bluuebunny/crossref_metadata_2025 huggingface dataset:
GLP-1 (Glucagon-Like Peptide-1) Is Physiologically Relevant for Chylomicron Secretion Beyond Its Known Pharmacological Role
Authors: Nahmias Avital , Stahel Priska , Tian Lili , Xiao Changting , Lewis Gary F.
Published: May 2021

Objective:

GLP-1R (glucagon-like peptide-1 receptor) agonists are increasingly used for the treatment of hyperglycemia in type 2 diabetes, with additional body weight reducing effects. Long-term administration of GLP-1R agonists has demonstrated cardioprotective effects, but the mechanism of cardiovascular protection is not currently known. Several studies in humans and animal models have shown suppression of intestinal CM (chylomicron) secretion and plasma TG (triglyceride) levels by pharmacological doses of GLP-1R agonists. The objective of this study was to assess the physiological role of endogenously secreted GLP-1 on CM secretion in rats.

Approach and Results:

Lymph flow, TG concentration, and TG output were assessed in mesenteric lymph duct-cannulated rats in response to an intraduodenal lipid bolus, preceded by an intraperitoneal injection of GLP-1R antagonist Ex (9–39; exendin 9–39) or vehicle. TG output was significantly enhanced in the presence of Ex (9–39) compared with vehicle over a 4-hour period post-lipid bolus (
P
=0.007). Total lymph volume (
P
=0.005) and TG mass (
P
<0.0001) cumulatively collected by the end of the 4-hour period were significantly increased by GLP-1R antagonist.

Conclusions:

GLP-1R antagonism enhanced intestinal TG output in rats through stimulation of lymph flow and increased lymph TG concentration. Endogenously secreted GLP-1 after a lipid bolus is sufficient to modulate CM secretion in the rat, with GLP-1 physiologically restraining CM secretion through the GLP-1R. It remains to be determined whether the lipid lowering actions of GLP-1R agonists play a role in the cardiovascular protective effects of these therapeutic agents.
Bridging With Extracorporeal Membrane Oxygenation Under the New Heart Allocation System: A United Network for Organ Sharing Database Analysis
Authors: Nordan Taylor , Critsinelis Andre C. , Mahrokhian Shant H. , Kapur Navin K. , Thayer Katherine L. , Chen Frederick Y. , Couper Gregory S. , Kawabori Masashi
Published: May 2021

Background:

The effect of the new donor heart allocation system on survival following bridging to transplantation with venous-arterial extracorporeal membrane oxygenation remains unknown. The new allocation system places extracorporeal membrane oxygenation–supported candidates at the highest status.

Methods:

The United Network for Organ Sharing database was queried for adults bridged to single-organ heart transplantation with extracorporeal membrane oxygenation from October 2006 to February 2020. Association between implementation of the new system and recipient survival was analyzed using Kaplan-Meier estimates, Cox proportional hazards models, and propensity score matching.

Results:

Of 364 recipients included, 173 and 191 were transplanted under new and old systems, respectively. Compared with the old system, waitlist time was halved under the new system (5 versus 10 days,
P
<0.01); recipients also demonstrated lower rates of prior cardiac surgery (32.9% versus 44.5%,
P
=0.03) and preoperative ventilation (30.6% versus 42.4%,
P
=0.02). Unadjusted 180-day survival was 90.2% (95% CI, 84.7%–94.2%) and 69.6% (95% CI, 62.6%–76.1%) under the new and old systems, respectively. Cox proportional hazards analysis demonstrated listing and transplantation under the new system to be an independent predictor of post-transplant survival (adjusted hazard ratio, 0.34 [95% CI 0.20–0.59]). Propensity score matching demonstrated a similar trend (hazard ratio, 0.36 [95% CI, 0.19–0.66]). Candidates listed under the new system were significantly less likely to experience waitlist mortality or deterioration (subhazard ratio, 0.38 [95% CI, 0.25–0.58]) and more likely to survive to transplant (subhazard ratio, 4.29 [95% CI, 3.32–5.54]).

Conclusions:

Recipients transplanted following extracorporeal membrane oxygenation bridging to transplantation under the new system achieve greater 180-day survival compared with the old and demonstrate less preoperative comorbidity. Waitlist outcomes have also improved significantly under the new allocation system.
Ischemia From Nonculprit Stenoses Is Not Associated With Reduced Culprit Infarct Size in Patients with ST-Segment–Elevation Myocardial Infarction
Authors: Ekström Kathrine , Nielsen Julie V.W. , Nepper-Christensen Lars , Ahtarovski Kiril A. , Kyhl Kasper , Göransson Christoffer , Bertelsen Litten , Ghotbi Adam A. , Kelbæk Henning , Høfsten Dan E. , Køber Lars , Schoos Mikkel M. , Vejlstrup Niels , Lønborg Jacob , Engstrøm Thomas
Published: May 2021

Background:

In patients with ST-segment–elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention, reperfusion injury accounts for a significant fraction of the final infarct size, which is directly related to patient prognosis. In animal studies, brief periods of ischemia in noninfarct-related (nonculprit) coronary arteries protect the culprit myocardium via remote ischemic preconditioning. Positive fractional flow reserve (FFR) documents functional significant coronary nonculprit stenosis, which may offer remote ischemic preconditioning of the culprit myocardium. The aim of the study was to investigate the association between functional significant, multivessel disease (MVD) and reduced culprit final infarct size or increased myocardial salvage (myocardial salvage index [MSI]) in a large contemporary cohort of STEMI patients.

