bluuebunny/crossref_metadata_2025 huggingface dataset:
First-principles study of phonon thermal transport in II–VI group graphenelike materials
Authors: Liu Jianye , Zhao Yinchang , Wang Weiqiang , Zhong Qi , Dai Zhenhong , Meng Sheng
Published: October 2020

Using the first-principles calculations and combining with the phonon Boltzmann transport equation, we systematically investigated the phonon thermal transport properties of II–VI group graphenelike materials (BeO, MgO, CaO, SrS, and SrSe). The lattice thermal conductivities κL’s of 118.68, 42.48, 11.13, 3.33, and 3.09 W/mK are obtained at 300 K in BeO, MgO, CaO, SrS, and SrSe, respectively, which is much lower than that of graphene. Strikingly, the κL of SrS and SrSe is lower than most two-dimensional materials. Further analyses revealed that (i) the lower phonon group velocity of SrS and SrSe caused by a larger atomic mass reduces the κL and (ii) strong anharmonicity and more available phonon scattering channels enhance phonon anharmonic scattering, resulting in lower κL. By means of the relationship between κL and the phonon mean-free path and the width of nanowires, the size dependence of lattice thermal conductivity is investigated as well, which provides a theoretical basis for the design of thermoelectric nanostructures.
Coaches’ Use of Positive Tactile Communication in Collegiate Basketball
Authors: Milius Inge , Gilbert Wade D. , Alexander Danielle , Bloom Gordon A.
Published: October 2020

There is a growing body of research on positive tactile communication and its impact on athlete performance and team dynamics. The purpose of the present study was to examine the profile and perceived impact of positive tactile communication as a coaching strategy in a high-performance team sport setting. Participants were members of a successful American collegiate women’s basketball team comprising the head coach, associate head coach, and 16 student-athletes. Methods of data collection included systematic observation and focus groups. Positive tactile communication was perceived to be an effective coaching strategy for enhancing relationships and athlete performance. To our knowledge, this is the first study to include both quantitative and qualitative data from multiple coaches on the same team, as well as athlete perceptions of coaches’ strategic use of positive tactile communication.
Self-regulated hirudin delivery for anticoagulant therapy
Authors: Xu Xiao , Huang Xuechao , Zhang Ying , Shen Shiyang , Feng Zhizi , Dong He , Zhang Can , Mo Ran
Published: October 2020

Polymeric nanogel with on-demand release of hirudin prevents and inhibits clot formation.
Cortical and striatal circuits together encode transitions in natural behavior
Authors: Sjöbom Joel , Tamtè Martin , Halje Pär , Brys Ivani , Petersson Per
Published: October 2020

Corticostriatal circuits encode action sequencing in natural behavior.
Is Once-Daily High-Dose Ceftriaxone plus Ampicillin an Alternative for Enterococcus faecalis Infective Endocarditis in Outpatient Parenteral Antibiotic Therapy Programs?
Authors: Herrera-Hidalgo Laura , de Alarcón Arístides , López-Cortes Luis Eduardo , Luque-Márquez Rafael , López-Cortes Luis Fernando , Gutiérrez-Valencia Alicia , Gil-Navarro María Victoria
Published: October 2020

Ceftriaxone administered as once-daily high-dose short infusion combined with ampicillin has been proposed for the treatment of
Enterococcus faecalis
infective endocarditis in outpatient parenteral antibiotic therapy programs (OPAT). This combination requires synergistic activity, but the attainment of ceftriaxone synergic concentration (Cs) with the regimen proposed for OPAT has not been studied. This phase II pharmacokinetic study enrolled healthy adult volunteers who underwent two sequential treatment phases.
Large-scale asymmetry in thickness of crustal accretion at the Southeast Indian Ridge due to deep mantle anomalies
Authors: Suo Yanhui , Li Sanzhong , Cao Xianzhi
Published: October 2020

