bluuebunny/crossref_metadata_2025 huggingface dataset:
P14.59 Rapid early progression of glioblastoma is not related to cortical/neural stem cells regions
Authors: Kazda T , Lakomy R , Selingerova I , Pospisil P , Hynkova L , Belanova R , Slampa P
Published: September 2021

BACKGROUND

Rapid early progression (REP) of glioblastoma after surgery observed on pre-radiotherapy MRI scan is common. Subventricular zone (SVZ) and hippocampal regions are supposed to harbor astrocyte-like neural stem cells (NSC) with tumors arising from these transformed stem cells threatening of higher risk of REP. REP is defined as a new enhancing tumor or >25% increase in enhancement before radiotherapy. Lim′s classification of initial glioblastoma location related to these NSC regions predicts invasive and multifocal tumor phenotype. Glioblastomas are classified preoperatively into four groups by the spatial relationship of the contrast-enhancing lesion with the SVZ and cortex. The aim of this retrospective single-institutional study is to evaluate the relations of this Lim classification on REP in unselected cohort of glioblastoma patients.

MATERIAL AND METHODS

Patients receiving radiotherapy between 2014–2017 were analyzed, 95 were evaluable. 47 patients (30.5%) were treated with the Stupp regimen. Lim1 classification (contact with cortex as well as SVZ) was presented in 74(48%) patients, Lim2 (contact with SVZ only) in 22(14.3%), Lim3 (contact with cortex only) in 50(32.5%) and Lim4 in 8(5.2%) patients. A total of 52% of patients developed REP.

RESULTS

Significantly better overall survival was with Stupp regimen (23.3 vs. 8.6 months, p<0.001) and without REP (18.5 vs. 10.2 months, p=0.001). There was no significant impact of time to start of radiotherapy. No significant relation between REP and Lim classification was observed.

CONCLUSION

The initial location is not predictive for REP. Patients experiencing REP have significantly worse overall survival and modification of their management represents an urgent unmet clinical need. Molecular and clinical biomarkers indicating an increased risk of REP are needed.Presented will also be an already published analysis of clinical factors associated with REP in glioblastoma and the effect of REP and treatment on survival outcomes. Newly, we will introduce the investigator-initiated prospective academic clinical trial (GlioMET) focused on optimization of glioblastoma radiotherapy by 11C-Methionine PET scan in patients with REP. Supported by Ministry of Health of the Czech Republic AZV, No.18-03-00469 and AZV NU20-03-00148.
P14.71 An assessment of the reporting and methodological quality of meningioma systematic reviews and meta-analyses
Authors: George A M , Gupta S , Keshwara S M , Mustafa M A , Gillespie C S , Richardson G E , Steele A C , Islim A I , Jenkinson M D , Millward C P
Published: September 2021

BACKGROUND

Systematic reviews and meta-analyses constitute the highest level of research evidence and for a disease with limited clinical trial activity, are often relied upon to help inform clinical practice. This review of reviews evaluates both the reporting & methodological quality of meningioma evidence syntheses.

MATERIAL AND METHODS

Potentially eligible meningioma reviews published between 1st January 1990 and 31st December 2020 were identified from eight electronic databases. Inclusion required the study to meet the Cochrane guideline definition of a systematic review or meta-analysis. Reviews concerning neurofibromatosis type 2, spinal and pediatric meningiomas were excluded. The reporting and methodological quality of articles were assessed against the following modified guidelines: Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), A MeaSurement Tool to Assess Systematic Reviews (AMSTAR2) and the Risk of Bias in Systematic Reviews (ROBIS) guidelines.

RESULTS

117 systematic reviews were identified, 57 of which included meta-analysis (48.7%). The number of meningioma systematic reviews published each year has increased with 63 studies (53.9%) published between 01/2018 and 12/2020. A median of 17 studies (IQR 9–29) were included per review. Impact factor of journals publishing a systematic review with or without a meta-analysis was similar (median 2.3 vs 1.8, P=0.397). The mean PRISMA scores for systematic reviews with a meta-analysis was 21.11 (SD 4.1, 78% adherence) and without was 13.89 (SD 3.4, 63% adherence). Twenty-nine systematic reviews with meta-analysis (51%) and 11 without meta-analysis (18%) achieved greater than 80% adherence to PRISMA recommendations. Methodological quality assessment using AMSTAR2 revealed one study (0.9%) as high quality whilst 111 (94.8%) studies were graded as critically low. One hundred and two articles (87.2%) did not utilize a comprehensive search strategy as defined by the AMSTAR2 tool. Ninety-nine studies (84.6%) obtained a high level of concern for potential bias as per the ROBIS assessment. One hundred and eight articles (92.3%) failed to present information that a protocol had been established prior to study commencement and 76 articles (65.0%) did not conduct a risk of bias assessment. Across the three tools, domains relating to the establishment of a protocol prior to review commencement and conducting appropriate risk of bias assessments were frequently low scoring.

CONCLUSION

Overall reporting and methodological quality of meningioma systematic reviews was sub-optimal. Established critical appraisal tools and reporting guidelines should be utilized a priori to assist in producing high-quality systematic reviews.
Health-Related Quality of Life as Measured by the 36-Item Short Form Survey Among Adults With Acute Bacterial Skin and Skin Structure Infections who Received Either Omadacycline or Linezolid in a Phase 3 Double-Blind, Double-Dummy Clinical Trial
Authors: Chitra Surya , Hinahara Jordan , Goss Thomas F , Gunter Kyle , LaPensee Kenneth
Published: September 2021

This analysis of data from a Phase 3 study of adults with acute bacterial skin and skin structure infections showed that successful oral treatment with omadacycline (n = 368) or linezolid (n = 367) was associated with improvement in health-related quality of life.
Physiological condition reflects polymorphism at the toll-like receptors in a colonial waterbird
Authors: Podlaszczuk Patrycja , Indykiewicz Piotr , Kamiński Maciej , Minias Piotr
Published: September 2021

Toll-like receptors (TLRs) are a crucial component of vertebrate innate immune response. Despite their importance, associations of TLR diversity with fitness-related traits have rarely been examined in wild animal populations. Here, we tested for associations of TLR polymorphism with physiological condition in a colonial waterbird, the Black-headed Gull (Chroicocephalus ridibundus). Physiological condition and polymorphism at 4 TLR loci were assessed in 60 gulls from a breeding colony in northern Poland. We found that blood hemoglobin and plasma albumin concentrations were positively associated with TLR diversity across all genotyped loci. Plasma concentrations of albumin and triglycerides were also associated with the presence of specific TLR variants and locus-specific diversity. All significant associations between physiological condition and TLRs were primarily apparent at the level of nucleotide, rather than amino acid allelic variants. Although the exact molecular mechanisms responsible for these associations require further investigation, our study provides strong correlational support for links between TLR diversity and physiological condition in a wild avian population, and it adds to the growing, but still modest, body of evidence for the fitness-related consequences of individual TLR repertoire in wild birds.
The Relationship Between Parenting and Identity Styles Among Adolescents in South Africa
Authors: Roman Nicolette Vanessa , van Heerden Marsha , Davids Eugene Lee , Adonis Kerstin
Published: September 2021

This chapter provides insight into the mother–adolescent relationship in a South African context, focusing on the relationship between identity styles and the mother’s parenting. The findings revealed that maternal involvement predicted adolescent identity style in a sample of non-White South African adolescents. Identity development is an important process in the lives of adolescents, and many changes and much decision-making occur during this phase. Maternal influence, it would seem, is vital in identity development of adolescents. As an understudied area of research in South Africa, this study offers tentative insights into the potential of harnessing the mother–adolescent relationship to enhance positive development of identity style and commitment.
Father Involvement in Different Family Systems Across Cultural Communities
Authors: Roopnarine Jaipaul L. , Mukara Matsantsa Ong'ayi Dickson , Dede Yildirim Elif
Published: September 2021

This chapter discusses paternal involvement in diverse living arrangements in high-, middle-, and low-income countries and their implications for childhood development. Men’s ideas about fathering roles and responsibilities are changing noticeably in the high-income countries but at a far slower pace in the rest of the world. This is a major hindrance to engaged fathering. Despite the prevalence of masculine norms in most regions of the world, men display levels of warmth toward children that are comparable to that of mothers, and in a few instances fathers exceed mothers in the display of affection to children. An area in which fathers seem to lag behind mothers is in their engagement in cognitively rich language and numeracy activities with children. This is particularly so in the low- and middle-income countries. Ultimately, the associations between father engagement and childhood outcomes are more consistent for families in high-income than low-income countries, and the associations are sometimes tempered by family union status, the quality of partner relationship, and material resources.
Grandparental Investment
Authors: Sheppard Paula
Published: September 2021

This chapter assesses the alloparental role that grandparents play in the human cooperative breeding system. Grandparenthood is an intriguing phenomenon and a fascinating chapter in the extraordinary human life-history story. Grandparental investment is well-defined as an adaptive strategy that enhances inclusive fitness. Although there is great diversity in grandparenting practices across human cultures, the evidence clearly demonstrates that grandparents help, and that that help is beneficial to the whole fitness unit. By applying an evolutionary ecological framework to understanding how differential grandparental solicitude emerges, and by understanding that these differences depend on genetic, ecological, and social factors, predictable patterns of investment can be derived.
The Effects of Maternal Prenatal Stress on Fetal and Child Development
Authors: Glover Vivette
Published: September 2021

This chapter describes the effects of maternal prenatal stress on fetal and child development. There is considerable evidence from both animal and human studies that if the mother is stressed during pregnancy this increases the likelihood of her offspring having a range of altered behavioral and other neurodevelopmental outcomes, together on occasion with increased stress reactions. It is possible to suggest adaptive reasons for many of these effects. The behavioral outcomes, such as increased anxiety in females, will make them more vigilant and able to detect danger. More aggression in males may make them better at dealing with this danger.

