Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

IntroductionImmunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.MethodsHere we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.ResultsWe show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.DiscussionThese data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20

Detection of Respiratory Viruses and Atypical Bacteria in Children's Tonsils and Adenoids▿

The tonsils and adenoids of 44 children were analyzed for the detection of respiratory syncytial virus, influenza virus, parainfluenza virus, adenovirus, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. Viruses were detected in 47.7% of the children and 37.3% of the specimens, with adenovirus and parainfluenza viruses being the most frequently detected microorganisms

A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146

Reinstating tissue-specific tolerance has attracted much attention as a means to treat autoimmune diseases. However, despite promising results in rodent models of autoimmune diseases, no established tolerogenic therapy is clinically available yet. In the experimental autoimmune myasthenia gravis (EAMG) model several protocols have been reported that induce tolerance against the prime disease-associated antigen, the acetylcholine receptor (AChR) at the neuromuscular junction. Using the whole AChR, the extracellular part or peptides derived from the receptor, investigators have reported variable success with their treatments, though, usually relatively large amounts of antigen has been required. Hence, there is a need for better formulations and strategies to improve on the efficacy of the tolerance-inducing therapies. Here, we report on a novel targeted fusion protein carrying the immunodominant peptide from AChR, mCTA1–T146, which given intranasally in repeated microgram doses strongly suppressed induction as well as ongoing EAMG disease in mice. The results corroborate our previous findings, using the same fusion protein approach, in the collagen-induced arthritis model showing dramatic suppressive effects on Th1 and Th17 autoaggressive CD4 T cells and upregulated regulatory T cell activities with enhanced IL10 production. A suppressive gene signature with upregulated expression of mRNA for TGFβ, IL10, IL27, and Foxp3 was clearly detectable in lymph node and spleen following intranasal treatment with mCTA1–T146. Amelioration of EAMG disease was accompanied by reduced loss of muscle AChR and lower levels of anti-AChR serum antibodies. We believe this targeted highly effective fusion protein mCTA1–T146 is a promising candidate for clinical evaluation in myasthenia gravis patients

Use of complementary and alternative medicine in children with recurrent acute otitis media in Italy

Controlling environmental factors, chemoprophylaxis, immunoprophylaxis and surgery are considered possible means of preventing recurrent acute otitis media (RAOM), but there are no available data concerning the paediatric use of complementary and alternative medicine (CAM). We evaluated the uses of CAM (homeopathy and/or herbal medicine) as means of preventing AOM in children with a history of RAOM. Eight hundred and forty Italian children with RAOM ( 653 episodes in six months) aged 1-7 years were surveyed in 2009 using a face-to-face questionnaire, filled by parents or caregivers, that explored the prevalence, determinants, reasons, cost, and perceived safety and efficacy of CAM. About one-half (46%) of the children used CAM, significantly more than the number who used immunoprophylaxis (influenza vaccine 15%; p<0.05), PCV-7 34%; p< 0.05) or chemoprophylaxis (2%; p<0.001). Use of CAM in the family was the only important factor positively associated with the use of CAM in children (adjusted OR 7.94; 95% CI: 5.26-11.99). The main reasons for using CAM were a fear of the adverse effects of conventional medicine (40%) and to increase host defences (20%). CAM was widely seen as safe (95%) and highly effective (68%). CAM prescribers were paediatricians in 50.7% of cases; self-initiation was reported by 23% of respondents. CAM expenditure was between \u20ac25 and \u20ac50/month in 27.6% of cases and 65 \u20ac50/month in 16%. Children with RAOM should be considered among the categories of subjects likely to be using CAM. Together with the fact that paediatricians are the main prescribers, this is worrying because of the current lack of evidence regarding the efficacy, safety and cost-effectiveness of CAM in the prevention of RAOM. Copyrigh

Molecular Tumor Board as a Clinical Tool for Converting Molecular Data Into Real-World Patient Care

