To assess the current status of climate models in simulating clouds, basic cloud climatologies from ten atmospheric general circulation models are compared with satellite measurements from the ...International Satellite Cloud Climatology Project (ISCCP) and the Clouds and Earth's Radiant Energy System (CERES) program. An ISCCP simulator is employed in all models to facilitate the comparison. Models simulated a four‐fold difference in high‐top clouds. There are also, however, large uncertainties in satellite high thin clouds to effectively constrain the models. The majority of models only simulated 30–40% of middle‐top clouds in the ISCCP and CERES data sets. Half of the models underestimated low clouds, while none overestimated them at a statistically significant level. When stratified in the optical thickness ranges, the majority of the models simulated optically thick clouds more than twice the satellite observations. Most models, however, underestimated optically intermediate and thin clouds. Compensations of these clouds biases are used to explain the simulated longwave and shortwave cloud radiative forcing at the top of the atmosphere. Seasonal sensitivities of clouds are also analyzed to compare with observations. Models are shown to simulate seasonal variations better for high clouds than for low clouds. Latitudinal distribution of the seasonal variations correlate with satellite measurements at >0.9, 0.6–0.9, and −0.2–0.7 levels for high, middle, and low clouds, respectively. The seasonal sensitivities of cloud types are found to strongly depend on the basic cloud climatology in the models. Models that systematically underestimate middle clouds also underestimate seasonal variations, while those that overestimate optically thick clouds also overestimate their seasonal sensitivities. Possible causes of the systematic cloud biases in the models are discussed.
Treating severe asthma: Targeting the IL‐5 pathway Principe, Stefania; Porsbjerg, Celeste; Bolm Ditlev, Sisse ...
Clinical & experimental allergy/Clinical and experimental allergy,
August 2021, Letnik:
51, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 ...inflammation and increased levels of interleukin (IL)‐4, IL‐5 and IL‐13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL‐5R and IL‐5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late‐onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non‐response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL‐5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non‐response.
CYP2D6
and
CYP2C19
polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and ...others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for
CYP2D6
and
CYP2C19
genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for
CYP2D6
and
CYP2C19
Genotypes and Dosing of Tricyclic Antidepressants.
Abstract Though widely used, the BCG vaccine has had little apparent effect on rates of adult pulmonary tuberculosis. Moreover, the risk of disseminated BCG disease in immunocompromised individuals ...means that improved TB vaccines ideally need to be able to efficiently prime mycobacterially-naïve individuals as well as boost individuals previously vaccinated with BCG. Protective immunity against Mycobacterium tuberculosis is thought to depend on the generation of a Th1-type cellular immune response characterized by interferon-gamma (IFN-γ) production. In the present study, we monitored safety and IFN-γ responses in healthy TB-naïve humans receiving an entirely novel vaccine, composed of the fusion protein Ag85B–ESAT-6, administered at 0 and 2 months either as recombinant protein alone or combined with two concentrations of the novel adjuvant IC31® . Vaccination did not cause local or systemic adverse effects besides transient soreness at the injection site, but it elicited strong antigen-specific T cell responses against H1 and both the Ag85B and the ESAT-6 components. These strong responses persisted through 2.5 years of follow-up, indicating the induction of a substantial memory response in the vaccine recipients.
Because survival benefits of treatment with radiotherapy are questionable and such treatment can cause substantial damage to the brain over time, the optimum management strategy for low-grade gliomas ...remains controversial. We aimed to identify the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy.
195 patients with low-grade glioma (of whom 104 had received radiotherapy 1–22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Our analyses aimed to differentiate between the effects of the tumour (eg, disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic drugs) on cognitive function and on relative risk of cognitive disability.
Low-grade glioma patients had lower ability in all cognitive domains than did low-grade haematological patients, and did even less well by comparison with healthy controls. Use of radiotherapy was associated with poorer cognitive function; however, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic drug use was strongly associated with disability in attentional and executive function.
Our findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention.
Purpose
Tumor-infiltrating lymphocytes (TILs) are associated with pathological complete response (pCR) and survival after neoadjuvant chemotherapy (NAC) in patients with early breast cancer. We ...investigated the prognostic and predictive role of TILs, macrophages, and HLA class 1 expression after NAC with or without the potentially immune modulating compound zoledronic acid (ZA).