An increased risk of other outcomes such as preterm delivery, earlier menarche, and reduced telomere length, reflect an accelerated life history pattern from birth to death. These too may be of evolutionary advantage in conditions of external threat.
Economic Interests and Grand Strategy
Authors: Narizny Kevin
Published: September 2021

Grand strategy and economic interests are tightly interconnected: a state’s economy affects its choice of strategy, and its choice of strategy affects its economy. A full account of this relationship must distinguish among three perspectives on state and societal preferences. Under most varieties of realism, the state is autonomous from society and motivated by survival. Wealth is a vital source of military power, and military power is necessary for survival; thus, the state seeks to increase its wealth relative to its rivals. This paradigm provides much insight into the dynamics of interstate competition, but its assumption that grand strategy is insulated from domestic politics sharply limits its analytic utility. Liberals, Marxists, and neoclassical realists go deeper. They do not ignore the survival motive, but they also consider how the state might be biased in favor of a particularist set of economic interests. When this bias is consistent, persisting across changes in government, it constitutes a national preference; when it varies across governments, it is a subnational preference. Research into the latter shows great promise for the development of new insights into the root causes of grand strategy.
Grand Strategy and Military Power
Authors: Vennesson Pascal
Published: September 2021

This chapter examines military power through the lens of grand strategy. It begins by identifying the First World War as the main origin of the distinctive idea of grand strategy resulting in its core meaning and ambivalence. It then shows how grand strategy acts as a force multiplier, before exploring the ways in which military successes and failures affect grand-strategic effectiveness. Finally, it discusses the ways in which military power as a component of peacetime grand strategy can produce its psychological effects on the will of the adversary through the display and threat of force or competitive defense procurement rather than actual fighting. The chapter concludes by arguing that the specific characteristics of military power help identify some of the limits of grand strategy, notably its underestimation of contingency arising from the dynamic interaction with a thinking adversary.
The Limits of Grand Strategy
Authors: Edelstein David M.
Published: September 2021

The benefits of grand strategy have been overstated. While its advocates claim that grand strategy allows states to coordinate their efforts, signal their interests to allies and adversaries, and shape the behavior of others, the ability of grand strategy effectively to achieve these goals is limited. Not only does grand strategy often struggle to accomplish these tasks, but it may also be counterproductive, leading states to bind their foreign policies to the detriment of their national interests. As an alternative, states ought to consider the adoption of a more pragmatic approach to their foreign policies. Rather than adopting a single, determined grand strategy, states would be better off embracing a more experimental approach to the conduct of their foreign policies. Especially in times of uncertainty, such an approach would allow them to protect their interests while identifying beneficial opportunities to pursue.
Rational Analysis of Grand Strategy
Authors: Glaser Charles L.
Published: September 2021

This chapter describes the basic structure of a rational analysis of grand strategy. Rational analysis is an approach, not a school or a theory. It is the approach that is required by and supports sound policy analysis; it is not controversial. Nevertheless, appreciating the structure and requirements of a rational analysis can provide guidance for performing high-quality analysis and for critiquing ongoing debates over grand strategy. All of the major schools of grand strategy in the US debate are built on a rational analysis. The chapter first addresses the terms “grand strategy” and “rational.” It then describes the basic components of a rational grand-strategic analysis: state’s interests (including the distinction between fundamental interests and “derivative interests”), the international environment, theories of state interaction, the options available to a state, the comparison of these options, and a conclusion about which grand strategy will best serve a state’s interests. The final section brief highlights the analytic value of understanding the structure and requirements of rational analyses of grand strategy.
STOP1 activates NRT1.1-mediated nitrate uptake to create a favorable rhizospheric pH for plant adaptation to acidity
Authors: Ye Jia Yuan , Tian Wen Hao , Zhou Miao , Zhu Qing Yang , Du Wen Xin , Zhu Ya Xin , Liu Xing Xing , Lin Xian Yong , Zheng Shao Jian , Jin Chong Wei
Published: September 2021

Protons (H+) in acidic soils arrest plant growth. However, the mechanisms by which plants optimize their biological processes to diminish the unfavorable effects of H+ stress remain largely unclear. Here, we showed that in the roots of Arabidopsis thaliana, the C2H2-type transcription factor STOP1 in the nucleus was enriched by low pH in a nitrate-independent manner, with the spatial expression pattern of NITRATE TRANSPORTER 1.1 (NRT1.1) established by low pH required the action of STOP1. Additionally, the nrt1.1 and stop1 mutants, as well as the nrt1.1 stop1 double mutant, had a similar hypersensitive phenotype to low pH, indicating that STOP1 and NRT1.1 function in the same pathway for H+ tolerance. Molecular assays revealed that STOP1 directly bound to the promoter of NRT1.1 to activate its transcription in response to low pH, thus upregulating its nitrate uptake. This action improved the nitrogen use efficiency (NUE) of plants and created a favorable rhizospheric pH for root growth by enhancing H+ depletion in the rhizosphere. Consequently, the constitutive expression of NRT1.1 in stop1 mutants abolished the hypersensitive phenotype to low pH. These results demonstrate that STOP1-NRT1.1 is a key module for plants to optimize NUE and ensure better plant growth in acidic media.
Do Investment-Based Models Explain Equity Returns? Evidence from Euler Equations
Authors: Delikouras Stefanos , Dittmar Robert F
Published: September 2021