Hot mantle plumes and ancient cold slabs have been observed beneath modern mid-ocean ridges, but their specific and detailed effects on mid-ocean ridge crustal accretion are poorly understood. The oceanic lithosphere beneath the Southeast Indian Ocean displays unique morphological, geophysical, and geochemical characteristics, which may reflect the influence of both mantle anomalies and upwelling plumes on seafloor spreading. In this study, we combined gravity-derived oceanic crustal thickness with plate tectonic reconstructions to investigate patterns of asymmetry in thickness of crust accreted at the Southeast Indian Ridge over the last 50 m.y. Our results reveal several distinct features: (1) small-scale, short-lived asymmetries in the thickness of crustal accretion of up to 0.75 km are alternatively distributed on the southern and northern flanks of the 90°–120°E Southeast Indian Ridge segment. These can be explained by variations in mantle depletion or mantle temperature. (2) Two large-scale, long-lived (duration of ∼50 m.y.) asymmetries in crustal accretion of >2.5 km are observed around the Kerguelen Plateau and Balleny Islands, which we attribute to excess crust from the off-axis Kerguelen and Balleny mantle plumes. (3) Two large-scale, long-lived (duration of ∼50 m.y.) asymmetries in crustal accretion of 0.75–2.5 km are observed on the northern flank of the westernmost (70°–80°E) Southeast Indian Ridge and the southern flank of the eastern (120°–140°E) Southeast Indian Ridge segment, respectively. We attribute these to asymmetry in mantle temperature of up to 20–53 °C. We suggest these asymmetric temperatures across the Southeast Indian Ridge are associated with the foundered lithospheric fragments of the Indian Craton triggered by the African Large Low-Shear-Velocity Province during the breakup of Gondwanaland and an intraplate subducted slab of the Paleo-Tethys Ocean, respectively. The remnant craton fragments and subducted oceanic slab may have moved north in concert with the northward-migrating Southeast Indian Ridge beginning at 50 m.y. ago.
Further improvement in glycemic control after switching from exenatide two times per day to exenatide once-weekly autoinjected suspension in patients with type 2 diabetes: 52-week results from the DURATION-NEO-1 study
Authors: Wysham Carol H , Rosenstock Julio , Vetter Marion L , Wang Hui , Hardy Elise , Iqbal Nayyar
Published: October 2020

Introduction

Investigate the effects of switching from two times per day exenatide to once-weekly exenatide administered by autoinjector (exenatide once-weekly suspension by autoinjector (QWS-AI)) or treatment with exenatide QWS-AI for 1 year.

Research design and methods

In this phase III open-label study, adults with type 2 diabetes were randomized to receive exenatide QWS-AI (2 mg) or exenatide two times per day (5 mcg for 4 weeks, followed by 10 mcg) for 28 weeks. During a subsequent non-randomized 24-week extension, patients who received exenatide two times per day were switched to exenatide QWS-AI and those randomized to exenatide QWS-AI continued this treatment. Efficacy measures included changes from baseline in glycated hemoglobin (A1C), fasting plasma glucose (FPG), and body weight.

Results

In total, 315 patients (mean baseline A1C of 8.5%) completed the initial 28 weeks of randomized treatment with exenatide QWS-AI (n=197) or exenatide two times per day (n=118) and were included in the 24-week extension (mean A1C of 7.0% and 7.3%, respectively, at week 28). From weeks 28–52, patients who switched from exenatide two times per day to exenatide QWS-AI had additional A1C reductions of approximately 0.5% (mean A1C change from baseline of –1.4% at week 52) and further reductions from baseline in FPG. Patients who continued exenatide QWS-AI treatment for 52 weeks showed clinically relevant A1C reductions (mean A1C change from baseline of –1.3% at week 52). Body-weight reductions achieved through week 28 were sustained at week 52 in both groups. There were no unexpected safety concerns or changes in the safety profile among patients who switched from exenatide two times per day to exenatide QWS-AI or those who continued exenatide QWS-AI treatment for 52 weeks.

Conclusions

Switching from exenatide two times per day to exenatide QWS-AI resulted in further A1C reductions and maintenance of earlier decreases in body weight, while continued therapy with exenatide QWS-AI for 52 weeks maintained A1C and body-weight reductions, without additional safety or tolerability concerns.

Trial registration number

NCT01652716.
Acute myocardial infarction incidence and survival in Aboriginal and non-Aboriginal populations: an observational study in the Northern Territory of Australia, 1992–2014
Authors: Coffey Cushla , Zhao Yuejen , Condon John R , Li Shu , Guthridge Steven
Published: October 2020

Objectives

To examine long-term trends in acute myocardial infarction (AMI) incidence and survival among Aboriginal and non-Aboriginal people.

Design

Retrospective cohort study.

Setting, participants

All first AMI hospital cases and deaths due to ischaemic heart disease in the Northern Territory of Australia (NT), 1992–2014.

Main outcome measures

Age standardised incidence, survival and mortality.

Results

The upward trend in Aboriginal AMI incidence plateaued around 2007 for males and 2001 for females. AMI incidence decreased for non-Aboriginal population, consistent with the national trends. AMI incidence was higher and survival lower for males, for Aboriginal people and in older age groups. In 2014, the age standardised incidence was 881 and 579 per 100 000 for Aboriginal males and females, respectively, compared with 290 and 187 per 100 000 for non-Aboriginal counterparts. The incidence disparity between Aboriginal and non-Aboriginal population was much greater in younger than older age groups. Survival after an AMI improved over time, and more so for Aboriginal than non-Aboriginal patients, because of a decrease in prehospital deaths and improved survival of hospitalised cases.

