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Mood monitoring in bipolar disorder: Is it always helpful?
No full textThis article offers a cautionary note about the use of mood monitoring in bipolar disorder. We propose that, although potentially helpful for some individuals, mood monitoring in bipolar disorder can at times be inappropriate and even harmful. We finish by offering tentative recommendations for future practice.Learning points: - There is cautionary evidence to suggest that mood monitoring is unhelpful for some people with a diagnosis of bipolar disorder. - We tentatively suggest that an individualised, collaborative and normalising approach to mood monitoring may be optimal and reduce potential limitations. <br/
Ivosidenib: an investigational drug for the treatment of biliary tract cancer
No full textIntroduction: Biliary tract cancer (including cholangiocarcinoma and gallbladder cancer) is rare and associated with poor survival; most patients have advanced disease at diagnosis. Current chemotherapy reference regimens include cisplatin and gemcitabine as first-line and oxaliplatin and 5-fluorouracil (FOLFOX) in second-line. Molecular profiling has identified several actionable targets and in this review we focus on isocitrate dehydrogenase (IDH)1 mutations. Ivosidenib is a reversible inhibitor of mutant IDH1; currently approved for the treatment of acute myeloid leukaemia, it has also been studied in patients with advanced cholangiocarcinoma. Areas covered: The mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy and safety of ivosidenib in advanced cholangiocarcinoma are discussed. Expert opinion: Ivosidenib is well-tolerated, with good oral exposure and long half-life as shown by phase I data. In a phase III study, ivosidenib has demonstrated improved progression-free survival compared to placebo (median 2.7 vs 1.4 months; hazard ratio 0.37; 95% confidence interval 0.25-0.54; one-sided p<0.0001) as well as a trend towards increased overall survival in patients with cholangiocarcinoma and disease progression on prior chemotherapy. Final survival data from this study are pending presentation. Increased use of molecular profiling will continue to identify potentially-therapeutic targets and thereby improve the prognosis of patients with these cancers
Impact of airway Exophiala spp. on children with cystic fibrosis
No full textIntroduction: Isolation of Exophiala species from sputum samples has become increasingly reported in Cystic Fibrosis (CF). However, the clinical significance of Exophiala spp. with regards to the paediatric CF population is unknown. Methods: A case control study was undertaken to compare CF children with and without chronic Exophiala spp. in their sputum samples. Demographic and clinical data were collected retrospectively for each case from the date of Exophiala isolation and for 12 months preceding isolation. Each case was compared to three age and year-matched controls. To determine the effect of Exophiala on clinical course, patients were then followed for 12 months post isolation. Results: In total, 27 of 244 eligible paediatric CF patients (11%) isolated Exophiala spp. on more than one occasion. There were no significant differences in the key clinical parameters: spirometry, mean number of intravenous (IV) antibiotic days and body mass index (BMI), between cases and controls (p=0.91, p=0.56 and p=0.63 respectively). A higher proportion of cases isolated Candida spp. (67% vs 21%, p<0.0001) and Aspergillus fumigatus (37% vs 26%, p=0.37). There was no clinically significant difference in spirometry, mean number of IV antibiotic days and BMI in cases pre and post Exophiala spp. isolation. Posaconazole was the only drug used that successfully eradicated Exophiala. Conclusion: Despite the frequent isolation of Exophiala spp. in this cohort, in most patients it is not associated with significant clinical deterioration. It does however seem to be associated with isolation of other fungi
Mechanisms underlying the association of chronic obstructive pulmonary disease with heart failure
