bluuebunny/crossref_metadata_2025 huggingface dataset:
Vγ usage distinguishes pro- and anti-tumor intestinal γδ T cell subsets
Authors: Reis Bernardo S. , Darcy Patrick W. , Khan Iasha Z. , Eleso Olawale , Zhu Caixia , Schernthanner Marina , Lockhart Ainsley , Reed Aubrey , Bortolatto Juliana , Castro Tiago B. R. , Bilate Angelina M. , Grivennikov Sergei , Mucida Daniel
Published: November 2021

γδ T cells physiologically scan the intestinal epithelium, representing a substantial fraction of infiltrating lymphocytes in colorectal cancer (CRC), albeit their role in CRC remains unclear. Using murine CRC models, we found that most γδ T cells in pre- or non-tumor colon express Vγ1+ or Vγ7+ and exhibit a cytotoxic profile. Targeting these γδ T cell subsets, as well as conditionally interfering with γδ T cell function at early stages of tumorigenesis led to heightened tumor development, suggesting anti-CRC functions for Vγ1+ and Vγ7+ subsets. In contrast, RORγt+ γδ T cell subsets, including Vγ4+ and microbiotadependent Vγ6+, accumulated during CRC progression. Conditional deletion of RORγt or Vγ chains revealed redundant roles for IL-17–producing Vγ4+ and Vγ6+ γδ T cells in promoting tumor growth. Our results uncover pro- and anti-tumor roles for γδ T cell subsets.
Cost-effectiveness analysis of BNT162b2 COVID-19 booster vaccination in the United States
Authors: Li Rui , Liu Hanting , Fairley Christopher K , Zou Zhuoru , Xie Li , Li Xinghui , Shen Mingwang , Li Yan , Zhang Lei
Published: November 2021

Background

Over 86% of older adults aged ≥65 years are fully vaccinated against SARS-COV-2 in the United States (US). Waning protection of the existing vaccines promotes the new vaccination strategies, such as providing a booster shot for those fully vaccinated.

Methods

We developed a decision-analytic Markov model of COVID-19 to evaluate the cost-effectiveness of a booster strategy of Pfizer-BioNTech BNT162b2 (administered 6 months after 2nd dose) in those aged ≥65 years, from a healthcare system perspective.

Findings

Compared with 2-doses of BNT162b2 without a booster, the booster strategy in a 100,000 cohort of older adults would incur an additional cost of $3.4 million, but save $6.7 million in direct medical costs in 180 days. This corresponds to a benefit-cost ratio of 1.95 and a net monetary benefit of $3.4 million. Probabilistic sensitivity analysis indicates that with a COVID-19 incidence of 9.1/100,000 person-day, a booster strategy has a high chance (67%) of being cost-effective. The cost-effectiveness of the booster strategy is highly sensitive to the population incidence of COVID-19, with a cost-effectiveness threshold of 8.1/100,000 person-day. This threshold will increase with a decrease in vaccine and booster efficacies. Doubling the vaccination cost or halving the medical cost for COVID-19 treatment alone would not alter the conclusion of cost-effectiveness, but certain combinations of the two might render the booster strategy not cost-effective.

Interpretation

Offering BNT162b2 boosters to older adults aged ≥65 years in the US is likely to be cost-effective. Less efficacious vaccines and boosters may still be cost-effective in settings of high SARS-COV-2 transmission.

Funding

National Natural Science Foundation of China. Berlina and Bill Gates Foundation
F0-F1 coupling and symmetry mismatch in ATP synthase resolved in every F0 rotation step
Authors: Kubo Shintaroh , Niina Toru , Takada Shoji
Published: November 2021

The F0F1 ATP synthase, essential for cellular energy production, is composed of the F0 and F1 rotary motors. While both F0 and F1 have pseudo-symmetric structures, their symmetries do not match. How the symmetry mismatch is solved remains elusive due to missing intermediate structures of rotational steps. Here, for ATP synthases with 3- and 10-fold symmetries in F1 and F0, respectively, we uncovered the mechanical couplings between F0 and F1 at every 36° rotation step via molecular dynamics simulations and comparison of cryo-electron microscopy structures from three species. We found that the frustration is shared by several elements. The F1 stator partially rotates relative to the F0 stator via elastic distortion of the b-subunits. The rotor can be distorted. The c-ring rotary angles can be deviated from symmetric ones. Additionally, the F1 motor may take non-canonical structures relieving stronger frustration. Together, we provide comprehensive understanding to solve the symmetry mismatch.
Fluctuating heat stress during development exposes reproductive costs and putative benefits
Authors: Rodrigues Leonor R. , McDermott Hayley A. , Villanueva Irene , Djukarić Jana , Ruf Lena C. , Amcoff Mirjam , Snook Rhonda R.
Published: November 2021

Temperature and thermal variability are increasing worldwide, with well‐known survival consequences. However, effects on other potentially more thermally sensitive reproductive traits are less understood, especially when considering thermal variation. Studying the consequences of male reproduction in the context of climate warming and ability to adapt is becoming increasingly relevant.

Our goals were to test how exposure to different average temperatures that either fluctuated or remained constant impacts different male reproductive performance traits and to assess adaptive potential to future heat stress.

