bluuebunny/crossref_metadata_2025 huggingface dataset:
Coping with COVID-19 in United Nations peacekeeping field hospitals: increased workload and mental stress for military healthcare providers
Authors: Zhang Yongxue , Xiang D , Alejok N
Published: November 2020

Introduction

This study aimed to explore the impact of COVID-19 on the United Nations peacekeeping field hospitals where medical supply and manpower are extremely insufficient.

Methods

A level II hospital was deployed in Wau, South Sudan, as the regional referral centre of the United Nations Mission in South Sudan (UNMISS). It had a total strength of 63 personnel with 47 medical staff (average age 38.3±8.0 years, 33 men). A new ‘appointment–triage–disinfection’ work pattern was adopted to cope with the COVID-19 outbreak in the mission. Data on medical service statistics and workload before/after the outbreak were collected and compared. The mental health of staff was analysed from the quarterly psychological survey, including Perceived Stress Scale (PSS)-10, Generalised Anxiety Disorder (GAD)-7 and Patient Health Questionnaire (PHQ)-9.

Results

The number of outpatients decreased slightly after the COVID-19 outbreak (41.9±11.9 to 37.6±11.8 per week, p=0.49), whereas the weekly hospital length of stay of inpatients increased significantly (0.4±1.0 to 3.1±3.9 days, p=0.02). Total weekly working hours increased from 1884.9±34.1 to 2023.5±67.3 hours (p<0.001). Elevated mental stress (PSS-10: 4.3±2.4 in February to 7.5±3.9 in May, p<0.001; GAD-7: 4.0±2.3 to 9.4±4.0, p<0.001; PHQ-9: 2.1±1.2 to 3.2±2.4, p<0.001) was documented among healthcare providers after the outbreak. The threat of COVID-19 infection, delay in rotation and family-related concerns constituted the main stressors.

Conclusion

COVID-19 imposes a huge pressure on peacekeeping field hospitals. Increased workload and mental stress among frontline healthcare providers deserve the attention of UNMISS officials. Facilitating the rotation of the medical staff might potentially improve the operational readiness of the hospital by bringing in well-trained personnel and sufficient medical supplies.
Use of implementation science in tobacco control intervention studies in the USA between 2000 and 2020: a scoping review protocol
Authors: Selove Rebecca , Neil-Sztramko Sarah , Leng Jennifer , Walker Philip J , Salloum Ramzi George , Ginossar Tamar , Heckman Carolyn , Scheuermann Taneisha S , Combs Todd , Qualls-Hampton Raquel , Armstrong Rebecca , Ellis Shellie
Published: November 2020

Introduction

Despite continuing efforts to reduce tobacco use in the USA, decline in smoking rates have stalled and smoking remains a major contributor to preventable death. Implementation science could potentially improve uptake and impact of evidence-based tobacco control interventions; however, no previous studies have systematically examined how implementation science has been used in this field. Our scoping review will describe the use of implementation science in tobacco control in the USA, identify relevant gaps in research and suggest future directions for implementation science application to tobacco control.

Methods and analysis

Our team, including a medical research librarian, will conduct a scoping review guided primarily by Arksey and O’Malley’s methodology. We will search English language peer-reviewed literature published from 2000 to 31 December 2020 for terms synonymous with ‘tobacco use’, ‘prevention’, ‘cessation’ and ‘implementation science’. The databases included in this search are MEDLINE (PubMed), Embase (Ovid), CINAHL (EBSCOhost), PsycINFO (ProQuest), ERIC (ProQuest) and the Cochrane Library (Wiley). We will include cohort and quasi-experimental studies, single-group experiments and randomised trials that report qualitative and/or quantitative data related to applying implementation science to the planning and/or delivery of interventions to prevent or decrease the use of tobacco products. Studies must target potential or active tobacco users, intervention providers such as educators or healthcare professionals, or US policy-makers. A minimum of two reviewers will independently examine each title and abstract for relevance, and each eligible full text for inclusion and analysis. Use of implementation science, demonstrated by explicit reference to implementation frameworks, strategies or outcomes, will be extracted from included studies and summarised.

Ethics and dissemination

This study is exempt from ethics board approval. We will document the equity-orientation of included studies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Equity Extension checklist. Results will be submitted for conferences and peer-reviewed journals.

Trial registration number

Open Science Framework Registry (6YRK8).
Readiness of health facilities for the outpatient management of non-communicable diseases in a low-resource setting: an example from a facility-based cross-sectional survey in Tanzania
Authors: Bintabara Deogratius , Ngajilo Dorothy
Published: November 2020

Objective

This study assessed the readiness of health facilities to provide outpatient management of non-communicable diseases using a nationally representative sample of health facilities from Tanzania as an example of a low-resource country.

Design

Facility-based cross-sectional survey.

Setting

This study analysed data collected from public and private-owned dispensaries/clinics, health centres and hospitals during the 2014–2015 Tanzania Service Provision Assessment survey.