No full textBackground: Chronic obstructive pulmonary disease (COPD) is associated with heart failure (HF), independent of shared risk factors. The underlying pathophysiological mechanism is unknown. Objectives: To determine why COPD is associated with HF. Specifically, whether COPD is associated with myocardial fibrosis, whether myocardial fibrosis is associated with hospitalisation for HF and death in COPD and whether COPD and smoking are associated with myocardial inflammation. Methods: A prospective, multicentre, longitudinal cohort study of 572 patients undergoing cardiac magnetic resonance imaging (MRI), including 450 patients with COPD and 122 age- and sex-matched patients, with median (interquartile range) 726 (492-1160) day follow-up. Multivariable analysis examined the relationship between COPD and myocardial fibrosis, measured using cardiac MRI. Cox regression examined the relationship between myocardial fibrosis and outcomes; primary endpoint: composite of hospitalisation for HF or all-cause mortality; secondary endpoints: hospitalisation for HF and all-cause mortality. Fifteen patients with COPD, 15 current smokers and 15 healthy volunteers underwent evaluation for myocardial inflammation, including ultrasmall superparamagnetic particles of iron oxide MRI. Results: COPD was independently associated with myocardial fibrosis (p<0.001). Myocardial fibrosis was independently associated with the primary outcome (hazard ratio (HR) 1.14; 95% confidence interval 1.08-1.20; p<0.001), hospitalisation for HF (HR 1.25 [1.14-1.36]); p<0.001) and all-cause mortality. Myocardial fibrosis was associated with outcome measurements more strongly than any other variable. Acute and stable COPD were associated with myocardial inflammation. Conclusions: The association between COPD, myocardial inflammation and myocardial fibrosis, and the independent prognostic value of myocardial fibrosis, elucidate a potential pathophysiological link between COPD and HF
A polarization census of bright pulsars using the Ultra-Wideband Receiver on the Parkes radio telescope
No full textWe present high signal-to-noise, full polarization pulse profiles for 40 bright, ‘slowly’-rotating (non-recycled) pulsars using the new Ultra-Wideband Low-frequency (UWL; 704–4032 MHz) receiver on the Parkes radio telescope. We obtain updated and accurate interstellar medium parameters towards these pulsars (dispersion measures and Faraday rotation measures), and reveal Faraday dispersion towards PSR J1721–3532 caused by interstellar scattering. We find general trends in the pulse profiles including decreasing fractional linear polarization and increasing degree of circular polarization with increasing frequency, consistent with previous studies, while also revealing new features and frequency evolution. This demonstrates results that can be obtained using UWL monitoring observations of slow pulsars, which are valuable for improving our understanding of pulsar emission and the intervening interstellar medium. The calibrated data products are publicly available
Substrate sulfoxidation by a biomimetic cytochrome P450 Compound I mimic: How do porphyrin and phthalocyanine equatorial ligand compare?
No full textThe cytochrome P450 enzymes are important enzymes in the liver that trigger drug metabolism reactions. In biotechnology and biomimetic chemistry, synthetic models of the active species of P450 have been developed and designed and often react differently. Here, we investigate a biomimetic P450 model complex with phthalocyanine equatorial ligand rather than heme or porphyrin and with and without four tert-butyl substituents to the periphery of the ligand. Density functional theory studies on the electronic properties of the iron(IV)-oxo ligand cation radical species and its reactivity in oxygen atom transfer were studied. The work shows that a phthalocyanine equatorial ligand rather than porphyrin leads to a dramatic effect on the orbital energy levels of the iron(IV)-oxo species and creates a species with close-lying doublet and quartet spin states with two unpaired electrons in *xz and *yz for the FeO interaction coupled to a ligand radical in an a1u-type orbital. The latter contrasts P450 Compound I that has the a1u orbital doubly occupied and a singly occupied a2u orbital instead, As a consequence, our biomimetic model gives a reduced redox potential as compared to a system with a porphyrin-based ligand. Nevertheless, the iron(IV)-oxo cation radical species with phthalocyanine ligand is shown to react with para-X-substituted thioanisole (X = CH3, Cl, CN, H, NO2, OCH3) substrates with small oxygen atom transfer barriers that align with the -Hammett parameter. The reactions are concerted with a single barrier leading to sulfoxide products
Defining Trajectories of Response in Psoriasis Patients Treated with Biologic Therapies