Methods:

Cardiac magnetic resonance was performed in 610 patients with STEMI at day 1 and 3 months after primary percutaneous coronary intervention. Patients were stratified into 3 groups according to FFR measurements in nonculprit stenosis (if any): angiographic single vessel disease (SVD), FFR nonsignificant MVD (functional SVD), or FFR-significant, functional MVD.

Results:

A total of 431 (71%) patients had SVD, 35 (6%) had functional SVD, and 144 (23%) had functional MVD. There was no difference in final infarct size (mean infarct size [%left ventricular mass] SVD, 9±3%; functional SVD, 9±3%; and functional MVD, 9±3% [
P
=0.82]) or in MSI between groups (mean MSI [%left] SVD, 66±23%; functional SVD, 68±19%; and functional MVD, 69±19% [
P
=0.62]). In multivariable analyses, functional MVD was not associated with larger MSI (
P
=0.56) or smaller infarct size (
P
=0.55).

Conclusions:

Functional MVD in nonculprit myocardium was not associated with reduced culprit final infarct size or increased MSI following STEMI. This is important knowledge for future studies examining a cardioprotective treatment in patients with STEMI, as a possible confounding effect of FFR-significant, functional MVD can be discarded.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01435408 (DANAMI 3-iPOST and DANAMI 3-DEFER) and NCT01960933 (DANAMI 3-PRIMULTI).
Cyclin D2 Overexpression Enhances the Efficacy of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes for Myocardial Repair in a Swine Model of Myocardial Infarction
Authors: Zhao Meng , Nakada Yuji , Wei Yuhua , Bian Weihua , Chu Yuxin , Borovjagin Anton V. , Xie Min , Zhu Wuqiang , Nguyen Thanh , Zhou Yang , Serpooshan Vahid , Walcott Gregory P. , Zhang Jianyi
Published: May 2021

Background:

Human induced pluripotent stem cells with normal (wild-type) or upregulated (overexpressed) levels of CCND2 (cyclin D2) expression were differentiated into cardiomyocytes (CCND2
WT
CMs or CCND2
OE
CMs, respectively) and injected into infarcted pig hearts.

Methods:

Acute myocardial infarction was induced by a 60-minute occlusion of the left anterior descending coronary artery. Immediately after reperfusion, CCND2
WT
CMs or CCND2
OE
CMs (3×10
7
cells each) or an equivalent volume of the delivery vehicle was injected around the infarct border zone area.

Results:

The number of the engrafted CCND2
OE
CMs exceeded that of the engrafted CCND2
WT
CMs from 6- to 8-fold, rising from 1 week to 4 weeks after implantation. In contrast to the treatment with the CCND2
WT
CMs or the delivery vehicle, the administration of CCND2
OE
CM was associated with significantly improved left ventricular function, as revealed by magnetic resonance imaging. This correlated with reduction of infarct size, fibrosis, ventricular hypertrophy, and cardiomyocyte apoptosis, and increase of vascular density and arterial density, as per histologic analysis of the treated hearts. Expression of cell proliferation markers (eg, Ki67, phosphorylated histone 3, and Aurora B kinase) was also significantly upregulated in the recipient cardiomyocytes from the CCND2
OE
CM-treated than from the CCND2
WT
CM-treated pigs. The cell proliferation rate and the hypoxia tolerance measured in cultured human induced pluripotent stem cell cardiomyocytes were significantly greater after treatment with exosomes isolated from the CCND2
OE
CMs (CCND2
OE
Exos) than from the CCND2
WT
CMs (CCND2
WT
Exos). As demonstrated by our study, CCND2
OE
Exos can also promote the proliferation activity of postnatal rat and adult mouse cardiomyocytes. A bulk miRNA sequencing analysis of CCND2
OE
Exos versus CCND2
WT
Exos identified 206 and 91 miRNAs that were significantly upregulated and downregulated, respectively. Gene ontology enrichment analysis identified significant differences in the expression profiles of miRNAs from various functional categories and pathways, including miRNAs implicated in cell-cycle checkpoints (G2/M and G1/S transitions), or the mechanism of cytokinesis.

Conclusions:

We demonstrated that enhanced potency of CCND2
OE
CMs promoted myocyte proliferation in both grafts and recipient tissue in a large mammal acute myocardial infarction model. These results suggest that CCND2
OE
CMs transplantation may be a potential therapeutic strategy for the repair of infarcted hearts.
Preparing for Military Action: Judith’s Purificatory Washing in Judith 12:7
Authors: Scales Joseph
Published: May 2021

In the twelfth chapter of the Book of Judith, the eponymous heroine departs from the Assyrian camp in order to bathe and pray over three successive nights. Judith’s bath has been interpreted as a ritual bath which achieves purification. Scholars have offered various reasons for Judith’s purificatory wash, but none fully account for all the details of this episode. This paper discusses the proposed solutions and offers a new suggestion to account for Judith’s bath; Judith bathes to prepare herself for the assassination of Holofernes.
A Restorative Response to Victims in Proceedings before the International Criminal Court: Reality or Chimaera?
Authors: Cuppini Alessandra
Published: May 2021

The integration of the framework of victims’ participation into the legal proceeding of the International Criminal Court (icc) has been seen as a transformation of the icc process beyond narrow retribution to better accommodate restorative justice (rj) values and practices. However, there is little research into whether, or how the icc metes out rj. This article argues that rj principles brought within icc emphasise the growing importance that victims’ participation in proceedings plays in achieving justice for victims. It then examines how the icc process aligns to the key elements of rj practice, namely victim-offender meeting; offender’s acknowledgement of responsibility and apology; collaborative conflict-resolution approach; victims’ healing and reconciliation; symbolic reparation and material restitution. This article demonstrates that these elements, developed to address ordinary juvenile criminality, are not structured to operate in the particular context of the icc, characterised by grave harm caused to victims and communities by mass atrocity.
Introduction
Authors: Capone Francesca , Longobardo Marco
Published: May 2021

