysis of 1007 consecutive patients who were scanned with 68Ga-PSMA-11 PET/CT (1 h after injection) from January 2014 to January 2017 to detect recurrent disease. Patients with untreated primary PCa or patients referred for PSMA radioligand therapy were excluded. The possible effects of different variables including PSA level and PSA doubling time (PSADT), PSA velocity (PSAVel), Gleason score (GSC, including separate analysis of GSC 7a and 7b), ongoing androgen deprivation therapy (ADT), patient age and amount of injected activity were evaluated. Results In 79.5% of patients at least one lesion with characteristics suggestive of recurrent PCa was detected. A pathological (positive) PET/CT scan was associated with PSA level and ADT. GSC, amount of injected activity, patient age, PSADT and PSAVel were not associated with a positive PET/CT scan in multivariate analysis. Conclusion 68Ga-PSMA-11 PET/CT detects tumour lesions in a high percentage of patients with recurrent PCa. Tumour detection is clearly associated with PSA level and ADT. Only a tendency for an association without statistical significance was found between higher GSC and a higher probability of a pathological PET/CT scan. No associations were found between a pathological 68Ga-PSMA-11 PET/CT scan and patient age, amount of injected activity, PSADT or PSAVel.

Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro- and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohn's disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn's disease in relation to their effects on the overall intestinal inflammatory process.

Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials.

BACKGROUND Bacillus calmette guerin (BCG) immunization has been associated with a reduction in Mycobacterium tuberculosis (MTB) infection. BCG immunization has been shown to enhance innate immunity. This effect of BCG can be explained by an enhancing effect on innate immunity. OBJECTIVE This study aimed to test the following hypotheses: (1) BCG immunization can prevent infection with MTB, (2) prevention of infection occurs via stimulation of NOD2 (nucleotide oligomerization domain) and toll-like receptors 2 (TLR2), and (3) the effect of BCG immunization on prevention of infection with MTB can be enhanced by giving stimulators of NOD2 and TLR2. METHODS To detect the influence of immunization on infection rates, the ultralow dose (ULD) infection model is used. The infection rate of mice vaccinated with BCG and exposed after 6 weeks to ULD of MTB and unvaccinated mice are compared via cultures of lung homogenates and interferon (IFN) gamma release assay. If a reduced infection rate by BCG immunization is confirmed, the experiment is repeated by giving BCG combined simultaneously or in time sequence with the enhancers of innate immunity murabutide or beta-glycan. The influence of murabutide or beta-glycan alone on infection rates is investigated. To quantify the contribution of innate immunity levels of tumor necrosis factor, IFN gamma expression, histone H3 K4me3 trimethylation, and concentrations of monocytes with features of activation of innate immunity as defined by the Ly6Chigh as well as CD11b positive phenotype in immunized versus unimmunized infected and uninfected mice in the various immunization protocols is compared. The experiments will be repeated with prior application of the inhibitors of epigenetic programming of innate immunity histone methyltransferase inhibitor 5’-deoxy-5’-methylthio-adenosine and histone acetyl transferase inhibitor epigallocatechin-3-gallate. The influence of BCG on innate immunity is further corroborated by a prospective observational study in human infants. RESULTS Investigations of derivatives of muramyl dipeptide (MDP) to enhance early immunity in the C57BL/6 mouse strain (mice aged 7 weeks) by another group used 300 micrograms per mouse of oil-associated 6-0-mycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine (mycol-MDP) 50/50 mixed with Freund’s incomplete adjuvant. Comparison of colony-forming unit (CFU) count in the lungs 3 weeks after aerosol challenge with Mycobacterium bovis of groups (n=5) between groups receiving mycol-MDP in oil emulsion (see above) versus controls (n=5) showed a significantly lower CFU count of 94.5 x106 (SD 22.0) in cases versus controls with 204.0 X 106 (SD 77.6). It is important to note that after elimination of T-cells in this model, a reduction of CFU in lungs of mice treated with mycol-MDP persisted albeit without statistical significance, which was possibly related to the small number of animals used. CONCLUSIONS Demonstration of a reduction of MTB infection by enhancement of innate immunity could show a new approach to improving vaccine efficacy against this pathogen. INTERNATIONAL REGISTERED REPOR PRR1-10.2196/13045