We investigate the empirical implications of the investment-based model of asset pricing for the Hansen-Jagannathan and Kozak-Nagel-Santosh discount factors in the linear span of equity returns. We find that the stochastic discount factors satisfying the Euler equation for equity returns cannot satisfy the Euler equation for investment returns because returns on corporate investment covary inversely with the sources of equity risk relative to returns on equity. As a result, the model fails to replicate the level of the risk premium. Our results suggest that joint restrictions on the optimality of investment and consumption pose stringent conditions for candidate production models.
Restoring the antibiotic R&D market to combat the resistance crisis
Authors: Böttcher Lucas , Gersbach Hans , Wernli Didier
Published: September 2021

Antibiotic resistance has developed into a major public health concern due to the widespread prevalence of bacterial infections such as sepsis and urethritis and the frequent occurrence of opportunistic infections in immunocompromised patients. Unfortunately, the pipeline for new antibiotics has been almost stagnant for more than three decades. The main reason is that the antibiotics R&D market is dysfunctional since antibiotics R&D is a very risky business model that is not profitable and attractive for investors under current market and policy conditions. Our work analyzes the main economic and policy challenges in antibiotics R&D and highlights the need of rapid action in developing new push and pull incentives for antibiotics R&D. We suggest three core elements of a redesign of the R&D market: (1) levying a fee on the nonhuman use of antibiotics, (2) using these revenues to pay for market entry rewards, and (3) rewarding companies for the development of new antibiotics that are effective against resistant bacteria (‘the resistance premium’).
Undergraduate Nursing Students and Management of Interruptions: Preparation of Students for Future Workplace Realities
Authors: Schroers Ginger , Ross Jennifer Gunberg , Moriarty Helene
Published: September 2021

AIM

The aim of this study was to investigate interruption management strategies and associative cues used by nursing students when interrupted during simulated medication administration.

BACKGROUND

Interruptions occur with high frequency in health care settings and are associated with increased medication errors and decreased task efficiency. The Altmann and Trafton memory for goals model, a cognitive-science model, proposes use of associative cues during an interruption to mitigate these negative effects.

METHOD

A mixed-methods, two-site study explored associative cues and other management strategies that nursing students used when interrupted during simulated medication administration. Data were collected via direct observation and semistructured interviews.

RESULTS

Students primarily multitasked (66.7 percent) during the interruption. Few students (5.5 percent) used associative cues. Students voiced the need for education and practice on how to manage interruptions.

CONCLUSION

Evidence-based strategies are required to prepare nursing students for workplace interruptions. Use of associative cues during interruptions warrants further investigation.
Ethical, Legal, and Social Implications of Fetal Gene Therapy
Authors: Brown Julia E.H. , Koenig Barbara A.
Published: September 2021

As fetal gene therapies move from experimental animal models to human in utero phase I clinical trials, there is a need to consider the ethical, legal, and social implications. While fetal gene therapies are attracting more regulatory oversight than previous fetal interventions such as fetal surgery, old sociological questions should be applied to this new context. As health care pathways around fetal therapy are shaped by the ways in which a pregnant person and the fetus are constituted, and as risks and benefits are evaluated, we cannot afford to lose sight of long-term consequences, especially those pertaining to social inclusion.
Enhancing the value to users of machine learning-based clinical decision support tools: A framework for iterative, collaborative development and implementation
Authors: Singer Sara J. , Kellogg Katherine C. , Galper Ari B. , Viola Deborah
Published: September 2021

Background

Health care organizations are integrating a variety of machine learning (ML)-based clinical decision support (CDS) tools into their operations, but practitioners lack clear guidance regarding how to implement these tools so that they assist end users in their work.

Purpose

We designed this study to identify how health care organizations can facilitate collaborative development of ML-based CDS tools to enhance their value for health care delivery in real-world settings.

Methodology/Approach

We utilized qualitative methods, including 37 interviews in a large, multispecialty health system that developed and implemented two operational ML-based CDS tools in two of its hospital sites. We performed thematic analyses to inform presentation of an explanatory framework and recommendations.

Results

We found that ML-based CDS tool development and implementation into clinical workflows proceeded in four phases: iterative solution coidentification, iterative coengagement, iterative coapplication, and iterative corefinement. Each phase is characterized by a collaborative back-and-forth process between the technology’s developers and users, through which both users’ activities and the technology itself are transformed.

Conclusion

Health care organizations that anticipate iterative collaboration to be an integral aspect of their ML-based CDS tools’ development and implementation process may have more success in deploying ML-based CDS tools that assist end users in their work than organizations that expect a traditional technology innovation process.

Practice Implications

Managers developing and implementing ML-based CDS tools should frame the work as a collaborative learning opportunity for both users and the technology itself and should solicit constructive feedback from users on potential changes to the technology, in addition to potential changes to user workflows, in an ongoing, iterative manner.
Diagnostic Utility of Serum IgG4 in Autoimmune Pancreatitis
Authors: Lee Shih-Ching , Yang Chung-Han , Chang Che-Tzu , Yu Kuang-Hui
Published: September 2021

Objectives:

Despite many studies suggesting an association between serum immunoglobulin G4 (sIgG4) and autoimmune pancreatitis (AIP), the evidence of utility in differentiation between AIP and pancreatic cancer (PC) remain uncertain.

