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.

Clinical impact of high platelet reactivity in patients with atrial fibrillation and concomitant percutaneous coronary intervention on dual or triple antithrombotic therapy.

High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario. The present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y12 dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y12 reactive unit; TAT, triple antithrombotic therapy. Created with BioRender.com.

Direct quantification of cytosolic delivery of drug nanocarriers using FlAsH-EDT2.

The delivery of therapeutics across the cell membrane and into the cytoplasm is a major challenge that limits the development of new therapies. This challenge is compounded by the lack of a general assay for cytosolic delivery. Here we develop this assay based on the pro-fluorophore CrAsH-EDT2, and provide cytosolic penetration results for a variety of drug delivery agents (polyethyleneimine, poly-arginine, Ferritin, poly [maleic anhydride-alt-isobutene] grafted with dodecylamine, and cationic liposomes) into HeLa and T98G cells. Our results show that this method can be widely applicable to different cells and drug delivery agents, and yield statistically robust results. We later use this method to optimize and improve a model drug delivery agent's (Ferritin) cytosolic penetration.

Using the Goldilocks Principle to model coral ecosystem engineering.

The occurrence and proliferation of reef-forming corals is of vast importance in terms of the biodiversity they support and the ecosystem services they provide. The complex three-dimensional structures engineered by corals are comprised of both live and dead coral, and the function, growth and stability of these systems will depend on the ratio of both. To model how the ratio of live : dead coral may change, the 'Goldilocks Principle' can be used, where organisms will only flourish if conditions are 'just right'. With data from particle imaging velocimetry and numerical smooth particle hydrodynamic modelling with two simple rules, we demonstrate how this principle can be applied to a model reef system, and how corals are effectively optimizing their own local flow requirements through habitat engineering. Building on advances here, these approaches can be used in conjunction with numerical modelling to investigate the growth and mortality of biodiversity supporting framework in present-day and future coral reef structures.

Predictors of incomplete viral response and virologic failure in patients with acute and early HIV infection. Results of Italian Network of ACuTe HIV InfectiON (INACTION) cohort.

OBJECTIVES: The aim of this study was to evaluate the factors that can influence an incomplete viral response (IVR) after acute and early HIV infection (AEHI). METHODS: This was a retrospective, observational study including patients with AEHI (Fiebig stages I-V) diagnosed between January 2008 and December 2014 at 20 Italian centres. IVR was defined by: (1) viral blip (51-1000 HIV-1 RNA copies/mL after achievement of < 50 HIV-1 RNA copies/mL); (2) virologic failure [> 1000 copies/mL after achievement of < 200 copies/mL, or ≥ 200 copies/mL after 24 weeks on an antiretroviral therapy (ART)]; (3) suboptimal viral response (> 50 copies/mL after 48 weeks on ART or two consecutive HIV-1 RNA levels with ascending trend during ART). Cox regression analysis was used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for IVR. RESULTS: In all, 263 patients were studied, 227 (86%) males, with a median [interquartile range (IQR)] age of 38 (30-46) years. During a median follow-up of 13.0 (5.7-31.1) months, 38 (14.4%) had IVR. The presence of central nervous system (CNS) symptoms was linked to a higher risk of IVR (HR = 4.70, 95% CI: 1.56-14.17), while a higher CD4/CD8 cell count ratio (HR = 0.13, 95% CI: 0.03-0.51 for each point increase) and first-line ART with three-drug regimens recommended by current guidelines (HR = 0.40, 95% CI: 0.18-0.91 compared with other regimens including four or five drugs, older drugs or non-standard backbones) were protective against IVR. CONCLUSIONS: Patients with lower CD4/CD8 ratio and CNS symptoms could be at a higher risk of IVR after AEHI. The use of recommended ART may be relevant for improving short-term viral efficacy in this group of patients.

Bacterial etiology of community-acquired pneumonia in immunocompetent hospitalized patients and appropriateness of empirical treatment recommendations: an international point-prevalence study.

