Fad diets and their effect on urinary stone formation

Abstract: The influence of unhealthy dietary habits on urinary stone formation has been widely recognized in literature. Dietary advice is indeed the cornerstone prescription for prevention of nephrolithiasis as well. However, only a small amount of medical literature has addressed the influence of popular or fad diets, often self-prescribed for the management of obesity and overweight or for cultural beliefs, on the risk of kidney stones. Thereby in this paper we analyze the current knowledge on the effects of some popular diets on overall lithogenic risk. High-protein diets, like Dukan diet, raise some concerns, since animal proteins are able to increase urinary calcium and to decrease urinary citrate excretion, thus leading to a high overall lithogenic risk. Low-carbohydrate diets, like Atkins diet or zone diet, may have a protective role against kidney stone formation, but there are also evidences stating that this dietary approach may rise calciuria and decrease citraturia, since it is generally associated to a relatively high intake of animal proteins. Vegan diet can be harmful for urinary stone disease, especially for the risk of hyperuricemia and micronutrient deficiencies, even if only few studies have addressed this specific matter. On the other side, the benefits of a lacto-ovo-vegetarian diet on kidney stone prevention have been largely emphasized, provided that the intake of calcium and oxalate is balanced. Traditional Mediterranean diet should exert a protective effect on nephrolithiasis as well, even if specific studies have not been carried out yet. High phytate and antioxidant content of this diet have however demonstrated to be beneficial in preventing the formation of new or recurrent calculi. Anyway, at the current state of knowledge, the most effective dietary approach to prevent kidney stone disease is a mild animal protein restriction, a balanced intake of carbohydrates and fats and a high intake of fruit and vegetables. Other fundamental aspects, which are often neglected in fad diets, are a normal intake of milk and dairy products and salt restriction. All these nutritional aspects should be greatly taken into account when patients who are willing to undergo fad or commercial diets ask for dietary advice

Comorbidities and disease severity as risk factors for carbapenem-resistant Klebsiella pneumoniae colonization: report of an experience in an internal medicine unit

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging multidrug-resistant nosocomial pathogen, spreading to hospitalized elderly patients. Risk factors in this setting are unclear. Our aims were to explore the contribution of multi-morbidity and disease severity in the onset of CRKP colonization/infection, and to describe changes in epidemiology after the institution of quarantine-ward managed by staff-cohorting

Simultaneous transcranial electrical and magnetic stimulation boost gamma oscillations in the dorsolateral prefrontal cortex

Neural oscillations in the gamma frequency band have been identified as a fundament for synaptic plasticity dynamics and their alterations are central in various psychiatric and neurological conditions. Transcranial magnetic stimulation (TMS) and alternating electrical stimulation (tACS) may have a strong therapeutic potential by promoting gamma oscillations expression and plasticity. Here we applied intermittent theta-burst stimulation (iTBS), an established TMS protocol known to induce LTP-like cortical plasticity, simultaneously with transcranial alternating current stimulation (tACS) at either theta (theta tACS) or gamma (gamma tACS) frequency on the dorsolateral prefrontal cortex (DLPFC). We used TMS in combination with electroencephalography (EEG) to evaluate changes in cortical activity on both left/right DLPFC and over the vertex. We found that simultaneous iTBS with gamma tACS but not with theta tACS resulted in an enhancement of spectral gamma power, a trend in shift of individual peak frequency towards faster oscillations and an increase of local connectivity in the gamma band. Furthermore, the response to the neuromodulatory protocol, in terms of gamma oscillations and connectivity, were directly correlated with the initial level of cortical excitability. These results were specific to the DLPFC and confined locally to the site of stimulation, not being detectable in the contralateral DLPFC. We argue that the results described here could promote a new and effective method able to induce long-lasting changes in brain plasticity useful to be clinically applied to several psychiatric and neurological conditions

Evaluation of HIV-1 integrase resistance emergence and evolution in patients treated with integrase inhibitors.