We took advantage of a set of Drosophila melanogaster isogenic lines of different genotypes, exposing them to four different thermal conditions. These conditions represented a benign and a stressful mean temperature, applied either constantly or fluctuating around the mean and experienced during development when heat stress avoidance is hindered because of restricted mobility. We measured subsequent male reproductive performance for mating success, fertility, number of offspring produced and offspring sex ratio, and calculated the influence of thermal stress on estimated heritability and evolvability of these reproductive traits.

Both costs and benefits to different thermal conditions on reproductive performance were found, with some responses varying between genotypes. Mating success improved under fluctuating benign temperature conditions and declined as temperature stress increased regardless of genotype. Fertility and productivity were severely reduced at fluctuating mean high temperature for all genotypes, but some genotypes were unaffected at constant high mean temperature. These more thermally robust genotypes showed a slight increase in productivity under the fluctuating benign condition compared to constant high temperature, despite both thermal conditions sharing the same temperature for 6 hr daily. Increasing thermal stress resulted in higher heritability and evolvability.

Overall, the effects of temperature on reproductive performance depended on the trait and genotype; performance of some traits slightly increased when high temperatures were experienced for short periods but decreased substantially even when experiencing a benign temperature for a portion of each day. While thermal stress increased genetic variation that could provide adaptive potential against climate warming, this is unlikely to compensate for the overall severe negative effect on reproductive performance as mean temperature and variance increase.
Functional responses of fisheries to hydropower dams in the Amazonian Floodplain of the Madeira River
Authors: Arantes Caroline C. , Laufer Juliana , Pinto Mac David da Silva , Moran Emilio F. , Lopez Maria Claudia , Dutka‐Gianelli Jynessa , Pinto Danielle Mendonça , Chaudhari Suyog , Pokhrel Yadu , Doria Carolina R. C.
Published: November 2021

Tropical river fisheries support food security for millions of people but are increasingly threatened by hydropower development. How dams affect these fisheries remains poorly known in most regions. Here, we used a functional traits approach to evaluate the extent to which compositions of fishery yields in the Madeira River Basin, the largest sub‐basin in the Amazon, respond to dam construction. We also explored how dams affected the monetary value of yields and fishing‐based income of the communities.

We collected fishing data in 17 locations distributed over 300 km across upstream, reservoir and downstream zones during pre‐and post‐dam construction periods. We interviewed 711 fishers from 13 communities to assess fishing income during pre‐ and post‐dam periods.

Catch‐per‐unit effort (CPUE) declined significantly, that is, by 37%, after dam construction. Multivariate analysis yielded six species clusters according to trait syndromes related to life history, migration, swimming performance/habitat‐use and economic value that were associated with the environmental data characteristic of pre‐ and post‐dam periods. Comparison of CPUE of each cluster indicated that large species with periodic life‐history strategy and regional or long‐distance migratory behaviour were most affected by dam construction, with CPUE declining by, on average, 31%. Declines in yields and shifts in functional composition of the fishery yields resulted in average decline of 21% in the monetary value of functional clusters and 30% in fishing income.

Synthesis and applications. Our study indicates that the implementation of the dams affected the functional composition of yields and reduced catches, negatively affecting the fishing‐based income of communities in the Madeira River. These results imply that hydropower expansion will cause detrimental effects for fisheries and the livelihoods they sustain. Our results underscore the urgent need for considering alternative sources of renewable energy (e.g. solar power and in‐stream turbines) to avoid irreversible socio‐environmental damages of large dam projects. In river reaches where dams are already in operation or under construction, minimizing impacts will require improving operational protocols to reduce hydrological alterations and developing research and technology to improve the functionality of fish passages. In these locations, addressing losses in fishery value and fishing‐based income will also require the implementation of fair compensation measures. Maintaining fish production requires conserving flow pulses and free‐flowing rivers and tributaries critical for completing life cycles of fish species with vulnerable traits.
Gestational weight gain in twin gestations and pregnancy outcomes: a systematic review and meta‐analysis
Authors: Lipworth H , Barrett JFR , Murphy KE , Redelmeier D , Melamed N
Published: November 2021

Background

Data on the association of inappropriate gestational weight gain (GWG) and adverse outcomes in twin pregnancies are limited and inconsistent.

Objectives

To perform a systematic review and meta‐analysis on the association between GWG and adverse outcomes in twin pregnancies.

Search strategy

Ovid, Medline, EMBASE and Cochrane Central databases from 1 January 1990 until 23 September 2020.

Selection criteria

Interventional and observational studies evaluating the association between GWG and adverse outcomes in twin pregnancies.

Data collection and analysis

Data were extracted by two independent reviewers. Summary odds ratios (OR) were calculated using a random‐effects model in a subset of studies that analysed GWG as a categorical variable in relation to the Institute of Medicine (IOM) recommendations. The primary outcome was preterm birth.

Main results

From 277 citations, 19 studies involving 36 023 women with twin pregnancies were included in the qualitative analysis, of which 14 were included in the meta‐analysis. Overall, 56.8% of women experienced inappropriate GWG: 35.4% (95% CI 30.0–41.0%) gained weight below and 21.4% (95% CI 14.2–29.5%) gained weight above IOM recommendations. Compared with GWG within IOM guidelines, GWG below IOM guidelines was associated with preterm birth before 32 weeks of gestation (OR 3.38; 95% CI 2.05–5.58), and a reduction in the risk of pre‐eclampsia (OR 0.68; 95% CI 0.48–0.97). GWG above IOM guidelines was associated with an increased risk of pre‐eclampsia that was consistent across all body mass index categories.

