Appearance and disappearance of superconductivity in SmFe1-xNixAsO (x = 0.0 to 1.0)

Bulk polycrystalline Ni-substituted SmFe1-xNixAsO (x = 0.0 to 1.0) samples are synthesized by solid state reaction route in an evacuated sealed quartz tube. The cell volume decreases with increase of Ni content in SmFe1-xNixAsO, thus indicating successful substitution of smaller ion Ni at Fe site. The resistivity measurements showed that the spin-density-wave (SDW) transition is suppressed drastically with Ni doping and subsequently superconductivity is achieved in a narrow range of x from 0.04 to 0.10 with maximum Tc of 9K at x = 0.06. For higher content of Ni (x > 0.10), the system becomes metallic and superconductivity is not observed down to 2K. The magneto-transport [R(T)H] measurements exhibited the upper critical field [Hc2(0)] of up to 300kOe. The flux flow activation energy (U/kB) is estimated ~98.37K for 0.1T field. Magnetic susceptibility measurements also confirms bulk superconductivity for x = 0.04, 0.06 and 0.08 samples. The lower critical field (Hc1) is around 100Oe at 2K for x = 0.06 sample. Heat capacity CP(T) measurements exhibited a hump like transition pertaining to SDW in Fe planes at around 150K and an AFM ordering of Sm spins below temperature of 5.4K for ordered Sm spins [TN(Sm)]. Though, the SDW hump for Fe spins disappears for Ni doped samples, the TN (Sm) remains unaltered but with a reduced transition height, i.e., decreased entropy. In conclusion, complete phase diagram of SmFe1-xNixAsO (x = 0.0 to 1.0) is studied in terms of its structural, electrical, magnetic and thermal properties.Comment: 18 pages text + Figures; comments suggestions welcome ([email protected]

Noncommutative Electromagnetism As A Large N Gauge Theory

We map noncommutative (NC) U(1) gauge theory on R^d_C X R^{2n}_{NC} to U(N -> \infty) Yang-Mills theory on R^d_C, where R^d_C is a d-dimensional commutative spacetime while R^{2n}_{NC} is a 2n-dimensional NC space. The resulting U(N) Yang-Mills theory on R^d_C is equivalent to that obtained by the dimensional reduction of (d+2n)-dimensional U(N) Yang-Mills theory onto R^d_C. We show that the gauge-Higgs system (A_\mu,\Phi^a) in the U(N -> \infty) Yang-Mills theory on R^d_C leads to an emergent geometry in the (d+2n)-dimensional spacetime whose metric was determined by Ward a long time ago. In particular, the 10-dimensional gravity for d=4 and n=3 corresponds to the emergent geometry arising from the 4-dimensional N=4 vector multiplet in the AdS/CFT duality. We further elucidate the emergent gravity by showing that the gauge-Higgs system (A_\mu,\Phi^a) in half-BPS configurations describes self-dual Einstein gravity.Comment: 25 pages; More clarifications, to appear in Eur. Phys. J.

Amine Containing Analogs of Sulindac for Cancer Prevention

Background: Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity. Objective: Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities. Method: A series of sulindac amine analogs were designed and synthesized and then further modified in a “libraries from libraries” approach to produce amide, sulfonamide and N,N-disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast). Results: Several active compounds were identified viain vitro cancer cell line screening with the most potent compound (26) in the nanomolar range. Conclusion: Compound 26 and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Acute kidney injury in patients treated with immune checkpoint inhibitors

BACKGROUND: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. METHODS: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. RESULTS: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. CONCLUSIONS: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury

Long COVID and cardiovascular disease: a prospective cohort study

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known. Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors. Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health. Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86). Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need

Accelarated immune ageing is associated with COVID-19 disease severity

Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. Results We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ( = 0.174, p = 0.043), with a major influence being disease severity ( = 0.188, p = 0.01). Conclusions Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease