Dolutegravir and Folic Acid Interaction during Neural System Development in Zebrafish Embryos.

Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 µM) and observed the disruption of the anterior-posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain-hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)+ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.

Long-term symptoms after SARS-CoV-2 infection in a cohort of people living with HIV.

BACKGROUND: Our Hospital in Northern Italy assists 3817 people living with HIV (PLWH) and has faced the impact of COVID-19. Little is known about the impact of HIV infection on the risk of post-COVID-19 conditions (PCCs) onset. We aim to assess the incidence of PCC in PLWH and the factors associated with its occurrence. METHODS: We performed a retrospective, observational study including all PLWH > 18 years registered in the Brescia Health Protection Agency database, assessing SARS-CoV-2 burden, vaccination status, socio-demographic, and viro-immunological parameters from February 2020 until May 2022. Persistence of self-reported symptoms (clustered into gastrointestinal, respiratory, osteo-muscular, and neuro-behavioral symptoms) was evaluated after 3 months by a telephone-administered questionnaire. We estimated the associations between all variables and outcomes through univariate and multivariable logistic models. RESULTS: In the study period, 653 PLWH were diagnosed with SARS-CoV-2 infection (17.1%). We observed 19 (2.9%) reinfections, 71 (10.9%) hospitalizations, and 3 (0.5%) deaths. We interviewed 510/653 PLWH (78%), and 178 (PCCs prevalence 34.9%; CI 95% 30.7-39.2) reported persistent symptoms. Asthenia/fatigue was the most reported symptom (60/178), followed by muscular pain (54/178). In the multivariate regression model, there was a lower risk of PCCs in males respect to females (adjusted OR = 0.64; CI 95% 0.99-3.66), while hospitalization during acute infection was associated with an increased the risk of PCCs (adjusted OR = 1.9; CI 95% 0.99-3.66). Notably, no viro-immunological variable modified the PCCs risk onset. CONCLUSIONS: Our study highlights a substantial prevalence of PCCs among PLWH, three months post-SARS-CoV-2 infection, independent of viro-immunological features or vaccination status.

Immunogenicity and safety of live attenuated and recombinant/inactivated varicella zoster vaccines in people living with HIV: A systematic review.

Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly recombinant vaccine (RZV) was recently introduced and approved for HZ prevention among adults. PLWH represents a population on which a particular attention should be applied, in order to guarantee the vaccine efficacy and safety. We performed a literature search in USNLM, PubMed, PubMed Central, PMC and Cochrane Library. From all the publications found eligible, data were extracted and processed per population, vaccine type, immunogenicity and ADRs. The review of the 13 included studies shows that both RZV and VZL are immunogenic and have an acceptable safety profile in adults and children living with HIV. However, given the lack of research available about vaccine efficacy in preventing VZV and HZ in PLWH, additional studies need to be performed, in order to achieve a full completeness of data.

The Impact of Immune System Aging on Infectious Diseases.

Immune system aging is becoming a field of increasing public health interest because of prolonged life expectancy, which is not paralleled by an increase in health expectancy. As age progresses, innate and adaptive immune systems undergo changes, which are defined, respectively, as inflammaging and immune senescence. A wealth of available data demonstrates that these two conditions are closely linked, leading to a greater vulnerability of elderly subjects to viral, bacterial, and opportunistic infections as well as lower post-vaccination protection. To face this novel scenario, an in-depth assessment of the immune players involved in this changing epidemiology is demanded regarding the individual and concerted involvement of immune cells and mediators within endogenous and exogenous factors and co-morbidities. This review provides an overall updated description of the changes affecting the aging immune system, which may be of help in understanding the underlying mechanisms associated with the main age-associated infectious diseases.

Inflammatory Response Associated with West Nile Neuroinvasive Disease: A Systematic Review.

