bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-23 blockade with guselkumab potentially modifies psoriasis pathogenesis: rationale and study protocol of a phase 3b, randomised, double-blind, multicentre study in participants with moderate-to-severe plaque-type psoriasis (GUIDE)
Authors: Eyerich Kilian , Weisenseel Peter , Pinter Andreas , Schäkel Knut , Asadullah Khusru , Wegner Sven , Muñoz-Elias Ernesto J , Bartz Holger , Taut Friedmann J H , Reich Kristian 
Published: September 2021

BackgroundGuselkumab is an interleukin (IL)-23 pathway blocker with proven efficacy in patients with moderate-to-severe plaque psoriasis. Early intervention with guselkumab may result in changes to the clinical disease course versus later intervention.Methods and analysisHere we present the rationale and design of a phase 3b, randomised, double-blind, multicentre study (GUIDE), comparing treatment effects of guselkumab in patients with short (≤2 years) or longer (>2 years) duration of plaque-type psoriasis, measured from first appearance of psoriatic plaques. Participants achieving skin clearance (Psoriasis Area and Severity Index (PASI)=0) by week 20 and maintaining complete clearance at week 28 visit (‘super-responders’ (SRe)) will be randomised to continue approved maintenance dosing every 8 weeks (q8w) versus an investigational maintenance dosing interval of 16 weeks (q16w) until week 68. Primary endpoint: proportion of participants in the q8w vs q16w arms with absolute PASI <3 at week 68. Participants with PASI <3 at week 68 will be withdrawn from guselkumab treatment for up to 48 weeks. Participants not achieving SRe criteria (non-SRe) will remain in the study with q8w guselkumab dosing through week 68. Additional to serum samples obtained from all patients, skin biopsies and whole-blood samples will be taken from SRe and non-SRe participants at various time points in optional substudies. Analyses include: genetics; immunophenotyping (fluorescence-activated cell sorting); gene and protein expression profiling; immunohistology. By merging clinical endpoints with mechanistic findings, this study aims to elucidate how IL-23 blockade with guselkumab can modify the disease course by altering molecular and cellular drivers that cause relapse after treatment withdrawal, particularly among SRe.Ethics and disseminationApproval obtained from ethics committee Medical Council Hamburg, Germany (PVN5925). GUIDE is compliant with the Declaration of Helsinki.Trial registration numberRegistered at ClinicalTrials.gov (NCT03818035). All primary endpoint results (prespecified analyses) will be submitted to peer-reviewed, international journals within 18 months after primary completion date.
Intensive versus standard blood pressure control in type 2 diabetes: a restricted mean survival time analysis of a randomised controlled trial
Authors: Shi Sandra , Gouskova Natalia , Najafzadeh Mehdi , Wei Lee-Jen , Kim Dae Hyun 
Published: September 2021

BackgroundRestricted mean survival time analysis offers an intuitive and robust summary of treatment effect compared with HRs.ObjectiveTo examine the effect of intensive versus standard blood pressure (BP) control on death or cardiovascular events in type 2 diabetes.DesignSecondary analysis of the Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial.Setting77 sites in the USA and Canada.Participants4733 adults with type 2 diabetes at high risk for cardiovascular events.InterventionsSystolic BP target <120 mm Hg (n=2371) versus <140 mm Hg (n=2362).MeasurementsComposite endpoint of death, non-fatal myocardial infarction or non-fatal stroke.ResultsThe mean event-free survival time over 5 years (1825 days) was similar between intensive and standard BP control (1716 vs 1714 days; mean difference, 1.3 (95% CI −18.1 to 20.7) days). However, intensive BP treatment was more beneficial for those assigned to standard glycaemic control (1725 vs 1697 days; mean difference, 28.1 (95% CI 0.4 to 55.9) days), but not for those assigned to intensive glycaemic control (1706 vs 1731 days; mean difference, −25.2 (95% CI −52.3 to 1.9) days) (p=0.008 for interaction). In subgroup analysis, the mean event-free survival time difference between intensive and standard BP treatment was −76.0 (95% CI –131.8 to –20.3) days for those with cognitive impairment and 21.8 (95% CI −24.0 to 67.5) days for those with normal cognitive function (p=0.008 for interaction). The effect was not different by age, sex and baseline cardiovascular disease status.ConclusionsIntensive BP treatment may reduce death and cardiovascular events among patients with type 2 diabetes receiving standard glycaemic treatment and without cognitive impairment.Trial registration numberNCT00000620; Post-results.
Impact of COVID-19 on patient health and self-care practices: a mixed-methods survey with German patients
Authors: Fiske Amelia , Schneider Antonius , McLennan Stuart , Karapetyan Siranush , Buyx Alena 
Published: September 2021