Conclusions

Inappropriate GWG affects over half of twin pregnancies, so is a common and potentially modifiable risk factor for preterm birth and pre‐eclampsia.
Risk of preterm birth in relation to history of preterm birth: a population‐based registry study of 213 335 women in Norway
Authors: Tingleff T , Vikanes Å , Räisänen S , Sandvik L , Murzakanova G , Laine K
Published: November 2021

Objective

To assess the association between preterm first birth and preterm second birth according to gestational age and to determine the role of placental disorder in recurrent preterm birth.

Design

Population‐based registry study.

Setting

Medical Birth Registry of Norway and Statistics Norway.

Population

Women (n = 213 335) who gave birth to their first and second singleton child during 1999–2014 (total n = 426 670 births).

Methods

Multivariate logistic regression analyses, adjusted for placental disorders, maternal, obstetric and socio‐economic factors.

Main outcome measures

Extremely preterm (<28+0 weeks), very preterm (28+0–33+6 weeks) and late preterm (34+0–36+6 weeks) second birth.

Results

Preterm birth (<37 weeks) rates were 5.6% for first births and 3.7% for second births. Extremely preterm second births (0.2%) occurred most frequently among women with an extremely preterm first birth (aOR 12.90, 95% CI 7.47–22.29). Very preterm second births (0.7%) occurred most frequently after an extremely preterm birth (aOR 12.98, 95% CI 9.59–17.58). Late preterm second births (2.8%) occurred most frequently after a previous very preterm birth (aOR 6.86, 95% CI 6.11–7.70). Placental disorders contributed 30–40% of recurrent extremely and very preterm births and 10–20% of recurrent late preterm birth.

Conclusion

A previous preterm first birth was a major risk factor for a preterm second birth. The contribution of placental disorders was more pronounced for recurrent extremely and very preterm birth than for recurrent late preterm birth. Among women with any category of preterm first birth, more than one in six also had a preterm second birth (17.4%).

Tweetable abstract

Preterm first birth is a major risk factor for subsequent preterm birth, regardless of maternal, obstetric or fetal risk factors.
Impact of prefilter dilution on IgG removal in membrane‐based therapeutic plasma exchange
Authors: Cabral Paul , Kaplan Andre A. , Phachu Deep , Shah Mamta , Attique Hassan Bin , Elali Ibrahim
Published: November 2021

Introduction

Previous studies have demonstrated that a “one plasma volume exchange” would result in an estimated 63% decline in pretreatment IgG levels. We evaluated the use of prefilter dilution with normal saline as a method to prevent filter failure without decreasing the efficiency of IgG removal.

Methods

Twenty‐one treatment sessions were analyzed and all received prefilter dilution with normal saline. Primary outcome was to determine whether prefilter dilution resulted in decreased treatment efficiency in removing the targeted IgG. Secondary outcome was filter failure in conjunction with the combined use of prefilter heparin and saline infusions.

Results

All 21 treatments (100%) received prefilter dilution with saline solution and 19/21 (90.47%) also received prefilter heparin (bolus and/or hourly infusion). We demonstrated a 60%–70% decline in pretreatment IgG levels.

Conclusion

Prefilter dilution during membrane‐based therapeutic plasma exchange based treatment did not result in a demonstrable decrease in efficiency of IgG removal while maintaining filter patency.
Adiponectin alleviated Alzheimer‐like pathologies via autophagy‐lysosomal activation
Authors: He Kaiwu , Nie Lulin , Ali Tahir , Wang Shujin , Chen Xiao , Liu Zizhen , Li Weifen , Zhang Kaiqin , Xu Jia , Liu Jianjun , Yu Zhi‐Jian , Yang Xifei , Li Shupeng
Published: November 2021

Adiponectin (APN) deficiency has also been associated with Alzheimer‐like pathologies. Recent studies have illuminated the importance of APN signaling in reducing Aβ accumulation, and the Aβ elimination mechanism remains rudimentary. Therefore, we aimed to elucidate the APN role in reducing Aβ accumulation and its associated abnormalities by targeting autophagy and lysosomal protein changes. To assess, we performed a combined pharmacological and genetic approach while using preclinical models and human samples. Our results demonstrated that the APN level significantly diminished in the plasma of patients with dementia and 5xFAD mice (6 months old), which positively correlated with Mini‐Mental State Examination (MMSE), and negatively correlated with Clinical Dementia Rating (CDR), respectively. APN deficiency accelerated cognitive impairment, Aβ deposition, and neuroinflammation in 5xFAD mice (5xFAD*APN KO), which was significantly rescued by AdipoRon (AR) treatment. Furthermore, AR treatment also markedly reduced Aβ deposition and attenuated neuroinflammation in APP/PS1 mice without altering APP expression and processing. Interestingly, AR treatment triggered autophagy by mediating AMPK‐mTOR pathway signaling. Most importantly, APN deficiency dysregulated lysosomal enzymes level, which was recovered by AR administration. We further validated these changes by proteomic analysis. These findings reveal that APN is the negative regulator of Aβ deposition and its associated pathophysiologies. To eliminate Aβ both extra‐ and intracellular deposition, APN contributes via the autophagic/lysosomal pathway. It presents a therapeutic avenue for AD therapy by targeting autophagic and lysosomal signaling.
Evidence that predator satiation drives reproductive synchrony in the desert masting grass, soft spinifex (Triodia pungens)
Authors: Wright Boyd R.
Published: November 2021

