Drugs for treating infections caused by non-tubercular mycobacteria: a narrative review from the study group on mycobacteria of the Italian Society of Infectious Diseases and Tropical Medicine.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are generally free-living organism, widely distributed in the environment, with sporadic potential to infect. In recent years, there has been a significant increase in the global incidence of NTM-related disease, spanning across all continents and an increased mortality after the diagnosis has been reported. The decisions on whether to treat or not and which drugs to use are complex and require a multidisciplinary approach as well as patients' involvement in the decision process. METHODS AND RESULTS: This review aims at describing the drugs used for treating NTM-associated diseases emphasizing the efficacy, tolerability, optimization strategies as well as possible drugs that might be used in case of intolerance or resistance. We also reviewed data on newer compounds highlighting the lack of randomised clinical trials for many drugs but also encouraging preliminary data for others. We also focused on non-pharmacological interventions that need to be adopted during care of individuals with NTM-associated diseases CONCLUSIONS: Despite insufficient efficacy and poor tolerability this review emphasizes the improvement in patients' care and the needs for future studies in the field of anti-NTM treatments.

Therapeutic strategies and outcomes of MDR and pre-XDR-TB in Italy: a nationwide study.

BACKGROUND: Treatment outcomes in multidrug-resistant TB (MDR-TB) patients are suboptimal in several low-incidence countries.METHODS: The primary outcome measure was the proportion of successfully treated patients in Italy during an 18-year period. Secondary outcomes were treatment outcomes in certain drug-containing regimens and the possibility for the WHO shorter MDR-TB regimen.RESULTS: In the 191 patients included (median age at admission: 33 years; 67.5% male, following drug-resistance patterns were found: MDR-TB in 68.6%, pre-extensively drug-resistant TB (pre-XDR-TB) in 30.4% and XDR-TB in 1.1% patients. The most frequently prescribed drugs were fluoroquinolones in 84.6% cases, amikacin in 48.7%, linezolid in 34.6% and meropenem/clavulanic acid in 29.5%. The median duration of treatment was 18 months. Treatment success was achieved in 71.2% patients, of whom, 44% were cured and 27.2% completed treatment. Treatment success rates did not statistically differ between the MDR- (68.8%) and pre-XDR-TB (77.6%) groups (P = 0.26). Treatment success rates had large variability between North and South of Italy (81.3% vs. 53.3%). Only 22.5% of the cases would have been eligible for shorter MDR-TB regimensCONCLUSION: Our study highlights variability in treatment outcomes in MDR- and pre-XDR-TB patients. Study findings confirmed the potential utility of linezolid and, for patients with limited oral options, meropenem/clavulanic acid and amikacin.

TB management in the European Union/European Economic Area: a multi-centre survey.

BACKGROUND: Essential TB care in the European Union/European Economic Area (EU/EEA) comprises 21 standards for the diagnosis, treatment and prevention of TB that constitute the European Union Standards for Tuberculosis Care (ESTC).METHODS: In 2017, we conducted an audit on TB management and infection control measures against the ESTC standards. TB reference centres in five EU/EEA countries were purposely selected to represent the heterogeneous European TB burden and examine geographic variability.RESULTS: Data from 122 patients, diagnosed between 2012 and 2015 with multidrug-resistant TB (n = 49), extensively drug-resistant TB (XDR-TB) (n = 11), pre-XDR-TB (n = 29) and drug-susceptible TB (n = 33), showed that TB diagnosis and treatment practices were in general in agreement with the ESTC.CONCLUSION: Overall, TB management and infection control practices were in agreement with the ESTC in the selected EU/EEA reference centres. Areas for improvement include strengthening of integrated care services and further implementation of patient-centred approaches.

Tuberculosis, COVID-19 and migrants: Preliminary analysis of deaths occurring in 69 patients from two cohorts.