ObjectiveThis study aimed to examine German patients’: (1) self-estimation of the impact of the pandemic on their health and healthcare; and (2) use of digital self-care practices during the pandemic.DesignCross-sectional mixed-methods survey.Setting and participantsGeneral practice patients from four physicians’ offices located in urban and rural areas of Bavaria, Germany, between 21 July 2020 and 17 October 2020. A total of 254 patients participated (55% response rate); 57% (262 of 459) identified as female and participants had an average age of 39.3 years. Patients were eligible to participate if they were 18 years or older and spoke German, and had access to the internet.Results(1) Healthcare for patients was affected by the pandemic, and the mental health of a small group of respondents was particularly affected. The risk of depression and anxiety disorder was significantly increased in patients with quarantine experience. (2) Self-care practices have increased; more than one-third (39%) of participants indicated that they started a new or additional self-care practice during the pandemic, and about a quarter (23%) of patients who were not previously engaged in self-care practices started new self-care activities for the first time; however, such practices were not necessarily digital.ConclusionsFurther investigation is required to understand the relationship between digital self-care and public health events such as the COVID-19 pandemic, and to develop strategies to alleviate the burden of the quarantine experience for patients.
Implementation and 1-year follow-up of the cardiovascular ICU standardised handover
Authors: Lupei Monica , Munshi Nishkruti , Kaizer Alexander M , Patten Luke , Wahr Joyce 
Published: September 2021

BackgroundMiscommunication during clinical handover can lead to partial information transfer and healthcare provider dissatisfaction. We hypothesised that a quality improvement project to standardise the cardiovascular intensive care unit (CVICU) handover could improve healthcare provider satisfaction and reduce information omission.MethodsAfter institutional review board approval, the operating room (OR) to CVICU handover was audited prior, post and 1 year after standardisation implementation. The medical information transferred, healthcare provider participation and satisfaction, and patient outcome data were collected. Additionally, surveys were sent to the OR and CVICU staff by email.ResultsThere were 68 handover processes observed. The odds of greater satisfaction with handover for providers were 18 times higher with the process post implementation (p<0.0001) and 26 times higher 1 year after implementation (p<0.0001). There was statistically significant difference between intensive care unit resident presence (45% vs 76% vs 91%, p=0.004), surgical faculty presence (10% vs 36% vs 45%, p=0.034) and surgical fellow presence (15% vs 64% vs 62%, p=0.001) between the three time periods. More information related to the surgeon (5% vs 52% vs 27%, p=0.002), the medical history (65% vs 96% vs 91%, p=0.014) and the cardiopulmonary bypass (47% vs 88% vs 76%, p=0.017) was conveyed. The duration of mechanical ventilation was shorter after implementation (2.2±2.6 days vs 1.2±1.9 days vs 0.5±1.2 days, p=0.026).ConclusionsOne year after the OR to CVICU standardised handover implementation, the healthcare provider satisfaction remained increased, more team members participated and the information transfer increased. Although some clinical outcomes improved, further studies are recommended to prove causality.
Associations between remote patient monitoring programme responsiveness and clinical outcomes for patients with COVID-19
Authors: Steinberg Rebecca , Anderson Bjorn , Hu Ziyue , Johnson Theodore M , O’Keefe James B , Plantinga Laura C , Kamaleswaran Rishi , Anderson Blake 
Published: September 2021

