bluuebunny/crossref_metadata_2025 huggingface dataset:
Projected Impact and Cost-effectiveness of Community-based Versus Targeted Azithromycin Administration Strategies for Reducing Child Mortality in Sub-Saharan Africa
Authors: Brander Rebecca L , Weaver Marcia R , Pavlinac Patricia B , John-Stewart Grace C , Hawes Stephen E , Walson Judd L
Published: January 2020

Background

Trials of mass drug administration (MDA) of azithromycin (AZM) report reductions in child mortality in sub-Saharan Africa. AZM targeted to high-risk children may preserve benefit while minimizing antibiotic exposure. We modeled the cost-effectiveness of MDA to children 1–59 months of age, MDA to children 1–5 months of age, AZM administered at hospital discharge, and the combination of MDA and postdischarge AZM.

Methods

Cost-effectiveness was modeled from a payer perspective with a 1-year time horizon, and was presented as cost per disability-adjusted life-year (DALY) averted and death averted, with probabilistic sensitivity analyses. The model included parameters for macrolide resistance, adverse events, hospitalization, and mortality sourced from published data.

Results

Assuming a base-case 1.64% mortality risk among children 1–59 months old, 3.1% among children 1–5 months old, 4.4% mortality risk postdischarge, and 13.5% mortality reduction per trial data, MDA would avert ~267 000 deaths at a cost of $14.26/DALY averted (95% uncertainty interval [UI], 8.72–27.08). MDA to only children 1–5 months old would avert ~186 000 deaths at a cost of $4.89/DALY averted (95% UI, 2.88–11.42), and postdischarge AZM would avert ~45 000 deaths, at a cost of $2.84/DALY (95% UI, 1.71–5.57) averted. Cost-effectiveness decreased with presumed diminished efficacy due to macrolide resistance.

Conclusions

Targeting AZM to children at highest risk of death may be an antibiotic-sparing and highly cost-effective, or even cost-saving, strategy to reduce child mortality. However, targeted AZM averts fewer absolute deaths and may not reach all children who would benefit. Any AZM administration decision must consider implications for antibiotic resistance.
Effect of Delaying Treatment on Efficacy of Ciprofloxacin and Levofloxacin in the African Green Monkey Model of Pneumonic Plague
Authors: Campbell Joseph L , Fay Michael P , Lanning Lynda L , Hewitt Judith A
Published: January 2020

Background

Ciprofloxacin and levofloxacin, 2 fluoroquinolone antimicrobials, are ≥90% effective for the treatment of inhalational plague when administered within 2–6 hours of fever onset in African green monkeys (AGM). Based on data in the AGM model, these antimicrobials were approved under the Food and Drug Administration’s Animal Efficacy Rule. However, that data did not address the issue of how long treatment with these antimicrobials would remain effective after fever onset.

Methods

The AGM model of pneumonic plague was used to explore the effect of delaying treatment with ciprofloxacin and levofloxacin on efficacy. In 2 studies, AGMs were challenged with inhaled lethal doses of Yersinia pestis. Treatment with ciprofloxacin and levofloxacin was initiated from 0 to up to 30 hours after fever onset.

Results

Challenged animals all developed fever within 78 hours and were treated with ciprofloxacin (n = 27) or levofloxacin (n = 29) at various predetermined time points postfever. When administered 10 hours after fever onset, 10 days of ciprofloxacin and levofloxacin treatment remained very effective (90 or 100%, respectively). The efficacy of both antimicrobials declined as treatment initiation was further delayed. Statistical analyses estimated the treatment delay times at which half of the AGMs were no longer expected to survive as 19.7 hours for ciprofloxacin and 26.5 hours for levofloxacin.

Conclusions

This study demonstrates that there is a narrow window following fever onset during which ciprofloxacin and levofloxacin are fully effective treatment options for pneumonic plague in AGMs. Since the timing of disease is similar in humans and AGMs, these AGM data are reasonably likely to predict response times for treatment in humans.
Outcome of Ileal Pouch-anal Anastomosis in Patients With Indeterminate Colitis: A Systematic Review and Meta-analysis
Authors: Emile Sameh Hany , Gilshtein Hayim , Wexner Steven D
Published: January 2020

Background

Indeterminate colitis [IC] is type of inflammatory bowel disease that exhibits features of both ulcerative colitis [UC] and Crohn’s disease [CD]. The present meta-analysis aimed to assess the outcomes of ileal pouch-anal anastomosis [IPAA] in patients with IC in comparison with patients with UC.