Little is known about the relationship between the COVID-19 and tuberculosis (TB). The aim of this study is to describe a group of patients who died with TB (active disease or sequelae) and COVID-19 in two cohorts. Data from 49 consecutive cases in 8 countries (cohort A) and 20 hospitalised patients with TB and COVID-19 (cohort B) were analysed and patients who died were described. Demographic and clinical variables were retrospectively collected, including co-morbidities and risk factors for TB and COVID-19 mortality. Overall, 8 out of 69 (11.6%) patients died, 7 from cohort A (14.3%) and one from cohort B (5%). Out of 69 patients 43 were migrants, 26/49 (53.1%) in cohort A and 17/20 (85.0%) in cohort B. Migrants: (1) were younger than natives; in cohort A the median (IQR) age was 40 (27-49) VS. 66 (46-70) years, whereas in cohort B 37 (27-46) VS. 48 (47-60) years; (2) had a lower mortality rate than natives (1/43, 2.3% versus 7/26, 26.9%; p-value: 0.002); (3) had fewer co-morbidities than natives (23/43, 53.5% versus 5/26-19.2%) natives; p-value: 0.005). The study findings show that: (1) mortality is likely to occur in elderly patients with co-morbidities; (2) TB might not be a major determinant of mortality and (3) migrants had lower mortality, probably because of their younger age and lower number of co-morbidities. However, in settings where advanced forms of TB frequently occur and are caused by drug-resistant strains of M. tuberculosis, higher mortality rates can be expected in young individuals.

Multidrug-Resistant Tuberculosis In A Referral Center In Rome: 2011- 2016.

PURPOSE: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in low incidence countries in Europe. The aim of this study was to attempt to have a better insight into the trends of MDR-TB in the metropolitan area of Rome, within the Italian and the foreign-born population, based on microbiological and demographic data. PATIENTS AND METHODS: We performed a prospective study, collecting microbiological data based on phenotypic drug-resistant testing (DST) of TB strains consecutively isolated in a referral hospital in Rome, the capital city of a low TB incidence country, over a 6-year period, and correlated them to the geographical origin of patients. This study was carried out in a referral hospital for patients with drug-resistant TB from the whole region. RESULTS: Drug-resistance data from 926 patients with a microbiological diagnosis of TB from 2011 to 2016 show a 5.5% rate of MDR-TB, mostly occurring in patients born in a single East European country, that has a high incidence of MDR-TB. The strains isolated from these patients frequently carry additional resistances, leading to an increased risk of developing extensively drug-resistant (XDR) TB. CONCLUSION: In the great metropolitan area of Rome, MDR-TB more frequently occurs in patients who were born in a single country from Eastern Europe known to have high rates of MDR-TB and long-time residents in Italy. Recent immigrants from non-European countries do not appear to contribute to the rates of MDR-TB reported in this article. This knowledge of local TB trends could help improve the measures of surveillance and prevention of disease.

Clinical evaluation of TRCReady M.TB for rapid automated detection of M. tuberculosis complex in respiratory samples.

SETTING: Timely diagnosis of tuberculosis (TB) is essential for effectively controlling and managing the disease. Although international guidelines recommend acid-fast bacilli staining and culture as the 'gold standard', new molecular methods are available to safely and rapidly identify positive samples. OBJECTIVE: To evaluate the performance of the newer and fully automated version of a molecular assay for rRNA amplification (TRCReady® M.TB) on 1028 respiratory samples collected from 378 patients for its possible use as a reliable screening method. Results were evaluated using culture as the reference test. RESULTS: Of four diagnostic protocols employed, best results were obtained when TRCReady M.TB was used together with microscopy on the first respiratory sample, followed by microscopy alone on a second one. The sensitivity and specificity were respectively 97% and 100%, with a turnaround time of 24 h. We propose a possible laboratory algorithm for rapid identification of patients with TB. CONCLUSIONS: TRCReady offers the advantages of full automation and avoidance of cross-contamination. As such, it should be considered as a more economical option for TB screening than other commercial assays that are currently available.

Three mitochondrial transporters of Saccharomyces cerevisiae are essential for ammonium fixation and lysine biosynthesis in synthetic minimal medium.