Primary outcome measures

Three outcome variables are included in this study, namely readiness of facilities to provide outpatient management for diabetes, hypertension and chronic respiratory diseases. These were composite variables measured based on availability of indicators identified in the WHO-Service Availability and Readiness Assessment manual. These indicators were grouped into three domains, viz staff training and guidelines, basic diagnostic equipment and basic medicines. Readiness was measured by assessing the presence of required indicators in each of these domains.

Results

Out of 1188 health facilities assessed, 52.1%, 64.8% and 60.9% reported providing services related to diabetes, hypertension and chronic respiratory diseases, respectively. A few facilities reported having treatment guidelines (33.2%) or staff trained to provide non-communicable disease services (10.4%). The availability of basic diagnostic equipment and medicines for these diseases was significantly lower in public lower level facilities than in their private counterparts (p<0.05). Facilities located in urban settings as well as higher level (health centre and hospitals) and publicly owned facilities were significantly associated with increased service readiness index for providing outpatient management of non-communicable diseases.

Conclusion

A fair distribution of resources through the ‘push’ system of refresher training, treatment guidelines, medicines and diagnostic equipment from higher authorities or other agencies may be one way of strengthening the readiness of lower level and public facilities to cope with the increasing burden of non-communicable diseases in low-resource countries such as Tanzania.
Incidence, nature and causes of avoidable significant harm in primary care in England: retrospective case note review
Authors: Avery Anthony J , Sheehan Christina , Bell Brian , Armstrong Sarah , Ashcroft Darren M , Boyd Matthew J , Chuter Antony , Cooper Alison , Donnelly Ailsa , Edwards Adrian , Evans Huw Prosser , Hellard Stuart , Lymn Joanne , Mehta Rajnikant , Rodgers Sarah , Sheikh Aziz , Smith Pam , Williams Huw , Campbell Stephen M , Carson-Stevens Andrew
Published: November 2020

Objective

To estimate the incidence of avoidable significant harm in primary care in England; describe and classify the associated patient safety incidents and generate suggestions to mitigate risks of ameliorable factors contributing to the incidents.

Design

Retrospective case note review. Patients with significant health problems were identified and clinical judgements were made on avoidability and severity of harm. Factors contributing to avoidable harm were identified and recorded.

Setting

Primary care.

Participants

Thirteen general practitioners (GPs) undertook a retrospective case note review of a sample of 14 407 primary care patients registered with 12 randomly selected general practices from three regions in England (total list size: 92 255 patients).

Main outcome measures

The incidence of significant harm considered at least ‘probably avoidable’ and the nature of the safety incidents.

Results

The rate of significant harm considered at least probably avoidable was 35.6 (95% CI 23.3 to 48.0) per 100 000 patient-years (57.9, 95% CI 42.2 to 73.7, per 100 000 based on a sensitivity analysis). Overall, 74 cases of avoidable harm were detected, involving 72 patients. Three types of incident accounted for more than 90% of the problems: problems with diagnosis accounted for 45/74 (60.8%) primary incidents, followed by medication-related problems (n=19, 25.7%) and delayed referrals (n=8, 10.8%). In 59 (79.7%) cases, the significant harm could have been identified sooner (n=48) or prevented (n=11) if the GP had taken actions aligned with evidence-based guidelines.

Conclusion

There is likely to be a substantial burden of avoidable significant harm attributable to primary care in England with diagnostic error accounting for most harms. Based on the contributory factors we found, improvements could be made through more effective implementation of existing information technology, enhanced team coordination and communication, and greater personal and informational continuity of care.
Rate of cannabis use in older adults with cancer
Authors: Rajasekhara Sahana , Portman Diane G , Chang Young D , Haas Meghan F , Randich Anthony L , Bromberg Hannah S , Rashid Saima , Donovan Kristine A
Published: November 2020

Objectives

Older adults with cancer are increasingly inquiring about and using cannabis. Despite this, few studies have examined cannabis use in patients with cancer aged 65 years and older as a separate group and identified characteristics associated with use. The current study sought to determine the rate of cannabis use in older adult patients with cancer and to identify demographic and clinical correlates of use.

Methods

We conducted a retrospective review of patients with cancer referred for specialised symptom management between January 2014 and May 2017 who underwent routine urine drug testing for tetrahydrocannabinol as part of their initial clinic visit.

Results

Approximately 8% (n=24) of patients with cancer aged 65 years and older tested positive for tetrahydrocannabinol compared with 30% (n=51) of young adults and 21% (n=154) of adults. At the univariate level, more cannabis users had lower performance status than non-users (p=0.02, Fisher’s exact test). There were no other demographic and clinical characteristics significantly associated with cannabis use in older adults.

Conclusions

Older adult patients made up nearly 25% (n=301) of the total sample and had a rate of cannabis use of 8%. As one of the first studies to assess cannabis use via objective testing rather than self-report, this study adds significantly to the emerging literature on cannabis use in people aged 65 years and older. Findings suggest the rate of use in older adults living with cancer is higher than that among older adults in the general population.
Tools for guiding interventions to address patient-perceived multidimensional unmet healthcare needs in palliative care: systematic literature review
Authors: Schmidt Ellie B , Blum David , Domeisen Benedetti Franzisca , Schlögl Mathias , Strasser Florian
Published: November 2020

Context

The unmet needs of patients with advanced disease are indicative of the patient centredness of healthcare. By tracking unmet needs in clinical practice, palliative interventions are aligned with patient priorities, and clinicians receive support in intervention delivery decisions for patients with overlapping, complex needs.

Objective

Identify tools used in everyday clinical practice for the purpose of identifying and addressing unmet healthcare needs for patients with advanced disease.

Methods

We conducted PubMed and Cumulative Index of Nursing and Allied Health Literature searches to include studies published between 1 January 2008 and 21 April 2020. Three concepts were used in constructing a search statement: (1) patient need, (2) validated instrument and (3) clinical practice. 2313 citations were reviewed according to predefined eligibility, exclusion and inclusion criteria. Data were collected from 17 tools in order to understand how instruments assess unmet need, who is involved in tool completion, the psychometric validation conducted, the tool’s relationship to delivering defined palliative interventions, and the number of palliative care domains covered.

Results

The majority of the 17 tools assessed unmet healthcare needs and had been validated. However, most did not link directly to clinical intervention, nor did they facilitate interaction between clinicians and patients to ensure a patient-reported view of unmet needs. Half of the tools reviewed covered ≤3 dimensions of palliative care. Of the 17 tools evaluated, 4 were compared in depth, but all were determined to be insufficient for the specific clinical applications sought in this research.

Conclusion

A new, validated tool is needed to track unmet healthcare needs and guide interventions for patients with advanced disease.
Immunogenic cell death pathway polymorphisms for predicting oxaliplatin efficacy in metastatic colorectal cancer
Authors: Arai Hiroyuki , Xiao Yi , Loupakis Fotios , Kawanishi Natsuko , Wang Jingyuan , Battaglin Francesca , Soni Shivani , Zhang Wu , Mancao Christoph , Salhia Bodour , Mumenthaler Shannon M , Weisenberger Daniel J , Liang Gangning , Cremolini Chiara , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef
Published: November 2020

Background

Immunogenic cell death (ICD) is a tumor cell death involving both innate and adaptive immune responses. Given published findings that oxaliplatin, but not irinotecan, drives ICD, we investigated whether single nucleotide polymorphisms (SNPs) in the ICD pathway are associated with the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer (mCRC).

Methods

Two randomized clinical trials data were analyzed: discovery cohort, FOLFOX/bevacizumab arm (MAVERICC); validation cohort, FOLFOXIRI/bevacizumab arm (TRIBE); and two control cohorts, FOLFIRI/bevacizumab arms (both trials). Genomic DNA extracted from blood samples was genotyped. Ten SNPs in the ICD pathway were tested for associations with clinical outcomes.

Results

In total, 648 patients were included. In the discovery cohort, three SNPs were significantly associated with clinical outcomes in univariate analysis: CALR rs1010222 with progression-free survival (G/G vs any A, HR=0.61, 95% CI 0.43–0.88), ANXA1 rs1050305 with overall survival (OS) (A/A vs any G, HR=1.87, 95% CI 1.04–3.35), and LRP1 rs1799986 with OS (C/C vs any T, HR=1.69, 95% CI 1.07–2.70). Multivariate analysis confirmed the trend, but statistical significance was not reached. In the validation cohort, ANXA1 rs1050305, and LRP1 rs1799986 were validated to have the significant associations with clinical outcome. No significant associations of these SNPs were observed in the two control cohorts. Treatment-by-SNP interaction test confirmed the predictive values.

Conclusions

The predictive utility of ICD-related SNPs for the efficacy of oxaliplatin-based chemotherapy was demonstrated, warranting further validation studies to be translated into personalized treatment strategies using conventional cytotoxic agents in mCRC.
Quadratus lumborum block type 3 versus lumbar plexus block in hip replacement surgery: a randomized, prospective, non-inferiority study
Authors: Polania Gutierrez Javier J , Ben-David Bruce , Rest Carl , Grajales Manuel Torres , Khetarpal Sharad Kumar
Published: November 2020

Introduction

The posterior lumbar plexus block (LPB) has been used for decades to provide acute pain management after hip surgery. Unfamiliarity with the technique and its perceived difficulty, potential risks, and possible adverse effects such as quadriceps weakness have limited broader use. The quadratus lumborum block (QLB) has been reported to be effective for postoperative pain control following hip surgery and may thus offer another regional alternative for practitioners. This study hypothesized that the QLB type 3 (QLB3) can produce a non-inferior analgesic effect compared with LPB for primary hip replacement.

Methods

This double-blinded, non-inferiority trial randomized 46 patients undergoing primary hip replacement to receive either QLB3 or LPB. Outcomes were assessed on postanesthesia care unit arrival and at postoperative hours 6, 12, and 24. The primary outcome measured was numeric rating scale (NRS) pain score 24 hours after surgery. Secondary outcomes included opioid consumption, presence of quadriceps weakness at first postoperative physical therapy (PT) session, and time to achieve 100 feet of walking.

