Classification of Neisseria meningitidis genomes with a bag-of-words approach and machine learning.

Whole genome sequencing of bacteria is important to enable strain classification. Using entire genomes as an input to machine learning (ML) models would allow rapid classification of strains while using information from multiple genetic elements. We developed a "bag-of-words" approach to encode, using SentencePiece or k-mer tokenization, entire bacterial genomes and analyze these with ML. Initial model selection identified SentencePiece with 8,000 and 32,000 words as the best approach for genome tokenization. We then classified in Neisseria meningitidis genomes the capsule B group genotype with 99.6% accuracy and the multifactor invasive phenotype with 90.2% accuracy, in an independent test set. Subsequently, in silico knockouts of 2,808 genes confirmed that the ML model predictions aligned with our current understanding of the underlying biology. To our knowledge, this is the first ML method using entire bacterial genomes to classify strains and identify genes considered relevant by the classifier.

Serum Immunoglobulin G (IgG) Subclasses in a Cohort of Systemic Sclerosis Patients.

OBJECTIVES: To assess serum immunoglobulin G (IgG) subclasses in a cohort of systemic sclerosis (SSc) patients and to evaluate the influence of IgG subclasses in the main complications of the disease. METHODS: The serum level of IgG subclasses was evaluated in 67 SSc patients and 48 healthy controls (HC), matched for sex and age. Serum samples were collected and measured IgG1-4 subclasses by turbidimetry. RESULTS: SSc patients had lower median total IgG [9.88 g/l (IQR 8.18-11.42 g/l) vs. 12.09 g/l (IQR 10.24-13.54 g/l), p < 0.001], IgG1 [5.09 g/l (IQR 4.25-6.38 g/l) vs. 6.03 g/l (IQR 5.39-7.90 g/l), p < 0.001], and IgG3 [0.59 g/l (IQR 0.40-0.77 g/l) vs. 0.80 g/l (IQR 0.46-1 g/l), p < 0.05] serum levels compared to HC. The logistic regression analysis showed IgG3 as the only variable associated with the diffusing capacity of the lung for carbon monoxide (DLco) ≤60% of the predicted [OR 9.734 (CI 95%: 1.312-72.221), p < 0.05] and modified Rodnan skin score (mRSS) [OR 1.124 (CI 95%: 1.019-1.240), p < 0.05], anti-topoisomerase I [OR 0.060 (CI 95%: 0.007-0.535), p < 0.05], and IgG3 [OR 14.062 (CI 95%: 1.352-146.229), p < 0.05] as variables associated with radiological interstitial lung disease (ILD). CONCLUSION: SSc patients have reduced levels of total IgG and an altered IgG subclass distribution compared to HC. Moreover, SSc patients show different serum IgG subclasses profiles according to the main involvement of the disease.

Safety of mRNA COVID-19 Vaccines in Patients with Inborn Errors of Immunity: an Italian Multicentric Study.

PURPOSE: Little is known about vaccine safety in inborn errors of immunity (IEI) patients during the current vaccination campaign for COVID-19. To better investigate the reactogenicity and adverse event profile after two, three, and four doses of mRNA vaccines, we conducted an observational, multicentric study on 342 PID patients from four Italian Referral Centres. METHODS: We conducted a survey on self-reported adverse reactions in IEI patients who received mRNA vaccine by administering a questionnaire after each dose. RESULTS: Over the whole study period, none of the patients needed hospitalization or had hypersensitivity reactions, including anaphylaxis and delayed injection site reaction. After two vaccination doses, 35.4% of patients showed only local reactogenicity-related symptoms (RrS), 44.4% reported both systemic and local RrS, and 5% reported only systemic RrS. In more than 60% of cases, local or systemic RrS were mild. After the first and second booster doses, patients showed fewer adverse events (AEs) than after the first vaccination course. Patients aged 50 years and older reported adverse events and RrS less frequently. Among AEs requiring treatment, one common variable immune deficiency patient affected by T cell large granular lymphocytic leukemia developed neutropenia and one patient had Bell's paralysis perhaps during herpes zoster reactivation. CONCLUSION: Although our follow-up period is relatively short, the safety data we reported are reassuring. This data would help to contrast the vaccine hesitancy often manifested by patients with IEI and to better inform their healthcare providers.