Conclusions

There was an important breakpoint in increasing trends of Aboriginal AMI incidence between 2001 and 2007. The disparity in AMI survival between the NT Aboriginal and non-Aboriginal populations reduced over time as survival improved for both populations.
Perioperative patient-controlled regional analgesia versus patient-controlled intravenous analgesia for patients with critical limb ischaemia: a study protocol for a randomised controlled trial
Authors: Chen Si , Xu Zhonghuang , Liu Hongju , Zhang Yuelun , Zhang Jiao , Chen Yuexin , Zheng Yuehong , Huang Yuguang
Published: October 2020

Introduction

Both regional analgesia and intravenous analgesia are frequently used perioperatively for patients with critical limb ischaemia (CLI). Nevertheless, the comparison of perioperative effect of regional and intravenous analgesia has not yet been thoroughly illustrated. This study will comprehensively compare patient-controlled regional analgesia (PCRA) and patient-controlled intravenous analgesia (PCIA) as two different perioperative analgesia approaches for patients with CLI. It investigates their effects on analgesia, reperfusion and the quality of recovery perioperatively, also aims to provide clinical evidence to those non-surgical patients with non-reconstructable arteries.

Methods and analysis

This trial is a randomised, single-centre, open-label, parallel trial with target sample size of 52 in total. Eligible participants will be randomly allocated to the PCRA group (group R) or the PCIA group (group I) after admission. Participants in group R will receive ultrasound-guided subgluteal sciatic catheterisation, followed by continuous PCRA infusion (0.2% ropivacaine 15 mL as loading dose, 8 mL/hour as background with a patient-controlled bolus of 6 mL). Participants in group I will receive PCIA (morphine is given in boluses of 1 mg as needed, background infusion at 1 mg/hour). Data will be collected at baseline (T0), 2 hours before revascularisation treatment (T1) and 2 hours before discharge (T2). The primary outcomes include the Numerical Rating Scale pain score at T1 and T2. The secondary outcomes include the perioperative transcutaneous oxygen pressure, the Tissue Haemoglobin Index, Hospital Anxiety and Depression Scale at T1 and T2; the Patient Global Impression of Change and patient satisfaction at T1 and T2; the perioperative cumulative morphine consumption, the length of postoperative hospital stay and adverse events.

Ethics and dissemination

This study received authorisation from the Institutional Review Board of Peking Union Medical College Hospital on 21 March 2017 (approval no. ZS-1289X). Study findings will be disseminated through presentations at scientific conferences or publications in peer-reviewed journals.

Trial registration number

Chinese Clinical Trial Registry (ChiCTR2000029298).

Protocol version

V.4CP.B2 (15 June 2020).
Understanding the importance of non-material factors in retaining community health workers in low-income settings: a qualitative case-study in Ethiopia
Authors: Arora Nikita , Hanson Kara , Spicer Neil , Estifanos Abiy Seifu , Keraga Dorka Woldesenbet , Welearegay Alemtsehay Tewele , Tela Freweini Gebrearegay , Hussen Yemisrach Ahmed , Mandefro Yordanos Semu , Quaife Matthew
Published: October 2020

Objectives

The motivation and retention of community health workers (CHWs) is a challenge and inadequately addressed in research and policy. We sought to identify factors influencing the retention of CHWs in Ethiopia and ways to avert their exit.

Design

A qualitative study was undertaken using in-depth interviews with the study participants. Interviews were audio-recorded, and then simultaneously translated into English and transcribed for analysis. Data were analysed in NVivo 12 using an iterative inductive-deductive approach.

Setting

The study was conducted in two districts each in the Tigray and Southern Nations, Nationalities and People’s Republic (SNNPR) regions in Ethiopia. Respondents were located in a mix of rural and urban settings.

Participants

Leavers of health extension worker (HEW) positions (n=20), active HEWs (n=16) and key informants (n=11) in the form of policymakers were interviewed.

Results

We identified several extrinsic and intrinsic motivational factors affecting the retention and labour market choices of HEWs. While financial incentives in the form of salaries and material incentives in the form of improvements to health facility infrastructure, provision of childcare were reported to be important, non-material factors like HEWs’ self-image, acceptance and validation by the community and their supervisors were found to be critical. A reduction or loss of these non-material factors proved to be the catalyst for many HEWs to leave their jobs.

Conclusion

Our study contributes new empirical evidence to the global debate on factors influencing the motivation and retention of CHWs, by being the first to include job leavers in the analysis. Our findings suggest that policy interventions that appeal to the social needs of CHWs can prove to be more acceptable and potentially cost-effective in improving their retention in the long run. This is important for government policymakers in resource constrained settings like Ethiopia that rely heavily on lay workers for primary healthcare delivery.
Development and pilot implementation of a standardised trauma documentation form to inform a national trauma registry in a low-resource setting: lessons from Tanzania
Authors: Sawe Hendry R , Reynolds Teri A , Weber Ellen J , Mfinanga Juma A , Coats Timothy J , Wallis Lee A
Published: October 2020

Objectives

Trauma registries are an integral part of a well-organised trauma system. Tanzania, like many low and middle-income countries, does not have a trauma registry. We describe the development, structure, implementation and impact of a context appropriate standardised trauma form based on the adaptation of the WHO Data Set for Injury (DSI), for clinical documentation and use in a national trauma registry.

Setting

Our study was conducted in emergency units of five regional referral hospitals in Tanzania.