BACKGROUND: West Nile virus (WNV) infection is a seasonal arbovirosis with the potential to cause severe neurological disease. Outcomes of the infection from WNV depend on viral factors (e.g., lineage) and host-intrinsic factors (e.g., age, sex, immunocompromising conditions). Immunity is essential to control the infection but may also prove detrimental to the host. Indeed, the persistence of high levels of pro-inflammatory cytokines and chemokines is associated with the development of blood-brain barrier (BBB) damage. Due to the importance of the inflammatory processes in the development of West Nile neuroinvasive disease (WNND), we reviewed the available literature on the subject. METHODS: According to the 2020 updated PRISMA guidelines, all peer-reviewed articles regarding the inflammatory response associated with WNND were included. RESULTS: One hundred and thirty-six articles were included in the data analysis and sorted into three groups (in vitro on-cell cultures, in vivo in animals, and in humans). The main cytokines found to be increased during WNND were IL-6 and TNF-α. We highlighted the generally small quantity and heterogeneity of information about the inflammatory patterns associated with WNND. CONCLUSIONS: Further studies are needed to understand the pathogenesis of WNND and to investigate the extent and the way the host inflammatory response either helps in controlling the infection or in worsening the outcomes. This might prove useful both for the development of target therapies and for the development of molecular markers allowing early identification of patients displaying an inflammatory response that puts them at a higher risk of developing neuroinvasive disease and who might thus benefit from early antiviral therapies.

Female Genital Schistosomiasis: A Neglected among the Neglected Tropical Diseases.

Schistosomiasis is a neglected parasitic disease linked to water, posing a global public health concern with a significant burden in sub-Saharan Africa. It is transmitted by Schistosoma spp., causing both acute and chronic effects affecting the urogenital or the hepato-intestinal system. Through granuloma formation, chronic schistosomiasis weakens host immunity, heightening susceptibility to coinfections. Notably, female genital schistosomiasis (FGS), a disregarded gynecological condition, adversely affects girls' and women's reproductive health and increases vulnerability to HIV. This review explores the intricate interplay between schistosomiasis and HIV, considering their geographical overlap. We delve into the clinical features of this coinfection, underlying mutual influences on transmission, diagnostic challenges, and therapeutic approaches. Understanding the dynamics of FGS and HIV coinfection is pivotal for integrated healthcare strategies in regions with co-endemicity, aiming to mitigate the impact of the two infections on vulnerable populations.

Characterization and outcomes of difficult-to-treat patients starting modern first-line ART regimens: Data from the ICONA cohort.

OBJECTIVES: Treatment failures to modern antiretroviral therapy (ART) raise concerns, as they could reduce future options. Evaluations of occurrence of multiple failures to modern ART are missing and their significance in the long run is unclear. METHODS: People with HIV (PWH) in the ICONA cohort who started a modern first-line ART were defined as 'difficult to treat' (DTT) if they experienced ≥1 among: i) ≥2 VF (2 viral loads, VL>200 copies/mL or 1 VL>1000 copies/mL) with or without ART change; ii) ≥2 treatment discontinuations (TD) due to toxicity/intolerance/failure; iii) ≥1 VF followed by ART change plus ≥1 TD due to toxicity/intolerance/failure. A subgroup of the DTT participants were matched to PWH that, after the same time, were non-DTT. Treatment response, analysing VF, TD, treatment failure, AIDS/death, and SNAE (Serious non-AIDS event)/death, were compared. Survival analysis by KM curves and Cox regression models were employed. RESULTS: Among 8061 PWH, 320 (4%) became DTT. Estimates of becoming DTT was 6.5% (95% CI: 5.8-7.4%) by 6 years. DTT PWH were significantly older, with a higher prevalence of AIDS and lower CD4+ at nadir than the non-DTT. In the prospective analysis, DTT demonstrated a higher unadjusted risk for all the outcomes. Once controlled for confounders, significant associations were confirmed for VF (aHR 2.23, 1.33-3.73), treatment failure (aHR 1.70, 1.03-2.78), and SNAE/death (aHR 2.79, 1.18-6.61). CONCLUSION: A total of 6.5% of PWH satisfied our definition of DTT by 6 years from ART starting. This appears to be a more fragile group who may have higher risk of failure.

Chronic Hepatitis C Cascade of Care in Prisoners-Is There Still Some Work to Do? Analysis of Two Large Penitentiaries in Northern Italy.

Penitentiaries have a higher burden of communicable diseases compared to the general population. Prisoners should be tested for hepatitis C virus (HCV) and have direct access to treatment. We analysed the HCV cascade of care in two penitentiaries in Brescia, Northern Italy. At admission, prisoners are offered a voluntary screening for HCV, while patients with known infections are tested with an HCVRNA measurement. We performed an observational retrospective study including all the subjects admitted to the penitentiaries from 1 January 2015 to 31 October 2021. We conducted a descriptive analysis. During the study period, 5378 admissions were registered, and 2932 (54.5%) screenings were performed. Hepatitis C virus antibody positivity was found in 269 tests (9.2%). Hepatitis C virus RNA was detectable in 169 people. During the study period, 77 treatments with direct-acting antivirals (DAAs) were administered. Follow-up was available in 45 patients, and sustained virological response (SVR) was documented in 44 of them. Retention in care occurred in less than half of the prisoners after release. Our data demonstrate poor screening adherence that could benefit from educational programs. Treatment rates could be improved with test-and-treat programs. More efforts are needed to eliminate HCV as a public threat by 2030. Dedicated local networks, including infectious diseases (ID) departments, substance abuse services and prisons, could mitigate these issues.

Finger nodules with a papulovesicular hands and feet eruption: a complicated human Orf virus infection.

BACKGROUND: Orf virus (ORFV) is the pathogen responsible for Orf, a zoonotic viral infection that can be spread to humans from sheep and goats. Here, we present a case of human Orf complicated by an immune-related reaction, to raise awareness of this under-recognized disease avoiding unnecessary investigations and overtreatment. CASE REPORT: A 51-year-old woman with no previous medical history presented with a one-week history of three asymptomatic swelling nodules with a grey necrotic center and red outer halo on her index finger. At physical examination there was also a pruritic papulovesicular eruption on her hands and feet. She reported a recent contact with a goat which had a similar nodular lesion in its mouth. A biopsy of the lesions was performed and a diagnosis of Orf complicated by widespread erythema multiforme was made based on the clinical and histopathological features. The lesions spontaneously resolved within the next 2 weeks. CONCLUSIONS: Orf is not very prevalent in our region, so we performed a biopsy of the lesion to guide us toward a diagnosis. However, we should remember that the diagnosis of ecthyma relies on clinical evaluation and epidemiological criteria.

Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals.

BACKGROUND: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. OBJECTIVE: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. METHODS: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor ß repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients. RESULTS: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert. CONCLUSIONS: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.

High frequency of type I interferon auto-antibodies in a group of middle-aged HIV-infected patients: A cross-sectional exploratory study.

BACKGROUND: Auto-antibodies neutralizing the activity of type I interferons have been recently described in patients infected by SARS-CoV-2. They can be present even before the onset of the infection. Since type I interferons exert a dichotomous role in the pathogenesis of acute versus chronic HIV infection and auto-antibodies are often found in untreated and anti-retroviral treated HIV+ patients, we investigated whether auto-antibodies anti-type I interferons are present at high prevalence in those HIV+ patients with concomitant opportunistic infections (OIs). METHODS: The analysis of auto-antibodies against two types of type I interferons (IFN-α2 and IFN-ω) was performed using the ELISA test in 60 patients chronically infected by HIV who showed concomitant infections caused by mycobacterium tuberculosis or nontuberculosis mycobacterium or with active cytomegalovirus infections. Results were compared with those of 283 SARS-CoV-2 swab positive patients showing mild to severe pneumonia. A chi-square (χ2 ) test or the Wilcoxon-Mann-Whitney test were used to compare the HIV+ patient categorical or continuous variables, respectively. RESULTS: A high prevalence of auto-antibodies to type I interferons was found in middle-aged HIV-infected patients with concomitant OIs (11.6% vs. 5.3% in COVID-19 subjects; p < .05). No statistically differences were found for viro/immunological characteristics (CD4 and CD8 cell counts and viral load) between patients with and without type I interferons auto-antibodies. CONCLUSIONS: This study, which is the first searching auto-antibodies against type I interferons in HIV-infected patients, demonstrated that their prevalence was higher than that expected by the age of these patients. Furthermore, it indicated that these auto-antibodies are nonspecifically increased in critical SARS-CoV-2 infection but can be found also in other infections.