Results

The QLB3 did not cross the non-inferiority delta of 2 points on the NRS pain score (mean difference −0.43 (95% CI −1.74 to 0.87)). There were no significant differences between groups in total opioid consumption at 24 hours or in time to achieve 100 feet of walking. Quadriceps weakness at first PT session was less common with QLB3 (26% vs 65%) and time to perform the block was significantly less with QLB3 (10 min vs 5 min).

Conclusion

This trial supported the hypothesis that the QLB3 yields non-inferior analgesia compared with LPB for hip replacement surgery.

Trial registration number

NCT03801265.
Strategy for reliable identification of ischaemic stroke, thrombolytics and thrombectomy in large administrative databases
Authors: Zachrison Kori S , Li Sijia , Reeves Mathew J , Adeoye Opeolu , Camargo Carlos A , Schwamm Lee H , Hsia Renee Y
Published: November 2020

Background

Administrative data are frequently used in stroke research. Ensuring accurate identification of patients who had an ischaemic stroke, and those receiving thrombolysis and endovascular thrombectomy (EVT) is critical to ensure representativeness and generalisability. We examined differences in patient samples based on mode of identification, and propose a strategy for future patient and procedure identification in large administrative databases.

Methods

We used non-public administrative data from the state of California to identify all patients who had an ischaemic stroke discharged from an emergency department (ED) or inpatient hospitalisation from 2010 to 2017 based on International Classification of Disease (ICD-9) (2010–2015), ICD-10 (2015–2017) and Medicare Severity-Diagnosis-related Group (MS-DRG) discharge codes. We identified patients with interhospital transfers, patients receiving thrombolytics and patients treated with EVT based on ICD, Current Procedural Terminology (CPT) and MS-DRG codes. We determined what proportion of these transfers and procedures would have been identified with ICD versus MS-DRG discharge codes.

Results

Of 365 099 ischaemic stroke encounters, most (87.70%) had both a stroke-related ICD-9 or ICD-10 code and stroke-related MS-DRG code; 12.28% had only an ICD-9 or ICD-10 code and 0.02% had only an MS-DRG code. Nearly all transfers (99.99%) were identified using ICD codes. We identified 32 433 thrombolytic-treated patients (8.9% of total) using ICD, CPT and MS-DRG codes; the combination of ICD and CPT codes identified nearly all (98%). We identified 7691 patients treated with EVT (2.1% of total) using ICD and MS-DRG codes; both MS-DRG and ICD-9/ICD-10 codes were necessary because ICD codes alone missed 13.2% of EVTs. CPT codes only pertain to outpatient/ED patients and are not useful for EVT identification.

Conclusions

ICD-9/ICD-10 diagnosis codes capture nearly all ischaemic stroke encounters and transfers, while the combination of ICD-9/ICD-10 and CPT codes are adequate for identifying thrombolytic treatment in administrative datasets. However, MS-DRG codes are necessary in addition to ICD codes for identifying EVT, likely due to favourable reimbursement for EVT-related MS-DRG codes incentivising accurate coding.
Acute Care Surgery Billing, Coding and Documentation Series Part 3: Coding of Additional Select Procedures; Modifiers; Telemedicine Coding; Robotic Surgery
Authors: Esposito Thomas , Reed Robert , Adams Raeanna C , Fakhry Samir , Carey Dolores , Crandall Marie L
Published: November 2020

This series of reviews has been produced to assist both the experienced surgeon and coder, as well as those just starting practice that may have little formal training in this area. Understanding this complex system will allow the provider to work “smarter, not harder” and garner the maximum compensation for their work. We hope we have been successful in achieving and that goal that this series will provide useful information and be worth the time invested in reading it by bringing tangible benefits to the efficiency of practice and its reimbursement. This third section deals with coding of additional select procedures, modifiers, telemedicine coding, and robotic surgery.
AAC Madawaska barley
Authors: Khanal Raja , Choo Thin Meiw , Ter Beek Sharon , Pageau Denis
Published: November 2020

AAC Madawaska is a two-row spring feed barley (Hordeum vulgare L.) cultivar with high grain yield and lodging resistance. AAC Madawaska was tested as CH2801-48 in the Maritime Two-Row Barley Registration and Recommendation Test and Ontario Barley Orthogonal Test in 2016 and 2017 before being registered by the Canadian Food Inspection Agency. The cultivar was released by the Ottawa Research and Development Centre, Agriculture and Agri-Food Canada, Ottawa, ON, in 2019. AAC Madawaska is recommended for barley growing areas in eastern Canada.
Casimir effect of a Lorentz-violating scalar in magnetic field
Authors: Erdas Andrea
Published: November 2020

In this paper, I study the Casimir effect caused by a charged and massive scalar field that breaks Lorentz invariance in a CPT-even, aether-like manner. I investigate the case of a scalar field that satisfies Dirichlet or mixed (Dirichlet–Neumann) boundary conditions on a pair of very large plane parallel plates. The case of Neumann boundary conditions is straightforward and will not be examined in detail. I use the [Formula: see text]-function regularization technique to study the effect of a constant magnetic field, orthogonal to the plates, on the Casimir energy and pressure. I investigate the cases of a timelike Lorentz asymmetry, a spacelike Lorentz asymmetry in the direction perpendicular to the plates, and a spacelike asymmetry in the plane of the plates and, in all those cases, derive simple analytic expressions for the zeta function, Casimir energy and pressure in the limits of small plate distance, strong magnetic field and large scalar field mass. I discover that the Casimir energy and pressure, and their magnetic corrections, all strongly depend on the direction of the unit vector that implements the breaking of the Lorentz symmetry.
Online corrective responses following target jump in altered gravitoinertial force field point to nested feedforward and feedback control
Authors: Chomienne L. , Blouin J. , Bringoux L.
Published: November 2020

We investigated the link between feedforward and feedback control when applying a double-step perturbation (visual target jump) during reaching movements performed in modified gravitoinertial environments. All together, kinematics and EMG analyses showed that movement corrections were highly effective in the different force fields, suggesting that, although feedforward and feedback control were driven by different sensory inputs, feedback control was remarkably functional from the very first time participants encountered a target jump in the altered force field.
New Chaotic Oscillator Derived from Class C Single Transistor-Based Amplifier
Authors: Petrzela Jiri
Published: November 2020

This paper describes a new autonomous deterministic chaotic dynamical system having a single unstable saddle-spiral fixed point. A mathematical model originates in the fundamental structure of the class C amplifier. Evolution of robust strange attractors is conditioned by a bilateral nature of bipolar transistor with local polynomial or piecewise linear feedforward transconductance and high frequency of operation. Numerical analysis is supported by experimental verification and both results prove that chaos is neither a numerical artifact nor a long transient behaviour. Also, good accordance between theory and measurement has been observed.
Preeclampsia, HELLP Syndrome, and Postpartum Renal Failure with Thin Basement Membrane Nephropathy: Case Report and a Brief Review of Postpartum Renal Failure
Authors: Janga K. C. , Chitamanni Pavani , Raghavan Shraddha , Kumar Kamlesh , Greenberg Sheldon , Jana Kundan
Published: November 2020

A 36-year-old primigravida female from a birthing center was referred for elevated blood pressure to the hospital two days after normal spontaneous vaginal delivery with nausea, vomiting, and diarrhea. During this two-day period, she was experiencing persistent vaginal bleeding and lower abdominal pains for which she took six doses of 600 mg ibuprofen. Further laboratory evaluation reflected leukocytosis, anemia, thrombocytopenia, elevation of liver enzymes, and renal failure with hyperkalemia requiring emergent hemodialysis once in the Medical Intensive Care Unit (MICU). She was diagnosed with HELLP syndrome with underlying preeclampsia. A week later, due to hypertension controlled with medications and nonoliguric renal failure with no active urine sediments, a renal biopsy was indicated to direct management. The renal biopsy supported the diagnosis of diffuse severe acute tubulointerstitial nephritis with hypereosinophilia and thin basement membrane nephropathy (see figures). She was subsequently treated with high-dose steroids which resulted in the normalization of blood pressures and renal function returning to baseline. We report the first case of acute tubulointerstitial nephritis in an individual with thin basement membrane nephropathy secondary to postpartum complications.
Comparison of Endothelial Cell Loss following the Big Bubble versus the Microbubble Incision Technique during Deep Anterior Lamellar Keratoplasty in Eyes with Keratoconus
Authors: Abuelkheir Amro , Goweida Mohamed Bahgat , Medhat Nada , Helaly Hany Ahmed
Published: November 2020

Introduction. Deep anterior lamellar keratoplasty (DALK) is now becoming an increasingly popular surgical technique in treating corneal stromal pathologies with healthy endothelium. Several advantages of DALK over penetrating keratoplasty (PKP) have been described such as maintenance of globe integrity, absence of endothelial rejection, and a low rate of chronic endothelial cell loss (ECL). ECL following PKP results in 50% cell loss after 2 years from the estimated graft endothelial cell density (ECD). Although there are several reports confirming that ECL following DALK is similar to the physiologic cell loss 2 years after surgery, few reports discussed the surgically induced ECL due to difficulty in preoperative imaging of ECD. Materials and Methods. This prospective, interventional study included 20 eyes of 20 patients, who underwent DALK surgery. 11 eyes underwent DALK using the big bubble technique, while 9 eyes underwent the microbubble technique. Postoperative evaluation was done 3 months after surgery and included best spectacle corrected visual acuity (BSCVA), keratometric readings, and refraction measured using an autokeratorefractometer (Topcon KR800, Japan) and endothelial cell density (ECD) using noncontact specular microscopy (Nidek CEM-530, Japan). Results. Regarding postoperative parameters such as postoperative logMAR visual acuity, postoperative mean K, and postoperative K max, there was no statistical difference found between both groups (