The predator satiation (PS) hypothesis of masting holds that seeding periodicity among plant populations enhances seed survival by starving granivores during low‐output periods and satiating reduced consumer populations during mast (high‐output) years. Although well‐studied in the northern hemisphere and in New Zealand, the PS hypothesis has received scant research attention in Australia. This is despite vegetation communities across nearly half the continent being dominated by masting species subject to high levels of seed predation (e.g. mulga [Acacia aneura] shrublands and spinifex [Triodia spp.] grasslands). Here, phenological monitoring and experimental testing of the PS hypothesis in the desert masting grass Triodia pungens (soft spinifex) occurred over 10 years at Deep Well station, central Australia. Field evidence supported the hypothesis that masting enhances seed escape from predators, as mean proportion seed survival at experimental bait stations was significantly greater during mast years (0.38 in 2012 and 0.33 in 2017) than during inter‐mast years (0.01 in 2016 and 2018). The possibility that seed decay as opposed to consumption affected results was controlled for by a deterioration experiment that indicated no significant loss of seed viability after 6‐months burial. The results support the hypothesis that masting in T. pungens is an adaptive trait related to the satiation of seed predators. However, whether masting enhances seed escape because predators are satiated at higher seed densities (i.e. masting causes a predator functional response) and/or because frequent low‐output periods reduce predator populations and make satiation more likely (i.e. a numerical predator masting response), remains unresolved. Aside from T. pungens, there are numerous other plants of the Australian arid zone that experience high levels of granivory and display masting. Seed predation may be a more important selective force acting on arid Australian plant reproduction than previously thought.
Seasonal biology of the wheat sheath miner Cerodontha australis (Diptera: Agromyzidae) in perennial ryegrass in Waikato, New Zealand
Authors: Jensen Joanne G. , Popay Alison J.
Published: November 2021

Cerodontha australis Malloch (wheat sheath miner) is a leaf mining fly native to New Zealand and eastern Australia that feeds on grasses and cereals. It is thought to have limited economic impact despite being one of the most widespread and common insects in New Zealand pastures. In this study, data on C. australis were gathered over an 18‐month period from field plots of endophyte‐free Lolium perenne. Observations from pot trials on parasitism and other leaf miner species are also presented. Larval numbers were highest in late spring to early summer. One distinct peak per year of eggs and pupae indicated that this species may not be multivoltine, contradicting previous literature. Damage levels were high in spring/summer, with leaf mining in up to 53% of tillers sampled and, in mid‐summer, extending into the pseudostem in up to 41% of sampled tillers. Measurement of cephaloskeleton lengths confirmed that this species has three larval instars. Generally, only one larva per tiller survives to pupation, indicating density dependent regulation of populations, and larval/ pupal parasitism can reach high levels in summer. This study provides new information on the seasonal biology of C. australis, and its potential impact on L. perenne pastures in Waikato, New Zealand.
Time since fire influences macropod occurrence in a fire‐prone coastal ecosystem
Authors: Chard Matthew , Foster Claire N. , Lindenmayer David B. , Cary Geoffrey J. , MacGregor Christopher I. , Blanchard Wade
Published: November 2021

Knowledge of animal responses to fire is fundamental to wildlife management in fire‐prone ecosystems. Fire can influence the occurrence of large herbivores by altering the structure and composition of vegetation. However, how fire affects herbivore occurrence in many ecosystems is poorly understood. Large herbivores may be attracted to burnt areas due to higher foraging quality. Conversely, herbivores may avoid burnt areas due to heightened predation risk. We tested the influence of vegetation type and fire history variables on the occurrence of macropods at Booderee National Park in south‐eastern Australia. We documented macropod occurrence at 107 long‐term monitoring sites using spotlighting surveys conducted between 2003 and 2019. We modelled relationships between the occurrence of the eastern grey kangaroo (Macropus giganteus) and the swamp wallaby (Wallabia bicolor) with three fire history variables; time since fire, fire frequency and burn context (the proportion of the area surrounding each site that was recently burnt), as well as their interaction with vegetation type. We found both macropod species selected recently burnt sites, likely due to a higher abundance of preferred plants at these sites. Increasing fire frequency was associated with a reduced occurrence of the eastern grey kangaroo. The occurrence of both macropod species was significantly higher in forest sites, possibly reflecting higher foraging quality of grass and shrub species compared to woodland, heathland and shrubland sites. We suggest that if fire is used as a management tool, it is important to recognise potential feedbacks from increased foraging pressure from large herbivores. Future fire management will need to avoid burning areas of sensitive vegetation if local herbivores display pyric herbivory responses, and/or avoid small‐scale burns, which may concentrate foraging pressure.
Evaluation of the effect of calcium hydroxide paste on sealer penetration into dentinal tubules by confocal laser scanning microscopy
Authors: Kanmaz Fatma , Altunbaş Demet
Published: November 2021