No full textBACKGROUND: The effectiveness and cost-effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of psoriasis is needed.OBJECTIVES: We aim to identify subgroups of psoriasis patients treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management.METHODS: Here we apply latent class mixed modelling, to identify trajectory-based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 subjects pooled across four clinical trials. RESULTS: We discovered four, discrete classes of global response trajectories, each characterised in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. Body Mass Index, baseline PASI, and prevalence of different manifestations. Our results were verified in a second cohort of clinical trials subjects, where similar trajectories following initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA-C*06:02 between our registry-identified trajectories. CONCLUSION: These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterising the subgroups with additional molecular and pharmacological data. <br/
CO2-plume geothermal processes: A parametric study of salt precipitation influenced by capillary-driven back flow
No full textThe effect of quench rate on the β-a″ martensitic transformation in Ti-Nb alloys
No full textWhile Ti-Nb binary alloys have been extensively studied over the years, there are discrepancies in the literature relating to the β-a″ martensitic transformation that indicate an incomplete understanding. In particular, there are inconsistencies regarding the phase constitution of asquenched material and the ability for a″ phase to be thermally-induced. To resolve these issues, the β-a″ phase transformation is studied in a Ti-24Nb (at.%) alloy subjected to two different water quench conditions. It is demonstrated that only the fastest quench rates (≳500°C/s) result in the formation of a″ phase, and these materials exhibit a reversible thermally-induced β-a″ transformation at low temperatures. In contrast, slightly slower water quench procedures lead to a β+ω microstructure, and these samples do not exhibit a thermally-induced β-a″ transformation, even when cooled to -168°C. Despite this, room temperature mechanical testing results indicate that a″ can be induced by stresses as low as 200 MPa. To explain these results, it is proposed that quenching stresses play a role in the competition between a″ and athermal ω phases at rapid quench rates. The present results are then reconciled with the body of literature and a broader understanding of phase stability in metastable β-titanium alloys
The Li-Fraumeni Spectrum: An International Agency for Research on Cancer TP53 Database Analysis
No full textImportance Li-Fraumeni syndrome is a cancer predisposition syndrome that is associated with a high, lifelong risk of a broad spectrum of cancers, caused by pathogenic TP53 germline variants. A definition that reflects the broad phenotypic spectrum that has evolved since the gene discovery is lacking and mechanisms leading to phenotypic differences remain largely unknown.Objective To define the phenotypic spectrum of Li-Fraumeni syndrome and to conduct phenotype-genotype correlations across the phenotypic spectrum.Design, Setting, Participants We propose the term "Li-Fraumeni spectrum" to encompass (1) phenotypic Li-Fraumeni syndrome, defined by the absence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting clinical Li-Fraumeni syndrome criteria; (2) Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting Li-Fraumeni syndrome testing criteria; (3) attenuated Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family with cancer not meeting Li-Fraumeni syndrome testing criteria; and (4) incidental Li- Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family without a history of cancer. We analyzed the germline variant dataset of the International Agency for Research on Cancer TP53 databasethat contains 3034 persons from 1282 families.Results Tumor spectra showed significant differences with a higher proportion of early adrenal, brain, connective tissue and bone tumors in patients meeting Li-Fraumeni syndrome genetic testing criteria, whereas carriers not meeting Li-Fraumeni syndrome genetic testing criteria had a higher proportion of breast and other cancers, 50% of them occurring after age 45 years. “Hotspot” variants were present in both groups. Several variants were exclusively found in patients with Li-Fraumeni syndrome while others where exclusively found in patients with attenuated Li-Fraumeni syndrome. In patients meeting Li-Fraumeni syndrome genetic testing criteria, most TP53 variants classified as pathogenic/likely pathogenic (80.7%), whereas about 38.8% of TP53 variants identified in patients not meeting the Li-Fraumeni syndrome genetic testing criteria were classified as variants of uncertain significance, conflicting results, likely benign, or benign.Conclusions and Relevance The new classification is a step towards understanding the factors leading to phenotypic differences and may serve as a model for other cancer predisposition syndromes