Fragility Index
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2021 ◽  
Vol 11 (1) ◽  
Michela Romanini ◽  
Roberto Macovez ◽  
Maria Barrio ◽  
Josep Lluís Tamarit

AbstractWe employ temperature- and pressure-dependent dielectric spectroscopy, as well as differential scanning calorimetry, to characterize benzophenone and the singly-substituted ortho-bromobenzophenone derivative in the liquid and glass states, and analyze the results in terms of the molecular conformations reported for these molecules. Despite the significantly higher mass of the brominated derivative, its dynamic and calorimetric glass transition temperatures are only ten degrees higher than those of benzophenone. The kinetic fragility index of the halogenated molecule is lower than that of the parent compound, and is found to decrease with increasing pressure. By a detailed analysis of the dielectric loss spectra, we provide evidence for the existence of a Johari–Goldstein (JG) relaxation in both compounds, thus settling the controversy concerning the possible lack of a JG process in benzophenone and confirming the universality of this dielectric loss feature in molecular glass-formers. Both compounds also display an intramolecular relaxation, whose characteristic timescale appears to be correlated with that of the cooperative structural relaxation associated with the glass transition. The limited molecular flexibility of ortho-bromobenzophenone allows identifying the intramolecular relaxation as the inter-enantiomeric conversion between two isoenergetic conformers of opposite chirality, which only differ in the sign of the angle between the brominated aryl ring and the coplanar phenyl-ketone subunit. The observation by dielectric spectroscopy of a similar relaxation also in liquid benzophenone indicates that the inter-enantiomer conversion between the two isoenergetic helicoidal ground-state conformers of opposite chirality occurs via a transition state characterized by a coplanar phenyl-ketone moiety.

2021 ◽  
Vol 21 (1) ◽  
Julien Riou ◽  
Carole Dupont ◽  
Silvia Bertagnolio ◽  
Ravindra K. Gupta ◽  
Roger D. Kouyos ◽  

Abstract Introduction The rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) threatens antiretroviral therapy's long-term success (ART). NNRTIs will remain an essential drug for the management of HIV-1 due to safety concerns associated with integrase inhibitors. We fitted a dynamic transmission model to historical data from 2000 to 2018 in nine countries of southern Africa to understand the mechanisms that have shaped the HIV-1 epidemic and the rise of pretreatment NNRTI resistance. Methods We included data on HIV-1 prevalence, ART coverage, HIV-related mortality, and survey data on pretreatment NNRTI resistance from nine southern Africa countries from a systematic review, UNAIDS and World Bank. Using a Bayesian hierarchical framework, we developed a dynamic transmission model linking data on the HIV-1 epidemic to survey data on NNRTI drug resistance in each country. We estimated the proportion of resistance attributable to unregulated, off-programme use of ART. We examined each national ART programme's vulnerability to NNRTI resistance by defining a fragility index: the ratio of the rate of NNRTI resistance emergence during first-line ART over the rate of switching to second-line ART. We explored associations between fragility and characteristics of the health system of each country. Results The model reliably described the dynamics of the HIV-1 epidemic and NNRTI resistance in each country. Predicted levels of resistance in 2018 ranged between 3.3% (95% credible interval 1.9–7.1) in Mozambique and 25.3% (17.9–33.8) in Eswatini. The proportion of pretreatment NNRTI resistance attributable to unregulated antiretroviral use ranged from 6% (2–14) in Eswatini to 64% (26–85) in Mozambique. The fragility index was low in Botswana (0.01; 0.0–0.11) but high in Namibia (0.48; 0.16–10.17), Eswatini (0.64; 0.23–11.8) and South Africa (1.21; 0.83–9.84). The combination of high fragility of ART programmes and high ART coverage levels was associated with a sharp increase in pretreatment NNRTI resistance. Conclusions This comparison of nine countries shows that pretreatment NNRTI resistance can be controlled despite high ART coverage levels. This was the case in Botswana, Mozambique, and Zambia, most likely because of better HIV care delivery, including rapid switching to second-line ART of patients failing first-line ART.

2021 ◽  
Vol 11 ◽  
pp. 239-251
Carl L. Herndon ◽  
Kyle L. McCormick ◽  
Anastasia Gazgalis ◽  
Elise C. Bixby ◽  
Matthew M. Levitsky ◽  

2021 ◽  
Vol 17 ◽  
Debdipta Bose ◽  
Mahanjit Konwar

Background: It is essential for Randomized controlled trials [RCTs] to report its results in a comprehensive manner. Hence, it is necessary to assess the robustness of the trials with statistically significant and as well as non-significant results. Robustness can be evaluated using fragility index (FI) and reverse fragility index [RFI] is for trials with statistically significant and as well as non-significant results. The primary aim of this study was to calculate FI and RFI for cardiovascular outcome trials [CVOT]. Materials & Methods: PubMed/MEDLINE was searched to identify all RCTs of antidiabetic drugs where the primary objective was to evaluate the cardiovascular outcomes. We recorded the trial characteristics of each CVOT trial. The FI, RFI, Fragility quotient [FQ] and reverse fragility quotient [FQ] was calculated to evaluate the robustness of the trials. Spearman rank correlation test was used for correlation. Findings: A total of 889 studies were identified and 24 RCTs was included. Among the 24 trials, 12 [50%] trials achieved statistical significance. The median FI and RFI were 29 [4-12] and 22.5 [1-37] for trials with statistically significant and non-significant results. The median FQ and RFQ were 0.0075 [0.002-0.013] and 0.0003 [0.0001-0.004] for trials with statistically significant and non-significant results. The hazard ratio, p value and NNT-B had strong negative relation with FI. Interpretation: Our study showed that half of the trials showing superiority of cardioprotective benefits have favourable FI. The trials failed to show superiority also have a reasonable RFI indicating the robustness of these trials. But the results pf the trials where patients lost to follow-up exceed the FI of that trial demands caution during interpretation.

Benjamin R. Baer ◽  
Mario Gaudino ◽  
Stephen E. Fremes ◽  
Mary Charlson ◽  
Martin T. Wells

2021 ◽  
Aho Glele Ludwig Serge ◽  
Emmanuel Simon ◽  
Camille Bouit ◽  
Maeva Serrand ◽  
Laurence Filipuzzi ◽  

Background: Wei et al. have published a meta-analysis (MA) which aimed to evaluate the association between SARS-CoV-2 infection during pregnancy and adverse pregnancy outcomes. Using classical random-effects model, they found that SARS-CoV-2 infection was associated with preeclampsia, preterm birth and stillbirth. Performing MA with low event rates or with few studies may be challenging as MA relies on several within and between study distributional assumptions. Methods: to assess the robustness of the results provided by Wei et al., we performed a sensitivity analysis using several frequentist and Bayesian meta-analysis methods. We also estimated fragility indexes. Results: For eclampsia (patients with Covid-19 vs without), the confidence intervals of most frequentist models contain 1. All beta-binomial models (Bayesian) lead to credible intervals containing 1. The prediction interval, based on DL method ranges from 0.75 to 2.38. The fragility index is 2 for the DL method. For preterm, the confidence (credible) intervals exclude 1. The prediction interval is broad, ranging from 0.84 to 20.61. The fragility index ranges from 27 to 10. For stillbirth, the confidence intervals of most frequentist models contain 1. Six Bayesian MA models lead to credible intervals containing 1.The prediction interval ranges from 0.52 to 8.49. The fragility index is 3. Interpretation: Given the available data and the results of our broad sensitivity analysis, we can only suggest that SARS-CoV-2 infection during pregnancy is associated to preterm, and may be associated to preeclampsia. For stillbirth, more data are needed as none of the Bayesian analyses are conclusive.

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