Short-, mid- and long-term efficacy of dupilumab in moderate to severe atopic dermatitis: a real life multicenter Italian study on 2576 patients

Background: The efficacy and safety of dupilumab in atopic dermatitis (AD) have been defined in clinical trials but limited real-world evidence on long term treatment outcomes are currently available to inform clinical decisions. Objectives: to describe long-term effectiveness and safety of dupilumab up to 48 months in patients with moderate-to-severe AD. Methods: a multicenter, retrospective, dynamic cohort study was conducted to assess long term effectiveness and safety of dupilumab in patients with moderate to severe AD in a real-world setting. Predictors of minimal disease activity (MDA) optimal treatment target criteria (defined as the simultaneous achievement of EASI90, itch NRS score ≤1, sleep NRS score ≤1 and DLQI ≤1) were investigated. Results: 2576 patients were enrolled from June 2018 to July 2022. MDA optimal treatment target criteria were achieved by 506 (21.91%), 769 (40.63%), 628 (50.36%), 330 (55.37%) and 58 (54.72%) of those that reached 4, 12, 24, 36 and 48 months of follow-up, respectively. Logistic regression revealed a negative effect on MDA achievement for conjunctivitis and food allergy at all timepoints. Adverse events (AE) were mild and were observed in 373 (15.78%), 166 (7.02%), 83 (6.43%), 27 (4.50%) and 5 (4.55%) of those that reached 4, 12, 24, 36 and 48 months of follow-up. Conjunctivitis was the most frequently reported AE during the available follow-up. AE led to treatment discontinuation in <1% of patients during the evaluated time periods. Conclusion: High long-term effectiveness and safety of dupilumab were confirmed in this dynamic cohort of patients with moderate to severe AD, regardless of clinical phenotype and course at baseline. Further research will be needed to investigate the effect of Th2 comorbidities and disease duration on the response to dupilumab and other newer therapeutics for AD

Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors

Background: Intervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/Principal Findings: We have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-gamma, IL-2, TNF-alpha production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8+ T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.Conclusions: Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Genetic variations in the endangered Sicilian endemic Brassica rupestris: proposals for a conservation strategy

Brassica rupestris Raf. is a chasmophyte species that includes two subspecies, both endemic to Central-Western Sicily (Italy). ISSR markers were used to detect genetic diversity within and among eight populations representative of the species’ distribution range. High levels of genetic diversity were revealed both at the population (PPB=53.88%, H S=0.212, Sh=0.309) and at the species level (PPB=96.55%, H T=0.307, Sh=0.464). The correlation between genetic and geographical distances was negative (Mantel test, r=−0.06 P<0.95). The two subspecies of B. rupestris, subsp. rupestris and subsp. hispida, showed remarkable genetic similarity and molecular data did not unequivocally support their distinctness. The pattern of genetic variation revealed by our study bears important consequences for conservation management: it is desirable to preserve B. rupestris populations in situ with a “dynamic” strategy, while, ex situ conservation programmes might be improved to safeguard maximum genetic diversity

Genetic variation in the Sicilian endangered populations of Brassica rupestris.