Methods:

The analysis based on published studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, diagnostic odds ratios (DOR), areas under summary receiver operating characteristic curves were calculated.

Results:

In the included thirteen studies, sIgG4 were measured in 594 patients with AIP and 958 patients with PC. The pooled sensitivity, specificity, DOR, and area under the curve were 0.72 [95% confidence interval (CI): 0.68-0.75], 0.93 (95% CI: 0.92-0.95), 51.37 (95% CI: 23.20-113.74), and 0.91 (95% CI: 0.87-0.95). Subgroup analyses of the DORs for region and year: Asia, (112.10; 95% CI: 27.72-453.32), non-Asia (26.01; 95% CI: 12.38-54.65), and year before 2011 (107.61; 95% CI: 39.30-294.68), year after 2011 (26.96; 95% CI: 9.78-74.32). Overall, sIgG4 was associated with AIP, the result revealed a moderate sensitivity 0.72 and high specificity 0.93. In the meta-analysis, the pooled DOR of sIgG4 levels of 2-fold upper limit 50.44 was similar with the DOR 51.37 when 1-fold cut-off value, but the summary receiver operating characteristic was 0.755 and 0.91. The higher specificity (from 93% to 98%) derived from the cut-off value (from 130-140 to 260-280 mg/dL) for sIgG4 occurred at a significant reduction in sensitivity (from 72% to 43%).

Conclusions:

The study revealed sIgG4 is a good marker of AIP. Screening of sIgG4 may help clinicians differentiate between AIP and PC, and the best cut-off value should be 140 rather than 280 mg/dL.
Coronavirus Disease 2019 Planning and Response
Authors: Chen Candice , Luo Qian , Chong Nicholas , Westergaard Sara , Brantley Erin , Salsberg Edward , Erikson Clese , Pillai Drishti , Green Katherine , Pittman Patricia
Published: September 2021

Background:

As coronavirus disease 2019 (COVID-19) rapidly progressed throughout the United States, increased demand for health workers required health workforce data and tools to aid planning and response at local, state, and national levels.

Objective:

We describe the development of 2 estimator tools designed to inform health workforce planning for COVID-19.

Research Design:

We estimated supply and demand for intensivists, critical care nurses, hospitalists, respiratory therapists, and pharmacists, using Institute for Health Metrics and Evaluation projections for COVID-19 hospital care and National Plan and Provider Enumeration System, Provider Enrollment Chain and Ownership System, American Hospital Association, and Bureau of Labor Statistics Occupation Employment Statistics for workforce supply. We estimated contact tracing workforce needs using Johns Hopkins University COVID-19 case counts and workload parameters based on expert advice.

Results:

The State Hospital Workforce Deficit Estimator estimated the sufficiency of state hospital-based clinicians to meet projected COVID-19 demand. The Contact Tracing Workforce Estimator calculated the workforce needed based on the 14-day COVID-19 caseload at county, state, and the national level, allowing users to adjust workload parameters to reflect local contexts.

Conclusions:

The 2 estimators illustrate the value of integrating health workforce data and analysis with pandemic response planning. The many unknowns associated with COVID-19 required tools to be flexible, allowing users to change assumptions on number of contacts and work capacity. Data limitations were a challenge for both estimators, highlighting the need to invest in health workforce data and data infrastructure as part of future emergency preparedness planning.
The Effect of National Health Service Corps Clinician Staffing on Medical and Behavioral Health Care Costs in Community Health Centers
Authors: Han Xinxin , Pittman Patricia , Ku Leighton
Published: September 2021

Objective:

Prior studies of community health centers (CHCs) have found that clinicians supported by the National Health Service Corps (NHSC) provide a comparable number of primary care visits per full-time clinician as non-NHSC clinicians and provide more behavioral health care visits per clinician than non-NHSC clinicians. This present study extends prior research by examining the contribution of NHSC and non-NHSC clinicians to medical and behavioral health costs per visit.

Methods:

Using 2013–2017 data from 1022 federally qualified health centers merged with the NHSC participant data, we constructed multivariate linear regression models with health center and year fixed effects to examine the marginal effect of each additional NHSC and non-NHSC staff full-time equivalent (FTE) on medical and behavioral health care costs per visit in CHCs.

Results:

On average, each additional NHSC behavioral health staff FTE was associated with a significant reduction of 3.55 dollars of behavioral health care costs per visit in CHCs and was associated with a larger reduction of 7.95 dollars in rural CHCs specifically. In contrast, each additional non-NHSC behavioral health staff FTE did not significantly affect changes in behavioral health care costs per visit. Each additional NHSC primary care staff FTE was not significantly associated with higher medical care costs per visit, while each additional non-NHSC clinician contributed to a slight increase of $0.66 in medical care costs per visit.

Conclusions:

Combined with previous findings on productivity, the present findings suggest that the use of NHSC clinicians is an effective approach to improving the capacity of CHCs by increasing medical and behavioral health care visits without increasing costs of services in CHCs, including rural health centers.
Contemporary strategies to assess and manage liver donor steatosis: a review
Authors: Tien Christine , Remulla Daphne , Kwon Yong , Emamaullee Juliet
Published: September 2021

Purpose of review

Due to a persistent shortage of donor livers, attention has turned toward ways of utilizing marginal grafts, particularly those with steatosis, without incurring inferior outcomes. Here we review the evaluation and utilization of steatotic liver allografts, highlight recently published data, and discuss novel methods of graft rehabilitation.

Recent findings

Although severe liver allograft (>60%) steatosis has been associated with inferior graft and recipient outcomes, mild (<30%) steatosis has not. There is ongoing debate regarding safe utilization of grafts with moderate (30–60%) steatosis. Presently, no established protocols for evaluating steatosis in donor candidates or utilizing such grafts exist. Liver biopsy is accepted as the gold standard technique, though noninvasive methods have shown promise in accurately predicting steatosis. More recently, machine perfusion has been shown to enhance ex situ liver function and reduce steatosis, emerging as a potential means of optimizing steatotic grafts prior to transplantation.

Steatotic liver allografts constitute a large proportion of deceased donor organs. Further work is necessary to define safe upper limits for the acceptable degree of steatosis, develop standardized evaluation protocols, and establish utilization guidelines that prioritize safety. Machine perfusion has shown promise in rehabilitating steatotic grafts and offers the possibility of expanding the deceased donor pool.
A historical perspective of sacral nerve stimulation (SNS) for bowel dysfunction
Authors: Weledji Elroy P. , Marti Lukas
Published: September 2021

The majority of patients with neuropathic incontinence and other pelvic floor conditions associated with straining at stool have damage to the pudendal nerves (S 2–4) distal to the ischial spine. Electronic searches of the medline (PubMed) database, Cochrane library, and science citation index were performed to identify original published studies on sacral nerve stimulation for bowel dysfunction. Relevant articles were searched from relevant chapters in specialized texts and all included. Sacral nerve stimulation appears to be a promising innovation and will probably be the treatment of choice for neuropathic fecal incontinence and following failed sphincter repair. Newer electrophysiological tests and improved anal endosonography would more effectively guide clinical decision-making. A better understanding of sacral nerve stimulation mechanism of action may explain why the efficacy may diminish with time.
Factor H binding protein (fHbp)-mediated differential complement resistance of a serogroup C Neisseria meningitidis isolate from cerebrospinal fluid of a patient with invasive meningococcal disease
Authors: Facchetti Alessandra , Wheeler Jun X. , Vipond Caroline , Whiting Gail , Lavender Hayley , Feavers Ian M. , Maiden Martin C. J. , Maharjan Sunil
Published: September 2021

During an outbreak of invasive meningococcal disease (IMD) at the University of Southampton, UK, in 1997, two

Neisseria meningitidis

serogroup C isolates were retrieved from a student (‘Case’), who died of IMD, and a close contact (‘Carrier’) who, after mouth-to-mouth resuscitation on the deceased, did not contract the disease. Genomic comparison of the isolates demonstrated extensive nucleotide sequence identity, with differences identified in eight genes. Here, comparative proteomics was used to measure differential protein expression between the isolates and investigate whether the differences contributed to the clinical outcomes. A total of six proteins were differentially expressed: four proteins (methylcitrate synthase, PrpC; hypothetical integral membrane protein, Imp; fructose-1,6-bisphosphate aldolase, Fba; aldehyde dehydrogenase A, AldA) were upregulated in the Case isolate, while one protein (Type IV pilus-associated protein, PilC2) was downregulated. Peptides for factor H binding protein (fHbp), a major virulence factor and antigenic protein, were only detected in the Case, with a single base deletion (ΔT366) in the Carrier fHbp causing lack of its expression. Expression of fHbp resulted in an increased resistance of the Case isolate to complement-mediated killing in serum. Complementation of fHbp expression in the Carrier increased its serum resistance by approximately 8-fold. Moreover, a higher serum bactericidal antibody titre was seen for the Case isolate when using sera from mice immunized with Bexsero (GlaxoSmithKline), a vaccine containing fHbp as an antigenic component. This study highlights the role of fHbp in the differential complement resistance of the Case and the Carrier isolates. Expression of fHbp in the Case resulted in its increased survival in serum, possibly leading to active proliferation of the bacteria in blood and death of the student through IMD. Moreover, enhanced killing of the Case isolate by sera raised against an fHbp-containing vaccine, Bexsero, underlines the role and importance of fHbp in infection and immunity.
Challenges on the development of a pseudotyping assay for Zika glycoproteins
Authors: Ruiz-Jiménez Fernando , Pérez-Olais Jose Humberto , Raymond Chidinma , King Barnabas J , McClure C. Patrick , Urbanowicz Richard A. , Ball Jonathan K.
Published: September 2021

Introduction. Zika virus (ZIKV) emerged as a public health concern on the American continent during late 2015. As the number of infected grew so did the concerns about its capability to cause long-term damage especially with the appearance of the congenital Zika syndrome (CZS). Proteins from the TAM family of receptor tyrosine kinases (RTKs) were proposed as the cellular receptors, however, due to the ability of the virus to infect a variety of cell lines different strategies to elucidate the tropism of the virus should be investigated.

Hypothesis. Pseudotyping is a powerful tool to interrogate the ability of the glycoprotein (GP) to permit entry of viruses.

Aim. We aimed to establish a highly tractable pseudotype model using lenti- and retro-viral backbones to investigate the entry pathway of ZIKV.

Methodology. We used different glycoprotein constructs and different lenti- or retro-viral backbones, in a matrix of ratios to investigate production of proteins and functional pseudotypes.

Results. Varying the ratio of backbone and glycoprotein plasmids did not yield infectious pseudotypes. Moreover, the supplementation of the ZIKV protease or the substitution of the backbone had no positive impact on the infectivity. We showed production of the proteins in producer cells implying the lack of infectious pseudotypes is due to a lack of successful glycoprotein incorporation, rather than lack of protein production.

Conclusion. In line with other reports, we were unable to successfully produce infectious pseudotypes using the variety of methods described. Other strategies may be more suitable in the development of an efficient pseudotype model for ZIKV and other flaviviruses.
Simultaneous Cardiac and Neurological Monitoring to Assess Chemical Exposures and Drug Toxicity in Xenopus Laevis
Authors: Xia Xing , Zhang Jimmy , Vishwanath Manoj , Sarafan Sadaf , Torres Ramses Seferino Trigo , Le Tai , Lau Michael P.H. , Nguyen Anh H. , Cao Hung
Published: September 2021

Simultaneous monitoring of electrocardiogram (ECG) and electroencephalogram (EEG) under chemical exposure requires innovative engineering techniques that can capture minute physiological changes in studied animal models. However, this is often administered with a bulky system that may cause signal distortions and discomfort for animals. We develop an integrated bioelectronic sensing system to provide simultaneous ECG and EEG assessment in real-time under chemical exposure for Xenopus laevis. The microelectrode array (MEA) membrane with integrated ECG and EEG sensing offers an opportunity to achieve multichannel noninvasive electrophysiological monitoring with favorable dimensions and spatial resolution. To validate the performance of our system, we assessed the ECG and EEG of Xenopus under exposure of Pentylenetetrazol (PTZ), an epilepsy-inducing drug. Effects of PTZ were detected with clear ECG and EEG alterations, including frequent ictal and interictal EEG events, 30 dB average EEG amplitude elevations, abnormal ECG morphology, and heart rate changes. Overall, our Xenopus-based real-time electrophysiology monitoring system holds high potential for many applications in drug screening and remote environmental toxicity monitoring.
Listeria monocytogenes TcyKLMN cystine/cysteine transporter facilitates glutathione synthesis and virulence gene expression
Authors: Brenner Moran , Friedman Sivan , Haber Adi , Borovok Ilya , Sigal Nadejda , Lewinson Oded , Herskovits Anat A.
Published: September 2021

Listeria monocytogenes (Lm) is a saprophyte and a human intracellular pathogen. Upon invasion into mammalian cells, it senses multiple metabolic and environmental signals that collectively trigger its transition to the pathogenic state. One of these signals is the tripeptide glutathione, which acts as an allosteric activator of Lm’s master virulence regulator, PrfA. While glutathione synthesis by Lm was shown to be critical for PrfA activation and virulence gene expression, it remains unclear how this tripeptide is synthesized under changing environments, especially in light of the observation that Lm is auxotrophic to one of its precursors, cysteine. Here, we show that the ABC transporter TcyKLMN is a cystine/cysteine importer that supplies cysteine for glutathione synthesis, hence mediating the induction of the virulence genes. Further, we demonstrate that this transporter is negatively regulated by three metabolic regulators: CodY, CymR and CysK, which sense and respond to changing concentrations of branched chain amino acids (BCAA) and cysteine. The data indicate that under low concentrations of BCAA, TcyKLMN is up-regulated, driving the production of glutathione by supplying cysteine, thereby facilitating PrfA activation. These findings provide molecular insight into the coupling of Lm metabolism and virulence, connecting BCAA sensing to cysteine uptake and glutathione biosynthesis, as a mechanism that controls virulence gene expression. This study exemplifies how bacterial pathogens sense their intracellular environment and exploit essential metabolites as effectors of virulence.

Importance

Bacterial pathogens sense the repertoire of metabolites in the mammalian niche and use this information to shift into a pathogenic state to accomplish successful infection. Glutathione is a virulence-activating signal that is synthesized by L. monocytogenes during infection of mammalian cells. In this study, we show that cysteine uptake via TcyKLMN drives glutathione synthesis and virulence gene expression. The data emphasize the intimate cross-regulation between metabolism and virulence in bacterial pathogens.
Artemisia annuahot-water extracts show potent activityin vitroagainst Covid-19 variants including delta
Authors: Nair M.S. , Huang Y. , Fidock D.A. , Towler M.J. , Weathers P.J.
Published: September 2021

Ethnopharmacological relevance

For millennia in Southeast Asia,Artemisia annuaL. was used to treat “fever”. This medicinal plant is effective against numerous infectious microbial and viral diseases and is used by many global communities as a source of artemisinin derivatives that are first-line drugs to treat malaria.

Aim of the Study

The SARS-CoV-2 (Covid-19) global pandemic has killed millions and evolved numerous variants, with delta being the most transmissible to date and causing break-through infections of vaccinated individuals. We further queried the efficacy ofA. annuacultivars against new variants.

Materials and Methods

Using Vero E6 cells, we measured anti-SARS-CoV-2 activity of dried-leaf hot-waterA. annuaextracts of four cultivars, A3, BUR, MED, and SAM, to determine their efficacy against five fully infectious variants of the virus: alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), and kappa (B.1.617.1).

Results

In addition to being effective against the original wild type WA1,A. annuacultivars A3, BUR, MED and SAM were also potent against all five variants. IC50and IC90values based on measured artemisinin content ranged from 0.3-8.4 μM and 1.4-25.0 μM, respectively. The IC50and IC90values based on dried leaf weight (DW) used to make the tea infusions ranged from 11.0-67.7 μg DW and 59.5-160.6 μg DW, respectively. Cell toxicity was insignificant at a leaf dry weight of ≤50 μg in the extract of any cultivar.

Conclusions

Results suggest that oral consumption ofA. annuahot-water extracts (tea infusions), could provide a cost-effective therapy to help stave off the rapid global spread of these variants, buying time for broader implementation of vaccines.
Efficient transgenesis and homology-directed gene targeting in monolayers of primary human small intestinal and colonic epithelial stem cells
Authors: Breau Keith A. , Ok Meryem T. , Gomez-Martinez Ismael , Burclaff Joseph , Kohn Nathan P. , Magness Scott T.
Published: September 2021

Background & Aims

2D monolayers of primary intestinal and colonic epithelial cells represent next-generation in vitro models of the gut. Efficient transgenesis and gene-editing in human intestinal stem cells (hISCs) would significantly improve utility of these models by enabling generation of reporter and loss/gain-of-function hISCs, but no published methods exist for transfecting 2D hISC monolayers. Electroporation has proven effective in other difficult-to-transfect cells; thus we applied this method to hISCs.

Methods

Twenty-four electroporation parameters were tested, and the optimal condition for efficiency and viability was validated on hISCs from six anatomical regions along the small intestine and colon. PiggyBac™ transposase and Cas9 ribonucleoprotein (RNP) complexes were used for stable genomic integration of reporter genes. High-throughput methods for clone isolation, expansion, and screening were developed. An hISC OLFM4-emGFP reporter was generated and validated by qPCR, organoid assays, and hISC compartmentalization on a planar crypt-microarray (PCM) device.

Results

Maximum electroporation efficiency was 79.9% with a mean survival of 65%. Transfection of 105 hISCs produced ∼142 (0.14%) stable transposase-mediated clones. Transfection of OLFM4-targetting RNPs yielded ∼35% editing and 99/220 (45%) of antibiotic-resistant colonies analyzed expressed emGFP. OLFM4-emGFP hISCs applied to PCMs remained emGFP+ and proliferative in high-Wnt3a/R-spondin3/Noggin zones yet differentiated to emGFP-/KRT20+ cells outside engineered crypt zones. OLFM4-emGFP levels correlated with endogenous OLFM4. Olfm4-emGFPhigh cells were LGR5high/KRT20low, and demonstrated high organoid-forming potential.

Conclusions

Electroporation of hISCs is highly efficient for stable transgenesis and transgenic lines can be generated in 3-4 weeks. Workflows mirror conventional culture methods, facilitating rapid integration into established tissue-culture operations. OLFM4high is a robust hISC marker with functional properties in culture.
An anti-SARS-CoV-2 non-neutralizing antibody with Fc-effector function defines a new NTD epitope and delays neuroinvasion and death in K18-hACE2 mice
Authors: Beaudoin-Bussières Guillaume , Chen Yaozong , Ullah Irfan , Prévost Jérémie , Tolbert William D. , Symmes Kelly , Ding Shilei , Benlarbi Mehdi , Gong Shang Yu , Tauzin Alexandra , Gasser Romain , Chatterjee Debashree , Vézina Dani , Goyette Guillaume , Richard Jonathan , Zhou Fei , Stamatatos Leonidas , McGuire Andrew T. , Charest Hughes , Roger Michel , Pozharski Edwin , Kumar Priti , Mothes Walther , Uchil Pradeep D. , Pazgier Marzena , Finzi Andrés
Published: September 2021

Emerging evidence in animal models indicate that both neutralizing activity and Fc- mediated effector functions of neutralizing antibodies contribute to protection against SARS-CoV-2. It is unclear if antibody effector functions alone could protect against SARS-CoV-2. Here we isolated CV3-13, a non-neutralizing antibody from a convalescent individual with potent Fc-mediated effector functions that targeted the N- terminal domain (NTD) of SARS-CoV-2 Spike. The cryo-EM structure of CV3-13 in complex with SAR-CoV-2 spike revealed that the antibody bound from a distinct angle of approach to a novel NTD epitope that partially overlapped with a frequently mutated NTD supersite in SARS-CoV-2 variants. While CV3-13 did not alter the replication dynamics of SARS-CoV-2 in a K18-hACE2 transgenic mouse model, an Fc-enhanced CV3-13 significantly delayed neuroinvasion and death in prophylactic settings. Thus, we demonstrate that efficient Fc-mediated effector functions can contribute to the in vivo efficacy of anti-SARS-CoV-2 monoclonal antibodies in the absence of neutralization.