The nuclear genes of Saccharomyces cerevisiae YHM2, ODC1 and ODC2 encode three transporters that are localized in the inner mitochondrial membrane. In this study, the roles of YHM2, ODC1 and ODC2 in the assimilation of nitrogen and in the biosynthesis of lysine have been investigated. Both the odc1Δodc2Δ double knockout and the yhm2Δ mutant grew similarly as the YPH499 wild-type strain on synthetic minimal medium (SM) containing 2% glucose and ammonia as the main nitrogen source. In contrast, the yhm2Δodc1Δodc2Δ triple knockout exhibited a marked growth defect under the same conditions. This defect was fully restored by the individual expression of YHM2, ODC1 or ODC2 in the triple deletion strain. Furthermore, the lack of growth of yhm2Δodc1Δodc2Δ on 2% glucose SM was rescued by the addition of glutamate, but not glutamine, to the medium. Using lysine-prototroph YPH499-derived strains, the yhm2Δodc1Δodc2Δ knockout (but not the odc1Δodc2Δ and yhm2Δ mutants) also displayed a growth defect in lysine biosynthesis on 2% glucose SM, which was rescued by the addition of lysine and, to a lesser extent, by the addition of 2-aminoadipate. Additional analysis of the triple mutant showed that it is not respiratory-deficient and does not display mitochondrial DNA instability. These results provide evidence that only the simultaneous absence of YHM2, ODC1 and ODC2 impairs the export from the mitochondrial matrix of i) 2-oxoglutarate which is necessary for the synthesis of glutamate and ammonium fixation in the cytosol and ii) 2-oxoadipate which is required for lysine biosynthesis in the cytosol. Finally, the data presented allow one to suggest that the yhm2Δodc1Δodc2Δ triple knockout is suitable in complementation studies aimed at assessing the pathogenic potential of human SLC25A21 (ODC) mutations.

Analytical evaluation of QuantiFERON- Plus and QuantiFERON- Gold In-tube assays in subjects with or without tuberculosis.

The QuantiFERON-TB Gold Plus (QFT-Plus) represents the new QuantiFERON-TB Gold In-tube (QFT-GIT) to identify latent tuberculosis infection (LTBI). The main differences is the addition of a new tube containing shorter peptides stimulating CD8 T-cells. Aim of this study is to evaluate the accuracy of QFT-Plus compared with QFT-GIT in a cross sectional study of individuals with or without tuberculosis (TB). We enrolled 179 participants: 19 healthy donors, 58 LTBI, 33 cured TB and 69 active TB. QFT-Plus and QFT-GIT were performed. The two tests showed a substantial agreement. Moreover we found a similar sensitivity in active TB and same specificity in healthy donors. A higher proportion of the LTBI subjects responded to both TB1 and TB2 compared to those with active TB (97% vs 81%). Moreover, a selective response to TB2 was associated with active TB (9%) and with a severe TB disease, suggesting that TB2 stimulation induces a CD8 T-cell response in absence of a CD4-response. In conclusion, QFT-Plus and QFT-GIT assays showed a substantial agreement and similar accuracy for active TB detection. Interestingly, a higher proportion of the LTBI subjects responded concomitantly to TB1 and TB2 compared to those with active TB, whereas a selective TB2 response associated with active TB.

Transurethral resection of the prostate (TURP) vs GreenLight photoselective vaporization of benign prostatic hyperplasia: analysis of BPH6 outcomes after 1 year of follow-up.

The surgical treatment of benign prostatic obstruction is changing over the time, thanks the increase evidence about the successful role of laser techniques in this surgery. We aimed to compare prostatic GreenLight photovaporization (PVP) to bipolar transurethral resection of the prostate (TURP) with regard to lower urinary tract symptoms (LUTS) improvement through the evaluation of BPH6. We enrolled 220 consecutive subjects affected by LUTS. We performed a propensity score matching using prostate volume, peak flow and International Prostate Symptoms Score (IPSS). A total of 110 (55 TURP and 55 PVP) were analyzed. We found after 1 year of follow-up that the rate of subjects resulting in greater BPH6 recovery in the PVP group vs TURP (45.6% vs 18.2%; P=0.001). The TURP treatment showed greater catheterization time (4.67 vs 1.25; P<0.01) while PVP showed greater recovery experience (82.4 vs 58.2; <0.01). Postoperative ejaculatory dysfunctions were observed in both groups, 58.8% in TURP and 34.5% in PVP group. The multivariate logistic regression analysis, adjusted for preoperative variables, showed that PVP was independently associated with BPH6 recovery end point (odds ratio=3.77; P<0.01). This study showed data in favor of PVP. Although IPSS and peak flow improvements were similar, PVP showed better clinical outcomes.