Procedures

Mixed methods participatory action research was employed. After an assessment of baseline trauma documentation, we conducted semi-structured interviews with a purposefully selected sample of 33 healthcare providers from all participating hospitals to understand, develop, pilot and implement a standardised trauma form. We compared the number and types of variables captured before and after the form was implemented.

Outcomes

Change in proportion of variables of DSI captured after implementation of a standardised trauma documentation form.

Results

Piloting and feedback informed the development of a context appropriate standardised trauma documentation paper form with carbonless copy that could be used as both the clinical chart and data capture. Among 721 patients (seen by 21 clinicians) during the initial 30-day pilot, overall variable capture was 86.4% of required variables. After modifications of the form and training of healthcare providers, the form was implemented for 7 months, during which the capture improved to 96.3% among 6302 patients (seen by 31 clinicians). The providers reported the form was user-friendly, resulted in less time documenting, and served as a guide to managing trauma patients.

Conclusions

The development and implementation of a contextually appropriate, standardised trauma form were successful, yielding increased capture rates of injury variables. This system will facilitate expansion of the trauma registry across the country and inform similar initiatives in Sub-Saharan Africa.
Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity
Authors: McGuinty Michaeline , Angel Jonathan B , Cooper Curtis L , Cowan Juthaporn , MacPherson Paul A , Kumar Ashok , Murthy Sanjay , Sy Richmond , Dennehy Michelle , Tremblay Nancy , Byrareddy Siddappa N , Cameron D William
Published: October 2020

Introduction

Continuous antiretroviral therapy (ART) suppresses HIV plasma viral load (pVL) to very low levels, which allows for some immune recovery. Discontinuation of ART leads to pVL rebound from reservoirs of persistence and latency, and progressive immunodeficiency. One promising but controversial strategy targeting CD4+ T lymphocytes with a monoclonal antibody (mAb) against α4β7 integrin has shown promise through sustained virological remission of pVL (SVR) in SIV239-infected rhesus macaques. We propose to assess the safety and tolerability of vedolizumab, a licensed humanised mAb against human α4β7 integrin, in healthy HIV-infected adults on ART. This study will also assess, by analytical treatment interruption (ATI), whether vedolizumab treatment can induce SVR beyond ART and vedolizumab treatment.

Methods and analysis

The HIV-ART-vedolizumab-ATI (HAVARTI) trial is a single-arm, dose-ranging pilot trial in healthy HIV-positive adult volunteers receiving ART. Twelve consenting persons will be enrolled in sequential groups of 4 to each serial dosing vedolizumab regimen (300 mg, 150 mg, 75 mg). The primary outcomes are: (1) to assess the safety and tolerability of seven serial infusions of vedolizumab at each of three doses; (2) to identify the immunovirological measures, including pVL and T-cell kinetics, that characterise HIV/ART cases before, during, after vedolizumab treatment and ATI; and (3) to seek SVR of pVL after ATI. Secondary outcomes will include immune reconstitution and pVL suppression as well as immune reconstitution and long-term safety following re-initiation of ART in the absence of SVR.

Ethics and dissemination

The study protocol was approved by the Ottawa Health Science Network-REB and by the Health Canada Therapeutic Products Directorate. A Data Safety Monitor will review safety information at regular intervals. The final manuscript will be submitted to an open access journal within a year of study completion.

Trial registration number

ClinicalTrials.gov NCT03147859; https://clinicaltrials.gov/ct2/show/NCT03147859
Effects of crowding in the emergency department on the diagnosis and management of suspected acute coronary syndrome using rapid algorithms: an observational study
Authors: Stoyanov Kiril M , Biener Moritz , Hund Hauke , Mueller-Hennessen Matthias , Vafaie Mehrshad , Katus Hugo A , Giannitsis Evangelos
Published: October 2020

Objectives

Fast diagnostic algorithms using high-sensitivity troponin (hsTn) in suspected acute coronary syndrome (ACS) are regarded as beneficial to expedite diagnosis and safe discharge of patients in crowded emergency departments (ED). This study investigates the effects of crowding on process times related to the diagnostic protocol itself or other time delays, and outcomes.

Design

Prospective single-centre observational study.

Setting

ED (Germany).

Participants

Final study population of 2525 consecutive patients with suspected ACS within 12 months, after exclusion of patients with ST-elevation myocardial infarction, missing blood samples, referral from other hospitals or repeated visits.

Interventions

Use of fast algorithms as per 2015 European Society of Cardiology guidelines.

Main outcome measures

Crowding was defined as mismatch between patient numbers and monitoring capacities, or mean physician time per case, categorised as normal, high and very high crowding. Outcome measures were length of ED stay, direct discharge from ED, laboratory turn around times (TAT), utilisation of fast algorithms, absolute and relative non-laboratory time, as well as mortality.