Abstract Objectives We evaluated the emergence of mutations associated to integrase strand transfer inhibitors (INSTI) resistance (INSTI-RMs) and the integrase evolution in HIV-1 infected patients treated with this drug class. Methods Emergence of INSTI-RMs and integrase evolution (estimated as genetic distance between integrase sequences under-INSTI and before-INSTI treatment) were evaluated in 107 INSTI-naive patients (19 drug-naive and 88 drug-experienced) with two plasma genotypic resistance tests available: one before and one under INSTI treatment. A logistic regression analysis was performed to evaluate factors associated with the integrase evolution under INSTI treatment. Results Patients were mainly infected by B subtype (72.0%). 87 patients were treated with raltegravir, 13 with dolutegravir and 7 with elvitegravir. Before INSTI treatment, one patient harboured the major INSTI-RM R263 K, and three patients the accessory INSTI-RMs T97A. Under INSTI treatment, the emergence of ≥1 INSTI-RM was found in 39 (36.4%) patients. The major INSTI-RMs which emerged more frequently were: N155H (17.8%), G140S (8.4%), Y143R (7.5%), Q148H (6.5%), Y143C (4.7%). Concerning integrase evolution, a higher genetic distance was found in patients with ≥1 INSTI-RM compared to those without emergence of resistance (0.024 [0.012-0.036] vs. 0.015 [0.009-0.024], p = 0.018). This higher integrase evolution was significantly associated with a longer duration of HIV-1 infection, a higher number of past regimens and non-B subtypes. Conclusions Our findings confirmed that in INSTI-naive patients, major INSTI-RMs occur very rarely. Under INSTI treatment, selection of drug-resistance follows the typical drug-resistance pathways; a higher evolution characterizes integrase sequences developing drug-resistance compared to those without any resistance

Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis B.

Background & aims In chronic HBV infection, mitochondrial functions and proteostasis are dysregulated in exhausted HBV-specific CD8 T cells. To better characterise the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion, we analysed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to simultaneously target both mitochondrial functions and proteostasis were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in patients with chronic HBV infection. Methods Lysosome-mediated degradation pathways were analysed by flow cytometry in virus-specific CD8 T cells from patients with chronic HBV infection. Mitochondrial function, intracellular proteostasis, and cytokine production were evaluated in HBV-peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol (RSV) and oleuropein (OLE) and their metabolites, either alone or in combination with other bioactive compounds. Results HBV-specific CD8 T cells from patients with CHB showed impaired autophagic flux. RSV and OLE elicited a significant improvement in mitochondrial, proteostasis and antiviral functions in CD8 T cells. Cytokine production was also enhanced by synthetic metabolites, which correspond to those generated by RSV and OLE metabolism in vivo, suggesting that these polyphenols may also display an effect after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalising effect of mitochondria-targeted antioxidants and of programmed cell death protein 1/programmed cell death ligand 1 blockade. Conclusions Simultaneously targeting multiple altered intracellular pathways with the combination of mitochondria-targeted antioxidants and natural polyphenols may represent a promising immune reconstitution strategy for the treatment of chronic HBV infection. Lay summary In chronic hepatitis B, antiviral T lymphocytes are deeply impaired, with many altered intracellular functions. In vitro exposure to polyphenols, such as resveratrol and oleuropein, can correct some of the deregulated intracellular pathways and improve antiviral T cell function. This effect can be further strengthened by the association of polyphenols with antioxidant compounds in a significant proportion of patients. Thus, the combination of antioxidants and natural polyphenols represents a promising strategy for chronic hepatitis B therapy

Evaluation of virological response and resistance profile in HIV-1 infected patients starting a first-line integrase inhibitor-based regimen in clinical settings

