Neural basis of anticipatory multisensory integration

The brain is able to gather different sensory information to enhance salient event perception, thus yielding a unified perceptual experience of multisensory events. Multisensory integration has been widely studied, and the literature supports the hypothesis that it can occur across various stages of stimulus processing, including both bottom-up and top-down control. However, evidence on anticipatory multisensory integration occurring in the fore period preceding the presentation of the expected stimulus in passive tasks, is missing. By means of event-related potentials (ERPs), it has been recently proposed that visual and auditory unimodal stimulations are preceded by sensory-specific readiness activities. Accordingly, in the present study, we tested the occurrence of multisensory integration in the endogenous anticipatory phase of sensory processing, combining visual and auditory stimuli during unimodal and multimodal passive ERP paradigms. Results showed that the modality-specific pre-stimulus ERP components (i.e., the auditory positivity-aP-and the visual negativity-vN-) started earlier and were larger in the multimodal stimulation compared with the sum of the ERPs elicited by the unimodal stimulations. The same amplitude effect was also present for the early auditory N1 and visual P1 components. This anticipatory multisensory effect seems to influence stimulus processing, boosting the magnitude of early stimulus processing. This paves the way for new perspectives on the neural basis of multisensory integration

Considerations for the optimal management of antibiotic therapy in elderly patients

Objectives: To maximise efficacy and minimise toxicity, special considerations are required for antibiotic prescription in elderly patients. This review aims to provide practical suggestions for the optimal management of antibiotic therapy in elderly patients. Methods: This was a narrative review. A literature search of published articles in the last 15 years on antibiotics and elderly patients was performed using the Cochrane Library and PubMed electronic databases. The three priority areas were identified: (i) pharmacokinetics/pharmacodynamics (PK/PD) for optimising dosage regimens and route of administration; (ii) antibiotic dosages in some special subpopulations; and (iii) treatment considerations relating to different antibiotic classes and their adverse events. Results: Clinicians should understand the altered PK/PD of drugs in this population owing to co-morbid conditions and normal physiological changes associated with ageing. The body of evidence justifies the need for individualised dose selection, especially in patients with impaired renal and liver function. Clinicians should be aware of the major drug–drug interactions commonly observed in the elderly as well as potential side effects. Conclusion: Antibiotic therapy in the elderly requires a comprehensive approach, including strategies to improve appropriate antibiotic prescribing, limit their use for uncomplicated infections and ensure the attainment of an optimal PK/PD target. To this purpose, further studies involving the elderly are needed to better understand the PK of antibiotics. Moreover, it is necessary to assess the role therapeutic drug monitoring in guiding antibiotic therapy in elderly patients in order to evaluate its impact on clinical outcome

Survival Outcomes and Effect of Early vs. Deferred cART Among HIV-Infected Patients Diagnosed at the Time of an AIDS-Defining Event: A Cohort Analysis

Objectives: We analyzed clinical progression among persons diagnosed with HIV at the time of an AIDS-defining event, and assessed the impact on outcome of timing of combined antiretroviral treatment (cART).Methods: Retrospective, European and Canadian multicohort study.. Patients were diagnosed with HIV from 1997-2004 and had clinical AIDS from 30 days before to 14 days after diagnosis. Clinical progression (new AIDS event, death) was described using Kaplan-Meier analysis stratifying by type of AIDS event. Factors associated with progression were identified with multivariable Cox regression. Progression rates were compared between those starting early (<30 days after AIDS event) or deferred (30-270 days after AIDS event) cART.Results: The median (interquartile range) CD4 count and viral load (VL) at diagnosis of the 584 patients were 42 (16, 119) cells/mu L and 5.2 (4.5, 5.7) log(10) copies/mL. Clinical progression was observed in 165 (28.3%) patients. Older age, a higher VL at diagnosis, and a diagnosis of non-Hodgkin lymphoma (NHL) (vs. other AIDS events) were independently associated with disease progression. Of 366 patients with an opportunistic infection, 178 (48.6%) received early cART. There was no significant difference in clinical progression between those initiating cART early and those deferring treatment (adjusted hazard ratio 1.32 [95% confidence interval 0.87, 2.00], p = 0.20).Conclusions: Older patients and patients with high VL or NHL at diagnosis had a worse outcome. Our data suggest that earlier initiation of cART may be beneficial among HIV-infected patients diagnosed with clinical AIDS in our setting