A number of genome-wide association studies (GWASs) and meta-analyses of genetic variants have been performed in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We reinterpreted previous studies using false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP). This study searched publications in PubMed and Excerpta Medica Database (EMBASE) up to February 2018. Identification of noteworthy associations were analyzed using FPRP and BFDP, and data (i.e., odds ratio (OR), 95% confidence interval (CI), p-value) related to significant associations were separately extracted. Using filtered gene variants, gene ontology (GO) enrichment analysis and protein&ndash, protein interaction (PPI) networks were performed. Overall, 241 articles were identified, and 7 were selected for analysis. Single nucleotide polymorphisms (SNPs) discovered by GWASs were shown to be noteworthy, whereas only 27% of significant results from meta-analyses of observational studies were noteworthy. Eighty-five percent of SNPs with borderline p-values (5.0 &times, 10&minus, 8 &lt, p &lt, 0.05) in GWASs were found to be noteworthy. No overlapping SNPs were found between PR3-ANCA and MPO-ANCA vasculitis. GO analysis revealed immune-related GO terms, including &ldquo, antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class II&rdquo, &ldquo, interferon-gamma-mediated (IFN-&gamma, ) signaling pathway&rdquo, By using FPRP and BFDP, network analysis of noteworthy genetic variants discovered genetic risk factors associated with the IFN-&gamma, pathway as novel mechanisms potentially implicated in the complex pathogenesis of ANCA-associated vasculitis.

Capillary leak syndrome (CLS) is a rare disease with profound vascular leakage, which can be associated with a high mortality. There have been several reports on CLS as an adverse effect of anti-cancer agents and therapy, but the incidence of CLS according to the kinds of anti-cancer drugs has not been systemically evaluated. Thus, the aim of our study was to comprehensively meta-analyze the incidence of CLS by different types of cancer treatment or after bone marrow transplantation (BMT). We searched the literatures (inception to July 2018) and among 4612 articles, 62 clinical trials (studies) were eligible. We extracted the number of patients with CLS, total cancer patients, name of therapeutic agent and dose, and type of cancer. We performed a meta-analysis to estimate the summary effects with 95% confidence interval and between-study heterogeneity. The reported incidence of CLS was categorized by causative drugs and BMT. The largest number of studies reported on CLS incidence during interleukin-2 (IL-2) treatment (n = 18), which yielded a pooled incidence of 34.7% by overall estimation and 43.9% by meta-analysis. The second largest number of studies reported on anti-cluster of differentiation (anti-CD) agents (n = 13) (incidence of 33.9% by overall estimation and 35.6% by meta-analysis) or undergoing BMT (n = 7 (21.1% by overall estimation and 21.7% by meta-analysis). Also, anti-cancer agents, including IL-2 + imatinib mesylate (three studies) and anti-CD22 monoclinal antibodies (mAb) (four studies), showed a dose-dependent increase in the incidence of CLS. Our study is the first to provide an informative overview on the incidence rate of reported CLS patients as an adverse event of anti-cancer treatment. This meta-analysis can lead to a better understanding of CLS and assist physicians in identifying the presence of CLS early in the disease course to improve the outcome and optimize management.

Introduction. We investigated whether reduced mobility is associated with a reduction in serum creatinine in otherwise well children with neurodisability. Materials and Methods. This was a record based retrospective study and creatinine levels of children in groups with Gross Motor Function Classification System (GMFCS) category 1, 2, or 3 (group I); GMFCS 4 or 5 (group II); and age matched controls (group III) were compared. Results. Creatinine values were significantly different (p=0.002) between patients with neurodisability (mean 32.0 (SD 9.3), n=88) compared to patients without (mean 36.5 SD (9.8), n=88). There was no significant difference in creatinine levels (p=0.684) between group I (mean 35.6 (9.1), n=23) and group III (mean 36.5 (9.8), n=88). A significantly lower creatinine level (p Conclusions. Children with neurodisability with severe mobility restriction had a significantly lower serum creatinine compared to controls with less severe or no neurodisability. Death in severe neurodisability may be associated with lower creatinine levels.

