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Lung cancer can present with unilateral atypical facial pain, a rare symptom due to vagus nerve involvement or paraneoplastic syndrome. This manifestation is usually missed, delaying the diagnosis and prognosis. We discuss a case of a 45-year-old male who presented with right-sided hemifacial pain and with normal neurological investigations.

Blood transfusion is an integral component in the management of children and adults with sickle cell disease (SCD). Concerns about blood safety due to the high risk of bloodborne infections in sub-Saharan Africa limits the application of this cost-effective strategy in the management of individuals with SCD. In a single-centre, retrospective, longitudinal study in southwest Nigeria, we hypothesised that the use of stringent blood donor selection, along with very sensitive enzyme-linked immunosorbent assay (ELISA) screening methods would reduce transfusion-transmitted infections (TTIs). Among 45 002 eligible blood donors at the Lagos University Teaching Hospital in Nigeria, over a 5-year review period (2015-2019), the seroprevalence rate of viral TTIs was 9.83%. The seroprevalence rates for human immunodeficiency, hepatitis B, and hepatitis C viruses were 1.37%, 6.2%, and 2.25% respectively. Among 172 children with SCD, 71% (122/172) on regular blood transfusion and 29% (50/172) who had never been transfused or had less than two transfusions per lifetime, none acquired any TTIs using our enhanced screening approach during the study period. Thus, safe blood transfusion practices can be provided for children with SCD in sub-Saharan Africa with the use of stringent donor selection protocols and fourth-generation ELISA kits for TTI screening.

Oraxol consists of an oral dosage form of the chemotherapeutic agent paclitaxel administered with a novel P-glycoprotein inhibitor encequidar methanesulfonate monohydrate (formerly named HM30181A), which allows oral treatment of cancers that would otherwise be treated with intravenous paclitaxel. Here we describe the population pharmacokinetics (popPK) analyses for oral paclitaxel in patients with advanced/metastatic solid tumors to characterize pharmacokinetic (PK) profiles and quantify sources of PK variability. The best fit popPK model for oral paclitaxel, based on data from seven clinical studies (197 patients with advanced/metastatic solid tumors), involves a linear two-compartment structural model containing first-order absorption with a short lag time and first-order elimination as well as a log additive error. In this popPK model, lower population estimates of central volume for Asian patients versus Caucasian patients did not translate into clinical meaningful differences in oral paclitaxel exposure. Age, sex, body weight or surface area, mild hepatic impairment, and mild to moderate renal impairment had no clinically meaningful effects on the systemic exposure of oral paclitaxel. Simulations were performed on clinical therapeutic dose (oral paclitaxel 205 mg/m

Although kidney transplantation (KT) has been shown to ameliorate adverse left ventricular (LV) remodelling associated with end stage kidney disease, its effects on the right ventricle have not been well studied. Recently, strain imaging has been shown to be a sensitive measure of early subclinical myocardial dysfunction. Using cardiac magnetic resonance imaging (MRI), we examined the effects of KT on right ventricular (RV) strain parameters. In a cohort of 81 patients (39 patients underwent KT and 42 patients remained on dialysis as control group), cardiac MRI studies were obtained at baseline and at 1 year follow-up. There were no significant differences in RV strain values between the groups at baseline. After 1 year, RV strain values did not significantly change in patients who received KT, and changes in RV strain over 1 year were not significantly different between the KT and the dialysis groups. Given the previously demonstrated improvement in LV strain post-KT, the current study suggests that RV and LV remodelling post-KT may have different mechanisms. Further studies elucidating the effects of KT on RV remodelling are needed.

There has been tremendous advancement in machine learning (ML) applications in computational chemistry, particularly in neural network potentials (NNP). NNPs can approximate potential energy surface (PES) as a high dimensional function by learning from existing reference data, thereby circumventing the need to solve the electronic Schrödinger equation explicitly. As a result, ML accelerates chemical space exploration and property prediction compared to quantum mechanical methods. Novel ML methods have the potential to provide efficient means for predicting the properties of molecules. However, this potential has been limited by the lack of standard comparative evaluations. In this work, we compare four selected models, that is, ANI, PhysNet, SchNet, and BAND-NN, developed to represent the PES of small organic molecules. We evaluate these models for their accuracy and transferability on two different test sets (i) Small organic molecules of up to eight-heavy atoms on which ANI and SchNet achieve root mean square error (RMSE) of 0.55 and 0.60 kcal/mol, respectively. (ii) On random selection of molecules from the GDB-11 database with 10-heavy atoms, ANI achieves RMSE of 1.17 kcal/mol and SchNet achieves RMSE of 1.89 kcal/mol. We examine their ability to produce smooth meaningful surface by performing PES scans for bond stretch, angle bend, and dihedral rotations on relatively large molecules to assess their possible application in molecular dynamics simulations. We also evaluate their performance for yielding minimum energy structures via geometry optimization using various minimization algorithms. All these models were also able to accurately differentiate different isomers of the same empirical formula