Knowledge and Attitudes towards HIV and HCV among the Population Attending the Fast-Track Cities Mobile Unit in Brescia, Italy.

The Infectious and Tropical Diseases Department of the University of Brescia organized free rapid screening tests for HIV and HCV as part of the Fast-Track City commitment. A cross-sectional study was conducted, consisting of an anonymous multiple-choice questionnaire that was administered to individuals who underwent the screening or consultation. The study aimed to compare knowledge and attitudes towards HIV and HCV between age groups (18-40 vs. >40) and sexual orientations (heterosexual vs. LGBTQ+). Overall, 333 questionnaires were completed. Overall, only 107 (32%) of respondents knew how HIV is transmitted. Major differences were shown between different age groups, where people under the age of 40 had a significantly higher correct response rate than people over 40 (n = 101; 39% versus n = 6; 7.8%, p < 0.00001). Similarly, almost half of LGBTQI+ people (n = 28; 44.4%) gave the correct answer, versus 30% (n = 79) of heterosexuals (p = 0.0359). Only 9.6% of the population demonstrated high levels of knowledge for both HIV and HCV. Our study highlights that misconceptions about HIV and HCV should be addressed in prevention and education programs, whose target should also be specific populations.

Convenience, efficacy, safety, and durability of INSTI-based antiretroviral therapies: evidence from the Italian MaSTER cohort.

BACKGROUND: Integrase strand transferase inhibitors (INSTI), including raltegravir (RAL), elvitegravir (ELV), and dolutegravir (DTG), have demonstrated better efficacy and tolerability than other combination antiretroviral therapy (cART) classes in clinical trials; however, studies of sustainability of INSTI-containing therapy in the long-term are sparse. The purpose of this study was to provide an epidemiological overview comparing the outcome performance of different INSTI-based regimens longitudinally, including the metrics of efficacy, safety, convenience, and durability among a large, nationally representative cohort of persons living with HIV in Italy. METHODS: We selected subjects in the MaSTER cohort (an Italian multicenter, hospital-based cohort established in the mid-1990s that currently has enrolled over 24,000 PLWH) who initiated an INSTI-based regimen either when naïve or following a regimen switch. Cox proportional hazards regression models were fitted to evaluate associations between therapy interruptions and age, sex, nationality, transmission risk group, viral suppression status, CD4 + T-cell count, diagnosis year, cART status (naïve or experienced), and hepatitis coinfection. Results were stratified by cART INSTI type. RESULTS: There were 8173 participants who initiated an INSTI-based cART regimen in the MaSTER cohort between 2009 and 2017. The population was majority male (72.6%), of Italian nationality (88.6%), and cART-experienced (83.0%). Mean age was 49.7 (standard deviation: 13.9) years. In total, interruptions of the 1st INSTI-based treatment were recorded in 34% of cases. The most frequently cited reason for interruption among all three drug types was safety problems. In the survival analysis, past history of cART use was associated with higher hazards of interruption due to poor efficacy for all three drug types when compared to persons who were cART naïve. Non-viral suppression and CD4 + T-cell count < 200/mm3 at baseline were associated with higher hazards of interruption due to efficacy, safety, and durability reasons. Non-Italian nationality was linked to higher hazards of efficacy interruption for RAL and EVG. Age was negatively associated with interruption due to convenience and positively associated with interruption due to safety reasons. People who injects drugs (PWID) were associated with higher hazards of interruption due to convenience problems. Hepatitis coinfection was linked to higher hazards of interruption due to safety concerns for people receiving RAL. CONCLUSION: One-third of the population experienced an interruption of any drugs included in INSTI therapy in this study. The most frequent reason for interruption was safety concerns which accounted for one-fifth of interruptions among the full study population, mainly switched to DTG. The hazard for interruption was higher for low baseline CD4 + T-cell counts, higher baseline HIV-RNA, non-Italian nationality, older age, PWID and possible co-infections with hepatitis viruses. The risk ratio was higher for past history of cART use compared to persons who were cART naive, use of regimens containing 3 drugs compared to regimens containing 2 drugs. Durability worked in favor of DTG which appeared to perform better in this cohort compared to RAL and EVG, though length of follow-up was significantly shorter for DTG. These observational results need to be confirmed in further perspective studies with longer follow-up.