Background: Numerous studies have identified the potential risk factors and biomarkers for autism spectrum disorder (ASD). We aim to study the strength and validity of the suggested environmental risk factors or biomarkers of ASD. Methods: We conducted an umbrella review and systematically appraised the relevant meta-analyses of observational studies (PROSPERO registration: CRD42014010715). We searched PubMed from inception to 10/17/2018 and screened the reference list of relevant articles. We obtained the summary effect, 95% confidence interval (CI), heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We performed analyses under credibility ceilings. Findings: A total of 46 eligible articles yielded data on 67 environmental risk factors (cases=544212, population=81708787) and 52 biomarkers (cases=15614, controls=15417). Evidence of association was convincing for greater maternal age (RR=1·31, 95% CI=1·18 to 1·45), maternal chronic hypertension (OR=1·48, 95% CI=1·29 to 1·70), maternal gestational hypertension (OR=1·37, 95% CI=1·21 to 1·54), maternal overweight (RR=1·28, 95% CI=1·19 to 1·36), preeclampsia (RR=1·32, 95% CI=1·20 to 1·45), pre-pregnancy maternal antidepressant exposure (RR=1·48, 95% CI=1·29 to 1·71), and selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy (OR=1·84, 95% CI=1·60 to 2·11). Only two associations, maternal overweight and SSRI during pregnancy, retained high level of evidence under subgroup sensitivity analyses. Evidence from biomarkers was limited. Interpretation: Convincing evidence suggests that maternal factors, such as age and features of metabolic syndrome are associated with risk of ASD. SSRI use during pregnancy was also convincingly associated with risk of ASD, but confounding from underlying maternal psychiatric disorders is possible. Funding: None. Declaration of Interest: We declare no competing interests. Ethical Approval: PROSPERO registration: CRD42014010715

Sensorineural hearing loss is mainly acquired and affects an estimated 1.3 billion humans worldwide. It is related to aging, noise, infection, ototoxic drugs, and genetic defects. It is essential to identify reversible and preventable causes to be able to reduce the burden of this disease. Inflammation is involved in most causes and leads to tissue injury through vasospasm-associated ischemia. Vasospasm is reversible. This review summarized evidence linking inflammation-induced vasospasm to several forms of acquired sensorineural hearing loss. The link between vasospasm and sensorineural hearing loss is directly evident in subarachnoid haemorrhage, which involves the release of vasoconstriction-inducing cytokines like interleukin-1, endothelin-1, and tumour necrosis factor. These proinflammatory cytokines can also be released in response to infection, autoimmune disease, and acute or chronically increased inflammation in the ageing organism as in presbyacusis or in noise-induced cochlear injury. Evidence of vasospasm and hearing loss has also been discovered in bacterial meningitis and brain injury. Resolution of inflammation-induced vasospasm has been associated with improvement of hearing in autoimmune diseases involving overproduction of interleukin-1 from inflammasomes. There is mainly indirect evidence for vasospasm-associated sensorineural hearing loss in most forms of systemic or injury- or infection-induced local vascular inflammation. This opens up avenues in prevention and treatment of vascular and systemic inflammation as well as vasospasm itself as a way to prevent and treat most forms of acquired sensorineural hearing loss. Future research needs to investigate interventions antagonising vasospasm and vasospasm-inducing proinflammatory cytokines and their production in randomised controlled trials of prevention and treatment of acquired sensorineural hearing loss. Prime candidates for interventions are hereby inflammasome inhibitors and vasospasm-reducing drugs like nitric oxide donors, rho-kinase inhibitors, and magnesium which have the potential to reduce sensorineural hearing loss in meningitis, exposure to noise, brain injury, arteriosclerosis, and advanced age-related and autoimmune disease-related inflammation.

Background Numerous studies have identified potential risk factors and biomarkers for autism spectrum disorder. We aimed to study the strength and validity of the suggested environmental risk factors or biomarkers of autism spectrum disorder. Methods We did an umbrella review and systematically appraised the relevant meta-analyses of observational studies. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for papers published between database inception and Oct 17, 2018, and screened the reference list of relevant articles. We obtained the summary effect, 95% CI, heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We did analyses under credibility ceilings. This review is registered with PROSPERO, number CRD42018091704. Findings 46 eligible articles yielded data on 67 environmental risk factors (544 212 cases, 81 708 787 individuals) and 52 biomarkers (15 614 cases, 15 433 controls). Evidence of association was convincing for maternal age of 35 years or over (relative risk [RR] 1.31, 95% CI 1.18-1.45), maternal chronic hypertension (odds ratio [OR] 1.48, 1.29-1.70), maternal gestational hypertension (OR 1.37, 1.21-1.54), maternal overweight before or during pregnancy (RR 1.28, 1.19-1.36), pre-eclampsia (RR 1.32, 1.20-1.45), prepregnancy maternal antidepressant use (RR 1.48, 1.29-1.71), and maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy (OR 1.84, 1.60-2.11). Only two associations, maternal overweight before or during pregnancy and SSRI use during pregnancy, retained their high level of evidence under subset sensitivity analyses. Evidence from biomarkers was scarce, being supported by p values close to the significance threshold and too few cases. Interpretation Convincing evidence suggests that maternal factors, such as age and features of metabolic syndrome, are associated with risk of autism spectrum disorder. Although SSRI use during pregnancy was also associated with such risk when exposed and non-exposed groups were compared, this association could be affected by other confounding factors, considering that prepregnancy maternal antidepressant use was also convincingly associated with higher risk of autism spectrum disorder. Findings from previous studies suggest that one possible confounding factor is underlying maternal psychiatric disorders. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Funding Agencies|Health Education England [ICA-CL-2017-03-001]; National Institute for Health Research (NIHR) [ICA-CL-2017-03-001]; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust; Maudsley Charity; Kings College London; NIHR South London Collaboration for Leadership in Applied Health Research and Care