An accurate knowledge of the epidemiology of community-acquired pneumonia (CAP) is key for selecting appropriate antimicrobial treatments. Very few etiological studies assessed the appropriateness of empiric guideline recommendations at a multinational level. This study aims at the following: (i) describing the bacterial etiologic distribution of CAP and (ii) assessing the appropriateness of the empirical treatment recommendations by clinical practice guidelines (CPGs) for CAP in light of the bacterial pathogens diagnosed as causative agents of CAP. Secondary analysis of the GLIMP, a point-prevalence international study which enrolled adults hospitalized with CAP in 2015. The analysis was limited to immunocompetent patients tested for bacterial CAP agents within 24 h of admission. The CAP CPGs evaluated included the following: the 2007 and 2019 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA), the European Respiratory Society (ERS), and selected country-specific CPGs. Among 2564 patients enrolled, 35.3% had an identifiable pathogen. Streptococcus pneumoniae (8.2%) was the most frequently identified pathogen, followed by Pseudomonas aeruginosa (4.1%) and Klebsiella pneumoniae (3.4%). CPGs appropriately recommend covering more than 90% of all the potential pathogens causing CAP, with the exception of patients enrolled from Germany, Pakistan, and Croatia. The 2019 ATS/IDSA CPGs appropriately recommend covering 93.6% of the cases compared with 90.3% of the ERS CPGs (p < 0.01). S. pneumoniae remains the most common pathogen in patients hospitalized with CAP. Multinational CPG recommendations for patients with CAP seem to appropriately cover the most common pathogens and should be strongly encouraged for the management of CAP patients.

Fatal respiratory infection due to ST308 VIM-1-producing Pseudomonas aeruginosa in a lung transplant recipient: case report and review of the literature.

BACKGROUND: Data regarding the prevalence of metallo-ß-lactamases (MBLs) among Pseudomonas aeruginosa isolates in cystic fibrosis patients are scarce. Furthermore, there is limited knowledge on the effect of MBL production on patient outcomes. Here we describe a fatal respiratory infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient and the results of the subsequent epidemiological investigation. CASE PRESENTATION: P. aeruginosa isolates collected in the index patient and among patients temporally or spatially linked with the index patient were analyzed in terms of antibiotic susceptibility profile and MBL production. Whole-genome sequencing and phylogenetic reconstruction were also performed for all P. aeruginosa isolates producing VIM-type MBLs. A VIM-producing P. aeruginosa strain was identified in a lung biopsy of a lung transplant recipient with cystic fibrosis. The strain was VIM-1-producer and belonged to the ST308. Despite aggressive treatment, the transplant patient succumbed to the pulmonary infection due to the ST308 strain. A VIM-producing P. aeruginosa strain was also collected from the respiratory samples of a different cystic fibrosis patient attending the same cystic fibrosis center. This isolate harbored the blaVIM-2 gene and belonged to the clone ST175. This patient did not experience an adverse outcome. CONCLUSIONS: This is the first description of a fatal infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient. The circulation of P. aeruginosa isolates harboring MBLs pose a substantial risk to the cystic fibrosis population due to the limited therapeutic options available and their spreading potential.

Determinants of high residual post-PCV13 pneumococcal vaccine-type carriage in Blantyre, Malawi: a modelling study.

BACKGROUND: In November 2011, Malawi introduced the 13-valent pneumococcal conjugate vaccine (PCV13) into the routine infant schedule. Four to 7 years after introduction (2015-2018), rolling prospective nasopharyngeal carriage surveys were performed in the city of Blantyre. Carriage of Streptococcus pneumoniae vaccine serotypes (VT) remained higher than reported in high-income countries, and impact was asymmetric across age groups. METHODS: A dynamic transmission model was fit to survey data using a Bayesian Markov-chain Monte Carlo approach, to obtain insights into the determinants of post-PCV13 age-specific VT carriage. RESULTS: Accumulation of naturally acquired immunity with age and age-specific transmission potential were both key to reproducing the observed data. VT carriage reduction peaked sequentially over time, earlier in younger and later in older age groups. Estimated vaccine efficacy (protection against carriage) was 66.87% (95% CI 50.49-82.26%), similar to previous estimates. Ten-year projected vaccine impact (VT carriage reduction) among 0-9 years old was lower than observed in other settings, at 76.23% (CI 95% 68.02-81.96%), with sensitivity analyses demonstrating this to be mainly driven by a high local force of infection. CONCLUSIONS: There are both vaccine-related and host-related determinants of post-PCV13 pneumococcal VT transmission in Blantyre with vaccine impact determined by an age-specific, local force of infection. These findings are likely to be generalisable to other Sub-Saharan African countries in which PCV impact on carriage (and therefore herd protection) has been lower than desired, and have implications for the interpretation of post-PCV carriage studies and future vaccination programs.

The burden of cutaneous adnexal carcinomas and the risk of associated squamous cell carcinoma: a population-based study.

BACKGROUND: Recent studies have shown an increasing incidence of cutaneous adnexal carcinomas (CACs). OBJECTIVES: The aim of our study was to evaluate incidence and survival for cases of CACs and investigate their association with other skin neoplasms. METHODS: We conducted a population-based study. Data on incident cases of CACs were obtained from the Tuscany Cancer Registry between 1985 and 2010. In order to determine whether the occurrence of squamous cell carcinoma (SCC) among patients with CAC is higher or lower than expected in the general population, the standardized incidence ratio (SIR) was calculated. RESULTS: A total of 242 patients with CAC were observed; the age-standardized incidence rate was 3·8 cases per million person-years. From 1997 to 2010 crude incidence rates increased by 159%. Age-specific incidence was higher in men over 80 years old than in women of the same age and younger individuals. Carcinomas of sweat gland origin prevailed; the most common histotype was porocarcinoma and the most frequently affected site was the head/neck. Overall, 88% of CACs were diagnosed at a localized stage. The 5-year overall survival and disease-specific survival rates were 59% [95% confidence interval (CI) 53-65] and 94% (95% CI 91-98), respectively. In the observation cohort, the number of SCCs was significantly higher than expected as the SIR was calculated to be 33·7 (P < 0·001). CONCLUSIONS: Increasing incidence warrants awareness and early diagnosis of CACs. Increased SCC incidence among patients with these tumours highlights the relevance of careful skin examination and follow-up.

Effects of a 3-month dietary intervention with a lacto-ovo-vegetarian diet on vitamin B12 levels in a group of omnivores: results from the CARDIVEG (Cardiovascular Prevention with Vegetarian Diet) study.

Previous studies have suggested that vegetarianism can result in a reduction of vitamin B12 circulating levels. The aim of the present study was to investigate the effects of a 3-month dietary intervention with a lacto-ovo-vegetarian diet (VD) on the levels of circulating vitamin B12 in a group of omnivores. We analysed fifty-four omnivorous subjects who followed a VD as a first dietary intervention within the CARDIVEG (Cardiovascular Prevention with Vegetarian Diet) study, a dietary intervention study. VD resulted in a significant reduction (P<0·001) of 51·2 % of vitamin B12 intake and in a significant reduction (P=0·005) of 6·2 % of the circulating levels of vitamin B12 (-24·5 pg/ml). Changes in vitamin B12 intake were significantly correlated with changes in circulating levels of vitamin B12 (R 0·61, P<0·001). Subgroup analyses showed that reduction in circulating vitamin B12 levels was more evident in participants who were younger, overweight, non-smokers and had hypercholesterolaemia. A logistic regression analysis showed that a reduction in vitamin B12 intake greater than the first quartile of the delta changes obtained in the study population (-28·5 %) conferred a significantly higher risk of experiencing a decrease in circulating vitamin B12 levels (OR 10·1; 95 % CI 1·3, 76·1). In conclusion, a 3-month VD period determined a significant reduction in circulating levels of vitamin B12, being significantly correlated with the reduction in vitamin B12 intake. Although a well-planned VD can provide adequate nutrition across all life stages, special care must be taken to ensure adequate vitamin B12 intake and to help prevent deficiency.

Mediterranean, but not lacto-ovo-vegetarian, diet positively influence circulating progenitor cells for cardiovascular prevention: The CARDIVEG study.

AIM: To evaluate the possible association between dietary habits and progenitor cells using data obtained from a randomized crossover trial using two different diets, lacto-ovo-vegetarian (VD) and Mediterranean (MD), the CARDIVEG study. METHODS AND RESULTS: Eighty clinically healthy subjects with a low-to-moderate cardiovascular risk profile (61 F; 19 M; mean age: 50.7 ± 11.6 years) were randomly assigned to isocaloric VD and MD diets lasting three months each, and then crossed. The two diets showed no effects on endothelial progenitor cells and circulating endothelial cells but opposite effects on circulating progenitor cells. In fact, VD determined significant (p < 0.05) and negative changes on circulating progenitor cells, with an average geometric variation of -130 cells/106 events for CD34+/CD45-/dim, -80 cells/106 events for CD133+/CD45-/dim, and -84 cells/106 events for CD34+/CD133+/CD45-/dim while MD determined significant (p < 0.05) and positive changes for CD34+/CD45-/dim levels, with a geometric mean increase of +54 cells/106 events. No significant correlations were observed between changes in progenitor cells and changes in inflammatory parameters during the VD phase. On the other hand, during the MD phase negative correlations between changes of CD34+/CD45-/dim and interleukin-6 (R = -0.324; p = 0.004) as well as interleukin-8 (R = -0.228; p = 0.04) and monocyte chemotactic protein-1 (R = -0.277; p = 0.01), were observed. These correlations remained significant also after adjustment for confounding factors only for CD34+/CD45-/dim and interleukin-6 (ß = -0.282; p = 0.018) and monocyte chemotactic protein-1 (ß = -0.254; p = 0.031). CONCLUSIONS: MD, but not VD, reported a significant and positive effect on circulating progenitor cells in a group of subjects at low-to-moderate cardiovascular risk, probably acting through the modulation of inflammatory parameters.

Aging process, adherence to Mediterranean diet and nutritional status in a large cohort of nonagenarians: Effects on endothelial progenitor cells.

BACKGROUND AND AIM: Adherence to the Mediterranean Diet (MD) has been associated with a longer and better life. The aim of this study was to examine the effects of adherence to the MD, and of nutritional habits on endothelial progenitor (EPCs) and circulating progenitor (CPCs) cells in a cohort of nonagenarians enrolled within the Mugello Study, an epidemiological study aimed at investigating both clinically relevant geriatric items and various health issues, including those related to nutritional status. METHODS AND RESULTS: Four hundred twenty-one nonagenarians (306 F, 115 M, mean age: 93.1 ± 3.2 years) were evaluated. Adherence to MD was assessed through the Mediterranean Diet Score. Elderly subjects who were in the fourth quartile of the Mediterranean diet score showed significantly higher EPCs than subjects grouped into the other three quartiles. After adjustment for confounders, elderly subjects who were in the highest quartile of adherence to the MD score reported to have EPCs' levels significantly higher than those who reported lower values of adherence to the MD. Furthermore, by analyzing different food categories, it was reported that daily consumption of olive oil and a higher consumption of fruit and vegetables showed higher CPCs CD34+ and EPCs CD34+/KDR+ than subjects with not daily or lower consumption. CONCLUSION: Our results support the hypothesis that the adherence to MD, as well as a daily consumption of olive oil and fruit and vegetables, characteristics of MD, may protect against the development of endothelial dysfunction through increasing EPCs and CPCs in older age.

Right pneumothorax secondary to colonoscopic perforation: a case.

AIM: The purpose of this study is to determine the anatomical aspects, mechanisms, risk factors and appropriate management of development of pneumothorax during a routine colonoscopy. CLINICAL CASE: We report a case of an accidental bowel wall injury during diagnostic colonoscopic with consequent pneumoperitoneum; this was followed by expansion of gas through diaphragmatic fenestration perhaps congenital, in right pleural cavity causing pneumothorax. DISCUSSION: Rarely, colonic perforation during colonoscopy can occur into the extraperitoneal space, thus leading to the passage and diffusion of air along the fascial planes and large vessels, possibly causing pneumoretroperitoneum, pneumomediastinum, pneumopericardium, pneumothorax, and subcutaneous emphysema. The combination of intraperitoneal and extraperitoneal perforation has also been reported. Pneumothorax following a colonoscopy sigmoid perforation is an extremely rare but severe and often lifethreatening complication. CONCLUSION: If the patient develops dyspnea and pneumoderma during or after this procedure, a chest radiogram or thoracoabdominal CT should be taken for diagnostic purposes. Urgent treatment, starting with chest tube insertion(s) and laparotomy or laparoscopy could be lifesaving.

Incidence and predictors of cardiovascular disease, chronic kidney disease, and diabetes in HIV/HCV-coinfected patients who achieved sustained virological response.

Data on the effects of sustained virologic response (SVR) to hepatitis C virus (HCV) therapy on the outcome of extrahepatic complications are scarce. We conducted this study to assess the impact of SVR on the occurrence of chronic kidney disease (CKD), diabetes mellitus (DM), and cardiovascular disease (CVD) in a cohort of human immunodeficiency virus (HIV)-infected patients. We analyzed coinfected HIV/HCV patients in the Management of Standardized Evaluation of Retroviral HIV Infection (MASTER) cohort. Only event-free patients with a serum HCV-RNA determination at baseline were included. Patients were divided into four groups: INF-exposed with SVR; INF-exposed without SVR; spontaneous HCV clearance; untreated viremic patients. We estimated the incidence of extrahepatic complications and employed Kaplan-Meier curves and Cox regression to assess the association of SVR/INF strata adjusted for a series of confounders. Data from 1676 patients were analyzed (20.29 % started an INF-based regimen). Overall, the incidence of CKD, DM, CVD, and death was 5.32 [95 % confidence interval (CI) 3.99-6.98], 10.13 (95 % CI 8.20-12.37), 6.79 (95 % CI 5.26-8.65), and 13.49 (95 % CI 11.29-16.0) per 1000 person-years of follow-up, respectively. In the Cox model for treated patients, SVR was not associated with a lower risk of CKD, DM, CVD, and death compared to non-SVR. Cirrhosis was significantly associated with a higher risk of CKD [hazard ratio (HR) 2.13; 95 % CI 1.06-4.31], DM (HR 3.48; 95 % CI 2.18-5.57), and death (HR 6.18; 95 % CI 4.1-9.31), but not of CVD (HR 1.14; 95 % CI 0.57-2.3). There are still many unknowns regarding the impact of SVR on the occurrence of extrahepatic complications in coinfected HIV/HCV patients. Further investigations are needed in order to elucidate the role of SVR as an independent prognostic factor for extrahepatic events.

Acral lentiginous melanoma treated with topical imiquimod cream: possible cooperation between drug and tumour cells.

An 85-year-old woman presented with a lesion on the sole of her right foot, which was histologically confirmed as acral lentiginous melanoma. Because of the large field involved and because the patient refused any invasive or painful treatment, topical treatment with imiquimod was commenced. At the 20-month follow-up, the patient was still continuing treatment with topical imiquimod, and no metastases to the lymph nodes or viscera were found, either clinically or in imaging studies. We believe that the success of the treatment cannot be explained only by the stimulation of the immune system induced by imiquimod. A possible explanation might be 'tumour dormancy', where a tumour grows very slowly because of a balance between the neoplasia and the immune (and nonimmune) mechanisms of tumour control. The use of imiquimod has so far allowed our patient to avoid surgery, and perturbation of the mechanisms of tumour regulation, such as local immunity and angiogenesis, has not taken place.