Results

Crowding was associated with increased length of ED stay (3.75–4.89 hours, p<0.001). While median TAT of the first hsTnT increased (53–57 min, p<0.001), total TAT of serial hsTnT did not increase significantly with higher crowding (p=0.170). Lower utilisation of fast algorithms (p=0.009) and increase of additional hsTnT measurements after diagnosis (p=0.001) were observed in higher crowding. Most importantly, crowding was significantly associated with prolonged absolute (p<0.001), and particularly relative non-laboratory time (63.3%–71.3%, p<0.001). However, there was no significant effect of crowding on mortality, even after adjustment for relevant clinical variables.

Conclusions

Process times, and particularly non-laboratory times, are prolonged in a crowded ED diminishing some positive effects of fast diagnostic algorithms in suspected ACS. Higher crowding levels were not significantly associated with higher all-cause mortality rates.

Trial registration number

NCT03111862.
Rhegmatogenous retinal detachment: a review of current practice in diagnosis and management
Authors: Sultan Ziyaad Nabil , Agorogiannis Eleftherios I , Iannetta Danilo , Steel David , Sandinha Teresa
Published: October 2020

Rhegmatogenous retinal detachment (RRD) is a common condition with an increasing incidence, related to the ageing demographics of many populations and the rising global prevalence of myopia, both well known risk factors. Previously untreatable, RRD now achieves primary surgical success rates of over 80%–90% with complex cases also amenable to treatment. The optimal management for RRD attracts much debate with the main options of pneumatic retinopexy, scleral buckling and vitrectomy all having their proponents based on surgeon experience and preference, case mix and equipment availability. The aim of this review is to provide an overview for the non-retina specialist that will aid and inform their understanding and discussions with patients. We review the incidence and pathogenesis of RRD, present a systematic approach to diagnosis and treatment with special consideration to managing the fellow eye and summarise surgical success and visual recovery following different surgical options.
Emergency department interventions for adult patients with low back pain: a systematic review of randomised controlled trials
Authors: Oliveira Crystian B , Amorim Hugo E , Coombs Danielle M , Richards Bethan , Reedyk Marco , Maher Chris G , Machado Gustavo C
Published: October 2020

Background

Most low back pain trials have limited applicability to the emergency department (ED) because they provide treatment and measure outcomes after discharge from the ED. We investigated the efficacy and safety of pharmacological and non-pharmacological interventions delivered in the ED to patients with non-specific low back pain and/or sciatica on patient-relevant outcomes measured during the emergency visit.

Methods

Literature searches were performed in MEDLINE, EMBASE and CINAHL from inception to week 1 February 2020. We included all randomised controlled trials investigating adult patients (≥18 years) with non-specific low back pain and/or sciatica presenting to ED. The primary outcome of interest was pain intensity. Two reviewers independently screened the full texts, extracted the data and assessed risk of bias of each trial using the Physiotherapy Evidence Database (PEDro) scale. The overall quality of evidence, or certainty, provided by a set of trials evaluating the same treatment was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which considers imprecision, inconsistency, indirectness and bias in the evidence.

Results

Fifteen trials (1802 participants) were included with 12 of 15 at low risk of bias (ie, PEDro score >6). Based on results from individual trials and moderate quality evidence, ketoprofen gel was more effective than placebo for non-specific low back pain at 30 min (mean difference (MD) −15.0, 95% confidence interval (CI) −21.0 to −9.0). For those with sciatica (moderate quality evidence), intravenous paracetamol (acetaminophen) (MD −15.7, 95% CI −19.8 to −11.6) and intravenous morphine (MD −11.4, 95% CI −21.6 to −1.2) were both superior to placebo at 30 min. Based on moderate quality of evidence, corticosteroids showed no benefits against placebo at emergency discharge for non-specific low back pain (MD 9.0, 95% CI −0.71 to 18.7) or sciatica (MD −6.8, 95% CI −24.2 to 10.6). There were conflicting results from trials comparing different pharmacological options (moderate quality evidence) or investigating non-pharmacological treatments (low quality evidence).

Conclusion

Ketoprofen gel for non-specific low back pain and intravenous paracetamol or morphine for sciatica were superior to placebo, whereas corticosteroids were ineffective for both conditions. There was conflicting evidence for comparisons of different pharmacological options and those involving non-pharmacological treatments. Additional trials measuring important patient-related outcomes to EDs are needed.
Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer
Authors: Chen Hanyu , Zheng Xiaobin , Zong Xiaoyu , Li Zitong , Li Na , Hur Jinhee , Fritz Cassandra DL , Chapman Jr William , Nickel Katelin B , Tipping Andrew , Colditz Graham A , Giovannucci Edward L , Olsen Margaret A , Fields Ryan C , Cao Yin
Published: October 2020

Objective

Factors that lead to metabolic dysregulation are associated with increased risk of early-onset colorectal cancer (CRC diagnosed under age 50). However, the association between metabolic syndrome (MetS) and early-onset CRC remains unexamined.

Design

We conducted a nested case–control study among participants aged 18–64 in the IBM MarketScan Commercial Database (2006–2015). Incident CRC was identified using pathologist-coded International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and controls were frequency matched. MetS was defined as presence of ≥3 conditions among obesity, hypertension, hyperlipidaemia and hyperglycaemia/type 2 diabetes, based on ICD-9-CM and use of medications. Multivariable logistic regressions were used to estimate ORs and 95% CIs.

Results

MetS was associated with increased risk of early-onset CRC (n=4673; multivariable adjusted OR 1.25; 95% CI 1.09 to 1.43), similar to CRC diagnosed at age 50–64 (n=14 928; OR 1.21; 95% CI 1.15 to 1.27). Compared with individuals without a metabolic comorbid condition, those with 1, 2 or ≥3 conditions had a 9% (1.09; 95% CI 1.00 to 1.17), 12% (1.12; 95% CI 1.01 to 1.24) and 31% (1.31; 95% CI 1.13 to 1.51) higher risk of early-onset CRC (ptrend<0.001). No associations were observed for one or two metabolic comorbid conditions and CRC diagnosed at age 50–64. These positive associations were driven by proximal (OR per condition 1.14; 95% CI 1.06 to 1.23) and distal colon cancer (OR 1.09; 95% CI 1.00 to 1.18), but not rectal cancer (OR 1.03; 95% CI 0.97 to 1.09).

Conclusions

Metabolic dysregulation was associated with increased risk of early-onset CRC, driven by proximal and distal colon cancer, thus at least in part contribute to the rising incidence of early-onset CRC.
Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors
Authors: Siu Lillian , Brody Joshua , Gupta Shilpa , Marabelle Aurélien , Jimeno Antonio , Munster Pamela , Grilley-Olson Juneko , Rook Alain H , Hollebecque Antoine , Wong Rebecca K S , Welsh James W , Wu Yuling , Morehouse Christopher , Hamid Oday , Walcott Farzana , Cooper Zachary A , Kumar Rakesh , Ferté Charles , Hong David S
Published: October 2020

Background

MEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.

Patients and methods

Eligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.

Results

From November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.

Conclusion

IT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.

Trial registration number

NCT02556463.
Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis
Authors: Apolo Andrea B , Ellerton John A , Infante Jeffrey R , Agrawal Manish , Gordon Michael S , Aljumaily Raid , Gourdin Theodore , Dirix Luc , Lee Keun-Wook , Taylor Matthew H , Schöffski Patrick , Wang Ding , Ravaud Alain , Manitz Juliane , Pennock Gregory , Ruisi Mary , Gulley James L , Patel Manish R
Published: October 2020

Background

Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma.

Methods

Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome.

Results

249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24–43), and median treatment duration was 2.8 months (range 0.5–42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses.

Conclusions

After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.
Baricitinib-associated changes in global gene expression during a 24-week phase II clinical systemic lupus erythematosus trial implicates a mechanism of action through multiple immune-related pathways
Authors: Dörner Thomas , Tanaka Yoshiya , Petri Michelle A , Smolen Josef S , Wallace Daniel J , Dow Ernst R , Higgs Richard E , Rocha Guilherme , Crowe Brenda , Benschop Robert J , Byers Nicole L , Silk Maria E , de Bono Stephanie , Fantini Damiano , Hoffman Robert W
Published: October 2020

Objective

To characterise the molecular pathways impacted by the pharmacologic effects of the Janus kinase (JAK) 1 and JAK2 inhibitor baricitinib in SLE.

Methods

In a phase II, 24-week, randomised, placebo-controlled, double-blind study (JAHH), RNA was isolated from whole blood in 274 patients and analysed using Affymetrix HTA2.0 array. Serum cytokines were measured using ultrasensitive quantitative assays.

Results

Gene expression profiling demonstrated an elevation ofSTAT1,STAT2and multiple interferon (IFN) responsive genes at baseline in patients with SLE. Statistical and gene network analyses demonstrated that baricitinib treatment reduced the mRNA expression of functionally interconnected genes involved in SLE includingSTAT1-target,STAT2-target andSTAT4-target genes and multiple IFN responsive genes. At baseline, serum cytokines IFN-α, IFN-γ, interleukin (IL)-12p40 and IL-6 were measurable and elevated above healthy controls. Treatment with baricitinib significantly decreased serum IL-12p40 and IL-6 cytokine levels at week 12, which persisted through week 24.

Conclusion

Baricitinib treatment induced significant reduction in the RNA expression of a network of genes associated with the JAK/STAT pathway, cytokine signalling and SLE pathogenesis. Baricitinib consistently reduced serum levels of two key cytokines implicated in SLE pathogenesis, IL-12p40 and IL-6.
A QM/MM investigation of the catalytic mechanism of acetylene hydratase: insights into engineering a more effective enzyme
Authors: Zhang Wenyuan , Bushnell Eric A.C.
Published: October 2020

In the present investigation, a QM/MM approach was used to better understand the effect of the second environmental shell of the active site on the catalytic conversion of acetylene to acetaldehyde by acetylene hydratase (AH). In addition, the effect of substituting W-coordinating sulfur atoms with selenium atoms was done to provide insight into the influence of the W-coordinating atoms on the catalytic reaction. From the results, it found that the presence of the second shell environment had a significant effect on the reaction. Specifically, in the absence of the MM second shell environment (i.e., QM-cluster model), the rate-determining step is defined by the first proton transfer step. In contrast, for the QM/MM model, the rate-determining step is defined by the water attacking step. Moreover, with the presence of the MM second shell environment, a key intermediate found in the DFT-cluster investigation does not exist in the QM/MM investigation. Rather, what was a two-step process in the DFT-cluster study was calculated to occur in a single step for the QM/MM study. Regarding the sulfur to selenium substitutions, it was found that Gibbs energy for the acetylene binding phase was significantly affected. Notably, the trans-position selenium made the binding of acetylene 65.6 kJ mol−1 less endergonic. Moreover, the overall reaction became 38.2 kJ mol−1 less endergonic compared with the wild type (WT) AH model. Thus, the substitution of key W-coordinating sulfur atoms with selenium atoms may offer a means to enhance the catalytic mechanism of AH considerably.
Gravity induced quantum interference on gravitational wave background
Authors: Ganjali Mohammad A. , Sedaghatmanesh Zainab
Published: October 2020

Gravity-induced quantum interference is an experiment that exhibits how a gravitational effect appears in quantum mechanics.1 In this famous experiment, gravity was added to the system just classically. In our study, we will do the related calculations on a gravitational wave background. We will argue that the effect of gravitational wave would be detectable in this quantum mechanical effect.
Deflection of light and shadow cast by a dual-charged stringy black hole
Authors: Kala Shubham , Saurabh  , Nandan Hemwati , Sharma Prateek
Published: October 2020

Gravitational lensing and black hole shadows are one of the strongest observational evidences to prove the existence of black holes in the universe. The gravitational lensing arises due to the deflection of light by the gravitational field of a gravitating body such as a black hole. Investigation of the shadow cast by a compact object as well as deflection of light around it may provide the useful information about physical nature of the particular compact object and other related aspects. In this paper, we study the deflection of light by a dual-charged stringy black hole space–time derived in dilaton-Maxwell gravity. The variation of deflection angle with the impact parameter for different values of electric and magnetic charges is studied. We also study the shadow of this black hole space–time to obtain the radius of shadow cast by it. We have considered an optically thin emission disk around it and observed that there are not significant changes in the shadow cast by this black hole compared to well-known Schwarzschild black hole space–time in GR.
Eigensolutions of Partially Reliable Decision Preferences Described by Matrices of Z-Numbers
Authors: Aliev Rafik A. , Pedrycz Witold , Huseynov Oleg H. , Aliyev Rafig R.
Published: October 2020

Eigenvalues and eigenvectors are widely used in various applications. Particularly, these concepts underlie analysis of consistency of a decision maker’s (DMs) preference knowledge. In real-world problems, DMs knowledge is inherently associated with imprecision and partial reliability. This involves combination of fuzzy and probabilistic information. The concept of a Z-number is a formal construct to describe such kind of information. In this study, we formulate the concepts of Z-number valued eigenvalue and eigenvector for matrices components of which are Z-numbers. A formal statement of the problem and a solution method for computation of Z-number valued eigensolutions are proposed. Numerical examples and an application devoted to foreign market selection problem are provided to show the usefulness of the proposed approach.
ENTRY INTO AND EXIT FROM INFORMAL MICROENTERPRISE ENTREPRENEURSHIP IN A SOUTH AFRICAN MUNICIPALITY: A TALE OF RESILIENCE
Authors: MAHADEA DARMA , KHUMALO SAMUKELISIWE
Published: October 2020

Although research on entrepreneurship in the micro and small firms has been the subject of much scholarly attention, it has been mostly on the formal rather than informal economy. Drawing on the push and pull theory, this paper uses Principal Component Analysis to examine the motivations influencing entrepreneurs to venture into informal sector entrepreneurship in a specific South African municipal context. Against a background of addressing their constraints to growth, the prospects of formalization were considered, using logistic regression. The results, based on a sample of 160 entrepreneurs, show that even in the informal economy, pull factors are the uppermost motivations, apparently stronger than push factors, in influencing individuals to partake in microenterprise entrepreneurship. The logistic results indicate that even when some internal and external growth constraints are addressed, the likelihood of the entrepreneurs’ formalizing their business is not encouraging. Although alleviation of the growth hurdles may assist in enhancing entrepreneurial competence, it does not necessarily favor formalization, but enables a lock-in contentment effect to the informal sector. Against this inertia, implications for policy makers are presented.
Pharmacology of Chimeric Antigen Receptor–Modified T Cells
Authors: Song Edward Z. , Milone Michael C.
Published: October 2020