PURPOSE The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments. PATIENTS AND METHODS Since May 2020, the institutional MTB set at Fondazione IRCCS Istituto Nazionale Tumori of Milan met weekly via teleconference to discuss molecular data and potential therapeutic options for patients with advanced/metastatic solid tumors. RESULTS Up to October 2021, among 1,996 patients evaluated, we identified >10,000 variants, 43.2% of which were functionally relevant (pathogenic or likely pathogenic). On the basis of functionally relevant variants, 711 patients (35.6%) were potentially eligible to targeted therapy according to European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets tiers, and 9.4% received a personalized treatment. Overall, larger NGS panels (containing >50 genes) significantly outperformed small panels (up to 50 genes) in detecting actionable gene targets across different tumor types. CONCLUSION Our real-world data provide evidence that MTB is a valuable tool for matching NGS data with targeted treatments, eventually implementing precision oncology in clinical practice

Role of polymorphisms of toll-like receptor (TLR) 4, TLR9, toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and FCGR2A genes in malaria susceptibility and severity in Burundian children

<p>Abstract</p> <p>Background</p> <p>Malaria caused by <it>Plasmodium falciparum</it> is one of the leading causes of human morbidity and mortality from infectious diseases, predominantly in tropical and sub-tropical countries. As genetic variations in the toll-like receptors (TLRs)-signalling pathway have been associated with either susceptibility or resistance to several infectious and inflammatory diseases, the supposition is that single nucleotide polymorphisms (SNPs) of TLR2, TLR4, TLR9, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and FCGR2A could modulate malaria susceptibility and severity.</p> <p>Methods</p> <p>This study was planned to make a further contribution to solving the problem of the real role of the most common polymorphisms of TLR4, TLR9, TIRAP and FCGR2A genes in modulating the risk of malaria and disease severity in children from Burundi, Central Africa. All the paediatric patients aged six months to 10 years admitted to the hospital of Kiremba, Burundi, between February 2011 and September 2011, for fever and suspicion of acute malaria were screened for malaria parasitaemia by light microscopy of thick and thin blood smears. In children with malaria and in uninfected controls enrolled during the study period in the same hospital, blood samples were obtained on filter paper and TLR4 Asp299Gly rs4986790, TLR9 G1174A rs352139, T-1486 C rs187084 TLR9 T-1237 C rs5743836, TIRAP Ser180Leu rs8177374 and the FCGR2A His131Arg rs1801274 polymorphisms were studied using an ABI PRISM 7900 HT Fast Real-time instrument.</p> <p>Results</p> <p>A total of 602 patients and 337 controls were enrolled. Among the malaria cases, 553 (91.9 %) were considered as suffering from uncomplicated and 49 (8.1 %) from severe malaria. TLR9 T1237C rs5743836CC was associated with an increased risk of developing malaria (p = 0.03), although it was found with the same frequency in uncomplicated and severe malaria cases. No other differences were found in all alleles studied and in genotype frequencies between malaria cases and uninfected controls as well as between uncomplicated and severe malaria cases.</p> <p>Conclusions</p> <p>TLR9 T1237C seems to condition susceptibility to malaria in Burundian children but not its severity, whereas none of the assessed SNPs of TLR4, TIRAP and FCGR2A seem to influence susceptibility to malaria and disease severity in this population.</p

Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis

: Erythropoietin (EPO) mediates a wide range of neuroprotective activities, including amelioration of disease and neuroinflammation in rat models of EAE. However, optimum dosing parameters are currently unknown. In the present study, we used a chronic EAE model induced in mice by immunization with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) to compare the effect of EPO given with different treatment schedules. EPO was administered intraperitoneally at 0.5, 5.0 or 50 microg/kg three times weekly starting from day 3 after immunization (preventive schedule), at the onset of clinical disease (therapeutic schedule) or 15 days after the onset of symptoms (late therapeutic schedule). The results show that EPO is effective even when given after the appearance of clinical signs of EAE, but with a reduced efficacy compared to the preventative schedule. To determine whether this effect requires the homodimeric EPO receptor (EPOR2)-mediated hematopoietic effect of EPO, we studied the effect of carbamylated EPO (CEPO) that does not bind EPOR2. CEPO, ameliorated EAE without changing the hemoglobin concentration. Another non-erythropoietic derivative, asialoEPO was also effective. Both EPO and CEPO equivalently decreased the EAE-associated production of TNF-alpha, IL-1beta and IL-1Ra in the spinal cord, and IFN-gamma by peripheral lymphocytes, indicating that their action involves targeting neuroinflammation. The lowest dosage tested appeared fully effective. The possibility to dissociate the anti-neuroinflammatory action of EPO from its hematopoietic action, which may cause undesired side effects in non-anemic patients, present new avenues to the therapy of multiple sclerosis

