Pretomanid for tuberculosis treatment: an update for clinical purposes

Coronavirus disease (COVID-19) pandemic determined a 10 years-set back in tuberculosis (TB) control programs. Recent advances in available therapies may help recover the time lost. While Linezolid (LZD) and Bedaquiline (BDQ), previously Group D second line drugs (SLDs) for TB, have been relocated to Group A, other drugs are currently being studied in regimens for drug resistant TB (DR-TB). Among these, Pretomanid (PA), a recently introduced antimycobacterial drug derived from nitroimidazole with both solid bactericidal and bacteriostatic effect, and with an excellent effectiveness and tolerability profile, is in the spotlight. Following promising data obtained from recently published and ongoing randomized controlled trials (RCTs), the World Health Organization (WHO) determined to include PA in its guidelines for the treatment of rifampicin-resistant (RR), multi drug resistant (MDR) and pre-extensively drug resistant TB (pre-XDR-TB) with BDQ, LZD and Moxifloxacine (MFX) in a 6-month regimen. Although further studies on the subject are needed, PA may also represent a treatment option for drug-susceptible TB (DS-TB), latent TB infection (LTBI) and non tuberculous mycobacteria (NTM). This narrative review aims to examine current implementation options and future possibilities for PA in the never-ending fight against TB

Efficacy of Bamlanivimab/Etesevimab and Casirivimab/Imdevimab in Preventing Progression to Severe COVID-19 and Role of Variants of Concern

Introduction: The aim of this study was to evaluate the risk of hospitalization or death in patients infected by SARS-CoV2 variants of concern (VOCs) receiving combinations of monoclonal antibodies (mAbs), bamlanivimab/etesevimab or casirivimab/imdevimab. Methods: Observational prospective study conducted in two Italian hospitals (University Hospital of Pisa and San Donato Hospital, Arezzo) including consecutive outpatients with COVID-19 who received bamlanivimab/etesevimab or casirivimab/imdevimab from March 20th to May 10th 2021. All patients were at high risk of COVID-19 progression according to FDA/AIFA recommendations. Patients were divided into two study groups according to the infecting viral strain (VOCs): Alpha and Gamma group. The primary endpoint was a composite of hospitalization or death within 30 days from mAbs infusion. A Cox regression multivariate analysis was performed to identify factors associated with the primary outcome in the overall population. Results: The study included 165 patients: 105 were infected by the VOC Alpha and 43 by the VOC Gamma. In the Alpha group, no differences in the primary endpoint were observed between patients treated with bamlanivimab/etesevimab or casirivimab/imdevimab. Conversely, in the Gamma group, a higher proportion of patients treated with bamlanivimab/etesevimab met the primary endpoint compared to those receiving casirivimab/imdevimab (55% vs. 17.4%, p = 0.013). On multivariate Cox-regression analysis, the Gamma variant and days from symptoms onset to mAbs infusion were factors independently associated with higher risk of hospitalization or death, while casirivimab/imdevimab was protective (HR 0.33, 95% CI 0.13–0.83, p = 0.019). Conclusions: In patients infected by the SARS-CoV-2 Gamma variant, bamlanivimab/etesevimab should be used with caution because of the high risk of disease progression

Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

Objective To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Methods Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. Results We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. Interpretation Here, we have developed a public resource () which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481Peer reviewe

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

The current and future off-label uses of dalbavancin: a narrative review

Dalbavancin is a novel long-acting semi-synthetic lipoglycopeptide. It is licensed for acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Many studies on dalbavancin alternative use in clinical practice have been published recently, including osteomyelitis, prosthetic joint infections (PJIs), and infective endocarditis (IE). Thus, we conducted a narrative review on dalbavancin efficacy in difficult-to-treat infections, such as osteomyelitis, PJIs, and IE. We performed a comprehensive literature search through electronic databases (PubMed-MEDLINE) and search engines (Google Scholar). We included peer-reviewed publications (articles and reviews), and grey literature on dalbavancin use in osteomyelitis, PJIs, and IE. No time or language restrictions have been established. Despite the great interest in clinical practice, only observational studies and case series on the use of dalbavancin in infections other than ABSSSI are available. The reported success rate was extremely variable between studies, ranging from 44% to 100%. A low success rate has been reported for osteomyelitis and joint infections, while in endocarditis, the success rate was higher than 70% in all studies. However, there is no literature agreement about the correct regimen of dalbavancin for this type of infection heretofore. Dalbavancin showed great efficacy and a good safety profile, not only in patients with ABSSSI but also in those with osteomyelitis, PJIs, and endocarditis. Further randomized clinical trials are needed to assess the optimal dosing schedule depending on the site of infection. Implementing therapeutic drug monitoring for dalbavancin may represent the future step to achieving optimal pharmacokinetic/pharmacodynamic target attainment

The current and future off-label uses of dalbavancin: a narrative review

: Dalbavancin is a novel long-acting semi-synthetic lipoglycopeptide. It is licensed for acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Many studies on dalbavancin alternative use in clinical practice have been published recently, including osteomyelitis, prosthetic joint infections (PJIs), and infective endocarditis (IE). Thus, we conducted a narrative review on dalbavancin efficacy in difficult-to-treat infections, such as osteomyelitis, PJIs, and IE. We performed a comprehensive literature search through electronic databases (PubMed-MEDLINE) and search engines (Google Scholar). We included peer-reviewed publications (articles and reviews), and grey literature on dalbavancin use in osteomyelitis, PJIs, and IE. No time or language restrictions have been established. Despite the great interest in clinical practice, only observational studies and case series on the use of dalbavancin in infections other than ABSSSI are available. The reported success rate was extremely variable between studies, ranging from 44% to 100%. A low success rate has been reported for osteomyelitis and joint infections, while in endocarditis, the success rate was higher than 70% in all studies. However, there is no literature agreement about the correct regimen of dalbavancin for this type of infection heretofore. Dalbavancin showed great efficacy and a good safety profile, not only in patients with ABSSSI but also in those with osteomyelitis, PJIs, and endocarditis. Further randomized clinical trials are needed to assess the optimal dosing schedule depending on the site of infection. Implementing therapeutic drug monitoring for dalbavancin may represent the future step to achieving optimal pharmacokinetic/pharmacodynamic target attainment

Uncommon Haemorrhagic Cystitis of Infectious Origin: A Narrative Review for Urologists

Francesca Ambrosini,1,2 Niccolò Riccardi,3,4 Sara Occhineri,3,4 Tommaso Matucci,3,4 Irene Paraboschi,5 Alessandro Calarco,6 Alfredo Berrettini,5 Giusy Tiseo,3 Diana Canetti,7 André Van Der Merwe,8 Carlo Terrone,1,2 Guglielmo Mantica1,2 1IRCCS Ospedale Policlinico San Martino, Genova, Italy; 2Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genova, Genova, Italy; 3Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 4StopTB Italia Onlus, Milan, Italy; 5Department of Pediatric Urology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 6Villa Pia Hospital, Via Folco Portinari 5, Rome, Italy; 7Infectious Diseases Unit, San Raffaele Scientific Institute, Milan, Italy; 8Department of Urology, Faculty of Medicine and Health Sciences, 26697 Stellenbosch University, Cape Town, South AfricaCorrespondence: Guglielmo Mantica, Department of Surgical and Diagnostic Intergrated Sciences (DISC), University of Genova, Genova, Italy, Tel +390105555960, Email [email protected]: Haemorrhagic cystitis may be due to different etiologies with infectious diseases representing an insidious cause to diagnose. The aim of this narrative review is to provide a comprehensive overview of less common but difficult-to-diagnose causes of infectious haemorrhagic cystitis of bacterial, mycobacterial, and parasitic origin, Moreover, we highlight possible diagnostic tools and currently available treatment options in order to give an updated tool for urologists to use in daily practice.Patients and Methods: The search engine PubMed was used to select peer-reviewed articles published from 1/Jan/2010 to 31/Aug/2022.Results: Bacteria, fungal, TB and schistosomiasis are uncommon causes of haemorrhagic cystitis burdened by high morbidity, especially if not promptly diagnosed.Conclusion: Because haemorrhagic cystitis ranges in severity from mild dysuria associated with pelvic discomfort to severe life-threatening haemorrhage, punctual diagnosis, and immediate treatment are essential to avoid further complications.Keywords: cystitis, haemorrhagic cystitis, schistosomiasis, tuberculosis, GUT

Genetic architecture of ALS in Sardinia

Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic amyotrophic lateral sclerosis (ALS) provide unique information on the genetics of the disease. Our aim was to describe the genetic profile of a consecutive series of ALS patients of Sardinian ancestry. All ALS patients of Sardinian ancestry, identified between 2008 and 2013 through the Italian ALS Genetic Consortium, were eligible to be included in the study. Patients and controls underwent the analysis of TARDBP, C9ORF72, SOD1, and FUS genes. Genetic mutations were identified in 155 out of 375 Sardinian ALS cases (41.3%), more commonly the p.A382T and p.G295S mutations of TARDBP and the GGGGCC hexanucleotide repeat expansion of C9ORF72. One patient had both p.G295S and p.A382T mutations of TARDBP and 8 carried both the heterozygous p.A382T mutation of TARDBP and a repeat expansion of C9ORF72. Patients carrying the p.A382T and the p.G295S mutations of TARDBP and the C9ORF72 repeat expansion shared distinct haplotypes across these loci. Patients with cooccurrence of C9ORF72 and TARDBP p.A382T missense mutation had a significantly lower age at onset and shorter survival. More than 40% of all cases on the island of Sardinia carry a mutation of an ALS-related gene, representing the highest percentage of ALS cases genetically explained outside of Scandinavia. Clinical phenotypes associated with different genetic mutations show some distinctive characteristics, but the heterogeneity between and among families carrying the same mutations implies that ALS manifestation is influenced by other genetic and nongenetic factors