Cell-based immunotherapies using T cells that are engineered to express a chimeric antigen receptor (CAR-T cells) are an effective treatment option for several B cell malignancies. Compared with most drugs, CAR-T cell products are highly complex, as each cell product is composed of a heterogeneous mixture of millions of cells. The biodistribution and kinetics of CAR-T cells, following administration, are unique given the ability of T cells to actively migrate as well as replicate within the patient. CAR-T cell therapies also have multiple mechanisms of action that contribute to both their antitumor activity and their toxicity. This review provides an overview of the unique pharmacology of CAR-T cells, with a focus on CD19-targeting and B cell maturation antigen (BCMA)-targeting CAR-T cells.
Editors’ Choice—4D Neutron and X-ray Tomography Studies of High Energy Density Primary Batteries: Part II. Multi-Modal Microscopy of LiSOCl2 Cells
Authors: Ziesche Ralf F. , Robinson James B. , Markötter Henning , Bradbury Robert , Tengattini Alessandro , Lenoir Nicolas , Helfen Lukas , Kockelmann Winfried , Kardjilov Nikolay , Manke Ingo , Brett Dan J. L. , Shearing Paul R.
Published: October 2020

The ability to track electrode degradation, both spatially and temporally, is fundamental to understand performance loss during operation of lithium batteries. X-ray computed tomography can be used to follow structural and morphological changes in electrodes; however, the direct detection of electrochemical processes related to metallic lithium is difficult due to the low sensitivity to the element. In this work, 4-dimensional neutron computed tomography, which shows high contrast for lithium, is used to directly quantify the lithium diffusion process in spirally wound Li/SOCl2 primary cells. The neutron dataset enables the quantification of the lithium transport from the anode and the accumulation inside the SOCl2 cathode to be locally resolved. Complementarity between the collected neutron and X-ray computed tomographies is shown and by applying both methods in concert we have observed lithium diffusion blocking by the LiCl protection layer and identified all cell components which are difficult to distinguish using one of the methods alone.
Inhibition of cardiac potassium currents by oxidation-activated protein kinase A contributes to early afterdepolarizations in the heart
Authors: Trum M. , Islam M. M. T. , Lebek S. , Baier M. , Hegner P. , Eaton P. , Maier L. S. , Wagner S.
Published: October 2020

Oxidation-activated PKA type I inhibits transient outward potassium current ( Ito) and inward rectifying potassium current ( IK1) and contributes to ROS-induced APD prolongation as well as generation of early afterdepolarizations in murine ventricular cardiomyocytes.
Traditional Chinese Medicine Formulation Huangqi Jianzhong Tang Improves Cardiac Function after Myocardial Infarction in Rats
Authors: Bao Ya-Ru , Jiang Wen-Yi , Yu Jia-Yu , Chen Jing-Wei , Zhang Guo-Xing
Published: October 2020

Huangqi Jianzhong Tang (HQJZT) is a traditional Chinese herbal formula consisting of seven different herbs: Radix Astragali, Radix Paeoniae Alba, Ramulus Cinnamomi, Fructus Jujubae, Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle, Rhizoma Zingiberis Recens, and Saccharum Granorum. The present study aims to evaluate the possible effects of HQJZT on cardiac function in acute myocardial infarction (AMI) and related mechanism. AMI model was established by ligation of the left anterior descending coronary artery followed by one‐week HQJZT treatment. Survival rate was calculated. Rat heart function was assessed by heart performance analysis system. 5‐Triphenyltetrazolium chloride (TTC) staining was used to observe myocardial infarct size. Terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling (TUNEL) staining and western blot were applied to evaluate tissue apoptotic level. Treatment with high dose of HQJZT improved cardiac function, reduced infarct size, number of apoptotic cells and expression of apoptotic proteins, Bax (a proapoptotic protein), and increased expression of antiapoptotic protein, Bcl2. However, enalapril (an angiotensin‐converting enzyme inhibitor) treatment did not show marked improvement of these parameters. Our present data suggest that HQJZT has potential therapeutic effects to improve cardiac function by regulation of apoptotic signaling pathway.
Potential Benefits of Acupuncture and Herbs for Obesity‐Related Chronic Inflammation by Adipokines
Authors: Kim Ji-Youn , Baek Seon-Eun , Ginting Rehna Paula , Lee Min-Woo , Yoo Jeong-Eun
Published: October 2020

The adipose tissue is an organ that stores energy in the form of fats. It also has been known as an endocrine playing an integral role in metabolic homeostasis by secreting various adipokines. In obesity, the adipokine components and secretion patterns are altered toward proinflammation with weight gain, causing low chronic inflammation, which is closely linked to various metabolic diseases. Acupuncture and herbs are used for the management of obesity and its comorbidities, and it has been observed that these therapies affect the amount of expression and concentration of adipokines with improved metabolic phenotypes in both animal and human metabolic diseases. In this review, we discuss the role of adipokines and summarize beneficial effects of the treatments such as electroacupuncture, pharmacopuncture, catgut embedding acupuncture, and single and multiple medicinal herbs on obesity and its relations to adipokine composition. It will provide a new insight for applying adipokines as surrogate markers in complementary and alternative medicine practice.