How We Treat Drug-Susceptible Pulmonary Tuberculosis: A Practical Guide for Clinicians

Tuberculosis (TB) remains one of the leading causes of morbidity and mortality worldwide and pulmonary TB (PTB) is the main variant responsible for fueling transmission of the infection. Effective treatment of drug-susceptible (DS) TB is crucial to avoid the emergence of Mycobacterium tuberculosis-resistant strains. In this narrative review, through a fictional suggestive case of DS PTB, we guide the reader in a step-by-step commentary to provide an updated review of current evidence in the management of TB, from diagnosis to post-treatment follow-up. World Health Organization and Centre for Diseases Control (CDC) guidelines for TB, as well as the updated literature, were used to support this manuscript

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

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

Valutazione dei livelli di Torque Teno Virus (TTV) in pazienti affetti da colite ulcerosa in terapia biologica con anti-TNF

TITOLO della TESI: Valutazione dei livelli di Torque Teno Virus (TTV) in pazienti affetti da Colite Ulcerosa in terapia biologica con anti-TNF. Candidata: Sara Occhineri Relatore: Nicola de Bortoli Introduzione: Allo stato attuale non esistono studi che indaghino il titolo di Torque-Teno virus (TTV) nel siero di pazienti affetti da Colite Ulcerosa (UC). TTV è un virus a DNA attualmente non correlato a nessuna patologia, la cui infezione è molto comune nella popolazione arrivando a coinvolgere, in alcune zone, anche più del 90% di adulti sani. Il sistema immunitario (IS) dell’ospite viene continuamente stimolato dalla presenza del virus e viceversa la viremia risente dell’immunosoppressione che si instaura nel paziente in particolari condizioni cliniche. Il comportamento del virus in soggetti candidati a trapianto d’organo rappresenta uno tra gli elementi che ha suscitato maggiore interesse negli ultimi anni. Quando, infatti, questi iniziano il trattamento immunosoppressivo in preparazione al trapianto, la carica virale aumenta seguendo il progressivo indebolimento del IS. Un utile risvolto nella pratica clinica è proprio la possibilità di impiegare il titolo di TTV come indice del grado di immunosoppressione dei pazienti e del loro rischio di incorrere in infezioni opportunistiche. Scopo dello studio: Conoscendo quindi questa relazione fra TTV e sistema immunitario, attraverso il nostro studio sperimentale siamo andati a valutare i livelli di carica virale in pazienti affetti da UC prima e dopo infusione di farmaci biologici anti-TNF. Materiali e metodi: Sono stati arruolati una serie di pazienti affetti da colite ulcerosa (UC) e avviati a trattamento con farmaci anti-TNF. I pazienti analizzati nel nostro lavoro sono stati tutti trattati con farmaci anti-TNF (Infliximab, Adalimumab e Golimumab) che, interagendo con il sistema immunitario, hanno il ruolo di interferire con la cascata citochinica tipica del processo infiammatorio che si instaura in corso di UC. Tutti i pazienti sono stati sottoposti a colonscopia e a valutazione anamnestica. Tutti i pazienti sono stati valutati con il Mayo Score per stimare la gravità di malattie e definire la risposta al trattamento. I pazienti sono stati sottoposti a due prelievi, uno prima dell’inizio del trattamento con farmaci anti-TNF (T0) e il secondo al termine della fase di induzione della terapia (T1). Tutti i campioni di plasma sono stati adeguatamente trattati per estrazione e valutazione del titolo del TTV (log copie/ml). I pazienti sono strati divisi in Responder (riduzione del Mayo Score di almeno 2 punti) e Non-Responder (mancata riduzione del Mayo Score) al termine dell’induzione. Risultati: sono stati arruolati 38 pazienti (16 donne e 22 uomini) affetti da UC di età comprese fra i 18 e i 65 anni con età media 41.5±13.6 anni. Circa 24/38 (63.2%) sono risultati responder all’induzione mentre 14/38 (36.8%) sono risultati non responder. Il titolo del TTV era simile in tutti i pazienti fra il primo ed il secondo prelievo (1.3±1.3 copie/ml; p=1.0). Al campionamento basale i livelli di TTV sono risultati nettamente superiori nel gruppo dei non-responder (2.4±0.8 vs 0.6±1.1 copie/ml; p<0.001). Tali valori si sono minimamente modificati nel secondo prelievo (T1) al termine dell’induzione (2.3±0.9 vs 0.7±1.1 copie/ml; p<0.001). Nel gruppo dei responder ben 17/24 (70.8%) non presentavano livelli dosabili di virus su plasma circolante mentre tutti i soggetti del gruppo non responder avevano livelli di virus dosabili (p<0.001). Dati simili sono stati osservati al momento del prelievo fatto al termine dell’induzione: il titolo di TTV era non-dosabile in 16/24 (66.6%) nei responder vs 1/14 (7.1%) nei non-responder (p<0.001). Conclusioni: i dati raccolti da questo studio preliminare, eseguito su una piccola coorte di soggetti affetti da CU, ci permettono di evidenziare che titoli bassi o non dosabili del TTV potrebbero rappresentare un marker predittivo di risposta alla terapia con farmaci biologici. I dati dovranno essere confermati con una valutazione a lungo termine e correlati con il mantenimento della risposta nel tempo. Inoltre, un’analisi più approfondita su una casistica più ampia potrebbe portare alla luce dati più conclusivi su questa tematica altamente affascinante

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

Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease

Alzheimer’s disease (AD) is a widespread multifactorial aging-related pathology, which includes cholinergic deficit among its main causes. Following a multi-target design strategy, the structure of the approved drug donepezil was taken as the starting point for generating some new potential multi-functional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayed against three different enzymes, namely the well-established targets acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studies confirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalytic anionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, which revealed that the inhibition potency seems to depend upon the length of the spacer and the number of polar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated. Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools. Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-target directed agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent and selective AChE inhibitor (IC50 = 0.8 nM) than donepezil, besides being able to bind bivalent copper cations (pCu= 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12) did not show significant cytotoxicity on SHSY5Y and HepG2 cells at the highest tested concentration (100 μM) in a MTT assay

Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

International audienceTo 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 (https://lng-nia.shinyapps.io/mrshiny) 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;85:470-481