P
=
0.754

,

P
=
0.119

, and

P
=
0.970

, respectively). Regarding change in specular endothelial cell density and percent change in the specular endothelial cell density, again there was no statistical difference between both groups with

P
=
0.057

and

P
=
0.126

, respectively (significance defined as

P
<
0.05

). Conclusion. ECD is not affected by failure of the big bubble to form and continuing DALK via the microbubble technique.
Improving Stem Cell Clinical Trial Design and Conduct: Development of a Quality Assessment Tool for Stem Cell Clinical Trials
Authors: Li Yixuan , Xie Li , Wang Jie , He Jinghang , Qian Ying , Zhang Weituo , Wu Zhaohui , Qian Biyun
Published: November 2020

Background. Clinical trials are at the cornerstone of evidence-based stem cell therapies, but the quality assessment for designing and conduct these sometimes-complex studies are scarce of evidence. This study is aimed at developing a handy quality assessment tool for stem cell clinical trials, enhancing capacity of the self-regulate overall quality, and participating protection. Methods. The framework of quality assessment tool was based on the PQRS (progress-quality-regulation-scientific) quality assessment tool, and detailed quality indicators were developed by leader group discussion, expert consulting, and literature review. Stem cell clinical trials were retrieved from the International Clinical Trials Registry Platform, and corresponding quality indicators were assessed and extracted. The validity and feasibility of conceptual quality assessment tool were further evaluated by using structural equation modeling. Results. The quality assessment tool for stem cell clinical trials contains four critical quality attributes, including participant protection, scientific value, quality control, and stem cell products, and 9 observed quality indicators. From 11 primary clinical trial registries in the International Clinical Trials Registry Platform, 9410 stem cell trial registrations were identified, and 1036 studies were eligible for publications and protocols screening. After reviewed full text, 37 studies were included in the validity and feasibility evaluation: 32 studies were completed, and 3 studies terminated early. Most of the studies (83.79%) were in the early phase, and 63.16% of the studies were investigator-initiated trial. To further tested for validity, the critical quality attributes and quality indicators (QIs) between expertise further validated by the SEM method, which showed a good fit for the model (

chi
−
square
=
26.008

;

P
=
0.353

;

TLI
=
0.967

;

CFI
=
0.978

;

RMSEA
=
0.048

). Compared with exploratory trials, evaluating using the quality assessment tool, confirmatory trials performed similarly in participant protection, scientific value, and quality control, but lower in stem cell products. Conclusions. The results of critical quality attributes and quality indicators between expertise and confirmatory validation analysis are basically consistent, indicating the feasibility and validity of applying this quality assessment tool for overall quality evaluation of stem cell trials.
The Alteration in Composition and Function of Gut Microbiome in Patients with Type 2 Diabetes
Authors: Zhao Xue , Zhang Yiding , Guo Ruixue , Yu Wei , Zhang Fanliang , Wu Feng , Shang Jin
Published: November 2020

Background. Diabetes mellitus (DM) has become one of the most common chronic metabolic diseases worldwide. Due to the increasing prevalence and various complications, diabetes brings about a huge financial burden to DM patients. Nowadays, more and more studies reveal the relationship between diseases and gut microbial community. We aimed to explore the alteration in composition and function of the gut microbiome in T2DM patients. Methods. A total of 137 patients with diabetes and 179 age- and gender-matched healthy controls selected from the healthy people sample center in the First Affiliated Hospital of Zhengzhou University were divided into the DM group and the Con group, respectively. We collected their venous blood for laboratory tests and stool samples for 16S rRNA sequencing. The comparison between the two groups including both composition and function of the gut microbiome is presented.Results. We found that the α-diversity of bacterial taxa in the DM group had an evident decrease compared to that in the Con group. At the phylum level, the DM group had an obvious decrease of Bacteroidetes and a marked increase of Proteobacteria, Actinobacteria, and Verrucomicrobia. At the genus level, Bacteroides and Prevotella decreased the most while Escherichia-Shigella, Lachnospiraceae_incertae_sedis, Subdoligranulum, Enterococcus, and Klebsiella had different degrees of expansion in the DM group. The ROC based on 246 optimum OTUs had very high test efficiency with an AUC of 92.25% in the training set and 90.48% in the test set. As for prediction of metabolic function, the gut microbiome of DM patients was predicted to be more active in environmental information processing and human diseases but less in metabolism. Conclusion. We observed alteration of composition and function of the gut microbiome in the DM group. These changes may provide a new treatment strategy for DM patients and new research targets.
Adaptability of the Cutter‐Head of the Earth Pressure Balance (EPB) Shield Machine in Water‐Rich Sandy and Cobble Strata: A Case Study
Authors: Wan Chaodong , Jin Zhiyi
Published: November 2020