Background: Virological response and resistance profile were evaluated in drug-naïve patients starting their first-line integrase inhibitors (INIs)-based regimen in a clinical setting. Study design: Virological success (VS) and virological rebound (VR) after therapy start were assessed by survival analyses. Drug-resistance was evaluated at baseline and at virological failure. Results: Among 798 patients analysed, 38.6 %, 27.1 % and 34.3 % received raltegravir, elvitegravir and dolutegravir, respectively. Baseline resistance to NRTIs, NNRTIs, PIs and INIs was: 3.9 %, 13.9 %, 1.6 % and 0.5 %, respectively. Overall, by 12 months of treatment, the probability of VS was 95 %, while the probability of VR by 36 months after VS was 13.1 %. No significant differences in the virological response were found according to the INI used. The higher pre-therapy viremia strata was (<100,000 vs. 100,000-500,000 vs. > 500,000 copies/mL), lower was the probability of VS (96.0 % vs. 95.2 % vs. 91.1 %, respectively, P < 0.001), and higher the probability of VR (10.2 % vs. 15.8 % vs. 16.6 %, respectively, P = 0.010). CD4 cell count <200 cell/mm3 was associated with the lowest probability of VS (91.5 %, P < 0.001) and the highest probability of VR (20.7 %, P = 0.008) compared to higher CD4 levels. Multivariable Cox-regression confirmed the negative role of high pre-therapy viremia and low CD4 cell count on VS, but not on VR. Forty-three (5.3 %) patients experienced VF (raltegravir: 30; elvitegravir: 9; dolutegravir: 4). Patients failing dolutegravir did not harbor any resistance mutation either in integrase or reverse transcriptase. Conclusions: Our findings confirm that patients receiving an INI-based first-line regimen achieve and maintain very high rates of VS in clinical practice

DECLINE OF PREVALENCE OF RESISTANCE ASSOCIATED SUBSTITUTIONS TO NS3 AND NS5A INHIBITORS AT DAA- FAILURE IN HEPATITIS C VIRUS IN ITALY OVER THE YEARS 2015 TO 2018

Background: A minority of patients fails to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens . Methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018 . The geno2pheno system and Sorbo MC et al. Drug Resistance Updates 2018 were used to infer HCV- genotype/subtype and predict drug resistance . The changes in prevalence of RASs over time were evaluated by chi-square test for trend, predictors of RASs at failure were analysed by logistic regression . Results: We included 386 HCV infected patients: 75% males, median age was 56 years (IQR 52-61), metavir fibrosis stage F4 in 76%; 106 (28%) were treatment- experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAAs. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype was 1b in 122 pts (32%), 3 in 109 (28%), 1a in 97 (25%), 4 in 37 (10%), 2 in 21 (5%). DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%) . The NS5A fasta-sequence was available for all patients, NS5B for 361 (94%), NS3 for 365 (95%) . According to the DAA failed the prevalence of any RASs was 90%, namely 80/135 (59%) in NS3, 313/359 (87%) in NS5A, 114/286 (40%) in NS5B . The prevalence of any RASs significantly declined from 2015 to 2018 (93% vs 70%, p=0.004): NS5A RASs from 90% to 72% (p=0 .29), NS3 RASs from 74% to 18% (p<0 .001), while NS5B RASs remained stable . Independent predictors of any RASs included advanced fibrosis (AOR 6.1, CI 95% 1.8-20.3, p=0 .004) and genotype (G2 vs G1a AOR 0 .03, CI 95% 0 .002- 0 .31, p=0 .004; G3 vs G1a AOR 0 .08, CI 95% 0 .01-0 .62, p=0 .02; G4 vs G1a AOR 0 .05, CI 95% 0 .006-0 .46, p=0 .008), after adjusting for age, previous HCV treatment and year of genotype . Notably, full activity was predicted for GLE/PIB in 75% of cases and for at least two components of VEL/SOF/VOX in 53% of cases, no case with full-resistance to either regimen was found . Conclusion: Despite decreasing prevalence over the years, RASs remain common at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. The identification of RASs after failure could play a crucial role in optimizing retreatment strategies

Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain‐1 interacts with cellular proteins inducing pro‐oncogenic pathways. Thus, we explore genetic variations in NS5A domain‐1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype‐1b infected DAA‐naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC‐group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell‐cycle regulation (p53, p85‐PIK3, and β‐ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV‐mediated oncogenesis. The role of these NS5A domain‐1 mutations in triggering pro‐oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation