Abstract
The objective of this study was to evaluate the development of resistance to raltegravir (RAL) in patients with viraemia between 40 and 400 copies/ml. All HIV-1-infected patients with ...multidrug-resistant virus, plasma HIV-1 RNA >1000 copies/ml and starting RAL were enrolled in this observational study and followed up until week 48. Sixty-seven patients with median plasma HIV-1 RNA at 4.3 log10 copies/ml and CD4 at 177 cells/mm3 were included. At week 24, 43 achieved full viral suppression (FVS; plasma HIV-1 RNA <40 copies/ml), 18 had incomplete viral suppression (IVS; plasma HIV-1 RNA 40-≤400 copies/ml) and 6 experienced virological failure (VF; plasma HIV-1 RNA >400 copies/ml). At week 48, all the FVS were sustained, 16 of the IVS patients retained a plasma HIV-1 RNA <400 copies/ml and only 2 of the IVS at week 24 experienced VF. No RAL resistance was detected in the persistent low viraemia. In contrast, integrase mutation was detected in 6 of the patients with VF. A genotypic sensitivity score equal to 0 was associated with plasma HIV-1 RNA >40 copies/ml at week 24 (OR 20.9, 95% CI 2.0-215.1) and with RAL resistance (OR 14.2, 95% CI 2.1-94.7). This study confirmed the high efficacy of a RAL-containing regimen under routine clinical conditions in infections caused by multidrug-resistant virus. If persistent low viraemia is observed over more than 48 weeks without the emergence of resistance, RAL should never be given as functional monotherapy, as it is associated with a maximal risk of VF and the emergence of RAL resistance.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Reliably scoring and ranking candidate models of protein complexes and assigning their oligomeric state from the structure of the crystal lattice represent outstanding challenges. A community‐wide ...effort was launched to tackle these challenges. The latest resources on protein complexes and interfaces were exploited to derive a benchmark dataset consisting of 1677 homodimer protein crystal structures, including a balanced mix of physiological and non‐physiological complexes. The non‐physiological complexes in the benchmark were selected to bury a similar or larger interface area than their physiological counterparts, making it more difficult for scoring functions to differentiate between them. Next, 252 functions for scoring protein‐protein interfaces previously developed by 13 groups were collected and evaluated for their ability to discriminate between physiological and non‐physiological complexes. A simple consensus score generated using the best performing score of each of the 13 groups, and a cross‐validated Random Forest (RF) classifier were created. Both approaches showed excellent performance, with an area under the Receiver Operating Characteristic (ROC) curve of 0.93 and 0.94, respectively, outperforming individual scores developed by different groups. Additionally, AlphaFold2 engines recalled the physiological dimers with significantly higher accuracy than the non‐physiological set, lending support to the reliability of our benchmark dataset annotations. Optimizing the combined power of interface scoring functions and evaluating it on challenging benchmark datasets appears to be a promising strategy.
Objective: To perform a quantitative estimate of the proportion of cancers attributable to occupational exposures in France in 2000. Methods: Exposure data for established carcinogens were obtained ...from a 1994 survey and other sources. Relative risks for 23 exposure-cancer combinations were derived from meta-analyses and pooled analyses. Results: A total of 4335 cases of cancer among men (2.7% of all cancers) and 403 cases among women (0.3% of all cancers) were attributed to occupational exposures. Asbestos, polycyclic aromatic hydrocarbons, and chromium VI were the main occupational carcinogens in men, and asbestos and involuntary smoking were the main carcinogens in women. Corresponding proportions for cancer deaths were 4.0% and 0.6% in men and women, respectively. Lung cancer represented 75% of deaths attributable to occupational exposures. Conclusion: Our estimates are comparable with those obtained for other countries in studies based on similar methodology.
To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes.
Patients (n = 150) were randomized ...to receive either four cycles of standard doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m(2) plus cyclophosphamide 600 mg/m(2), with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates.
There were no significant differences in DFS (P =.44), DDFS (P =.67), or OS (P =.99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P =.01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P <.001).
This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m(2) with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.
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