Background South Korea is one of the few countries that has succeeded in flattening the curve of new COVID-19 cases and avoiding a second outbreak by implementing multiple strategies, ranging from an individual level to the population level. Objective We aim to discuss the unique strategies and epidemiological characteristics of COVID-19 in South Korea and present a summary of policies implemented by the Korean government during the COVID-19 pandemic. Methods We designed a cross-sectional study of epidemiological data published by the Korea Centers for Disease Control and Prevention on October 1, 2020. We analyzed detailed epidemiological information of COVID-19 cases, including the number of confirmed cases and resulting deaths. Results As of October 1, 2020, a total of 23,889 confirmed COVID-19 cases and 415 deaths were reported in South Korea. In this paper, we present data on the epidemiological characteristics and transmission of the disease and discuss how the South Korean government, health care providers, and society responded to the COVID-19 outbreak. Conclusions Understanding the epidemiological characteristics of COVID-19 in South Korea and the government’s successful efforts in managing the spread of the disease can provide important insights to other countries dealing with the ongoing pandemic.

Type I diabetes mellitus (DM) has been associated with abnormalities of T cells. Our objective was to assess whether antibody responses to T-cell-dependent and -independent antigens in children with DM are lower than those of children without DM. We performed a case-control study matching children with DM to children without DM by age and by assessing antibody levels to pneumococcal serotypes, Haemophilus influenzae , and tetanus and diphtheria toxoids and reassessing antibody levels in patients with antibody levels below protective thresholds after booster immunization. We recruited 36 children with DM and 36 age-matched controls. The mean age was 10 years. There was no difference between groups in antibody levels against the antigens tested. Pneumococcal antibody levels below the protective threshold were found in 35.9% of DM patients after conjugate pneumococcal vaccination with no difference between groups. Booster immunization with unconjugated pneumococcal vaccine resulted in a median level against pneumococcal serotypes of 2.3 μg/ml (range, 0.05 to 664.7 μg/ml) in children with DM and 6.1 μg/ml (0.12 to 203.36 μg/ml) in children without DM ( P = 0.013). Over 85% of children had levels above the protective threshold after booster immunization with no difference between groups. There was no evidence for a reduced antibody response to T-cell-dependent antigens given during childhood immunizations in children with DM. There was a reduced antibody response to antigens of pneumococcal strains in children with DM given unconjugated pneumococcal polysaccharide vaccine compared to that of children without DM without being associated with a difference in percentage of antibody levels below the protective threshold between groups.

The prostate-specific membrane antigen (PSMA) has received increased consideration during the past few years as an excellent target for both imaging and therapy of prostate cancer. After many years of outstanding preclinical research, the first significant step forward in clinical use was achieved in 2008 with the first human experience with the small-molecule PSMA inhibitors 123I-MIP-1972 and 123I-MIP-1095. A clinical breakthrough followed in 2011 with 68Ga-PSMA-11 for PET imaging and 131I-MIP-1095 for endoradiotherapy of metastatic prostate cancer. Since then, PET/CT with 68Ga-PSMA-11 has rapidly spread worldwide, and endoradiotherapy with PSMA ligands has been conducted at increasing numbers of centers. 68Ga-PSMA-11 is currently the subject of multicenter studies in different countries. Since 2013, 131I-related PSMA therapy has been replaced by 177Lu-labeled ligands, such as PSMA-617, which is also the subject of multicenter studies. Alternative PSMA ligands for both imaging and therapy are available. Among them is 99mTc-MIP-1404, which has recently entered a phase 3 clinical trial. This article focuses on the highlights of the development and clinical application of PSMA ligands.