Is HCV elimination among persons living with HIV feasible? Data from the NoCo study in the setting of the ICONA cohort.

BACKGROUND AND AIMS: Whether the HCV test-and-treat strategy impacted on the rate of new HCV infections among PLWH in Italy is unknown. METHODS: Prospective study of PLWH in the ICONA network. At baseline, PLWH were tested for HCV-Ab; HCV-RNA (if HCV-Ab positive) and, if positive, treated with DAA. SVR12 indicated eradication. Seroconversions and re-infections were evaluated yearly in HCV-Ab neg and HCV-RNA neg at first screening. We estimated the following: HCV seroconversions, incidence of HCV reinfections, and access to DAA and SVR12 rates tighter with factors associated with each outcome. Data were analysed by Cox regression, Poisson regression and logistic regression models. RESULTS: Sixteen thousand seven hundred and forty-three PLWH were included; 27.3% HCV-Ab positive; of these, 39.3% HCV-RNA positive. HCV seroconversion incidence: .48/100 PYFU (95% CI: .36-.65); re-infections incidence: 1.40/100 PYFU (95% CI: .91-2.04). The risk factor for HCV re-infection was young age: aIRR 1.85, 95% CI: 1.17-2.95) per 10 years younger. 86.4% of HCV viremic in follow-up started DAA. PWID vs. heterosexuals (aHR .75, 95% CI .62-.90), HIV-RNA >50 copies/mL (aHR .70, 95% CI .56-.87), HCV genotype other than G1, G2, G3, G4 or with multiple/missing HCV genotype and post-COVID-19 calendar periods were associated with lower DAA access. 922/965 (95.5%) PLWH achieved SVR12. We estimated 72% reduction of chance to achieve SVR12 in PLWH with a CD4 count <200/mm3 (vs. CD4 ≥200/mm3 aOR .18, 95% CI: .07-.46). 95.5% of DAA-treated individuals eradicated HCV, but they represent only 53.2% of HCV viremic PLWH and 66.4% of those in follow-up. HCV-RNA positivity by year decreased from 41.7% in 2017 to 11.7% in 2022. CONCLUSIONS: The screening-and-treat campaign implemented in Italy, even if only partially effective, resulted in a dramatic drop in HCV circulation in our cohort.

Comparison of Efavirenz and Doravirine Developmental Toxicity in an Embryo Animal Model.

In the past, one of the most widely used non-nucleoside reverse transcriptase inhibitors (NNRTI) in first-line antiretroviral therapy (ART) of HIV infection was efavirenz (EFV), which is already used as a cost-effective treatment in developing countries due to its efficacy, tolerability, and availability. However, EFV also demonstrates several adverse effects, like hepatotoxicity, altered lipid profile, neuropsychological symptoms, and behavioral effects in children after in utero exposure. In 2018, another NNRTI, doravirine (DOR), was approved due to its similar efficacy but better safety profile. Preclinical safety studies demonstrated that DOR is not genotoxic and exhibits no developmental toxicity or effects on fertility in rats. Zebrafish (Danio rerio) embryos have been widely accepted as a vertebrate model for pharmacological and developmental studies. We used zebrafish embryos as an in vivo model to investigate the developmental toxicity of DOR compared to EFV. After exposure of the embryos to the drugs from the gastrula stage up to different developmental stages (30 embryos for each arm, in three independent experiments), we assessed their survival, morphology, hatching rate, apoptosis in the developing head, locomotion behavior, vasculature development, and neutral lipid distribution. Overall, DOR showed a better safety profile than EFV in our model. Therapeutic and supra-therapeutic doses of DOR induced very low mortality [survival rates: 92, 90, 88, 88, and 81% at 1, 5, 10, 25, and 50 µM, respectively, at 24 h post fecundation (hpf), and 88, 85, 88, 89, and 75% at the same doses, respectively, at 48 hpf] and mild morphological alterations compared to EFV exposure also in the sub-therapeutic ranges (survival rates: 80, 77, 69, 63, and 44% at 1, 5, 10, 25, and 50 µM, respectively, at 24 hpf and 72, 70, 63, 52, and 0% at the same doses, respectively, at 48 hpf). Further, DOR only slightly affected the hatching rate at supra-therapeutic doses (97, 98, 96, 87, and 83% at 1, 5, 10, 25, and 50 µM, respectively, at 72 hpf), while EFV already strongly reduced hatching at sub-therapeutic doses (83, 49, 11, 0, and 0% at 1, 5, 10, 25, and 50 µM, respectively, at the same time endpoint). Both DOR at therapeutic doses and most severely EFV at sub-therapeutic doses enhanced apoptosis in the developing head during crucial phases of embryo neurodevelopment and perturbed the locomotor behavior. Furthermore, EFV strongly affected angiogenesis and disturbed neutral lipid homeostasis even at sub-therapeutic doses compared to DOR at therapeutic concentrations. Our findings in zebrafish embryos add further data confirming the higher safety of DOR with respect to EFV regarding embryo development, neurogenesis, angiogenesis, and lipid metabolism. Further studies are needed to explore the molecular mechanisms underlying the better pharmacological safety profile of DOR, and further human studies are required to confirm these results in the zebrafish animal model.