Mortality in Severe Antibody Deficiencies Patients during the First Two Years of the COVID-19 Pandemic: Vaccination and Monoclonal Antibodies Efficacy.

Patients with severely impaired antibody responses represent a group at-risk in the SARS-CoV-2 pandemic due to the lack of Spike-specific neutralizing antibodies. The main objective of this paper was to assess, by a longitudinal prospective study, COVID-19 infection and mortality rates, and disease severity in the first two years of the pandemic in a cohort of 471 Primary Antibody Defects adult patients. As secondary endpoints, we compared SARS-CoV-2 annual mortality rate to that observed over a 10-year follow-up in the same cohort, and we assessed the impact of interventions done in the second year, vaccination and anti-SARS-CoV-2 monoclonal antibodies administration on the disease outcome. Forty-one and 84 patients were infected during the first and the second year, respectively. Despite a higher infection and reinfection rate, and a higher COVID-19-related mortality rate compared to the Italian population, the pandemic did not modify the annual mortality rate for any cause in our cohort compared to that registered over the last ten years in the same cohort. PADs patients who died from COVID-19 had an underlying end-stage lung disease. We showed a beneficial effect of MoAbs administration on the likelihood of hospitalization and development of severe disease. In conclusion, COVID-19 did not cause excess mortality in Severe Antibody Deficiencies.

Active Galactic Nuclei Jets as the Origin of Ultrahigh-Energy Cosmic Rays and Perspectives for the Detection of Astrophysical Source Neutrinos at EeV Energies.

We demonstrate that a population of active galactic nuclei (AGN) can describe the observed spectrum of ultra-high-energy cosmic rays (UHECRs) at and above the ankle, and that the dominant contribution comes from low-luminosity BL Lacertae objects. An additional, subdominant contribution from high-luminosity AGN is needed to improve the description of the composition observables, leading to a substantial neutrino flux that peaks at exaelectronvolt (EeV) energies. We also find that different properties for the low- and high-luminosity AGN populations are required; a possibly similar baryonic loading can already be excluded from current IceCube Neutrino Observatory observations. We also show that the flux of neutrinos emitted from within the sources should outshine the cosmogenic neutrinos produced during the propagation of UHECRs. This result has profound implications for the ultra-high-energy (∼EeV) neutrino experiments, since additional search strategies can be used for source neutrinos compared to cosmogenic neutrinos, such as stacking searches, flare analyses, and multimessenger follow-ups.

Relevance of Adherence Monitoring in Adult Patients With Growth Hormone Deficiency Under Replacement Therapy: Preliminary Monocentric Data With EasypodTM Connect.

Purpose: Non-compliance to recombinant human growth hormone (r-hGH) therapy in adult growth hormone deficiency (aGHD) is a major concern for endocrinologist, as it affects significantly efficacy outcomes. This 12-month observational study was aimed to assess adherence in GHD patients treated with r-hGH administered via EasypodTM, an electronic, fully automated injection device designed to track the time, date and dose administered. Methods: 65 patients receiving r-hGH therapy were included in the study and 32 completed the study. The primary endpoint, adherence to treatment, was calculated as the proportion of injections correctly administered during the observational period out of the expected total number of injections. Adherence, tracked by the EasypodTM, was evaluated at months 6 (V1) and 12 (V2) after baseline (V0). As secondary end-point, serum IGF-1 levels were also determined. Results: The EasypodTM data showed a median adherence of 80% throughout the period V0-V2. Females are more compliant than males. Adherence levels are correlated to IGF-1 ones. Conclusions: Adherence is connected with therapy efficacy in aGHD. The injection-recording system and other characteristics of EasypodTM could enhance the ability of physicians to monitor adherence to r-hGH treatment, identifying non-compliant patients, thus enabling physicians to modify their management to maximize the benefits of the treatment.