ObjectiveTo assess whether engagement in a COVID-19 remote patient monitoring (RPM) programme or telemedicine programme improves patient outcomes.MethodsThis is a retrospective cohort study analysing patient responsiveness to our RPM survey or telemedicine visits and outcomes during the COVID-19 pandemic. Daily text message surveys and telemedicine consultations were offered to all patients who tested positive for SARS-CoV-2 at our institutional screening centres. Survey respondents with alarm responses were contacted by a nurse. We assessed the relationship between virtual engagement (telemedicine or RPM survey response) and clinical outcomes using multivariable logistic regression.ResultsBetween 10 July 2020 and 2 January 2021, 6822 patients tested positive, with 1230 (18%) responding to at least one survey. Compared with non-responders, responders were younger (49 vs 53 years) and more likely to be white (40% vs 33%) and female (65% vs 55%) and had fewer comorbidities. After adjustment, individuals who engaged virtually were less likely to experience an emergency department visit, hospital admission or intensive care unit–level care.ConclusionTelemedicine and RPM programme engagement (vs no engagement) were associated with better outcomes, but this was likely due to differences in groups at baseline rather than the efficacy of our intervention alone.
How to analyse the injury based on 24Model: a case study of coal mine gas explosion injury
Authors: Li Jing , Qin Yaru , Wang Zhen , Xin Yanli 
Published: September 2021

BackgroundCoal mine gas explosion injury has caused mass casualties, which have resulted in widespread concern.MethodsIn order to prevent gas explosion injury in coal mine, 24Model is proposed to analyse the risk in this paper. 24Model is a human-oriented and organisation-oriented risk analysis method. Based on the 24Model, we propose a general procedure for analysing the causes of injury within the organisation.ResultsA coal mine gas explosion case was analysed using the 24Model and the proposed analysis method, and the evolution of injury and the interaction of various causes was showed, and 6 unsafe conditions, 25 unsafe acts, 13 safety knowledge, 13 safety management systems and 13 safety cultures were obtained.ConclusionCase analysis results show that by using the 24Model and analysis method the proposed effect can help employees to clearly see the evolution and identify the causes of the injury, to better understand the logical relationship with the causes of the injury, improve the effectiveness of training and effectively prevent similar injury. The case study provides a practical procedure for injury investigation and analysis, and thus, preventive measures can be made according to the various causations at different levels.
Exploring the low $$\tan \beta $$ region of two Higgs doublet models at the LHC
Authors: Su Wei , White Martin , Williams Anthony G. , Wu Yongcheng 
Published: September 2021

AbstractCurrent interpretations of the LHC results on two Higgs doublet models (2HDM) underestimate the sensitivity due to neglecting higher order effects. In this work, we revisit the impact of these effects using the current cross-section times branching ratio limits of the $$A\rightarrow hZ, H \rightarrow VV$$

A
→
h
Z
,
H
→
V
V

and $$H\rightarrow hh$$

H
→
h
h

channels. With a degenerate heavy Higgs mass $$m_\varPhi $$

m
Φ

, we find that the LHC searches gain sensitivity to the small $$\tan \beta $$

tan
β

region after including loop corrections, even close to $$\cos (\beta -\alpha )=0$$

cos
(
β
-
α
)
=
0

which is not reachable at tree level for all types of 2HDM. For a benchmark point with $$m_\varPhi =300$$

m
Φ

=
300

GeV, $$\tan \beta <1.8(1.2)$$

tan
β
<
1.8
(
1.2
)

can be probed for the Type-I(II) 2HDM model for $$\cos (\beta -\alpha )=0$$

cos
(
β
-
α
)
=
0

. When the deviation from $$\cos (\beta -\alpha )=0$$

cos
(
β
-
α
)
=
0

is larger, the region for which current searches have exclusion potential becomes larger.
A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
Authors: Atrafi Florence , Boix Oliver , Subbiah Vivek , Diamond Jennifer R. , Chawla Sant P. , Tolcher Anthony W. , LoRusso Patricia M. , Eder Joseph P. , Gutierrez Martin , Sankhala Kumar , Rajagopalan Prabhu , Genvresse Isabelle , Langer Simon , Mathijssen Ron H.J. , Verweij Jaap , Bruns Ingmar , Lolkema Martijn P. 
Published: September 2021

Abstract

Purpose:
Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination.