The predicted expansion of international law ultimately resulted in the imposition on States of several and far reaching obligations to criminalise certain offences, in order to, inter alia, uniform States’ criminal law framework to the maximum extent possible. The aim of the special issue is to provide a forum to discuss the many and multifaceted aspects connected to obligations of domestic criminalisation, using Italy as a case study. The special issue is divided in three sections, addressing, respectively, broad issues of general application, Italy’s implementation of obligations to criminalise conducts amounting to international crimes, and further ambits of analysis (i.e. gender based violence, cyber crimes against minors and corruption).
Three Women in Time: Beatrice Edgell, Josephine Nash Curtis, and Mary Sturt
Authors: Wearden John H.
Published: May 2021

This article discusses research on time perception published by three women (Beatrice Edgell, Josephine Nash Curtis, and Mary Sturt) active in the early years of the 20th. Century. Edgell (On time judgment, Am. J. Psychol., 1903) was involved in psychophysical studies on the perception of brief durations, in the tradition of Vierordt and other mostly German authors. Curtis (Duration and the temporal judgment, Am. J. Psychol., 1916) provided detailed reports of introspections from participants performing timing tasks, in the manner of her supervisor, Titchener. Sturt (via the article by Oakden & Sturt, The development of the knowledge of time in children, Br. J. Psychol., 1922, an article by Sturt herself, Experiments on the estimate of duration, Br. J. Psychol. 1923, and her book The Psychology of Time, 1925) was involved in extensive developmental studies on the understanding of everyday time concepts, such as years, months, and dates, as well as other work involving variations in time judgements as a function of different conditions, such as when receiving painful stimulation.
Taxonomy of the Neolycaena (Rhymnaria) davidi (Oberthür, 1881) species group, with the description of two new taxa from Russia and China (Lepidoptera, Lycaenidae)
Authors: KRUPITSKY ANATOLY V.
Published: May 2021

Poorly known taxa of the Neolycaena (Rhymnaria) davidi (Oberthür, 1881) species group are reviewed in the light of modern findings. The taxon kozlovi Zhdanko, 1996 previously considered a subspecies of N. (R.) davidi is recognised here as a separate species, N. (R.) kozlovi Zhdanko, 1996, stat. rev., including the subspecies N. (R.) kozlovi namkhaidorji Churkin, 2004, comb. nov., based on morphological differences, the geographic isolation and ecological specialisation. A new species, N. (R.) markhasiovi sp. n., is described from Xinjiang Uyghur Autonomous Region in China (Eastern Tian Shan, the Karlik Mountains) on the basis of distinct genitalia morphology and features of the external morphology, including colouration of the female abdomen. Populations of the subgenus Rhymnaria from southern Tuva in Russia (the Tannu-Ola Mountains) are described as a separate subspecies, N. (R.) davidi tannuola ssp. n. A checklist of the taxa of the N. (R.) davidi species group including data on their distribution and host plants is presented, as well as a key to the species of the group.
A Modeling Investigation of the Potential Impacts of Pollution Aerosols on Hurricane Harvey
Authors: Cotton William R , Walko Robert
Published: May 2021

We examine the potential role of aerosol pollution on the rainfall and intensity of hurricane Harvey. For this study, we use the global model, OLAM, with aerosol estimates from the global atmospheric chemistry model GEOS-Chem. Two sets of simulations of hurricane Harvey were performed. Simulations in the first set cover the intensification phase of Harvey until initial landfall in Texas and focus on the sensitivity of storm track and intensity, while simulations in the second set examine the sensitivity of storm track and precipitation during the period after initial landfall when record flooding occurred near Houston. During each period, simulations were performed with no anthropogenic sources of aerosol, with both natural and anthropogenic aerosol sources, and with both sources enhanced ten times.

During the rapid intensification phase, the results indicate that aerosol amounts had very little impact on storm motion. Moreover, very little difference was found on the intensity of the simulated storm to aerosol amounts for the no-anthropogenic vs the GEOS-Chem estimated amounts with anthropogenic sources. However, when both natural and anthropogenic aerosol amounts were enhanced ten times, the simulated storm intensity was enhanced appreciably in terms of minimum sea-level pressure.

During the second period of the simulation, through which Harvey remained a tropical storm, the main result was that very little sensitivity was found in precipitation or any other TC characteristic to aerosol concentrations. We cannot definitively state why the individual convective cells did not respond to high aerosol concentrations during this phase of the storm. However, the abundant precipitation in all three simulations scavenged the vast majority of aerosol as it flowed radially inward, and we speculate that this modulated the potential impact of aerosols on the inner TC and eyewall

Overall, the simulated response of hurricane Harvey to aerosols was far less spectacular than what has been simulated in the past. We conclude that this is because hurricane Harvey was a strongly dynamically-driven storm system that as a result was relatively impervious to the effects of aerosols.
CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children’s Oncology Group
Authors: Tarlock Katherine , Lamble Adam J. , Wang Yi-Cheng , Gerbing Robert B. , Ries Rhonda E. , Loken Michael R. , Brodersen Lisa Eidenschink , Pardo Laura , Leonti Amanda , Smith Jenny L. , Hylkema Tiffany A. , Woods William G. , Cooper Todd M. , Kolb E. Anders , Gamis Alan S. , Aplenc Richard , Alonzo Todd A. , Meshinchi Soheil
Published: May 2021