The study evaluated sealer penetration after calcium hydroxide (Ca(OH)2) removal from the root canals. Sixty single‐rooted mandibular premolars were divided into six groups. Ca(OH)2 paste placed into the root canals except for the control group (CG) was removed using the following irrigation techniques: conventional needle irrigation (CNI), EndoActivator (EA), EndoVac (EV), passive ultrasonic irrigation (PUI) and photon‐induced photoacoustic streaming (PIPS) technique. After canal filling, the penetration depth, penetration area and penetration percentage of the sealer were determined using confocal microscopy. The CG and EA had a greater penetration depth than CNI in the middle section. The CG exhibited a higher dentinal tubule penetration area than CNI, EV and PUI in the middle section. EA was significantly more effective than PUI in the coronal section for the percentage of sealer penetration. EA and PIPS removed Ca(OH)2 from root canals effectively because they presented similar penetration to the CG in all sections.
A review of the current concepts in canine urinary tract infections
Authors: Teh H
Published: November 2021

Traditionally, urinary tract infections (UTIs) have been categorised as either uncomplicated or complicated in veterinary medicine, with treatment differing for the two categories. In human medicine, there is an additional category: Asymptomatic bacteriuria, which is the presence of bacteriuria without symptoms of infection. Escherichia coli (E.coli) is the most common bacterial species involved in UTIs in dogs. Clinical signs can be absent in dogs with complicated UTIs, and this has been likened to asymptomatic bacteriuria (ASB) in people and has been termed subclinical bacteriuria (SBU) with the treatment recommendations for SBU in dogs have been adapted from human recommendations. There is a shift in the current treatment of UTIs to help minimise the development of antimicrobial resistance. Routine screening of dogs with conditions that may predispose them to UTIs has been discouraged as has the treatment of SBU. This has been due to the increase in antimicrobial resistance (AMR).
A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid‐targeted bromodomain and extra‐terminal domain inhibitor
Authors: Brown Jack A. , Bal Joanne , Simeoni Monica , Williams Peter , Mander Palwinder K. , Soden Peter E. , Daga Shruti , Fahy William A. , Wong Gabriel K. , Bloomer Jackie C. , Erwig Lars , Cui Yi , Fernando Disala , Carnaghan Helen , Banham‐Hall Edward J. , Hopkins Sarah , Davis Bill G. , Oliveira Joao J. D. , Prinjha Rabinder K.
Published: November 2021

Aims

GSK3358699 is a mononuclear myeloid‐targeted bromodomain and extra‐terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first‐in‐human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995).

Methods

Part A (N = 23) included three dose‐escalating periods of 1‐40 mg of GSK3358699 or placebo in two cohorts in a single ascending‐dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts.

Results

In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half‐life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1‐40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1‐hour post‐dose following 10 mg of GSK3358699 and 1 and 4 hours post‐dose following 20‐40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide‐induced monocyte chemoattractant protein (MCP)‐1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)‐6 and tumour necrosis factor (TNF).

The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization.

Conclusions

Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac‐related AEs, resulting in an inability to identify a suitable repeat‐dose regimen and study termination.
Meropenem pharmacokinetics in critically ill patients with or without burn treated with or without continuous veno‐venous haemofiltration
Authors: Selig Daniel J. , Akers Kevin S. , Chung Kevin K. , Pruskowski Kaitlin A. , Livezey Jeffrey R. , Por Elaine D.
Published: November 2021

Introduction

Severe burn injury involves widespread skin and tissue damage leading to systemic inflammation, hypermetabolism and multi‐organ failure. The hypermetabolic phase of burn injury has been associated with increased systemic antibiotic clearance; however, critical illness in the absence of burn may also induce similar physiologic changes. Continuous renal replacement therapy (CRRT) is often implemented in critically ill patients and may also affect antibiotic clearance. Although the pharmacokinetics (PK) of meropenem has been described in both the burn and non‐burn critically ill populations, direct comparative data is lacking.

Methods

For this study, we evaluated PK parameters of meropenem from 23 critically ill patients, burn or non‐burn, treated with or without continuous veno‐venous haemofiltration (CVVH) to determine the contribution of burn and CVVH to the variability of therapeutic meropenem levels.

Results

A two‐compartment model best described the data and revealed creatinine clearance (CrCl) and total burn surface area (TBSA) as significant covariates on clearance (CL) and peripheral volume of distribution (Vp), respectively. Of interest, non‐burn patients on CVVH displayed an overall lower inherent CL as compared to burn patients on CVVH (6.43 vs. 12.85 L/h). Probability of target attainment (PTA) simulations revealed augmented renal clearance (ARC) may necessitate dose adjustments, but TBSA and CVVH would not.

