Structure and Evolution of Nearby Stars with Planets. I. Short-Period Systems

Using the Yale stellar evolution code, we have calculated theoretical models for nearby stars with planetary-mass companions in short-period nearly circular orbits: 51 Pegasi, Tau Bootis, Upsilon Andromedae, Rho Cancri, and Rho Coronae Borealis. We present tables listing key stellar parameters such as mass, radius, age, and size of the convective envelope as a function of the observable parameters (luminosity, effective temperature, and metallicity), as well as the unknown helium fraction. For each star we construct best models based on recently published spectroscopic data and the present understanding of galactic chemical evolution. We discuss our results in the context of planet formation theory, and, in particular, tidal dissipation effects and stellar metallicity enhancements.Comment: 48 pages including 13 tables and 5 figures, to appear in Ap

An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/ Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8 + T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. Significance: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade

Rotation and activity in the solar-metallicity open cluster NGC2516

We report new measures of radial velocities and rotation rates (v sin i) for 51 F and early-G stars in the open cluster NGC2516, and combine these with previously published data. From high signal-to-noise spectra of two stars, we show that NGC2516 has a relative iron abundance with respect to the Pleiades of delta([Fe/H])= +0.04 +/- 0.07 at the canonical reddening of E(B - V) = 0.12, in contrast to previous photometric studies that placed the cluster 0.2 to 0.4 dex below solar. We construct a color-magnitude diagram based on radial velocity members, and explore the sensitivity of photometric determinations of the metallicity and distance to assumed values of the reddening. For a metal abundance near solar, the Hipparcos distance to NGC2516 is probably underestimated. Finally, we show that the distribution of rotation rates and X-ray emission does not differ greatly from that of the Pleiades, when allowance is made for the somewhat older age of NGC2516.Comment: Accepted for publication in the Astrophysical Journal. 35 pages including 7 figure

Real world, multicentre patterns of treatment and survival in metastatic renal cell carcinoma with the UK Renal Oncology Collaborative ( UK ROC ): Is it time to look favourably on first‐line immunotherapy containing combinations in all IMDC groups?

Introduction: Clinical trials show improved progression‐free survival (PFS) and overall survival (OS) in first‐line metastatic renal cell carcinoma (mRCC) patients with immunotherapy containing systemic anti‐cancer therapies (SACT). However, in the favourable international metastatic renal cell cancer database consortium (IMDC) group there is no trial evidence for OS benefit despite clear PFS improvement when comparing anti‐VEGF tyrosine kinase inhibitor (TKI) monotherapy and (immunotherapy and TKI) IO/TKI combinations. Objective: To assess the impact of first‐line SACT choice on the clinical outcomes of PFS and OS in mRCC. To evaluate this impact of initial SACT for allcomers and the favourable IMDC group. Methods: A multicentre retrospective review of patients who started SACT for mRCC (01/01/2018–30/06/2021) at 17 UK NHS trusts. Patient demographics and IMDC group were analysed. Survival data were compared using Kaplan–Meier curves, and the statistical significance of differences in outcome between the groups was assessed with the log‐rank test. Univariable and multivariable Cox proportional hazard modelling estimate the hazard ratios (HRs) for survival outcomes associated with IMDC and treatment subtype. Results: One thousand three hundred and nineteen patients were identified with a median age of 64. 294 (22.3%), 695 (52.7%) and 321 (24.3%) were IMDC group favourable, intermediate and poor, respectively. 311 (23.6%), 197 (14.9%) and 778 (59%) patients received checkpoint inhibitor and anti‐CTLA4 monoclonal antibody (IO/IO), IO/TKI and TKI first‐line SACT across all IMDC groups. Significant PFS improvement favouring IO/TKI versus TKI was demonstrated in allcomers HR = 0.61. In the favourable risk group, Log rank testing demonstrated a significant benefit for IO/TKI over TKI for PFS (HR = 0.60, 95% CI [0.39, 0.91]) and OS (HR = 0.42, 95% CI [0.18, 0.99]). Conclusion: In this real‐world evidence cohort, we have shown OS and PFS benefit with IO/TKI versus TKI in the favourable IMDC risk group. This has not been previously reported from trial outcomes and would support use of front‐line IO/TKI in mRCC favourable risk patients

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN):an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial

Background: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. Methods: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. Findings: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference –7·00% [95% CI –12·69 to –1·32]; p=0·016). Interpretation: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. Funding: British Heart Foundation and Pharmacosmos.</p

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN):an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial

Background: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. Methods: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. Findings: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference –7·00% [95% CI –12·69 to –1·32]; p=0·016). Interpretation: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. Funding: British Heart Foundation and Pharmacosmos.</p

Intravenous iron for heart failure, iron deficiency definitions, and clinical response:the IRONMAN trial

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure?METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin &lt; 100 µg/L or transferrin saturation (TSAT) &lt; 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death.RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction &lt; .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT &lt; 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant.CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT &lt; 20% with ferritin &gt; 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.</p

Intravenous iron for heart failure, iron deficiency definitions, and clinical response:the IRONMAN trial

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure?METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin &lt; 100 µg/L or transferrin saturation (TSAT) &lt; 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death.RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction &lt; .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT &lt; 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant.CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT &lt; 20% with ferritin &gt; 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.</p

Vitamin K supplementation to improve vascular stiffness in CKD:The K4Kidneys randomized controlled trial

BACKGROUND:Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS:To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS:We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS:Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com)

Analysis of SARS-CoV-2 antibody seroprevalence in Northern Ireland during 2020–2021

BackgroundWith the spread of SARS-CoV-2 impacting upon public health directly and socioeconomically, further information was required to inform policy decisions designed to limit virus spread during the pandemic. This study sought to contribute to serosurveillance work within Northern Ireland to track SARS-CoV-2 progression and guide health strategy.MethodsSera/plasma samples from clinical biochemistry laboratories were analysed for anti-SARS-CoV-2 antibodies. Samples were assessed using an Elecsys anti-SARS-CoV-2 or anti-SARS-CoV-2 S ECLIA (Roche) on an automated cobas e 801 analyser. Samples were also assessed via an anti-SARS-CoV-2 ELISA (Euroimmun). A subset of samples assessed via the Elecsys anti-SARS-CoV-2 ECLIA were subsequently analysed in an ACE2 pseudoneutralisation assay using a V-PLEX SARS-CoV-2 Panel 7 for IgG and ACE2 (Meso Scale Diagnostics).ResultsAcross three testing rounds (June–July 2020, November–December 2020 and June–July 2021 (rounds 1–3 respectively)), 4844 residual sera/plasma specimens were assayed for anti-SARS-CoV-2 antibodies. Seropositivity rates increased across the study, peaking at 11.6 % (95 % CI 10.4%–13.0 %) during round 3. Varying trends in SARS-CoV-2 seropositivity were noted based on demographic factors. For instance, highest rates of seropositivity shifted from older to younger demographics across the study period. In round 3, Alpha (B.1.1.7) variant neutralising antibodies were most frequently detected across age groups, with median concentration of anti-spike protein antibodies elevated in 50–69 year olds and anti-S1 RBD antibodies elevated in 70+ year olds, relative to other age groups.ConclusionsWith seropositivity rates of &lt;15 % across the assessment period, it can be concluded that the significant proportion of the Northern Ireland population had not yet naturally contracted the virus by mid-2021