Biallelic CEBPA mutations are associated with favorable outcomes in acute myeloid leukemia (AML). We evaluated the clinical and biologic implications of CEBPA-basic leucine zipper (CEBPA-bZip) mutations in children and young adults with newly diagnosed AML. CEBPA-bZip mutation status was determined in 2958 patients with AML enrolled on Children’s Oncology Group trials (NCT00003790, NCT0007174, NCT00372593, NCT01379181). Next-generation sequencing (NGS) was performed in 1863 patients (107 with CEBPA mutations) to characterize the co-occurring mutations. CEBPA mutational status was correlated with disease characteristics and clinical outcomes. CEBPA-bZip mutations were identified in 160 (5.4%) of 2958 patients, with 132 (82.5%) harboring a second CEBPA mutation (CEBPA-double-mutated [CEBPA-dm]) and 28 (17.5%) had a single CEBPA-bZip only mutation. The clinical and laboratory features of the 2 CEBPA cohorts were very similar. Patients with CEBPA-dm and CEBPA-bZip experienced identical event-free survival (EFS) of 64% and similar overall survival (OS) of 81% and 89%, respectively (P = .259); this compared favorably to EFS of 46% and OS of 61% in patients with CEBPA-wild-type (CEBPA-WT) (both P < .001). Transcriptome analysis demonstrated similar expression profiles for patients with CEBPA-bZip and CEBPA-dm. Comprehensive NGS of patients with CEBPA mutations identified co-occurring CSF3R mutations in 13.1% of patients and GATA2 mutations in 21.5% of patients. Patients with dual CEBPA and CSF3R mutations had an EFS of 17% vs 63% for patients with CEBPA-mutant or CSF3R-WT (P < .001) with a corresponding relapse rate (RR) of 83% vs 22%, respectively (P < .001); GATA2 co-occurrence did not have an impact on outcome. CEBPA-bZip domain mutations are associated with favorable clinical outcomes, regardless of monoallelic or biallelic status. Co-occurring CSF3R and CEBPA mutations are associated with a high RR that nullifies the favorable prognostic impact of CEBPA mutations.
Transbronchial mediastinal cryobiopsy in the diagnosis of mediastinal lesions: a randomised trial
Authors: Zhang Jing , Guo Jie-Ru , Huang Zan-Sheng , Fu Wan-Lei , Wu Xian-Li , Wu Na , Kuebler Wolfgang M. , Herth Felix J.F. , Fan Ye
Published: May 2021

Background

Guidelines recommend endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an initial investigatory technique for mediastinal nodal staging in lung cancer. However, EBUS-TBNA can be limited by the inadequacy of intact tissues, which might restrict its diagnostic yield in mediastinal lesions of certain aetiologies. We have previously shown that EBUS-guided transbronchial mediastinal cryobiopsy can provide intact samples with greater volume.

Methods

This randomised study determined the diagnostic yield and safety of transbronchial mediastinal cryobiopsy monitored by endosonography for the diagnosis of mediastinal lesions. Patients with a mediastinal lesion of ≥1 cm in the short axis were recruited. Following identification of the mediastinal lesion by linear EBUS, fine-needle aspiration and cryobiopsy were sequentially performed in a randomised order. Primary end-points were diagnostic yield, defined as the percentage of patients for whom mediastinal biopsy provided a definite diagnosis, and procedure-related adverse events.

Results

In total, 197 patients were enrolled and randomly allocated. The overall diagnostic yield was 79.9% and 91.8% for TBNA and transbronchial mediastinal cryobiopsy, respectively (p=0.001). Diagnostic yields were similar for metastatic lymphadenopathy (94.1%versus95.6%, p=0.58), while cryobiopsy was more sensitive than TBNA in uncommon tumours (91.7%versus25.0%, p=0.001) and benign disorders (80.9%versus53.2%, p=0.004). No significant differences in diagnostic yield were detected between “TBNA first” and “Cryobiopsy first” groups. We observed two cases of pneumothorax and one case of pneumomediastinum.

Conclusions

Transbronchial cryobiopsy performed under EBUS guidance is a safe and useful approach that offers diagnostic histological samples of mediastinal lesions.
Association of performance in a stair-climbing test with complications and survival after lung cancer resection in the video-assisted thoracoscopic surgery era: population-based outcomes
Authors: Helminen Olli , Valo Johanna , Andersen Heidi , Söderström Johan , Sihvo Eero
Published: May 2021

Introduction

With a population-based cohort in the video-assisted thoracoscopic surgery (VATS) era, we aimed to evaluate the value of the stair-climbing test (SCT) on short- and long-term outcomes of lung cancer surgery.

Methods

All patients operated due to primary lung cancer in Central Finland and Ostrobothnia from 2013 to June 2020 were included. For the analysis, clinical variables including the outcome of SCT and cause-specific mortality were available. Short- and long-term outcomes were compared between <11 m (n=66) and >12 m SCT (n=217) groups.

Results

Patients with poor performance (<11 m) had more comorbidities and worse lung function but did not differ in tumour stage or treatment. No differences between groups were observed in major morbidity rate (10.6%versus11.1%, p=0.918) or median hospital stay (5 (IQR 4–7)versus4 (IQR 3–7), p=0.179). At 1-year, fewer patients were alive and living at home in the climbing <11 m group (81.3%) compared to the >12 m group (94.2%), p=0.002. No difference was observed in cancer-specific 5-year survival. Non-cancer-specific survival (62.9%versus83.1%, p<0.001) and overall survival (49.9%versus70.0%, p<0.001) were worse in the <11 m group. After adjustment for confounding factors, SCT remained as a significant predictor for non-cancer-specific (HR 4.28; 95% CI 2.10–8.73) and overall mortality (HR 2.38; 95% CI 1.43–3.98).

Conclusions

With SCT-based exercise testing, VATS can be performed safely, with a similar major morbidity rate in the poor performance group (<11 m) compared to >12 m group. Poor exercise performance increases non-cancer-specific mortality. Being a major predictor of survival, exercise capacity should be included in prognostic models.
Can perioperative hemodilution be monitored with non-invasive measurement of blood hemoglobin?
Authors: Hahn Robert G. , Wuethrich Patrick Y. , Zdolsek Joachim H.
Published: May 2021

Background

Trends in non-invasive measurements of blood hemoglobin (Hb) may be useful for identifying the need for transfusion in the perioperative period.

Methods

Crystalloid fluid (5–20 mL/kg) was administered intravenously or by mouth to 30 volunteers and 33 surgical patients in five non-randomized clinical studies where Hb was measured on 915 occasions by non-invasive (Radical-7™) and invasive methodology. The hemodilution curves were compared by volume kinetic analysis and linear regression, with the slope and scattering of the data as key outcome measures.

Results

The slope was 1.0, indicating unity between the two modes of measuring Hb when crystalloid fluid was infused in volunteers; however, only 40–45% of the variability in the non-invasive Hb could be explained by the invasive Hb. Patients undergoing major surgery, who showed the most pronounced hemodilution (median 24 g/L); non-invasive Hb explained 72% of the variability but indicated only half the magnitude of the invasive Hb changes (slope 0.48, P < 0.001 versus the volunteers). Simulations based on volume kinetic parameters from the volunteers showed 25% less plasma volume expansion after infusion when based on non-invasive as compared to invasive Hb, while no difference was found during infusion.

Conclusions

In volunteers the non-invasive Hb had good accuracy (low bias) but poor precision. In surgical patients the non-invasive Hb had good precision but systematically underestimated the hemodilution. Despite severe limitations, the non-invasive technology can be used to follow Hb trends during surgery if supported by occasional invasive measurements to assure acceptable quality of the hemodilution curve.

Trial registrations

ControlledTrials.gov NCT01195025, NCT01062776, NCT01458678, NCT03848507, and NCT01360333 on September 3, 2010, February 4, 2010, October 25, 2011, February 20, 2019, and May 25, 2011, respectively.
A strategy for optimal fitting of multiplicative and additive hazards regression models
Authors: Lefebvre François , Giorgi Roch
Published: May 2021

Background

In survival analysis, data can be modeled using either a multiplicative hazards regression model (such as the Cox model) or an additive hazards regression model (such as Lin’s or Aalen’s model). While several diagnostic tools are available to check the assumptions underpinning each type of model, there is no defined procedure to fit these models optimally. Moreover, the two types of models are rarely combined in survival analysis. Here, we propose a strategy for optimal fitting of multiplicative and additive hazards regression models in survival analysis.

Methods

This section details our proposed strategy for optimal fitting of multiplicative and additive hazards regression models, with a focus on the assumptions underpinning each type of model, the diagnostic tools used to check these assumptions, and the steps followed to fit the data. The proposed strategy draws on classical diagnostic tools (Schoenfeld and martingale residuals) and less common tools (pseudo-observations, martingale residual processes, and Arjas plots).

Results

The proposed strategy is applied to a dataset of patients with myocardial infarction (TRACE data frame). The effects of 5 covariates (age, sex, diabetes, ventricular fibrillation, and clinical heart failure) on the hazard of death are analyzed using multiplicative and additive hazards regression models. The proposed strategy is shown to fit the data optimally.

Conclusions

Survival analysis is improved by using multiplicative and additive hazards regression models together, but specific steps must be followed to fit the data optimally. By providing different measures of the same effect, our proposed strategy allows for better interpretation of the data.
Evaluating the measures taken to contain a Candida auris outbreak in a tertiary care hospital in South India: an outbreak investigational study
Authors: Sathyapalan Dipu Thareparambil , Antony Remya , Nampoothiri Vrinda , Kumar Anil , Shashindran Nandita , James Jini , Thomas Jisha , Prasanna Preetha , Sudhir Akkulath Sangita , Philip Jeslyn Mary , Edathadathil Fabia , Prabhu Binny , Singh Sanjeev , Moni Merlin
Published: May 2021

Background

Candida auris infections are an emerging global threat with poor clinical outcome, high mortality rate, high transmission rate and outbreak potential. The objective of this work is to describe a multidisciplinary approach towards the investigation and containment of a Candida auris outbreak and the preventive measures adopted in a resource limited setting.

Methods

This outbreak investigational study was conducted at a 1300-bedded tertiary care academic hospital in South India. The study included 15 adult inpatients with laboratory confirmed Candida auris isolates. The outbreak cluster was identified in adult patients admitted from September 2017 to 2019. The system response consisted of a critical alert system for laboratory confirmed Candida auris infection and multidisciplinary ‘Candida auris care team’ for patient management. The team implemented stringent Infection Prevention and Control (IPC) measures including patient cohorting, standardized therapy and decolonization, staff training, prospective surveillance and introduction of Candida auris specific care bundle.

Results

Two outbreak clusters were identified; first cluster occurring between October and November 2017 and the second cluster in May 2018. The cohorts consisted of 7 and 8 Candida auris positive patients in the first and second waves of the outbreak respectively with a total survival rate of 93% (14/15). Deployment of containment measures led to gradual decline in the incidence of adult Candida auris positive cases and prevented further cluster formation.