Genotypic HIV-1 tropism determination might help to identify people with exhausted treatment options and advanced disease

Objectives: To evaluate HIV-1 tropism in 1382 combined antiretroviral therapy (cART)-experienced patients failing therapy to characterize those with exhausted therapeutic options. Methods: HIV-1 genotypic tropism was inferred through Geno2Pheno by estimating the false-positive-rate (FPR) values. Cumulative resistance and drug activity were evaluated by Stanford algorithm. Results: Overall, median (IQR) CD4 count (cells/mm3) nadir and at last genotypic resistance test (GRT) available were 98 (33-211) and 312 (155-517), respectively. Considering HIV-1 tropism, 30.5% had X4/dual-mixed strains (FPR ≤5%: 22.2%; FPR 5%-10%: 8.3%). By stratifying according to tropism, by decreasing FPR, a significant decrease of CD4 nadir and at last GRT was observed. The proportion of individuals with CD4 count &lt;200 cells/mm3, who were perinatally infected and with a long treatment history significantly increased as FPR levels decreased. Regarding resistance, 933 (67.5%) individuals accumulated at least one class resistance, with 52.7%, 48.2%, 23.5% and 13.2% of individuals showing resistance to NRTIs, NNRTIs, PIs and INIs; while 23.2%, 27.2%, 14.3% and 2.8% harboured resistance to 1, 2, 3 and 4 classes, respectively. Individuals with FPR ≤5% showed a significantly higher level of resistance to PIs, NRTIs and INIs compared with others. The proportion of individuals harbouring strains susceptible to ≤2 active drugs was only about 2%; nonetheless, this proportion doubled (4.6%) in patients infected with FPR ≤5%. Conclusions: Our findings showed that a small proportion of cART failing individuals have limited therapeutic options. However, tropism determination might help to identify people who have accumulated a high level of resistance and have a greater risk of advanced disease

Temporal trend of drug-resistance and APOBEC editing in PBMC genotypic resistance tests from HIV-1 infected virologically suppressed individuals

Background: We aimed at evaluating the temporal trend of drug-resistance and APOBEC editing from HIV-DNA genotypic resistance tests (GRT) in virologically suppressed individuals.Material and methods: Major resistance mutations (MRM), genotypic susceptibility score (GSS) for the current regimen and APOBEC-related mutations (APO-M) were evaluated. Potential changes in trends of MRM and APO-M over-time were assessed and predictors of MRM detection or sub-optimal GSS (GSS&lt;2) at HIV-DNA-GRT were estimated through logistic regression analyses.Results: Among the 1126 individuals included, 396 (35.2%) harboured at least one MRM (23.4% to NRTI, 18.8% to NNRTI, 7.7% to PI and 1.4% to INSTI [N=724]); 132 (12.3%) individuals showed a GSS &lt;2. APO-M and stop codons were found in 229 (20.3%) and 105 (9.3%) individuals, respectively. APO-DRMs were found in 16.8% of individuals and were more likely observed in those individuals with stop codons (40.0%) compared to those without (14.4%, P&lt;0.001). From 2010 to 2021 no significant changes of resistance or APO-M were found. Positive predictors of MRM detection at HIV-DNA GRT were drug abuse, subtype B infection, and a prolonged and complex treatment history. Perinatal infection and having at least 2 stop codons were associated with a current suboptimal regimen.Conclusions: In virologically suppressed individuals, resistance in HIV-DNA and the extent of APOBEC editing were generally stable in the last decade. A careful evaluation of APOBEC editing might be helpful to improve the reliability of HIV-DNA GRT. Further investigations are required to understand how to apply the estimation of APOBEC editing in refining genotypic evaluation

Dasabuvir and Ombitasvir/Paritaprevir/Ritonavir with or without Ribavirin in Patients with HIV-HCV Coinfection. Real Life Interim Analysis of an Italian Multicentre Compassionate Use Program

Background and Aims: An HCV cure is now possible in a large proportion of HIV-HCV patient. We present real life results of a compassionate use program promoted by SIMIT (Infectious and Tropical Diseases Italian Society) of Dasabuvir and Ombitasvir/Paritaprevir/Ritonavir ± Ribavirin for 12 weeks in 213 HIV-HCV genotype 1 patients. Data on efficacy and tolerability of this strategy in HIV patients have been reported until now only in 43 non cirrhotic HIV subjects

Novel genetic association of TNF-α-238 and PDCD1-7209 polymorphisms with long-term non-progressive HIV-1 infection.

About 2-5% of HIV-1-infected subjects, defined as long-term non-progressors (LTNPs), remain immunologically stable for a long time without treatment. The factors governing this condition are known only in part, and include genetic factors. Thus, we studied 20 polymorphisms of 15 genes encoding proinflammatory and immunoregulatory cytokines, chemokines and their receptors, genes involved in apoptosis, and the gene HCP5. METHODS: We analyzed 47 Caucasian LTNPs infected for &gt;9 years, compared with 131 HIV-1-infected Caucasian patients defined as 'usual progressors'. The genotypes were determined by methods based upon PCR, and the statistical analysis was performed by univariate logistic regression. RESULTS: The well-known CCR5Δ32 del32 allele, the cell death-related TNF-α-238 A and PDCD1-7209 T alleles, and HCP5 rs2395029 G, a non-coding protein associated with the HLA-B*5701, were found positively associated with the LTNP condition. No association was observed for other single nucleotide polymorphisms (SDF-1-801, IL-10-592, MCP-1-2518, CX3CR1 V249I, CCR2V64I, RANTES-403, IL-2-330, IL-1β-511, IL-4-590, FASL IVS3nt-169, FAS-670, FAS-1377, FASL IVS2nt-124, PDCD1-7146, MMP-7-181, and MMP7-153). CONCLUSIONS: The novel genetic associations between allelic variants of genes TNF-α-238 and PDCD1-7209 with the LTNP condition underline the importance of host genetic factors in the progression of HIV-1 infection and in immunological preservation

Towards inherently chiral Ionic liquids: molecular design strategies and electrochemical properties

Chiral Ionic Liquids (CILs) constitute a class of chiral solvents of steadily increasing importance in the last years; they are employed inter alia as chiral solvents for asymmetric synthesis and stereoselective polymerization, as chiral phases in gas chromatography and as chiral shift reagents in NMR spectroscopy. Although their application to electrochemical processes is a field still requiring exploration, they should have a huge impact for instance in asymmetric electropolymerizations and in regioregular electrochemically activated polymerizations, as well as in preparative electrosynthetic processes of chiral compounds. The current general design of CILs follows rather intuitive strategies. The use of a chiral anion (e.g. from lactic acid, \uf061-aminoacids, 10-camphorsulfonic acid, 1,1\u2019- binaphthylphosphoric acid) is a simple but scarcely innovative strategy. More possibilities are afforded by the chiral cation approach; in this case a wide range of building blocks have been so far explored to confer chirality, from the classical 1- phenylethyl group to derivatives of tartaric acid, pinene, myrtanol, citronellol, menthol, carvone, etc. Our group has recently proposed electroactive thiophene-based polyconjugated films of unprecedented chirality manifestations and enantiorecognition ability[1] based on the concept of the whole electroactive backbone coinciding with the stereogenic element, consisting in a tailored torsion induced by an atropisomeric bithiophene scaffold. Now we are trying to apply the same "inherent chirality" approach to the development of inherently chiral ionic liquids, hopefully endowed with high enantioselectivity, like the formerly developed inherently chiral electrodes. An overview will be given of the first structures obtained and of their electrochemical properties. The new molecules are based on cations including different atropisomeric bis-benzimidazolium groups acting as the stereogenic element, responsible for both the molecular chirality and the IL properties of the material, modulated by the number, position and length of alkyl chain substituents