Inflammasomes are caspase-1-activating molecular platforms that produce active interleukin (IL)-1β and are implicated in various central nervous system (CNS) diseases. These multi-protein complexes can be activated by exposure of cells to low osmolality. The inflammasome nucleotide-binding and oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) is hereby the main sensor of cellular osmolality. IL-1β was found to stimulate the secretion of antidiuretic hormone (ADH) from the posterior pituitary gland either by action of prostaglandins or indirectly by causing the release of IL-6. Based on these findings, we hypothesize that the hyponatremia caused by a wide range of CNS diseases is able to induce significant cell swelling with induction of a hyposmotic intracellular environment, which activates the NLRP3 inflammasome, causing the release of IL-1β and induced by IL-1β, IL-6, which increases the production of ADH that leads to more profound hyponatremia. Supportive evidence for this hypothesis is the finding that IL-1 injection can induce ADH release and hyposmotic effect of ADH induced hyponatremia can, via the mechanical effect of cell swelling, activate transient receptor potential channels, which via transforming growth factor β-activated kinase 1 activate NLRP3. Implications of this hypothesis, if confirmed, would include that hyponatremia can be exacerbated through this vicious cycle but also that the inflammasomes are key mediators of this process. Confirmation of this hypothesis would have implications for prevention and clinical management of changes in patients sodium levels related to syndrome of inappropriate antidiuretic hormone secretion (SIADH) with interventions targeting inflammatory mediator production and function of inflammasomes with the potential of prevention of permanent brain damage in a wide range of CNS diseases.

There are over 300 new cases of imported paediatric malaria in the UK each year and this has been increasing over the last 20 years. Malaria in children is particularly difficult to diagnose because the initial presenting features are subtler than in adults and do not display the classical presenting features. However, they are also more likely to deteriorate rapidly and to develop severe malaria. The 'gold standard' for ruling out the diagnosis of malaria if clinically suspected is three negative thin and thick blood films, which require serial phlebotomy and the availability of trained technicians. There are now a range of other tests, including rapid diagnostic tests and PCR, as well as clinical features that make the diagnosis more or less likely. We explore the different tests available and whether these might replace the three negative blood films currently needed. We also look at whether we are able to use clinical features to aid the tests used for a diagnosis of imported malaria.

Key issues for prostate cancer patients are the detection of recurrent disease and the treatment of metastasized cancer. Early detection is a major challenge for all conventional imaging modalities. Furthermore, therapy of patients with hormone-resistant tumor lesions presents a major clinical challenge. Because the prostate-specific membrane antigen (PSMA) is frequently overexpressed in prostate cancer, several PSMA-targeting molecules are under development to detect and treat metastatic castration-resistant prostate cancer (mCRPC). mCRPC represents a situation where cure is no longer achievable and novel therapeutic approaches for palliation and increase of survival are needed. In this article, we discuss the recent development for noninvasive detection of recurrent disease and therapy of mCRPC with corresponding PSMA-targeted radioligands. Clin Cancer Res; 22(1); 9–15. ©2016 AACR.

Systemic capillary leak syndrome (SCLS) is a rare disease characterized by shock caused by capillary hyperpermeability. The disease can occur in cancer patients and effective therapeutic strategies have not been established yet. The aim of the study was to analyze the clinical and laboratory data, treatment modalities, and mortality rate of patients and to identify contributing factors leading to mortality of SCLS in cancer. We searched MEDLINE (inception to July 2018) and of 4612 articles, we identified 62 case reports on SCLS associated with cancer or cancer-related drugs in a total of 53 articles. SCLS was associated with cancer itself in 43.6%, with anti-cancer agents in 51.6% and bone marrow transplantation (BMT) in 4.8%. Among anti-cancer agents, granulocyte-colony stimulating factor (G-CSF) was the most frequently associated drug (14.6%), followed by interleukin (IL)-2 (11.4%). The most common associated malignancies were hematologic (61.3%) with non-Hodgkin lymphoma (22.7%) and multiple myeloma (12.9%) being the leading causes. Common symptoms and signs included dyspnea (27.4%), edema (67.7%), hypotension (32.2%), pleural effusion (29.0%), ascites (22.7%), oliguria (22.7%), and weight gain (21.0%). Patients with SCLS were treated with steroids (59.7%), volume replacement (33.8%), diuretics (24.2%), inotropes (9.6%), methylxanthines (12.8%), &beta, 2 agonists (4.8%), while intravenous immunoglobulins (IVIG) were administered in 2 patients (3.2%) only. Among sixteen deaths during follow-up, four were directly attributed to SCLS. Hematologic malignancies were associated with an increased risk for mortality (hazard ratio (HR) 8.820, 95% confidence interval (CI) 1.126&ndash, 69.063, p = 0.038). Taken together, SCLS can be one important adverse event in cancer patients and careful monitoring of fluid volume is required in the management of SCLS.