Conclusions

We recommend a standard dose of 1000 mg every 8 hours; however, if ARC is suspected, or the severity of illness requires a more stringent therapeutic target, we recommend a loading dose of 1000–2000 mg infused over 30 minutes to 1 hour followed by continuous infusion (3000–6000 mg over 24 hours), or intermittent infusion of 2000 mg every 8 hours.
What reduces prejudice in the real world? A meta‐analysis of prejudice reduction field experiments
Authors: Hsieh Wing , Faulkner Nicholas , Wickes Rebecca
Published: November 2021

Despite advances to promote acceptance and equity in many countries, prejudice remains a significant social problem. Promoting intergroup harmony requires knowledge about what works to reduce prejudice in community settings. This meta‐analysis of field experiments reveals the most effective intervention types and conditions for reducing negative attitudes towards minority groups in real‐world settings. Across 69 intervention arms and 24,378 participants, results reveal that prejudice reduction interventions are effective at improving attitudes towards minority groups in real‐world settings (d = 0.51, 95% CI [0.33; 0.68]). The prediction interval was −0.90 to 1.92. In this case, the prediction interval was particularly wide because of the high degree of heterogeneity detected in effect size. Subgroup analyses indicate that less commonly explored approaches, such as perceived variability, may have larger effect sizes than contact‐based interventions. Still, more research is needed to confirm the effects of these less‐researched approaches. Additionally, results show that interventions are more effective for school and college cohorts than for adults, and that the effects of prejudice reduction interventions endure over time.
Detrital zircons record the evolution of the Cathaysian Coastal Mountains along the South China margin
Authors: Chen Yan , Meng Jun , Liu Hao , Wang Chengshan , Tang Ming , Liu Tao , Zhao Yinan
Published: November 2021

The Cathaysian Coastal Mountains are thought to be an ancient high‐topographic feature that existed along the margin of South China. They are characterised by extensive Jurassic–Cretaceous magmatism; however, their formation mechanism and timing remains uncertain. In this paper, we present sedimentological and detrital zircon analyses from Cretaceous–Eocene strata and drainage sediments from Hainan Island. Our analyses show a change in provenance from a proximal Cathaysian Coastal arc source in Cretaceous strata to a widely distributed intra‐island granite source in the Eocene strata and modern river sediments. Reconstruction of the crustal thickness evolution for the South China margin from Eu/Eu*‐in‐zircon proxy shows significant crustal thickening during the Late Jurassic–Cretaceous, thereby suggesting the existence of the Cathaysian Coastal Mountains. Together with a compilation of detrital zircon U‐Pb ages in the northern basins of the South China Sea margin, we conclude that the Cathaysian Coastal Mountains extended from the Red River region to Taiwan along the South China margin during the Late Jurassic–Cretaceous and then collapsed/eroded from northeast to southwest during the Eocene–Miocene. This large mountain range supplied detrital sediments to the marginal basins in the northern South China Sea and formed a topographic barrier that prohibited moist Pacific air to reach the relatively arid inland area of South China during the Late Jurassic–Cretaceous.
The prognostic influence of lymphatic endothelium–specific hyaluronan receptor 1 in cancer: A systematic review
Authors: Karinen Sini , Hujanen Roosa , Salo Tuula , Salem Abdelhakim
Published: November 2021

Lymphangiogenesis is a key process in cancer development and metastasis. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE‐1) is a widely used marker for lymphatic endothelial cells (LEC), which also mediates immune and cancer cell migration. Recently, LYVE‐1–positive tumor cells were shown to acquire LEC‐like phenotype and exploit this receptor for lymphatic dissemination. Furthermore, selective targeting of LYVE‐1 impaired the growth of cancer‐related vasculature and reduced metastasis in vivo, signifying its role in therapeutic and prognostic applications. Although numerous studies have investigated the role of LYVE‐1 in cancer, a unifying detailed review of its prognostic utility is lacking to date. Thus, we compiled and critically appraised evidence from clinical studies comprising a total of 2352 patients diagnosed with different types of cancer and using a variety of experimental approaches. Collectively, most studies revealed a significant association between LYVE‐1 overexpression and dismal outcome of at least one survival estimate. Furthermore, the importance of vasculature location, intra‐ or peritumoral, and the influence of various lymphangiogenesis‐related parameters, such as lymphatic vessel density and invasion, were discussed. However, the specificity of LYVE‐1 staining is challenged by its expression in non‐LEC cells, implying the need for double labelling to better estimate its prognostic significance. In conclusion, this is to our knowledge the first comprehensive systematic review on the prognostic value of LYVE‐1 in cancer. More well‐designed studies across different populations and the development of standardized protocols would be paramount for the consistency of LYVE‐1 findings and for its potential transferability to clinical practice in future.
Labour Migration and Dislocation in India’s Silicon Valley
Authors: Bowers Rebecca
Published: November 2021

The migrant families who build India’s cities do so to meet practical and ritual aspirations rooted in the village, undergoing spatial and temporal fragmentation to maintain rural longevity and the possibilities of ritual time. This article contributes an alternative position to linear‐framed presumptions of migration and urbanity, illustrating instead how everyday experiences of dislocation can be productive through labor, timespace, and imagination; bridging the gulf between residence on urban construction sites in Bengaluru, southern India, and desired village homes. However, lived experiences of dislocation remain stratified by gender and class, leading to highly conjugated experiences of precarity, mobility, and possibility. Despite the urban ambivalence felt by women and girls as a result, a shared experience of dislocation enables entire families to undertake the grueling yet regenerative work of circular migration, ensuring the continuation and renewal of village life and ritual time through its incompleteness.
Clinical usefulness of red dichromatic imaging in hemostatic treatment during endoscopic submucosal dissection: First report from a multicenter, open‐label, randomized controlled trial
Authors: Fujimoto Ai , Saito Yutaka , Abe Seiichiro , Hoteya Syu , Nomura Kosuke , Yasuda Hiroshi , Matsuo Yasumasa , Uraoka Toshio , Kuribayashi Shiko , Tsuji Yosuke , Ohki Daisuke , Maehata Tadateru , Kato Motohiko , Yahagi Naohisa
Published: November 2021

Objectives

To verify the efficacy and safety of red dichromatic imaging (RDI) in hemostatic procedures during endoscopic submucosal dissection (ESD).