Earth Pressure Balance (EPB) shield machines are considered to be the most efficient tunneling method for Metro tunnels due to their adaptability to a great variety of ground conditions, higher construction efficiency, and providing a safer working environment. There are many guidelines available for EPB shield machine selection. However, these guidelines are very general and cannot be used directly for an upcoming project. This paper takes Chengdu Metro Line 6 in China as the engineering background; the studied area is typical of a water‐rich sandy and cobble stratum with high content of cobble. Three types of EPBs in the two continuous intervals exhibit significant differences in performance and encounter many difficulties such as wear of the cutter disc and tools, clogging, and severe surface settlement during the operation. These difficulties prevent the construction efficiency, increase the cost of the project, and cause delays in construction period. The causes of these difficulties are summarized by recording and comparing the operational parameters of the three types of EPBs. These parameters that are summarized include the advance rate, total thrust, torque, and the rate of rotation of the cutter‐head. In addition, the surface settlements are also compared. The results indicate that the opening rate, maximum opening size, and the opening position of the cutter‐head are key factors that affected the geological adaptability of the shield machine in water‐rich sandy and cobble strata. Among the three factors, the maximum opening size and opening position are the most important factors influencing the strata adaptability of the cutter‐head. To avoid frequent jams of the cutter‐head, the maximum torque should be not less than 6,500 kNm. The maximum opening size should not be less than 420 mm × 420 mm. The effect of increasing the central opening of the cutter‐head is that large cobbles and boulders can be discharged through the central opening when they cannot be discharged through the opening near the original position of the cobbles and boulders. This paper provides specific guidance on the selection of cutter‐head for shield machines in water‐rich sandy and cobble strata.
Effects of the Glutamine Administration on T Helper Cell Regulation and Inflammatory Response in Obese Mice Complicated with Polymicrobial Sepsis
Authors: Yeh Chiu-Li , Su Li-Han , Wu Jin-Ming , Yang Po-Jen , Lee Po-Chu , Chen Po-Da , Huang Chun-Chieh , Hsieh Der-Yirng , Wang Hsueh-Ju , Yeh Sung-Ling , Lin Ming-Tsan
Published: November 2020

This study investigated the impacts of GLN on inflammation and T cell dysregulation in obese mice complicated with sepsis. Mice were divided into normal control (NC) and high-fat diet groups. The high-fat diet provided 60% of energy from fat and was administered for 10 weeks to induce obesity. Mice fed with a high-fat diet were then assigned to sham (SH) and sepsis with saline (SS) or GLN (SG) groups. The SH group was subjected to laparotomy, while the sepsis group underwent cecal ligation and puncture (CLP). The SS group was intravenously injected with saline. The SG group was intravenously administered GLN after CLP. Mice were sacrificed at 12, 24, or 48 h post-CLP, respectively. Results demonstrated that in the presence of obesity, sepsis drove CD4+ T cells toward the helper T (Th)2 and Th17 lineages. Also, expressions of inflammatory cytokines and macrophage infiltration markers in adipose tissues and lungs were elevated. Treatment of obese mice with GLN after sepsis reversed Th polarization and downregulated macrophage infiltration and inflammatory cytokine, whereas the tight junction-associated protein expression increased in the lungs. These findings suggest that the intravenous administration of GLN to obese mice after sepsis modulated a more balanced Th cell lineage, alleviated inflammation, and attenuated lung injury.
Numerical Study of the Air Ingress Accident of the HTR-PM and Possible Mitigation Measures
Authors: Xu Wei , Zhang Han , Xie Heng , Shi Lei , Sun Jun
Published: November 2020

The double-ended guillotine break (DEGB) of the horizontal coaxial gas duct of a high-temperature gas-cooled reactor is an extremely hypothetical accident, which could cause the air to enter into the primary circuit and react with graphite in the reactor core. The performance of the HTR-PM plant under this extremely hypothetical accident has been studied by the system code TINTE in this work. The results show that the maximum fuel temperature will not reach the temperature design limitation, and the graphite oxidation will not cause unacceptable consequences even under some conservative assumptions. Moreover, nitrogen and helium injected from the fuel charging tube were studied as the possible mitigation measures to further alleviate the consequences of this air ingress accident. The preliminary results show that only the flow rate of nitrogen injected reaches a certain value, which can effectively alleviate the consequences, while for helium injection, both high and small flow rate can prevent or cut off the natural circulation and alleviate the consequences. The reason is that helium is much lighter than nitrogen, and the density difference between the coolant channel and the reactor core is small when helium is injected. Considering the injection velocity, the total usage amount, and the start time of gas injection, helium injected with a small flow rate is suggested.
Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice
Authors: Zhao Wei , Zhao Lianhua , Guo Zaiyu , Hou Yanwei , Jiang Jiafeng , Song Yijun
Published: November 2020

Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.
Lower Airway Dysbiosis Affects Lung Cancer Progression
Authors: Tsay Jun-Chieh J. , Wu Benjamin G. , Sulaiman Imran , Gershner Katherine , Schluger Rosemary , Li Yonghua , Yie Ting-An , Meyn Peter , Olsen Evan , Perez Luisannay , Franca Brendan , Carpenito Joseph , Iizumi Tadasu , El-Ashmawy Mariam , Badri Michelle , Morton James T. , Shen Nan , He Linchen , Michaud Gaetane , Rafeq Samaan , Bessich Jamie L. , Smith Robert L. , Sauthoff Harald , Felner Kevin , Pillai Ray , Zavitsanou Anastasia-Maria , Koralov Sergei B. , Mezzano Valeria , Loomis Cynthia A. , Moreira Andre L. , Moore William , Tsirigos Aristotelis , Heguy Adriana , Rom William N. , Sterman Daniel H. , Pass Harvey I. , Clemente Jose C. , Li Huilin , Bonneau Richard , Wong Kwok-Kin , Papagiannakopoulos Thales , Segal Leopoldo N.
Published: November 2020

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node–metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers.

Significance:

Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.

See related commentary by Zitvogel and Kroemer, p. 224.

This article is highlighted in the In This Issue feature, p. 211
Targeted Deletion of CXCR2 in Myeloid Cells Alters the Tumor Immune Environment to Improve Antitumor Immunity
Authors: Yang Jinming , Yan Chi , Vilgelm Anna E. , Chen Sheau-Chiann , Ayers Gregory D. , Johnson Christopher A. , Richmond Ann
Published: November 2020

Recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment (TME) contributes to cancer immune evasion. MDSCs express the chemokine receptor CXCR2, and inhibiting CXCR2 suppresses the recruitment of MDSCs into the tumor and the premetastatic niche. Here, we compared the growth and metastasis of melanoma and breast cancer xenografts in mice exhibiting or not exhibiting targeted deletion of Cxcr2 in myeloid cells (CXCR2myeΔ/Δ vs. CXCR2myeWT). Detailed analysis of leukocyte populations in peripheral blood and in tumors from CXCR2myeΔ/Δ mice revealed that loss of CXCR2 signaling in myeloid cells resulted in reduced intratumoral MDSCs and increased intratumoral CXCL11. The increase in intratumoral CXCL11 was derived in part from tumor-infiltrating B1b cells. The reduction in intratumoral MDSCs coupled with an increase in intratumoral B1b cells expressing CXCL11 resulted in enhanced infiltration and activation of effector CD8+ T cells in the TME of CXCR2myeΔ/Δ mice, accompanied by inhibition of tumor growth in CXCR2myeΔ/Δ mice compared with CXCR2myeWT littermates. Treatment of tumor-bearing mice with a CXCR2 antagonist (SX-682) also inhibited tumor growth, reduced intratumoral MDSCs, and increased intratumoral B1b cells expressing CXCL11, leading to an increase in activated CD8+ T cells in the tumor. Depletion of B220+ cells or depletion of CD8+ T cells reversed the tumor-inhibitory properties in CXCR2myeΔ/Δ mice. These data revealed a mechanism by which loss of CXCR2 signaling in myeloid cells modulates antitumor immunity through decreasing MDSCs and enriching CXCL11-producing B1b cells in the TME, which in turn increases CD8+ T-cell recruitment and activation in tumors.
Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer
Authors: Sun Hong-Wei , Chen Jing , Wu Wen-Chao , Yang Yan-Yan , Xu Yi-Tuo , Yu Xing-Juan , Chen Hai-Tian , Wang Zilian , Wu Xiao-Jun , Zheng Limin
Published: November 2020

Metabolism is reprogrammed in cancer to fulfill the demands of malignant cells for cancer initiation and progression. Apart from its effects within cancer cells, little is known about whether and how reprogramed metabolism regulates the surrounding tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) are key regulators of the TME and greatly affect tumor progression and therapeutic responses. In this study, our results revealed that retinol metabolism–related genes and enzymes were significantly downregulated in human colorectal cancer compared with adjacent colonic tissues, and tumors exhibited a defect in retinoic acid (RA) synthesis. Reduced ADH1-mediated retinol metabolism was associated with attenuated RA signaling and accumulated MDSCs in colorectal cancer tumors. Using an in vitro model, generating MDSCs from CD34+ myeloid precursors, we found that exogenous RA could abrogate the generation of polymorphonuclear MDSCs (PMN-MDSC) with negligible impact on myeloid differentiation. Mechanistically, RA could restrain the glycolytic capacity of myeloid cells, which in turn activated the AMP-activated protein kinase (AMPK) pathway, further impairing the suppressive capacity of myeloid cells. Supplementation with RA could significantly delay tumor growth, with reduced arginase-1–expressing myeloid cells and increased CD8+ and granzyme B+ T cells in both colitis-associated and implanted MC38 mouse colorectal cancer models. Our results indicated that the defect in ADH1-mediated RA synthesis could provide a possible mechanism that fosters the generation of PMN-MDSCs in colorectal cancer and that restoring RA signaling in the TME could serve as a promising therapeutic strategy to abrogate the generation of PMN-MDSCs.