Patients and Methods:
Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination.

Results:
In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 (P&lt; 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD.

Conclusions:
The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.
FLT3L Release by Natural Killer Cells Enhances Response to Radioimmunotherapy in Preclinical Models of HNSCC
Authors: Bickett Thomas E. , Knitz Michael , Darragh Laurel B. , Bhatia Shilpa , Van Court Benjamin , Gadwa Jacob , Bhuvane Shiv , Piper Miles , Nguyen Diemmy , Tu Hua , Lenz Laurel , Clambey Eric T. , Barry Kevin , Karam Sana D. 
Published: September 2021

AbstractPurpose:Natural killer (NK) cells are type I innate lymphoid cells that are known for their role in killing virally infected cells or cancer cells through direct cytotoxicity. In addition to direct tumor cell killing, NK cells are known to play fundamental roles in the tumor microenvironment through secretion of key cytokines, such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although radiotherapy is the mainstay treatment in most cancers, the role of radiotherapy on NK cells is not well characterized.Experimental Design:This study combines radiation, immunotherapies, genetic mouse models, and antibody depletion experiments to identify the role of NK cells in overcoming resistance to radiotherapy in orthotopic models of head and neck squamous cell carcinoma.Results:We have found that NK cells are a crucial component in the development of an antitumor response, as depleting them removes efficacy of the previously successful combination treatment of radiotherapy, anti-CD25, and anti-CD137. However, in the absence of NK cells, the effect can be rescued through treatment with FLT3L. But neither radiotherapy with FLT3L therapy alone nor radiotherapy with anti-NKG2A yields any meaningful tumor growth delay. We also identify a role for IL2 in activating NK cells to secrete FLT3L. This activity, we show, is mediated through CD122, the intermediate affinity IL2 receptor, and can be targeted with anti-CD25 therapy.Conclusions:These findings highlight the complexity of using radio-immunotherapies to activate NK cells within the tumor microenvironment, and the importance of NK cells in activating dendritic cells for increased tumor surveillance.
Spatial Mapping and Immunomodulatory Role of the OX40/OX40L Pathway in Human Non–Small Cell Lung Cancer
Authors: Porciuncula Angelo , Morgado Micaela , Gupta Richa , Syrigos Kostas , Meehan Robert , Zacharek Sima J. , Frederick Joshua P. , Schalper Kurt A. 
Published: September 2021

Abstract

Purpose:
To evaluate the tissue distribution and clinical significance of OX40 and OX40L in human non–small cell lung cancer (NSCLC).

Experimental Design:
Using multiplexed quantitative immunofluorescence, we conducted simultaneous and localized measurements of OX40 and OX40L proteins, major T-cell subsets, and conventional type 1 dendritic cells (cDC1) in 614 primary NSCLCs from three independent cohorts represented in tissue microarrays. We also measured OX40L protein in samples from a phase I clinical trial of intratumor administration of a lipid nanoparticle encapsulated mRNA encoding OX40L (mRNA-2416) in human solid tumors. Finally, we studied the OX40 pathway in 212 uterine/ovarian serous carcinomas.

Results:
OX40 protein was expressed in approximately 90% of NSCLCs, and OX40L was detected in approximately 10% of cases. Increased expression of OX40 was associated with higher CD4+ and CD8+ T lymphocytes, as well as cDC1s. Elevated expression of OX40L was consistently associated with increased CD4+ tumor-infiltrating lymphocytes and longer overall survival. No association was found between OX40 or OX40L levels and oncogenic driver mutations in EGFR and KRAS in lung adenocarcinomas. Delivering OX40L mRNA using intratumor mRNA-2416 injection mediated increased local OX40L protein levels that was most prominent in a patient with ovarian serous carcinoma. Detectable OX40L protein levels were observed in 15% of primary uterine/ovarian serous malignancies and associated with longer survival.