Nasopharyngeal biofilm-producing otopathogens in children with nonsevere recurrent acute otitis media

Objective. Bacterial biofilms have been detected in biopsies of the adenoid and middle ear mucosa of otitis-prone children and children with chronic middle otitis media. However, the invasiveness of biopsy makes it unsuitable for routine clinical practice, especially in pediatrics. This study aimed to investigate nasopharyngeal biofilm-producing otopathogens (BPOs) of nasopharyngeal swabs (NPS) in children with a history of nonsevere recurrent acute otitis media (RAOM) and healthy controls.Study Design. A cross-sectional study with planned data collection.Setting. University of Milan.Subjects and Methods. Transoral NPS were taken from infants and children aged 10 months to 11 years with nonsevere RAOM or healthy controls without adenoid hypertrophy. Nasopharyngeal colonization by otopathogens was assessed by means of microbiological cultures and standard bacterial identification, as well as nasopharyngeal BPOs by means of spectrophotometric analysis.Results. The study involved 113 children (56.6% males; median age 40 months; range, 10-132 months): 58 with a history of nonsevere RAOM (51.3%) and 55 controls (48.7%). Otopathogens were significantly more frequently detected in the RAOM group (24/58, 41.4%) than in controls (8/55, 14.5%; P =.003); the main pathogens were respectively Haemophilus influenzae (12/24, 50.0%) and Streptococcus pyogenes (3/8, 37.5%). Nasopharyngeal BPOs were more frequently isolated in the RAOM group (17/58, 29.3%) than in controls (6/55, 10.9%; P =.02). H influenzae (12/17, 70.6%) was confirmed as the main pathogen in the RAOM group.Conclusion. The presence of nasopharyngeal BPOs is an important factor favoring RAOM; it is therefore useful investigating biofilms even in children with nonsevere recurrences of AOM without adenoid hypertrophy

Zinc deficiency suppresses the development of oral tolerance in rats

Oral tolerance is a specific immune unresponsiveness to food antigens to prevent hypersensitivity reactions. We investigated whether zinc deficiency affects oral tolerance. Rats were fed a control (C) or zincdeficient (ZD) diet, or pair-fed (PF) to ZD rats for 28 d. Beginning on d 7, rats were administered ovalbumin (OVA) orally to induce tolerance, or PBS 3 times/wk, and were then immunized by OVA injection. The proliferation of mesenteric lymph node (MLN) and spleen lymphocytes after in vitro OVA stimulation and the delayed-type hypersensitivity were higher in OVA-fed ZD than in OVA-fed C rats and not different between OVA- and PBS-fed ZD rats, indicating a suppression of tolerance. Lymphocyte proliferation did not differ between PF and C rats. Expressions of cytokines involved in oral tolerance, i.e., interleukin (IL)-4, IL-10 and transforming growth factor- , were higher in OVA- than in PBS-fed C rats, but not in ZD rats. Apoptosis was higher in OVA- than in PBS-fed C rats but not different between OVA- and PBS-fed ZD rats. Inflammation and ulcerations that were not present in ZD rats on d 7 (ZD7 ) developed in OVA- or PBS-fed ZD rats. Compared with ZD7 rats, tumor necrosis factor- and cytokine-induced neutrophil chemoattractant were higher in OVA- and PBS-fed ZD rats, whereas interferon- increased only in OVA-fed ZD rats. In conclusion, zinc deficiency suppresses oral tolerance through dysregulation of cytokine expression and lack of antigen-specific clonal deletion. We suggest that abrogation of tolerance may lead to development of mucosal inflammation and damage.L'articolo è disponibile sul sito dell'editore http://jn.nutrition.or