Methods

This is a multicenter randomized controlled trial of 404 patients who underwent ESD of the esophagus, stomach, colorectum. Patients who received hemostatic treatments by RDI during ESD were defined as the RDI group (n = 204), and those who received hemostatic treatments by white light imaging (WLI) were defined as the WLI group (n = 200). The primary endpoint was a shortening of the hemostasis time. The secondary endpoints were a reduction of the psychological stress experienced by the endoscopist during the hemostatic treatment, a shortened treatment time, and a non‐inferior perforation rate, in RDI versus WLI.

Results

The mean hemostasis time in RDI (n = 860) was not significantly shorter than that in WLI (n = 1049) (62.3 ± 108.1 vs. 56.2 ± 74.6 s; P = 0.921). The median hemostasis time was significantly longer in RDI than in WLI (36.0 [18.0–71.0] vs. 28.0 [14.0–66.0] s; P = 0.001) in a sensitivity analysis. The psychological stress was significantly lower in RDI than in WLI (1.71 ± 0.935 vs. 2.03 ± 1.038; P < 0.001). There was no significant difference in the ESD treatment time between RDI (n = 161) and WLI (n = 168) (58.0 [35.0–86.0] vs. 60.0 [38.0–88.5] min; P = 0.855). Four perforations were observed, but none of them took place during the hemostatic treatment.

Conclusions

Hemostatic treatment using RDI does not shorten the hemostasis time. RDI, however, is safe to use for hemostatic procedures and reduces the psychological stress experienced by endoscopists when they perform hemostatic treatment during ESD.

UMIN000025134.
A case for associational resistance: Apparent support for the stress gradient hypothesis varies with study system
Authors: Adams Amy E. , Besozzi Elizabeth M. , Shahrokhi Golya , Patten Michael A.
Published: November 2021

According to the stress gradient hypothesis (SGH), ecological interactions between organisms shift positively as environmental stress increases. In the case of associational resistance, habitat is modified to ameliorate stress, benefitting other organisms. The SGH is contentious due to conflicting evidence and theoretical perspectives, so we adopted a meta‐analytic approach to determine if it is widely supported across a variety of contexts, including different kingdoms, ecosystems, habitats, interactions, stressors, and life history stages. We developed an extensive list of Boolean search criteria to search the published ecological literature and successfully detect studies that both directly tested the hypothesis, and those that were relevant but never mentioned it. We found that the SGH is well supported by studies that feature bacteria, plants, terrestrial ecosystems, interspecific negative interactions, adults, survival instead of growth or reproduction, and drought, fire, and nutrient stress. We conclude that the SGH is indeed a broadly relevant ecological hypothesis that is currently held back by cross‐disciplinary communication barriers. More SGH research is needed beyond the scope of interspecific plant competition, and more SGH research should feature multifactor stress. There remains a need to account for positive interactions in scientific pursuits, such as associational resistance in tests of the SGH.
Protective factors for subjective cognitive decline individuals: trajectories and changes in a longitudinal study with Italian elderly
Authors: Mondini Sara , Pucci Veronica , Montemurro Sonia , Rumiati Raffaella Ida
Published: November 2021

Background and purpose

Many different factors have been hypothesized to modulate cognition in an aging population according to their functioning at baseline.

Methods

This retrospective study quantifies the relative contribution of age and sex as demographic factors, comorbidity, education and occupation (classified with the International Standard Classification of Occupation 2008) as cognitive reserve proxies in accounting for cognitive aging. All participants (3081) were evaluated at baseline with a complete neuropsychological test battery (T1) and those with unimpaired profiles were classified as subjective cognitive decline, those mildly impaired as mild neurocognitive decline and those severely impaired as major neurocognitive decline. From the first assessment 543 individuals were assessed a second time (T2), and 125 a third time (T3). Depending on whether they maintained or worsened their profile, based on their initial performance, participants were then classified as resistant or declining.

Results

At baseline, all individuals showed education and occupation as the best predictors of performance, in addition to age. Furthermore, across assessments, the resistant had higher levels of education and occupation than the declining. In particular, the education and occupation predicted cognitive performance in all groups considered, from the subjective cognitive decline to the one with the most severely impaired participants.

Conclusions

This study highlights the role of working activity in protecting from cognitive decline across all fragile elderly groups and even more so the individuals who are at very high risk of decline.
Phospholipid scrambling by a TMEM16 homolog of Arabidopsis thaliana
Authors: Boccaccio Anna , Picco Cristiana , Di Zanni Eleonora , Scholz‐Starke Joachim
Published: November 2021

Membrane asymmetry is important for cellular physiology and established by energy‐dependent unidirectional lipid translocases, which have diverse physiological functions in plants. By contrast, the role of phospholipid scrambling (PLS), the passive bidirectional lipid transfer leading to the break‐down of membrane asymmetry, is currently still unexplored. The Arabidopsis thaliana genome contains a single gene (At1g73020) with homology to the eukaryotic TMEM16 family of Ca2+‐activated phospholipid scramblases. Here, we investigated the protein function of this Arabidopsis homolog. Fluorescent AtTMEM16 fusions localized to the ER both in transiently expressing Arabidopsis protoplasts and HEK293 cells. A putative scrambling domain (SCRD) was identified on the basis of sequence conservation and conferred PLS to transfected HEK293 cells, when grafted into the backbone of the non‐scrambling plasma membrane‐localized TMEM16A chloride channel. Finally, AtTMEM16 ‘gain‐of‐function’ variants gave rise to cellular phenotypes typical of aberrant scramblase activity, which were reversed by the additional introduction of a ‘loss‐of‐function’ mutation into the SCRD. In conclusion, our data suggest AtTMEM16 works as an ER‐resident lipid scramblase in Arabidopsis.
Balancing Spatial and Non‐Spatial Variation in Varying Coefficient Modeling: A Remedy for Spurious Correlation
Authors: Murakami Daisuke , Griffith Daniel A.
Published: November 2021

This study discusses the importance of balancing spatial and non‐spatial variation in spatial regression modeling. Unlike spatially varying coefficients (SVC) modeling, which is popular in spatial statistics, non‐spatially varying coefficients (NVC) modeling has largely been unexplored in spatial fields. Nevertheless, as we will explain, consideration of non‐spatial variation is needed not only to improve model accuracy but also to reduce spurious correlation among varying coefficients, which is a major problem in SVC modeling. We consider a Moran eigenvector approach modeling spatially and non‐spatially varying coefficients (S&NVC). A Monte Carlo simulation experiment comparing our S&NVC model with existing SVC models suggests both modeling accuracy and computational efficiency for our approach. Beyond that, somewhat surprisingly, our approach identifies true and spurious correlations among coefficients nearly perfectly, even when usual SVC models suffer from severe spurious correlations. It implies that S&NVC model should be used even when the analysis purpose is modeling SVCs. Finally, our S&NVC model is employed to analyze a residential land price data set. Its results suggest existence of both spatial and non‐spatial variation in regression coefficients in practice. The S&NVC model is now implemented in the R package spmoran.
Blocking T‐cell egress with FTY720 extends DNA vaccine expression but reduces immunogenicity
Authors: Mann Jamie F. S. , McKay Paul F. , Klein Katja , Pankrac Joshua , Tregoning John S. , Shattock Robin J.
Published: November 2021

Optimal immunogenicity from nucleic acid vaccines requires a balance of antigen expression that effectively engages the host immune system without generating a cellular response that rapidly destroys cells producing the antigen and thereby limiting vaccine antigen expression. We investigated the role of the cellular response on the expression and antigenicity of DNA vaccines using a plasmid DNA construct expressing luciferase. Repeated intramuscular administration led to diminished luciferase expression, suggesting a role for immune‐mediated clearance of expression. To investigate the role of cell trafficking, we used the sphingosine 1‐phosphate receptor (S1PR) modulator, FTY720 (Fingolimod), which traps lymphocytes within the lymphoid tissues. When lymphocyte trafficking was blocked with FTY720, DNA transgene expression was maintained at a constant level for a significantly extended time period. Both continuous and staggered administration of FTY720 prolonged transgene expression. However, blocking lymphocyte egress during primary transgene administration did not result in an increase of transgene expression during secondary administration. Interestingly, there was a disconnect between transgene expression and immunogenicity, as increasing expression by this approach did not enhance the overall immune response. Furthermore, when FTY720 was administered alongside a DNA vaccine expressing the HIV gp140 envelope antigen, there was a significant reduction in both antigen‐specific antibody and T‐cell responses. This indicates that the developing antigen‐specific cellular response clears DNA vaccine expression but requires access to the site of expression in order to develop an effective immune response.
BCG‐mediated protection against M. tuberculosis is sustained post‐malaria infection independent of parasite virulence
Authors: Tangie Emily , Walters Avril , Hsu Nai‐jen , Fisher Michelle , Magez Stefan , Jacobs Muazzam , Keeton Roanne
Published: November 2021

Tuberculosis (TB) and malaria remain serious threats to global health. Bacillus Calmette‐Guerin (BCG), the only licensed vaccine against TB protects against severe disseminated forms of TB in infants but shows poor efficacy against pulmonary TB in adults. Co‐infections have been reported as one of the factors implicated in vaccine inefficacy. Given the geographical overlap of malaria and TB in areas where BCG vaccination is routinely administered, we hypothesized that virulence‐dependent co‐infection with Plasmodium species could alter the BCG‐specific immune responses thus resulting in failure to protect against Mycobacterium tuberculosis. We compared virulent Plasmodium berghei and non‐virulent Plasmodium chabaudi, their effects on B cells, effector and memory T cells, and the outcome on BCG‐induced efficacy against M. tuberculosis infection. We demonstrate that malaria co‐infection modulates both B‐ and T‐cell immune responses but does not significantly alter the ability of the BCG vaccine to inhibit the growth of M. tuberculosis irrespective of parasite virulence. This malaria‐driven immune regulation may have serious consequences in the early clinical trials of novel vaccines, which rely on vaccine‐specific T‐cell responses to screen novel vaccines for progression to the more costly vaccine efficacy trials.