Conclusions:
The OX40 pathway is expressed in a fraction of NSCLCs and is associated with a favorable immune contexture. Although OX40L is uncommonly expressed in NSCLC and serous malignancies, it is associated with better prognosis and can be introduced using exogenous mRNA.
Macrophage MST1/2 Disruption Impairs Post-Infarction Cardiac Repair via LTB4
Authors: Liu Mingming , Yan Meng , He Jinlong , Lv Huizhen , Chen Zhipeng , Peng Liyuan , Cai Wenbin , Yao Fang , Chen Chen , Shi Lei , Zhang Kai , Zhang Xu , Wang Dao-Wen , Wang Li , Zhu Yi , Ai Ding 
Published: September 2021

Rationale:
Timely inhibition of inflammation and initiation of resolution are important to repair injured tissues. MST1/2 (mammalian STE20-like protein kinase 1/2) acts as a regulator of macrophage-associated immune responses to bacterial infections. However, the role of MST1/2 in regulating macrophage phenotype and function in myocardial infarction (MI) remains unclear.

Objective:
To determine the function and underlying mechanism of macrophage MST1/2 in cardiac repair post-MI.

Methods and Results:

Using
LysMCre
-mediated
Mst1/2
-deficient mice, we found that MST1 deficiency exacerbated cardiac dysfunction after MI. Single-cell RNA sequencing assay indicated that the effect was attributed to a shift of macrophage subtypes from those expressing
Cxcl2
and
Cd163
toward
Ccl2
and
Ccl4
expression. Mass spectrometry identified LTB4 (leukotriene B4) as the lipid mediator that was upregulated in the absence of MST1. We found that MST1 phosphorylated 5-LOX (5-lipoxygenase) at its T218 residue, disrupting the interaction between 5-LOX and 5-LOX-activating protein, resulting in a reduction of LTB4 production. In contrast, a 5-LOX
T218A
variant showed no response to MST1. Moreover, treatment of peritoneal macrophages with LTB4 or medium conditioned by
Mst1
-deficient macrophages resulted in high
Ccl2
and
Ccl4
expression and low
Cxcl2
and
Cd163
expression, except when the cells were co-treated with the BLT1 (LTB4 receptor 1) antagonist CP105696. Furthermore, CP105696 ameliorated cardiac dysfunction in
LysMCre
-mediated
Mst1/2
-deficient mice and enhanced cardiac repair in wild-type mice treated with XMU-MP-1 (4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide) after MI.

Conclusions:
Taken together, our results demonstrate that inhibition of MST1/2 impaired post-MI repair through activating macrophage 5-LOX–LTB4–BLT1 axis.
Sodium‐Glucose Cotransporter 2 Inhibitors, All‐Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta‐Analysis and Meta‐Regression
Authors: Odutayo Ayodele , da Costa Bruno R. , Pereira Tiago V. , Garg Vinay , Iskander Samir , Roble Fatimah , Lalji Rahim , Hincapié Cesar A. , Akingbade Aquila , Rodrigues Myanca , Agarwal Arnav , Lawendy Bishoy , Saadat Pakeezah , Udell Jacob A. , Cosentino Francesco , Grant Peter J. , Verma Subodh , Jüni Peter 
Published: September 2021

Background
This study aimed to assess the effectiveness of sodium‐glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes.

Methods and Results
We conducted a Bayesian meta‐analysis of randomized controlled trials comparing sodium‐glucose cotransporter 2 inhibitors with placebo. We used meta‐regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty‐three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63–0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69–1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72–1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61–1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63–1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71–1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all‐cause and cardiovascular mortality. There was no association between treatment effects for all‐cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%–95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke.

Conclusions
Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause and cardiovascular mortality versus placebo. Treatment effects of sodium‐glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.