Glycovaccine Design: Optimization of Model and Antitubercular Carrier Glycosylation via Disuccinimidyl Homobifunctional Linker

Conjugation via disuccinimidyl homobifunctional linkers is reported in the literature as a convenient approach for the synthesis of glycoconjugate vaccines. However, the high tendency for hydrolysis of disuccinimidyl linkers hampers their extensive purification, which unavoidably results in side-reactions and non-pure glycoconjugates. In this paper, conjugation of 3-aminopropyl saccharides via disuccinimidyl glutarate (DSG) was exploited for the synthesis of glycoconjugates. A model protein, ribonuclease A (RNase A), was first considered to set up the conjugation strategy with mono- to tri- mannose saccharides. Through a detailed characterization of synthetized glycoconjugates, purification protocols and conjugation conditions have been revised and optimized with a dual aim: ensure high sugar-loading and avoid the presence of side reaction products. An alternative purification approach based on hydrophilic interaction liquid chromatography (HILIC) allowed the formation of glutaric acid conjugates to be avoided, and a design of experiment (DoE) approach led to optimal glycan loading. Once its suitability was proven, the developed conjugation strategy was applied to the chemical glycosylation of two recombinant antigens, native Ag85B and its variant Ag85B-dm, that are candidate carriers for the development of a novel antitubercular vaccine. Pure glycoconjugates (≥99.5%) were obtained. Altogether, the results suggest that, with an adequate protocol, conjugation via disuccinimidyl linkers can be a valuable approach to produce high sugar-loaded and well-defined glycovaccines

Early versus delayed antiretroviral therapy based on genotypic resistance test: Results from a large retrospective cohort study

Rapid start of antiretroviral therapy (ART) pending genotypic resistance test (GRT) has been recently proposed, but the effectiveness of this strategy is still debated. The rate of virological success (VS), defined as HIV-RNA\u2009<\u200950 copies/ml, with and without GRT was compared in drug-na\uefve individuals enrolled in the Italian ARCA cohort who started ART between 2015 and 2018. 521 individuals started ART: 397 without GRT (pre-GRT group) and 124 following GRT (post-GRT group). Overall, 398 (76%) were males and 30 (6%) were diagnosed with AIDS. In the pre-GRT group, baseline CD4+\u2009cell counts were lower (p\u2009<\u20090.001), and viral load was higher (p\u2009<\u20090.001) than in the post-GRT group. The estimated probability of VS in pre-GRT versus post-GRT group was 72.54% (CI95 : 67.78-76.60) versus 66.94% (CI95 : 57.53-74.26) at Week 24 and 92.40% (CI95 : 89.26-94.62) versus 92.92% (CI95 : 86.35-96.33) at Week 48, respectively (p\u2009=\u20090.434). At Week 48, VS was less frequent among individuals with baseline CD4+\u2009cell counts <200 versus >500 (90.33% vs. 97.33%), log viral load <5.00 versus >5.70 log10 cps/ml (97.17% vs 78.16%; p\u2009<\u20090.001), and those treated with protease inhibitors or non-nucleoside reverse transcriptase inhibitors versus those treated with integrase strand transfer inhibitors (p\u2009<\u20090.001). The rate of VS does not seem to be affected by an early ART initiation pending GRT results, but it could be influenced by the composition of the ART regimen, as well as immuno-virological parameters

Analysis of Italian requests for compensation in cases of responsibility for healthcare-related infections: A retrospective study

IntroductionThe aim of this study was to examine the type of compensation claims for alleged medical malpractice in the field of healthcare-related infections in Italy.MethodsIt was analyzed which was the most frequent clinical context, the characteristics of the disputes established, which were the alleged damages most often complained of, which were the possibly censurable behaviors of the health professionals, and which were the reasons for acceptance or rejection of the request for compensation.ResultsIn 90.2%, the issue questioned regarded surgical site infections. The most common pathogens involved were coagulase-negative Staphylococci (34.1%) and Staphylococcus aureus (24.4%). The lack or non-adherence to protocols of prophylaxis and/or prevention of healthcare-related infections was the most reported cause of acceptance of the request of compensation.DiscussionAccording to our data, a stronger effort should be made in terms of risk management perspective in order to ensure the develop and application of protocols for prevention of Gram-positive healthcare-related infections and strengthen infection control and antimicrobial stewardship programs

Superinfections caused by carbapenem-resistant Enterobacterales in hospitalized patients with COVID-19: a multicentre observational study from Italy (CREVID Study)

Objectives To describe clinical characteristics and outcomes of COVID-19 patients who developed secondary infections due to carbapenem-resistant Enterobacterales (CRE). Methods Retrospective observational study including COVID-19 patients admitted to 12 Italian hospitals from March to December 2020 who developed a superinfection by CRE. Superinfection was defined as the occurrence of documented bacterial infection >48 h from admission. Patients with polymicrobial infections were excluded. Demographic, clinical characteristics and outcome were collected. Isolates were classified as KPC, metallo-beta-lactamase (MBL) and OXA-48-producing CRE. A Cox regression analysis was performed to identify factors independently associated with 30 day mortality. Results Overall, 123 patients (median age 66 years, IQR 59-75) were included. The majority of infections occurred in the ICU (81, 65.9%), while 42 (34.1%) in medical wards. The most common types of infection were bloodstream infections (BSI) (n = 64, 52%), followed by urinary-tract infections (UTI) (n = 28, 22.8%), hospital-acquired/ventilator-associated pneumonia (HAP/VAP) (n = 28, 22.8%), intra-abdominal infections (n = 2, 1.6%) and skin infections (n = 1, 0.8%). Sixty-three (51.2%) infections were caused by KPC-, 54 (43.9%) by MBL-, and 6 (4.8%) by OXA-48-producing CRE. Thirty-day mortality was 33.3% (41/123). On Cox regression analysis, HAP/VAP compared with UTI (HR 7.23, 95% CI 2.09-24.97, P = 0.004), BSI compared with UTI (HR 3.96, 95% CI, 1.33-11.77, P = 0.004), lymphopenia on admission (HR 3, 95% CI 1.44-6.26, P = 0.003) and age (HR 1.05, 95% CI 1.02-1.08, P = 0.002) were predictors of 30 day mortality. Conclusions Superinfections by CRE were associated with high risk of 30 day mortality in patients with COVID-19. HAP/VAP was the strongest predictor of death in these patients

Tocilizumab and corticosteroids for covid-19 treatment in elderly patients

Background. The mortality rate for coronavirus disease-19 (COVID-19) increases with age. Some anti-inflammatory drugs such as tocilizumab or steroids have been proposed for the treatment of severe disease; however, few data are available in the elderly. Methods. A retrospective case-series of patients hospitalized between March 1st and June 15th, 2020 with confirmed COVID-19 by RT-PCR testing on throat/nasopharyngeal swabs and age ≥ 65 years was analysed. Patients were retrospectively divided into three groups according to the chosen treatment [standard of care (SOC), tocilizumab or corticosteroids] and patient characteristics and occurrence of adverse events were compared among groups. Results. Overall, 206 patients were included, 148 treated with standard of care, 42 with steroids and 16 with tocilizumab. Patients treated with steroids or Tocilizumab presented more frequently with fever (p = .003), dyspnea (p < .001), bilateral opacities/infiltrates at chest X-ray (p =.026) or CT-scan (p = .020), and more frequently required non-invasive/invasive ventilation (p < .001). Crude mortality was 27%, without differences among groups (p = .074). No specific adverse events were observed during/after the administration of steroids or tocilizumab; however, a trend towards an increased risk of secondary infections was described compared to SOC (p = .097). At multivariate logistic regression, only tocilizumab administration was an independent predictor of secondary infections (aOR = 6.72, 95% CI = 1.43-31.39, p = .015). Conclusions. Tocilizumab and corticosteroid could have a possible role for severe form of pneumonia in course of COVID-19 also in elderly patients, even if great attention to the monitoring of infectious complications should be paid in this special population

Stool Xpert MTB/RIF as a possible diagnostic alternative to sputum in Africa: a systematic review and meta-analysis

IntroductionWorldwide, COVID-19 pandemic lead to a large fall in the number of newly reported TB cases. In sub-Saharan Africa, microbiological diagnosis of TB is generally based on smear microscopy and Xpert MTB/RIF on sputum samples, but good quality sputum samples are often difficult to obtain, leading clinicians to rely on more invasive procedures for diagnosis. Aim of this study was to investigate pooled sensitivity and specificity of Xpert MTB/RIF on stool samples compared to respiratory microbiological reference standards in African countries.MethodsFour investigators independently searched PubMed, SCOPUS, and Web of Science until 12th October 2022, then screened titles and abstracts of all potentially eligible articles. The authors applied the eligibility criteria, considered the full texts. All the studies reported the data regarding true positive (TP), true negative (TN), false positive (FP) and false negative (FN). Risk of bias and applicability concerns were assessed with the Quadas-2 tool.Resultsoverall, among 130 papers initially screened, we evaluated 47 works, finally including 13 papers for a total of 2,352 participants, mainly children. The mean percentage of females was 49.6%, whilst the mean percentage of patients reporting HIV was 27.7%. Pooled sensitivity for Xpert MTB/RIF assay for detecting pulmonary tuberculosis was 68.2% (95%CI: 61.1–74.7%) even if characterized by a high heterogeneity (I2=53.7%). Specificity was almost 100% (99%, 95%CI: 97–100%; I2 = 45.7%). When divided for reference standard, in the six studies using sputum and nasogastric aspirate the accuracy was optimal (AUC = 0.99, SE = 0.02), whilst in the studies using only sputum for tuberculosis detection the AUC was 0.85 (with a SE = 0.16). The most common source of bias was exclusion of enrolled patients in the analysis.ConclusionsOur study confirms that, in Africa, stool Xpert MTB/RIF may be a useful rule-in test for children above and below 5 years of age under evaluation for pulmonary tuberculosis. Sensitivity increased substantially when using both sputum and nasogastric aspirate as reference samples

HIV and Co-Infections: Updates and Insights

: Co-infections are frequent in HIV patients; some of them may be AIDS-defining, while others share the same underlying virus mechanism [...]

What do clinicians mean by epidemics' preparedness

Background: Infectious disease pandemics and epidemics pose significant global threats, and the risk of emerging infectious diseases has increased because of factors such as international connections, travel, and population density. Despite investments in global health surveillance, much of the world remains unprepared to manage infectious disease threats. Objectives: This review article discusses the general considerations and lessons learned from the COVID-19 pandemic in terms of epidemic preparedness. Sources: Non-systematic search on PubMed, scientific society websites, and scientific newspapers (performed in April 2023). Content: Key factors for preparedness include robust public health infrastructure, adequate allocation of resources, and effective communication between stakeholders. This narrative review emphasizes the need for timely and accurate dissemination of medical knowledge, as well as addressing the challenges of misinformation and infodemics. It also highlights the importance of quick availability of diagnostic tests and vaccines, ensuring equitable access to these technologies. The role of scientific coordination in developing treatment strategies and the safety and mental well-being of healthcare workers are discussed. Lastly, it should be emphasized the need for medical training, multidisciplinary teams, new technologies and artificial intelligence, and the active role of infectious disease physicians in epidemic preparedness efforts. Implications: From clinicians' perspective, healthcare authorities play a crucial role in epidemic preparedness even by providing resource management plans, ensuring availability of essential supplies and training, facilitating communication, and improving safe infection management

Targeted therapies for autoimmune/idiopathic nonmalignant diseases: risk and management of opportunistic infections

The management of patients affected by autoimmune/idiopathic diseases has been revolutionized by the development of targeted therapies (TT). However, the use of TT is complicated by several adverse events, like opportunistic infections (OIs). The potential of TT to predispose to OIs mainly depends on the site of action; nevertheless, such associations are far from being deterministic, because many factors could increase the infection risk