The diabetes-tuberculosis co-epidemic: the role of international migration.

SETTING: A tuberculosis (TB) referral centre in Rome, Italy. OBJECTIVE: To identify demographic and epidemiological characteristics associated with diabetes mellitus (DM) among patients with TB and to compare the clinical presentation of TB and TB-DM in the light of the growing worldwide burden of DM. DESIGN: We performed a retrospective study of TB cases diagnosed from 2007 to 2012. RESULTS: Among 971 TB patients, 723 were foreign-born and 63 (6.5%) had DM. DM prevalence was 12.7% (8/63) among those born in countries with DM prevalence ⩾8%, 4.7% (31/660) among patients from countries with DM prevalence <8% and 9.7% among Italian patients (24/248). In multivariable analysis, DM was independently associated with older age, and with being born in countries other than Italy, compared to Italians; this latter association was stronger in older patients. DM patients were also significantly more likely to be male and less likely to test positive for the human immunodeficiency virus. The presence of cavities was significantly associated with DM. CONCLUSIONS: As individuals born in high TB incidence and high DM prevalence countries emerge as a vulnerable population, greater attention to bidirectional low-cost screening in people from these countries is needed.

Behaviour of dental pulp stem cells on different types of innovative mesoporous and nanoporous silicon scaffolds with different functionalizations of the surfaces.

Dental pulp stem cells (DPSCs) are stem cells found in the dental pulp. The ability of DPSCs to differentiate towards odontoblastic and osteoblastic phenotype was reported first in the literature, then in the following years, numerous studies on odontogenesis were carried out, starting from mesenchymal stem cells isolated from tissues of dental and oral origin. The aim of this research was to evaluate the behaviour of DPSCs grown on silicon nanoporous and mesoporous matrices and differentiated towards the osteogenic phenotype, but also to investigate the use of DPSCs in pilot studies focused on the biological compatibility of innovative dental biomaterials. Twenty-eight silicon samples were created with standardized procedures. These scaffolds were divided into samples made of silicon bulk, nanoporous silicon, mesoporous silicon, nanoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS) and methanol (MeOH), nanoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS)/toluene, mesoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS) and methanol (MeOH) andmesoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS)/toluene. DPSC proliferation on the tested silicon scaffolds was analyzed at 3 and 5 days. The assay showed that DPSCs proliferated better on mesoporous scaffolds functionalized with APTMS/toluene compared to a silicon one. These results show that the functionalization of silicon scaffold with APTMS/toluene supports the growth of DPSCs and could be used for future applications in tissue engineering.

Vigilancia activa de masas renales pequeñas diagnosticadas en pacientes de edad avanzada o con comorbilidad: en busca de la mejor estrategia de tratamiento / Active surveillance for small renal masses diagnosed in elderly or comorbid patients: Looking for the best treatment strategy

Introducción: El objetivo de este trabajo es proporcionar nuestros resultados tras un protocolo de vigilancia activa (VA) a largo plazo de masas renales pequeñas (MRP), e informar de los resultados obtenidos en pacientes que permanecieron bajo VA comparándolos con aquellos sometidos a intervenciones quirúrgicas tardías. Pacientes y métodos: Se llevó a cabo una revisión retrospectiva de nuestra base de datos de 58 pacientes a los que se había diagnosticado 60 MRP captantes de contraste y con sospecha de cáncer de células renales (CCR). Todos los pacientes tenían una revisión de seguimiento clínico y radiológico cada 6 meses. Se evaluaron las diferencias entre los pacientes que permanecieron bajo VA y aquellos sometidos a intervenciones quirúrgicas tardías. Resultados: La media de edad era de 75 años y la duración media del seguimiento fue de 88,5 meses. El tamaño medio del tumor en el inicio fue de 2,6 cm, y se estimó que el tamaño medio tumoral era de 8,7 cm3. La tasa media de crecimiento lineal del grupo fue de 0,7 cm/año y el crecimiento volumétrico medio fue de 8,8 cm3/año. Se produjo el fallecimiento de 2 pacientes debido a enfermedad metastásica (3,4%). No se encontró ninguna relación entre el tamaño tumoral inicial y el grado de crecimiento. Las tasas medias de crecimiento lineal y volumétrico del grupo de pacientes sometidos a cirugía fueron más elevadas que las de aquellos que permanecieron bajo vigilancia (1,9 frente a 0,4 cm/año y 16,1 frente a 4,6 cm3/año, respectivamente; p < 0,001).Conclusiones: La mayoría de las MRP presentan una evolución poco activa y un potencial metastásico reducido. La enfermedad maligna podría presentar tasas de crecimiento lineal y volumétrico más rápidas, sugiriendo así la necesidad de una intervención quirúrgica tardía. En los pacientes adecuadamente seleccionados, con baja esperanza de vida, la VA podría ser una opción razonable en el manejo de las MRP

Introduction: Aim of this study is to provide our results after long-term active surveillance (AS) protocol for small renal masses (SRMs), and to report the outcomes of patients who remained in AS compared to those who underwent delayed surgical intervention. Patients and methods: We retrospectively reviewed our database of 58 patients diagnosed with 60 contrast enhancing SRMs suspicious for renal cell carcinoma (RCC). All patients had clinical and radiological follow-up every 6 months. We evaluated the differences between patients who remained on AS and those who underwent surgical delayed intervention. Results: The mean age was 75 years, the mean follow-up was 88.5 months. The median initial tumor size at presentation was 2.6 cm, and the median estimated tumor volume was 8.7 cm3. The median linear growth rate of the cohort was 0.7 cm/year, and the median volumetric growth rate was 8.8 cm3/year. Death for metastatic disease occurred in 2 patients (3.4%). No correlation was found between initial tumor size and size growth rate. The mean linear and volumetric growth rates of the group of patients who underwent surgery were higher than in those who remained on surveillance (1.9 vs. 0.4 cm/year and 16.1 vs. 4.6 cm3/year, respectively; p < 0.001). Conclusions: Most of SRMs demonstrate to have an indolent course and low metastatic potential. Malignant disease could have faster linear and volumetric growth rates, thus suggesting the need for a delayed surgical intervention. In properly selected patients with low life-expectancy, AS could be a reasonable option in the management of SRMs

Active surveillance for small renal masses diagnosed in elderly or comorbid patients: looking for the best treatment strategy.

INTRODUCTION: Aim of this study is to provide our results after long-term active surveillance (AS) protocol for small renal masses (SRMs), and to report the outcomes of patients who remained in AS compared to those who underwent delayed surgical intervention. PATIENTS AND METHODS: We retrospectively reviewed our database of 58 patients diagnosed with 60 contrast enhancing SRMs suspicious for renal cell carcinoma (RCC). All patients had clinical and radiological follow-up every 6 months. We evaluated the differences between patients who remained on AS and those who underwent surgical delayed intervention. RESULTS: The mean age was 75 years, the mean follow-up was 88.5 months. The median initial tumor size at presentation was 2.6cm, and the median estimated tumor volume was 8.7cm(3). The median linear growth rate of the cohort was 0.7cm/year, and the median volumetric growth rate was 8.8 cm(3)/year. Death for metastatic disease occurred in 2 patients (3.4%). No correlation was found between initial tumor size and size growth rate. The mean linear and volumetric growth rates of the group of patients who underwent surgery was higher than in those who remained on surveillance (1.9 vs. 0.4cm/year and 16.1 vs. 4.6 cm(3)/year, respectively; P<.001). CONCLUSIONS: Most of SRMs demonstrate to have an indolent course and low metastatic potential. Malignant disease could have faster linear and volumetric growth rates, thus suggesting the need for a delayed surgical intervention. In properly selected patients with low life-expectancy, AS could be a reasonable option in the management of SRMs.

Insight into mechanism of in vitro insulin secretion increase induced by antipsychotic clozapine: role of FOXA1 and mitochondrial citrate carrier.