Methods
Baseline tumor biopsies from 196 patients in the NEOZOTAC trial were analyzed for CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), CD68 (macrophages), and HLA class I (HCA2/HC10) expression by immunohistochemistry and subsequently related to pCR and disease-free survival (DFS).
Results
A strong intratumoral CD8+ infiltration or expression of HLA class 1 by cancer cells was associated with a higher pCR rate (
p
< 0.05). Clinical benefit of high CD8+ T-cell infiltration was found when cancer cells expressed HLA class 1 (pCR: 21.8% vs. 6.7%,
p
= 0.04) but not when HLA class 1 expression was lost or downregulated (pCR: 5.9% vs. 0%,
p
= 0.38). Interaction analyses revealed survival benefit between HLA class 1 expression and strong CD8+ T-cell infiltration, whereas in the absence or downregulation of HLA class 1 expression, high levels of CD8+ T-cells were associated with survival disadvantage (p for interaction 0.01; hazard ratio 0.41, 95% CI 0.15–1.10,
p
= 0.08 and hazard ratio 7.67, 95% CI 0.88–66.4,
p
= 0.07, respectively). Baseline immune markers were not related to ZA treatment.
Conclusions
Strong baseline tumor infiltration with CD8+ T-cells in the presence of tumoral HLA class 1 expression in patients with HER2-negative breast cancer is related to a higher pCR rate and a better DFS after NAC.
Short-range correlated (SRC) nucleon pairs are a vital part of the nucleus, accounting for almost all nucleons with momentum greater than the Fermi momentum (k_{F}). A fundamental characteristic of ...SRC pairs is having large relative momenta as compared to k_{F}, and smaller center of mass (c.m.) which indicates a small separation distance between the nucleons in the pair. Determining the c.m. momentum distribution of SRC pairs is essential for understanding their formation process. We report here on the extraction of the c.m. motion of proton-proton (pp) SRC pairs in carbon and, for the first time in heavier and ansymetric nuclei: aluminum, iron, and lead, from measurements of the A(e,e^{'}pp) reaction. We find that the pair c.m. motion for these nuclei can be described by a three-dimensional Gaussian with a narrow width ranging from 140 to 170 MeV/c, approximately consistent with the sum of two mean-field nucleon momenta. Comparison with calculations appears to show that the SRC pairs are formed from mean-field nucleons in specific quantum states.
Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes ...in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent.
The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID).
137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients.
HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration.
•HRQoL differs between intermediate-fit & frail patients before start of MM therapy.•HRQoL improves in both intermediate-fit & frail patients during initial MM therapy.•Frail patients show faster & larger improvements in HRQoL during first treatment.•Improvements in HRQoL persist during post-treatment follow-up.•Physicians should not refrain from treating frail patients in fear of HRQoL loss.
Hypoxia and low concentrations of nitric oxide have been reported to upregulate in vitro gene expression of 48 proteins of the dormancy (DosR) regulon of Mycobacterium tuberculosis. These proteins ...are thought to be essential for the survival of bacteria during persistence in vivo and are targeted by the immune system during latent infection in humans. Here we have analyzed the immunogenicity of eight DosR regulon-encoded antigens by plasmid DNA vaccination of BALB/c and C57BL/6 mice, i.e., Rv1733c, Rv1738, Rv2029c (pfkB), Rv2031c/hspX (acr), Rv2032 (acg), Rv2626c, Rv2627c, and Rv2628. Strong humoral and/or cellular Th1-type (interleukin-2 and gamma interferon) immune responses could be induced against all but one (Rv1738) of these antigens. The strongest Th1 responses were measured following vaccination with DNA encoding Rv2031c and Rv2626c. Using synthetic 20-mer overlapping peptides, 11 immunodominant, predicted major histocompatibility complex class II-restricted epitopes and one Kd-restricted T-cell epitope could be identified. BALB/c and (B6D2)F₁ mice persistently infected with M. tuberculosis developed immune responses against Rv1733c, Rv2031c, and Rv2626c. These findings have implications for proof-of-concept studies in mice mimicking tuberculosis (TB) latency models and their extrapolation to humans for potential new vaccination strategies against TB.
Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).
...This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.
Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 29% of 72 patients) than with placebo (37 53% of 70 patients; hazard ratio 0·46, 95% CI 0·27–0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.
The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.
Pfizer.
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