Boll. Mus. Ist. Biol. Univ. Genova, 73, 2011 106° Congresso Società Botanica Italiana – Genova 21-23 settembre 2011 163 GENETIC VARIATION IN THE SICILIAN ENDANGERED BRASSICA RUPESTRIS F.M. RAIMONDO1, A. SCIALABBA1, G. ZECCA2, F. GRASSI2, G. CASAZZA3, L. MINUTO3 1 Department of Environment Biology and Biodiversity, University of Palermo, Via Archirafi 38, I-90123 Palermo, Italy. [email protected]; [email protected]; 2 Botanical Garden, Department of Biology, Università di Milano, Via Celoria 26, 20133 Milano, Italy. [email protected]; [email protected]; 3Department for the Study of Territory and its Resources, University of Genova, Corso Dogali 1M, I-16136 Genova, Italy. [email protected]; [email protected] Brassica rupestris Raf. is an endemic plant belonging to the Brassica section. It grows in rocky places and cliffs of the Central-Western Sicily (Italy). Rare and endangered species are susceptible to loss of genetic variation through genetic drift in small populations. Management decisions for the conservation of rare taxa necessitate an understanding of their biology and other factors, including genetic variability. For this reason the gathering of data on population genetic structure of rare species has become a common prelude to their conservation planning (Ellstrand & Elam, 1993). In the present study the ISSR technique was used to examine natural populations of B. rupestris (both subsp. rupestris and subsp. hispida) for the following purposes: 1) to evaluate the genetic diversity both at species and subspecies levels, 2) to assess the genetic differentiation of populations and 3) to provide suggestions for effective conservation programs. Six natural populations of B. rupestris subsp. rupestris and two populations of B. rupestris subsp. hispida, covering the whole range of the two subtaxa, were investigated and mapped using GPS (Garmin) in order to evaluate their genetic diversity. Six were from Palermo province: S. Calogero, Capo Zafferano, P.so Scuro - Castelbuono, Mt. Pellegrino, Mt. Kumeta, Mt. Pizzuta; one from Agrigento province: Gole Tardara - Sciacca; one from Reggio Calabria province: Stilo. ISSR were used to detect the genetic diversity within and among populations representative of the species distribution range. From each site, a variable number (8< N <10) according to the availability of individuals were randomly sampled (n = 76); 1-2 leaves per plant were dried in situ in silica gel, washed in laboratory and total genomic DNA extracted by using DNeasy Plant Mini Kit (Qiagen) following the manufacturer‘s instructions. High levels of genetic diversity were revealed both at population (PPB = 53.88%, HS = 0.2115, Sh = 0.3085) and at species level (PPB = 96.55%, HT = 0.3070, Sh = 0.4638). The correlation between genetic and geographic distances was negative (Mantel test, r = -0.23). Our data on B. rupestris revealed that about 67% of genetic variation is detectable within the population while 23% among populations within infraspecific taxa. This fact is also confirmed by the quite good value of migration rate among populations and it could be explained by hypothesizing the self-incompatibility systems, often found in many Brassica populations (Geraci et al., 2004). The information on the pattern of genetic variation obtained in the present work bear important inferences for conservation management, and in particular for ex situ conservation programmes. The populations showing local markers (Gole Tardara, San Calogero, and Mt. Pellegrino) deserve particular attention for their important presence in a seeds bank. This research was supported by PRIN 2007JNJ7MX_003 project. Ellstrand C. & Elam D.R., 1993. Population genetic consequences of small population size: implications for plant conservation. Annu Rev Ecol Syst 24:217–242. Geraci A., Chèvre A.M., Divaret I., Eber F. & Raimondo FM., 2004. Isozyme analysis of genetic diversity in wild Sicilian populations of Brassica sect. Brassica in view of genetic resources management. Genet. Resources Crop Evol. 51:137–146. INDICEBoll. Mus. Ist. Biol. Univ. Genova, 73, 2011 106° Congresso Società Botanica Italiana – Genova 21-23 settembre 2011 163 GENETIC VARIATION IN THE SICILIAN ENDANGERED BRASSICA RUPESTRIS F.M. RAIMONDO1, A. SCIALABBA1, G. ZECCA2, F. GRASSI2, G. CASAZZA3, L. MINUTO3 1 Department of Environment Biology and Biodiversity, University of Palermo, Via Archirafi 38, I-90123 Palermo, Italy. [email protected]; [email protected]; 2 Botanical Garden, Department of Biology, Università di Milano, Via Celoria 26, 20133 Milano, Italy. [email protected]; [email protected]; 3Department for the Study of Territory and its Resources, University of Genova, Corso Dogali 1M, I-16136 Genova, Italy. [email protected]; [email protected] Brassica rupestris Raf. is an endemic plant belonging to the Brassica section. It grows in rocky places and cliffs of the Central-Western Sicily (Italy). Rare and endangered species are susceptible to loss of genetic variation through genetic drift in small populations. Management decisions for the conservation of rare taxa necessitate an understanding of their biology and other factors, including genetic variability. For this reason the gathering of data on population genetic structure of rare species has become a common prelude to their conservation planning (Ellstrand & Elam, 1993). In the present study the ISSR technique was used to examine natural populations of B. rupestris (both subsp. rupestris and subsp. hispida) for the following purposes: 1) to evaluate the genetic diversity both at species and subspecies levels, 2) to assess the genetic differentiation of populations and 3) to provide suggestions for effective conservation programs. Six natural populations of B. rupestris subsp. rupestris and two populations of B. rupestris subsp. hispida, covering the whole range of the two subtaxa, were investigated and mapped using GPS (Garmin) in order to evaluate their genetic diversity. Six were from Palermo province: S. Calogero, Capo Zafferano, P.so Scuro - Castelbuono, Mt. Pellegrino, Mt. Kumeta, Mt. Pizzuta; one from Agrigento province: Gole Tardara - Sciacca; one from Reggio Calabria province: Stilo. ISSR were used to detect the genetic diversity within and among populations representative of the species distribution range. From each site, a variable number (8< N <10) according to the availability of individuals were randomly sampled (n = 76); 1-2 leaves per plant were dried in situ in silica gel, washed in laboratory and total genomic DNA extracted by using DNeasy Plant Mini Kit (Qiagen) following the manufacturer‘s instructions. High levels of genetic diversity were revealed both at population (PPB = 53.88%, HS = 0.2115, Sh = 0.3085) and at species level (PPB = 96.55%, HT = 0.3070, Sh = 0.4638). The correlation between genetic and geographic distances was negative (Mantel test, r = -0.23). Our data on B. rupestris revealed that about 67% of genetic variation is detectable within the population while 23% among populations within infraspecific taxa. This fact is also confirmed by the quite good value of migration rate among populations and it could be explained by hypothesizing the self-incompatibility systems, often found in many Brassica populations (Geraci et al., 2004). The information on the pattern of genetic variation obtained in the present work bear important inferences for conservation management, and in particular for ex situ conservation programmes. The populations showing local markers (Gole Tardara, San Calogero, and Mt. Pellegrino) deserve particular attention for their important presence in a seeds bank. This research was supported by PRIN 2007JNJ7MX_003 project. Ellstrand C. & Elam D.R., 1993. Population genetic consequences of small population size: implications for plant conservation. Annu Rev Ecol Syst 24:217–242. Geraci A., Chèvre A.M., Divaret I., Eber F. & Raimondo FM., 2004. Isozyme analysis of genetic diversity in wild Sicilian populations of Brassica sect. Brassica in view of genetic resources management. Genet. Resources Crop Evol. 51:137–146. INDIC

The abundance & diversity of arbuscular mycorrhizal fungi are linked to the soil chemistry of screes & to slope in the Alpic paleo-endemic Berardia subacaulis

Berardia subacaulis Vill. is a monospecific genus that is endemic to the South-western Alps, where it grows on alpine screes, which are extreme habitats characterized by soil disturbance and limiting growth conditions. Root colonization by arbuscular mycorrhizal fungi (AMF) is presumably of great importance in these environments, because of its positive effect on plant nutrition and stress tolerance, as well as on structuring the soil. However, there is currently a lack of information on this topic. In this paper, we tested which soil characteristics and biotic factors could contribute to determining the abundance and community composition of AMF in the roots of B. subacaulis, which had previously been found to be mycorrhizal. For such a reason, the influence of soil properties and environmental factors on AMF abundance and community composition in the roots of B. subacaulis, sampled on three different scree slopes, were analysed through microscopic and molecular analysis. The results have shown that the AMF community of Berardia roots was dominated by Glomeraceae, and included a core of AMF taxa, common to all three scree slopes. The vegetation coverage and dark septate endophytes were not related to the AMF colonization percentage and plant community did not influence the root AMF composition. The abundance of AMF in the roots was related to some chemical (available extractable calcium and potassium) and physical (cation exchange capacity, electrical conductivity and field capacity) properties of the soil, thus suggesting an effect of AMF on improving the soil quality. The non-metric multidimensional scaling (NMDS) ordination of the AMF community composition showed that the diversity of AMF in the various sites was influenced not only by the soil quality, but also by the slope. Therefore, the slopeinduced physical disturbance of alpine screes may contribute to the selection of disturbancetolerant AMF taxa, which in turn may lead to different plant-fungus assemblages

Liver fibrosis stage based on the four factors (FIB-4) score or Forns index in adults with chronic hepatitis C

BACKGROUND: The presence and severity of liver fibrosis are important prognostic variables when evaluating people with chronic hepatitis C (CHC). Although liver biopsy remains the reference standard, non-invasive serological markers, such as the four factors (FIB-4) score and the Forns index, can also be used to stage liver fibrosis. OBJECTIVES: To determine the diagnostic accuracy of the FIB-4 score and Forns index in staging liver fibrosis in people with chronic hepatitis C (CHC) virus, using liver biopsy as the reference standard (primary objective). To compare the diagnostic accuracy of these tests for staging liver fibrosis in people with CHC and explore potential sources of heterogeneity (secondary objectives). SEARCH METHODS: We used standard Cochrane search methods for diagnostic accuracy studies (search date: 13 April 2022). SELECTION CRITERIA: We included diagnostic cross-sectional or case-control studies that evaluated the performance of the FIB-4 score, the Forns index, or both, against liver biopsy, in the assessment of liver fibrosis in participants with CHC. We imposed no language restrictions. We excluded studies in which: participants had causes of liver disease besides CHC; participants had successfully been treated for CHC; or the interval between the index test and liver biopsy exceeded six months. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We performed meta-analyses using the bivariate model and calculated summary estimates. We evaluated the performance of both tests for three target conditions: significant fibrosis or worse (METAVIR stage ≥ F2); severe fibrosis or worse (METAVIR stage ≥ F3); and cirrhosis (METAVIR stage F4). We restricted the meta-analysis to studies reporting cut-offs in a specified range (+/-0.15 for FIB-4; +/-0.3 for Forns index) around the original validated cut-offs (1.45 and 3.25 for FIB-4; 4.2 and 6.9 for Forns index). We calculated the percentage of people who would receive an indeterminate result (i.e. above the rule-out threshold but below the rule-in threshold) for each index test/cut-off/target condition combination. MAIN RESULTS: We included 84 studies (with a total of 107,583 participants) from 28 countries, published between 2002 and 2021, in the qualitative synthesis. Of the 84 studies, 82 (98%) were cross-sectional diagnostic accuracy studies with cohort-based sampling, and the remaining two (2%) were case-control studies. All studies were conducted in referral centres. Our main meta-analysis included 62 studies (100,605 participants). Overall, two studies (2%) had low risk of bias, 23 studies (27%) had unclear risk of bias, and 59 studies (73%) had high risk of bias. We judged 13 studies (15%) to have applicability concerns regarding participant selection. FIB-4 score The FIB-4 score's low cut-off (1.45) is designed to rule out people with at least severe fibrosis (≥ F3). Thirty-nine study cohorts (86,907 participants) yielded a summary sensitivity of 81.1% (95% confidence interval (CI) 75.6% to 85.6%), specificity of 62.3% (95% CI 57.4% to 66.9%), and negative likelihood ratio (LR-) of 0.30 (95% CI 0.24 to 0.38). The FIB-4 score's high cut-off (3.25) is designed to rule in people with at least severe fibrosis (≥ F3). Twenty-four study cohorts (81,350 participants) yielded a summary sensitivity of 41.4% (95% CI 33.0% to 50.4%), specificity of 92.6% (95% CI 89.5% to 94.9%), and positive likelihood ratio (LR+) of 5.6 (95% CI 4.4 to 7.1). Using the FIB-4 score to assess severe fibrosis and applying both cut-offs together, 30.9% of people would obtain an indeterminate result, requiring further investigations. We report the summary accuracy estimates for the FIB-4 score when used for assessing significant fibrosis (≥ F2) and cirrhosis (F4) in the main review text. Forns index The Forns index's low cut-off (4.2) is designed to rule out people with at least significant fibrosis (≥ F2). Seventeen study cohorts (4354 participants) yielded a summary sensitivity of 84.7% (95% CI 77.9% to 89.7%), specificity of 47.9% (95% CI 38.6% to 57.3%), and LR- of 0.32 (95% CI 0.25 to 0.41). The Forns index's high cut-off (6.9) is designed to rule in people with at least significant fibrosis (≥ F2). Twelve study cohorts (3245 participants) yielded a summary sensitivity of 34.1% (95% CI 26.4% to 42.8%), specificity of 97.3% (95% CI 92.9% to 99.0%), and LR+ of 12.5 (95% CI 5.7 to 27.2). Using the Forns index to assess significant fibrosis and applying both cut-offs together, 44.8% of people would obtain an indeterminate result, requiring further investigations. We report the summary accuracy estimates for the Forns index when used for assessing severe fibrosis (≥ F3) and cirrhosis (F4) in the main text. Comparing FIB-4 to Forns index There were insufficient studies to meta-analyse the performance of the Forns index for diagnosing severe fibrosis and cirrhosis. Therefore, comparisons of the two tests' performance were not possible for these target conditions. For diagnosing significant fibrosis and worse, there were no significant differences in their performance when using the high cut-off. The Forns index performed slightly better than FIB-4 when using the low/rule-out cut-off (relative sensitivity 1.12, 95% CI 1.00 to 1.25; P = 0.0573; relative specificity 0.69, 95% CI 0.57 to 0.84; P = 0.002). AUTHORS' CONCLUSIONS: Both the FIB-4 score and the Forns index may be considered for the initial assessment of people with CHC. The FIB-4 score's low cut-off (1.45) can be used to rule out people with at least severe fibrosis (≥ F3) and cirrhosis (F4). The Forns index's high cut-off (6.9) can be used to diagnose people with at least significant fibrosis (≥ F2). We judged most of the included studies to be at unclear or high risk of bias. The overall quality of the body of evidence was low or very low, and more high-quality studies are needed. Our review only captured data from referral centres. Therefore, when generalising our results to a primary care population, the probability of false positives will likely be higher and false negatives will likely be lower. More research is needed in sub-Saharan Africa, since these tests may be of value in such resource-poor settings