Dalbavancin in Bone and Joint Infections: A Systematic Review.

BACKGROUND: Approved for acute bacterial skin and skin structure infections, dalbavancin (DBV) has gradually acquired over the years a role as an off-label treatment for several infections caused by Gram-positive bacteria even in other anatomical sites. Osteoarticular (OA) infections are one of the most difficult-to-treat infections and, since the absence of recommendations, clinicians use different and heterogenic DBV dosing schedule regimens for the off-label treatment of osteomyelitis, spondylodiscitis, and septic arthritis. Our aim is to systematically review the current literature to describe DBV administration schedules and their outcome in OA infections. METHODS: According to the 2020 updated PRISMA guidelines, all peer-reviewed articles regarding the use of DBV in OA infections were included. We conducted a literature search on PubMed and Cochrane Controlled Trials. RESULTS: A total of 23 studies and 450 patients were included, prevalently male (144/195, 73.8%) and diabetic (53/163, 32.5%). Overall, 280 (280/388, 72.2%) osteomyelitis, 79 (79/388, 20.4%) spondylodiscitis, and 29 (29/388, 7.5%) septic arthritis were considered. Staphylococcus aureus (164/243, 67.5%) was the most common pathogen isolated. A previous treatment failure (45/96, 46.9%) was the main reason for a switch to a long-acting antibiotic. Most patients were successfully cured with DBV (318/401, 79.3%). A source control was performed in most patients with a favourable outcome (80.4%), while MRSA was prevalently isolated in people with an unfavourable outcome (57%). While a higher percentage of success was found in people who received three doses of DBV 1 week apart (92.3%), a higher rate of treatment failure was recorded in cases of when the DBV cycle was composed of less than two or more than four doses (27.8%). CONCLUSIONS: DBV has shown to be effective as a treatment for OA infections. The most favourable outcome was found in patients receiving three doses of DBV and with an adequate surgical management prior to antibiotic treatment. Although a rigorous administration schedule does not exist, DBV is a viable treatment option in the management of OA infections.

Human Orf with Immune-Mediated Reactions: A Systematic Review.

Background: Orf is a highly contagious zoonosis caused by Orf virus (ORFV), which is endemic in sheep and goats worldwide. Human Orf is usually a self-limiting disease, but potential complications, including immune-mediated reactions, may occur. Methods: We included all articles regarding Orf-associated immunological complications published in peer-reviewed medical journals. We conducted a literature search of the United States National Library of Medicine, PubMed, MEDLINE, PubMed Central, PMC, and the Cochrane Controlled Trials. Results: A total of 16 articles and 44 patients were included, prevalently Caucasian (22, 95.7%) and female (22, 57.9%). The prevailing immunological reaction was erythema multiforme (26, 59.1%), followed by bullous pemphigoid (7, 15.9%). In most cases, the diagnosis was made on the basis of clinical and epidemiological history (29, 65.9%), while a biopsy of secondary lesions was performed in 15 patients (34.1%). A total of 12 (27.3%) patients received a local or systemic treatment for primary lesions. Surgical removal of primary lesion was described in two cases (4.5%). Orf-immune-mediated reactions were treated in 22 cases (50.0%), mostly with topical corticosteroids (12, 70.6%). Clinical improvement was reported for all cases. Conclusions: Orf-related immune reactions can have a varied clinical presentation, and it is important for clinicians to be aware of this in order to make a prompt diagnosis. The main highlight of our work is the presentation of complicated Orf from an infectious diseases specialist's point of view. A better understanding of the disease and its complications is essential to achieve the correct management of cases.

Timing and implications for immune response to vaccine in SARS-CoV-2 breakthrough infections.

COVID-19 vaccines elicit a strong anti-S antibodies response. We aim to describe antibody titers in peri-vaccination SARS-CoV-2 infections. This is a retrospective longitudinal single-cohort study. Serological tests were performed at the time of the first SARS-CoV-2 vaccine dose (T0) and 60 (T1), 120 (T2), and 240 (T3) days after. The study included 4,682 subjects. Group A had the infection without an anti-S Ig response. Group B and C seroconverted for anti-N Ig between T0 and T1 and between T1 and T2, respectively. Group D was persistently anti-N Ig negative. Group B showed an initial sub-optimal response, reaching the highest titer at T3. Those who received the second dose 120 days after the infection had higher titers compared to those who received it 21 days after the first dose. The immune response depends on the number and the timing of vaccine doses, highlighting the need for a more personalized approach to vaccination.

Autoantibodies to Interferons in Infectious Diseases.

Anti-cytokine autoantibodies and, in particular, anti-type I interferons are increasingly described in association with immunodeficient, autoimmune, and immune-dysregulated conditions. Their presence in otherwise healthy individuals may result in a phenotype characterized by a predisposition to infections with several agents. For instance, anti-type I interferon autoantibodies are implicated in Coronavirus Disease 19 (COVID-19) pathogenesis and found preferentially in patients with critical disease. However, autoantibodies were also described in the serum of patients with viral, bacterial, and fungal infections not associated with COVID-19. In this review, we provide an overview of anti-cytokine autoantibodies identified to date and their clinical associations; we also discuss whether they can act as enemies or friends, i.e., are capable of acting in a beneficial or harmful way, and if they may be linked to gender or immunosenescence. Understanding the mechanisms underlying the production of autoantibodies could improve the approach to treating some infections, focusing not only on pathogens, but also on the possibility of a low degree of autoimmunity in patients.

Case report: An occult hepatitis B virus infection reactivation in an HIV/HCV coinfected patient during an immune reconstitution inflammatory syndrome.

The natural history of occult hepatitis B virus infection (OBI) and the mechanism involved in HBV reactivation are only partially understood. As regards people living with HIV (PLWH), HBV reactivation is estimated to occur with an incidence ratio of 0.019 cases per 100 person-year. Here we report the case of OBI reactivation in a HIV/HCV co-infected patient followed for 25 years at our Infectious Diseases Unit, but, unfortunately, lost to follow-up about 19 months after Direct-acting antivirals (DAAs) treatment. At re-engagement, blood tests showed high replication of plasmatic HIV-RNA along with severe immunosuppression and normal levels of liver enzymes. However, 3 months after ART reintroduction, an immune reconstitution inflammatory syndrome (IRIS) was diagnosed with high detectable HBV-DNA load and transaminase elevation. Our case report shows how the balance between the virus and the host immune system is quite a dynamic process that might significantly impact the course of the disease. The aim of this case report is to bring to the attention of physicians that, although OBI reactivation is a rather rare occurrence, even amongst PLWH, its potential consequences compel to a high alertness on the matter. Therefore, especially in patients with an impaired immune system and on a tenofovir or lamivudine-sparing regimen, HBV serological and virological markers should always be strictly monitored, even in the absence of a hepatitis flare.