The use of clozapine and other antipsychotic drugs is known to be associated with a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be, at least in part, the result of impaired islet cell function and abnormal insulin secretion, although the underlying mechanisms are unknown. The aim of this study is the identification of targets for clozapine related to the abnormal insulin secretion. We identify a specific activation of the transcriptional factor FOXA1, but not FOXA2 and FOXA3, by clozapine in HepG2 cells. Clozapine enhances FOXA1 DNA-binding and its transcriptional activity, increasing mitochondrial citrate carrier gene expression, which contains a FOXA1 site in its promoter. Haloperidol, a conventional antipsychotic drug, does not determine any increase of FOXA1 gene expression. We also demonstrate that clozapine upregulates FOXA1 and CIC gene expression in INS-1 cells only at basal glucose concentration. In addition, we find that abnormal insulin secretion in basal glucose conditions could be completely abolished by FOXA1 silencing in INS-1 cells treated with clozapine. The identification of FOXA1 as a novel target for clozapine may shed more light to understand molecular mechanism of abnormal insulin secretion during clozapine treatment.

Two cases of giant cell hepatitis in HIV-infected patients.

Giant cell hepatitis (GCH) has been rarely described in adult HIV patients, and its outcome remain unknown. We report two cases of GCH among 81 HIV patients co-infected with the hepatitis C virus (HCV). Both patients had a sustained virological response, suppression of HCV viral load and HIV viral suppression after highly active antiretroviral therapy. Our findings would suggest that the presence of giant cells does not influence the clinical course of hepatitis.

Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis.

Pathological changes occur in areas of CNS tissue remote from inflammatory lesions in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). To determine if oxidative stress is a significant contributor to this non-inflammatory pathology, cortex tissues from mice with clinical signs of EAE were examined for evidence of inflammation and oxidative stress. Histology and gene expression analysis showed little evidence of immune/inflammatory cell invasion but reductions in natural antioxidant levels and increased protein oxidation that paralleled disease severity. Two-dimensional oxyblots and mass-spectrometry-based protein fingerprinting identified glutamine synthetase (GS) as a particular target of oxidation. Oxidation of GS was associated with reductions in enzyme activity and increased glutamate/glutamine levels. The possibility that this may cause neurodegeneration through glutamate excitotoxicity is supported by evidence of increasing cortical Ca(2+) levels in cortex extracts from animals with greater disease severity. These findings indicate that oxidative stress occurs in brain areas that are not actively undergoing inflammation in EAE and that this can lead to a neurodegenerative process due to the susceptibility of GS to oxidative inactivation.

N0332 phase 2 trial of weekly irinotecan hydrochloride and docetaxel in refractory metastatic breast cancer: a North Central Cancer Treatment Group (NCCTG) Trial.

BACKGROUND: Because of the single-agent activity of irinotecan hydrochloride, combination of irinotecan and docetaxel treatment against metastatic breast cancer (MBC) should be evaluated. PATIENTS AND METHODS: Single-stage phase 2 study of irinotecan and docetaxel to evaluate tumor response, toxicity, time to progression, and overall survival was carried out. Regimen of docetaxel (25 mg/m(2)) and irinotecan (70 mg/m(2)) was administered on days 1 and 8 of each 3-week cycle. Patients had histologically confirmed breast adenocarcinoma and metastatic cancer measurable with RECIST. RESULTS: Of 70 patients enrolled, 64 were assessable. Prior treatment with an anthracycline and a taxane was required. Eighteen (28%) patients [95% confidence interval (CI) 15% to 31%] had tumor response, plus four patients had stable disease (less than 30% decrease in sum of longest diameter and less than 20% increase) for >6 months. The clinical benefit rate was 34% overall. Median duration of tumor response was 6.7 months (95% CI 4.2-37.7 months); median follow-up was 18.6 months (range 8.5-37.7 months). The most common severe adverse events included fatigue [n = 16 (25%)] and neutropenia [n = 13 (20%)]. CONCLUSIONS: Weekly dosing of combination of irinotecan and docetaxel is active against MBC. However, the response rate to our regimen was not significantly better than single-agent docetaxel. Other schedules of irinotecan plus docetaxel should be considered for future studies.