Conclusions

The sustained implementation of guideline and evidence-based IPC measures and training of healthcare workers for improving awareness on systematically following standardized protocols of Candida auris related IPC practices successfully contained Candida auris outbreaks at our hospital. This demonstrates the feasibility of establishing a multidisciplinary model and bundling of practices for preventing Candida auris outbreaks in a Low- and Middle-income country.
Left atrial minimal volume: association with diastolic dysfunction and heart failure in patients in sinus rhythm or atrial fibrillation with preserved ejection fraction
Authors: Ben-Arzi Assaf , Hazanov Evgeni , Ghanim Diab , Rozen Guy , Marai Ibrahim , Grosman-Rimon Liza , Kachel Erez , Amir Offer , Carasso Shemy
Published: May 2021

Background

Evidence of diastolic dysfunction (DD) required for the diagnosis of heart failure with preserved ejection fraction (HFpEF) is elusive in atrial fibrillation (AF). Left ventricular (LV) and left atrial (LA) speckle-tracking echocardiography (STE) may provide rhythm independent indications of DD. We aimed to find common LV/LA myocardial mechanics parameters to demonstrate DD, using STE in patients with AF.

Methods

176 echocardiographic assessments of patients were studied retrospectively by STE. 109 patients with history of AF were divided in three groups: sinus with normal diastolic function (n = 32, ND), sinus with DD (n = 35, DD) and patients with AF during echocardiography (n = 42). These assessments were compared to 67 normal controls. Demographic, clinical, echocardiographic and myocardial mechanic characteristics were obtained.

Results

The patients with DD in sinus rhythm and patients with AF were similar in age, mostly women, and had cardiovascular risk factors as well as higher dyspnea prevalence compared to either controls or patients with ND. In the AF group, LV ejection fraction (LVEF) (p = 0.008), global longitudinal strain and LA emptying were lower (p < 0.001), whereas LA volumes were larger (p < 0.001) compared to the other groups. In a multivariable analysis of patients in sinus rhythm, LA minimal volume indexed to body surface area (Vmin-I) was found to be the single significant factor associated with DD (AUC 83%). In all study patients, Vmin-I correlated with dyspnea (AUC 80%) and pulmonary hypertension (AUC 90%).

Conclusions

Vmin-I may be used to identify DD and assist in the diagnosis of HFpEF in patients with AF.
Progesterone levels on the human chorionic gonadotropin trigger day affect the pregnancy rates for embryos transferred at different stages of development in both general and selected IVF/ICSI populations
Authors: Merviel P. , Bouée S. , Jacamon A. S. , Chabaud J. J. , Le Martelot M. T. , Roche S. , Rince C. , Drapier H. , Perrin A. , Beauvillard D.
Published: May 2021

Background

Two meta-analyses have shown that pregnancy and birth rates are significantly higher after blastocyst transfer than after cleaved embryo transfer. Other studies have revealed that a serum progesterone level > 1.5 ng/ml on the trigger day is responsible for premature luteinization and is associated with a low pregnancy rate. The objectives of this retrospective study were to determine whether blastocyst transfer gave higher pregnancy rates than cleaved embryo transfer at day 3 in both the general and selected IVF/ICSI populations, and whether the serum progesterone level influenced the pregnancy rate.

Method

We studied IVF/ICSI cycles with GnRH antagonist - FSH/hMG protocols in a general population (n = 1210) and a selected “top cycle” population (n = 677), after blastocyst transfer on day 5 or cleaved embryo transfer on day 3. The selected couples had to meet the following criteria: female age < 35, first or second cycle, and one or two embryos transferred. We recorded predictive factors for pregnancy and calculated the progesterone to oocyte index (POI), the progesterone:estradiol ratio (P:E2 ratio), and the progesterone to follicle (> 14 mm) index (PFI).

Results

In the general population, the clinical pregnancy rate was significantly higher after blastocyst transfer (33.3%) than after cleaved embryo transfer (25.3%; p <  0.01); the same was true for the birth rate (32.1 and 22.8%, respectively, p <  0.01). The differences between blastocyst and embryo transfer groups were not significant in the selected population (respectively 35.7% vs. 35.8% for the clinical pregnancy rate, and 33.9 and 34.9% for the birth rate). The serum progesterone levels on the eve of the trigger day and on the day itself were significantly lower in the pregnant women (p <  0.01). We found a serum progesterone threshold of 0.9 ng/ml, as also reported by other researchers. The POI and the PFI appear to have predictive value for cleaved embryos transfers.

Conclusions

Blastocyst transfers were associated with higher clinical pregnancy and birth rates than cleaved embryo transfers in a general population but not in a selected population. The serum progesterone levels on the eve of the trigger day and on the day itself predicted the likelihood of pregnancy.
Discrepancy in p16 expression in patients with HPV-associated head and neck squamous cell carcinoma in Thailand: clinical characteristics and survival outcomes
Authors: Arsa Lalida , Siripoon Teerada , Trachu Narumol , Foyhirun Sasithorn , Pangpunyakulchai Duangjai , Sanpapant Suda , Jinawath Natini , Pattaranutaporn Poompis , Jinawath Artit , Ngamphaiboon Nuttapong
Published: May 2021

Background

Lower prevalence HPV infection has been previously reported in Thai population when compared with Western countries. p16 expression indicates HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but not non-OPSCC. We therefore evaluated the characteristic and association of p16 and HPV in Thai patients with HNSCC.