Amino acid side chains are key to fine-tuning the microenvironment polarity in proteins composed of polar amide bonds. Here, we report that substituting an oxygen atom of the backbone amide bond with sulfur atom desolvates the thioamide bond, thereby increasing its lipophilicity. The impact of such local desolvation by O to S substitution in proteins was tested by synthesizing thioamidated variants of Pin1 WW domain. We observe that a thioamide acts in synergy with nonpolar amino acid side chains to reduce the microenvironment polarity and increase protein stability by more than 14 °C. Through favorable van der Waals and hydrogen bonding interactions, this single atom substitution significantly stabilizes proteins without altering the amino acid sequence and structure of the native protein.

Herein, a new type of carbodicarbene (CDC) comprising two different classes of carbenes is reported; NHC and CAAC as donor substituents and compare the molecular structure and coordination to Au(I)Cl to those of NHC-only and CAAC-only analogues. The conjugate acids of these three CDCs exhibit notable redox properties. Their reactions with [NO][SbF6] were investigated. The reduction of the conjugate acid of CAAC-only based CDC with KC8 results in the formation of hydrogen abstracted/eliminated products, which proceed through a neutral radical intermediate, detected by EPR spectroscopy. In contrast, the reduction of conjugate acids of NHC-only and NHC/CAAC based CDCs led to intermolecular reductive (reversible) carbon–carbon sigma bond formation. The resulting relatively elongated carbon–carbon sigma bonds were found to be readily oxidized. They were, thus, demonstrated to be potent reducing agents, underlining their potential utility as organic electron donors and n-dopants in organic semiconductor molecules.

Barium yttrium phosphate (BYP) phosphor doped with trivalent praseodymium ions (BaY(1-x) (PO4 )3 :Pr3+ (x = 0, 0.01, 0.05, 0.1, 0.15, and 0.2 wt%) was synthesized using a high temperature solid-state reaction method. Structural properties were analyzed through X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. XRD patterns confirmed the structure of the synthesized phosphor and average crystalline size was estimated (approximately 63.8 A). Vibrational functional groups were identified using FTIR spectroscopy. The emission spectrum was recorded under an 444 nm excitation wavelength, which showed various emission transitions of Pr3+ ions. Commission Internationale de l'eclairage coordinates, colour purity, and colour correlated temperature values were calculated for the BYP:Pr3+ phosphors and these coordinate values fell in the yellow region of the visible spectrum.

Recent studies have reported on an association between endurance sport, atrial enlargement and the development of lone atrial fibrillation in younger, male cohorts. The atrial morphology and function of middle‐aged, physically‐active males and females have not been well studied. We hypothesized that middle‐aged males would demonstrate larger left atrium (LA) and right atrium (RA) volumes compared to females, but atrial function would not differ. LA and RA volume and function were evaluated at rest in healthy adults, using a standardized 3.0Tesla cardiac magnetic resonance protocol. Physical activity, medical history, and maximal oxygen consumption (V˙O2peak) were also assessed. Physically‐active, middle‐aged men (n = 60; 54 ± 5 years old) and women (n = 30; 54 ± 5 years old) completed this study. Males had a higher body mass index, systolic blood pressure, and V˙O2peak than females (p

First-line palliative chemotherapy regimens in advanced pancreatic adenocarcinoma include triplet chemotherapy with 5-fluorouracil, oxaliplatin, and irinotecan, and the doublet of nab-paclitaxel plus gemcitabine. Use of triplet chemotherapy in real-world populations is limited by tolerability and nab-paclitaxel is not universally available. Regimens using the combination of cisplatin, capecitabine, gemcitabine, and either epirubicin or docetaxel may be better tolerated, more widely available, and similarly effective, but no published real-world data exist.A retrospective cohort review of patients with metastatic or unresectable locally advanced pancreatic adenocarcinoma treated with first-line palliative cisplatin, capecitabine, gemcitabine, and either epirubicin or docetaxel chemotherapy at Auckland City Hospital between July 1, 2013 and July 30, 2020. The primary outcome was overall survival (OS). Secondary outcomes were rates of grade 3 or 4 hematological toxicity, rate of febrile neutropenia, number of cycles received, and reasons for discontinuation.Eighty-eight patients were included. Median age was 66 years (range 39-79), 28.4% had unresectable, locally advanced disease and 71.6% metastatic disease. Median OS was 8.5 months. Patients stopped treatment due to disease progression (53.4%), completing 12 cycles (19.3%), or toxicity (10.2%). Grade 4 neutropenia was experienced by 21.6%; 10.2% had febrile neutropenia. There were four treatment-related deaths.This retrospective study in a real-world population demonstrates that chemotherapy with cisplatin, capecitabine, and gemcitabine with epirubicin (PEXG) or docetaxel (PDXG) had similar effectiveness to more commonly used combination regimens. PDXG/PEXG are viable alternatives to nab-paclitaxel plus gemcitabine in countries that have restricted drug funding.

The UK’s referendum vote to leave the EU in June 2016 generated deep divisions in British politics. It led to the resignation of incumbent Prime Minister David Cameron the following day, and an inability to deliver Brexit led to the resignation of his successor Theresa May in 2019. In addition, it has led to a number of legal challenges to the policies and processes of implementing these by both May’s and Boris Johnson’s governments. Those who support leaving the EU have characterised this period as one of ‘crisis’, in which politicians—unable to agree on a means of leaving—were pitted against the electorate or public will. Judicial challenges to the terms of exit and means of achieving Brexit were further incorporated into notions of crisis to the extent that failure to implement Brexit was portrayed as a crisis affecting the entire political system, or a constitutional crisis. In this article, we unpack this discourse, and by distinguishing between different forms of crises challenge the existing understanding of Brexit as a constitutional crisis. Rather, we suggest that these problems stemmed from constitutional weaknesses, specifically that the constitution is based on a reductionist understanding of power.

Breast cancer is a major cause of cancer‐related death in women worldwide. Non‐coding RNAs are a potential resource to be used as an early diagnostic biomarker for breast cancer. Circular RNAs are a recently identified group of non‐coding RNA with a significant role in disease development with potential utility in diagnosis/prognosis in cancer. In this study, we identified 26 differentially expressed circular RNAs associated with early‐stage breast cancer. RNA sequencing and two circRNA detection tools (find_circ and DCC) were used to understand the circRNA expression signature in breast cancer. We identified hsa_circ_0006743 (circJMJD1C) and hsa_circ_0002496 (circAPPBP1) to be significantly up‐regulated in early‐stage breast cancer tissues. Co‐expression analysis identified four pairs of circRNA‐miRNA (hsa_circ_0023990 : hsa‐miR‐548b‐3p, hsa_circ_0016601 : hsa_miR‐1246, hsa_circ_0001946 : hsa‐miR‐1299 and hsa_circ_0000117:hsa‐miR‐502‐5p) having potential interaction. The miRNA target prediction and network analysis revealed mRNA possibly regulated by circRNAs. We have thus identified circRNAs of diagnostic implications in breast cancer and also observed circRNA‐miRNA interaction which could be involved in breast cancer development.

Aims To analyse the rate of heart failure hospitalization for older adults prescribed a sodium-glucose co-transporter-2 (SGLT2) inhibitor. Materials and methods The study cohort included adults aged 66 years and older diagnosed with diabetes mellitus in Ontario, Canada, between July 2015 and March 2019, who received either an SGLT2 inhibitor or a dipeptidyl peptidase-4 (DPP-4) inhibitor. The primary outcome was a composite of heart failure hospitalization and all-cause mortality. Secondary outcomes included diabetic ketoacidosis and hypoglycaemia. Results A total of 29 916 adults prescribed an SGLT2 inhibitor were compared with 29 916 adults prescribed a DPP-4 inhibitor. The mean age was 72 years, 60% were men, the baseline glycated haemoglobin concentration was 8.2% and the baseline creatinine was 89 μmol/L. The incidence rate of the primary outcome was 19/1000 person-years for adults prescribed an SGLT2 inhibitor compared to 38/1000 person-years in those prescribed a DPP-4 inhibitor. This resulted in a hazard ratio (HR) of 0.49 (95% confidence interval [CI] 0.45, 0.54) and a rate difference (RD) of 19 fewer events per 1000 person-years (RD -19 [95% CI -22, -17]). Patients prescribed an SGLT2 inhibitor also had a lower rate of hypoglycaemia (HR 0.61 [95% CI 0.46, 0.81); RD -1.6 [95% CI -2.4, -0.8]), but a higher rate of diabetic ketoacidosis (HR 1.84 [95% CI 1.26, 2.70]; RD 1.0 [95% CI 0.4, 1.6]). Conclusions Older adults prescribed an SGLT2 inhibitor had a lower rate of heart failure hospitalization or death, and a lower rate of hypoglycaemia, but an increased rate of diabetic ketoacidosis compared to older adults prescribed a DPP-4 inhibitor.