Methods

We used immunohistochemistry and qPCR, respectively, to detect p16 and HPV DNA in archrival formalin-fixed paraffin-embedded HNSCC tissues. Patient characteristics and survival were analyzed.

Results

p16 expression was detected in tumors of 72 of 662 (10.9%) patients with HNSCC and was significantly associated with higher-grade histology, advanced nodal stage, and oropharynx. p16 was expressed in 28 and 6.5% of patients with OPSCC or non-OPSCC, respectively, and HPV DNA was detected in 15.6 and 1% of patients, respectively. Using p16 as a surrogate for HPV status, sensitivities were 80 and 25% in OPSCC and non-OPSCC, respectively. Positive and negative predictive rates of OPSCC were 38 and 95%. Discordance rates between HPV and p16 were 23 and 7% in OPSCC and non-OPSCC, respectively. Overall survival (OS) were significantly longer in both p16-positive OPSCC (p = 0.049), and non-OPSCC (p = 0.003).

Conclusions

Low prevalence of p16 and HPV associated OPSCC and non-OPSCC were confirmed in Thai patients. High discordance and low positive predictive rates of p16 were observed in HPV-associated OPSCC. p16 was a significant prognostic factor for OS for patients with OPSCC or non-OPSCC. Therefore, HPV testing should be performed to assess the association of HPV with HNSCC regardless of p16 expression.
Randomized phase II study of daily and alternate-day administration of S-1 for adjuvant chemotherapy in completely-resected stage I non-small cell lung cancer: results of the Setouchi Lung Cancer Group Study 1301
Authors: Okumura Norihito , Soh Junichi , Suzuki Hiroyuki , Nakata Masao , Fujiwara Toshiya , Nakamura Hiroshige , Sonobe Makoto , Fujinaga Takuji , Kataoka Kazuhiko , Gemba Kenichi , Kataoka Masafumi , Hotta Katsuyuki , Yoshioka Hiroshige , Matsuo Keitaro , Sakamoto Junichi , Date Hiroshi , Toyooka Shinichi
Published: May 2021

Background

The aim of this multicenter, randomized phase II study was to analyze the feasibility and safety of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological stage I (tumor diameter > 2 cm) non-small cell lung cancer (NSCLC).

Methods

Patients were randomly assigned to receive adjuvant chemotherapy for 1 year comprising either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Group A) or a 2-week oral administration of S-1 (80 mg/m2/day) followed by 1 week of rest (Group B). The primary endpoint was feasibility, which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more.

Results

Ninety-three patients were enrolled of whom 90 patients received S-1 treatment. Median follow-up was 66.9 months. The treatment completion rate based on an RDI of 70% or more for 6 months was 84.4% (95%CI; 70.5–93.5%) in group A and 64.4% (95%CI; 48.8–78.1%) in group B. There were no grade 4 adverse events in either group. Moderate or severe adverse events (grade 2 or grade 3) were significantly more frequent in group B (67%) compared with group A (29%, P = 0.001). The 5-year relapse-free survival rate was 87.0 and 80.9% for group A and B, respectively (P = 0.451). The 5-year overall survival rate for all patients (n = 93) was 100 and 89.4% for group A and B, respectively (P = 0.136).

Conclusion

Alternate-day oral administration of S-1 for 1 year as adjuvant chemotherapy was demonstrated to be feasible with low toxicity in completely resected stage I (tumor diameter > 2 cm) NSCLC.

Trial registration

Trial registration number: UMIN000011994.

Date of registration: 10/8/2013.
Geospatial analysis, web-based mapping and determinants of prostate cancer incidence in Georgia counties: evidence from the 2012–2016 SEER data
Authors: Aheto Justice Moses K. , Utuama Ovie A. , Dagne Getachew A.
Published: May 2021

Background

Prostate cancer (CaP) cases are high in the United States. According to the American Cancer Society, there are an estimated number of 174,650 CaP new cases in 2019. The estimated number of deaths from CaP in 2019 is 31,620, making CaP the second leading cause of cancer deaths among American men with lung cancer been the first. Our goal is to estimate and map prostate cancer relative risk, with the ultimate goal of identifying counties at higher risk where interventions and further research can be targeted.

Methods

The 2012–2016 Surveillance, Epidemiology, and End Results (SEER) Program data was used in this study. Analyses were conducted on 159 Georgia counties. The outcome variable is incident prostate cancer. We employed a Bayesian geospatial model to investigate both measured and unmeasured spatial risk factors for prostate cancer. We visualised the risk of prostate cancer by mapping the predicted relative risk and exceedance probabilities. We finally developed interactive web-based maps to guide optimal policy formulation and intervention strategies.

Results

Number of persons above age 65 years and below poverty, higher median family income, number of foreign born and unemployed were risk factors independently associated with prostate cancer risk in the non-spatial model. Except for the number of foreign born, all these risk factors were also significant in the spatial model with the same direction of effects. Substantial geographical variations in prostate cancer incidence were found in the study. The predicted mean relative risk was 1.20 with a range of 0.53 to 2.92. Individuals residing in Towns, Clay, Union, Putnam, Quitman, and Greene counties were at increased risk of prostate cancer incidence while those residing in Chattahoochee were at the lowest risk of prostate cancer incidence.

Conclusion

Our results can be used as an effective tool in the identification of counties that require targeted interventions and further research by program managers and policy makers as part of an overall strategy in reducing the prostate cancer burden in Georgia State and the United States as a whole.
Evaluation of a self-help intervention to promote the health and wellbeing of marginalised people including those living with leprosy in Nepal: a prospective, observational, cluster-based, cohort study with controls
Authors: Shrestha Dilip , Napit Indra B. , Ansari Subi , Choudhury Sopna Mannan , Dhungana Bishnu , Gill Paramjit , Griffiths Frances , Gwyther Holly , Hagge Deanna , Kandel Shovakhar , Puri Suraj , Sartori Jo , Watson Samuel Ian , Lilford Richard
Published: May 2021

Background

People affected by leprosy are at increased risk of ulcers from peripheral nerve damage. This in turn can lead to visible impairments, stigmatisation and economic marginalisation. Health care providers suggest that patients should be empowered to self-manage their condition to improve outcomes and reduce reliance on services. Self-care involves carrying out personal care tasks with the aim of preventing disabilities or preventing further deterioration. Self-help, on the other hand, addresses the wider psychological, social and economic implications of leprosy and incorporates, for example, skills training and microfinance schemes. The aim of this study, known as SHERPA (Self-Help Evaluation for lepRosy and other conditions in NePAl) is to evaluate a service intervention called Integrated Mobilization of People for Active Community Transformation (IMPACT) designed to encourage both self-care and self-help in marginalised people including those affected by leprosy.

Methods

A mixed-method evaluation study in Province 5, Nepal comprising two parts. First, a prospective, cluster-based, non-randomised controlled study to evaluate the effectiveness of self-help groups on ulcer metrics (people affected by leprosy only) and on four generic outcome measures (all participants) - generic health status, wellbeing, social integration and household economic performance. Second, a qualitative study to examine the implementation and fidelity of the intervention.

Impact

This research will provide information on the effectiveness of combined self-help and self-care groups, on quality of life, social integration and economic wellbeing for people living with leprosy, disability or who are socially and economically marginalised in low- and middle- income countries.
A qualitative study of governance predicament on dengue prevention and control in Malaysia: the elite experience
Authors: Manaf Rosliza Abdul , Mahmud Aidalina , NTR Anthony , Saad Siti Rohana
Published: May 2021

Background

The challenges faced by healthcare personnel in relation to dengue prevention and control are perennial but noticeably unexplored. It is often difficult to translate policies and decision making by the elite into astute management in consonance with the needs of rank-and-file personnel. In this study, we assess the impact of governance on dengue prevention and control activities in Malaysia as narrated by the elite.

Methods

A qualitative study using a case-study approach was conducted between January 2019 and November 2019 in the districts of Gombak and Klang, where the relevant key informants were located. Nineteen interviews were conducted among elite healthcare personnel from different divisions: management, vector, laboratory, inspectorate, health promotion and entomology. Semi-structured interviews were conducted. The sample size was determined through saturation point criteria. Purposive sampling techniques were used to recruit the participants. The interviews were audio recorded, and the transcribed text was analysed with deductive thematic analysis.

Results

Data analysis led to the development of 5 themes and 13 categories. The major principles of governance were embodied in a milieu of predicament, linked to constraints but also opportunities. The constraints resulted from inherent determinants of dengue outbreaks, the serviceability of governing policies and the macro-economics of budget allocation. The opportunities to sustain governance at the local operating level stem from a prevalent supportive internal management system, collaborative efforts among corresponding external government agencies and willingness to innovate and embrace novel technology.

Conclusion

Elites are influential, often well-informed personnel tasked with making decisions that can reverberate across an organisation, impacting future plans and strategic policies. Political arrangements at higher levels will reflect in advance the tone of how governance in dengue prevention and control is operationalised by entities and individuals at lower levels of the health system. The prevailing centralised structure in the Malaysian health system will continue to entrench the position of the elite and intertwine it with governance and its predicaments.
The protective role of serum uric acid against premature membrane rupture in gestational diabetes: a cross-sectional study
Authors: Guo Meixiang , Lu Jun , Yu Xuemei , Hu Xiaowen , Hou Wenjing , Pang Shuguang
Published: May 2021

Background

Uric acid has strong antioxidant activity, whereas its oxidative damage is closely related to many diseases. We assessed the association between serum uric acid (SUA) levels and premature rupture of membranes (PROM) in pregnant women with gestational diabetes (GDM) in China.

Methods

In this cross-sectional study, a total of 456 pregnant women were enrolled. Anthropometric parameters for pregnant women were collected within 12 weeks of gestation. Weight gain during pregnancy was obtained from the patients’ records. GDM was diagnosed according to 75-g oral glucose tolerance tests at the 24-28th week of gestation, and SUA was determined simultaneously. PROM was identified as the natural rupture of foetal membranes before the first stage of labour. Logistic models were fitted to identify the presence of PROM using clinical characteristics with (Model 2) or without serum uric acid (Model 1).

Results

There were differences in BMI, haemoglobin A1c, fasting blood glucose, 1-h postprandial glucose (PG), 2-h PG, insulin levels, triglycerides,weight gain during pregnancy, the rate of macrosomia, fetus birth weight and PROM between women with and without GDM (all P < 0.05). Furthermore, GDM women with PROM had lower levels of SUA compared to those without PROM (P = 0.030). The odds ratio of PROM decreased with increasing SUA levels. The area under the receiver operating characteristic curves for PROM based on Model 2 was larger than that in Model 1 (0.86 versus 0.71, P < 0.05).

Conclusion

Relatively elevated SUA levels at the 24-28th weeks of gestation were associated with a lower risk of PROM in women with GDM. Therefore, SUA may be a protective factor for PROM in GDM patients. The optimal concentration of uric acid in different diseases and different populations needs to be further studied.