Methods

A PRISMA-compliant systematic review of the outcome of IPAA in patients with IC was conducted. Electronic databases were searched, and full-text articles were reviewed to extract essential data. Main outcome measures were pouch failure and pouch-related complications.

Results

A total of 17 studies were included in this meta-analysis. There were 1057 patients with IC and 6511 patients with UC. The weighted mean pouch failure rate in patients with IC was 7.5 (95% confidence interval [CI]: 4.8–10.2) and the weighted mean complication rate was 67 [95% CI: 53.5–80.5]. As compared with patients with UC, patients with IC had significantly higher odds of developing complications after IPAA (odds ratio [OR]: 2.6, p <0.001): pouch fistula [OR:4.98, p <0.001], pelvic sepsis [OR:3.98, p =0.002], pelvic or cuff abscess [OR: 4.5, p <0.001], perineal complications [OR: 5.13, p <0.001], and ultimate diagnosis of CD [OR: 2.57, p <0.001]. Patients with IC and UC had similar odds of pouch failure, pouchitis, anastomotic leak, stricture, and small bowel obstruction.

Conclusions

Patients with IC had similar pouch failure rates, yet higher overall complication rates than patients with UC. Complications that tend to be higher after IPAA for patients with IC include pouch fistula, pelvic sepsis, abscess, perineal complications, and ultimate diagnosis of Crohn’s disease.
Diversification economies in dairy farming – empirical evidence from Germany
Authors: Wimmer Stefan , Sauer Johannes
Published: January 2020

This article explores how farm size is related to economic benefits from diversification. Using a data set pertaining to Bavarian dairy farms (2000–2014), we estimate an input distance function (IDF) to derive cost complementarities between distinct outputs. A Bayesian estimation technique is used to improve the theoretical consistency of the IDF. The results show that small dairy farms are more likely to benefit from diversification between milk and livestock production, while larger farms tend to benefit from diversification between milk and crop production. Both managerial and policy implications are discussed.
Informal Caregiver Burden, Benefits, and Older Adult Mortality: A Survival Analysis
Authors: Pristavec Teja , Luth Elizabeth A
Published: January 2020

Objective

Informal caregivers are crucial to maintaining older adults’ health, but few studies examine how caregiving receipt is associated with older person longevity. In a nationally representative sample, we prospectively explore whether and how having an informal caregiver is associated with older adult overall mortality, and how caregivers’ burden and benefits perceptions relate to care recipient mortality.

Methods

We match six National Health and Aging Trends Study waves (2011–2016) with 2011 National Study of Caregiving data, conducting survival analysis on 7,369 older adults and 1,327 older adult-informal caregiver dyads.

Results

Having an informal caregiver is associated with 36% (p < .001) higher mortality risk over 6-year follow-up, adjusting for demographic, economic, and health factors. Older adults whose caregivers perceive only burden have 38% higher (p < .05) mortality risk than those with caregivers reporting neither burden nor benefits. This risk is reduced from 38% higher to 5% higher (p < .001) for older adults with caregivers reporting benefits alongside burden, compared to those with caregivers reporting neither perception.

Discussion

Having a caregiver may signal impending decline beyond known mortality factors. However, interventions to increase caregivers’ benefit perceptions and reduce their burden may decrease mortality risk for older adults with declining health and functional ability.
Application of temporal reweighting to ambient noise cross-correlation for improved seismic Green's function
Authors: Li Jiangtao , Weaver Richard L , Yoritomo John Y , Song Xiaodong
Published: January 2020

Due to the partly diffuse character of ambient noise, the retrieval of amplitude information and attenuation from noise cross-correlations has been difficult. Here, we apply the temporal reweighting method proposed by Weaver & Yoritomo to seismic data from the USArray in the central-midwest US. The results show considerable improvements in retrieved Green's functions in both symmetry and causality. The reweighting is able to make the effective incident noise field more isotropic (though not yet truly isotropic). It produces more robust amplitude measurements and also makes both the causal and anticausal parts usable. This suggests that it could be widely applicable for retrieval of Green's functions from ambient noise for attenuation study. The results also suggest an alternative measure of signal-to-noise ratio that complements the conventional one.
The sialyltransferase ST6GAL1 protects against radiation-induced gastrointestinal damage
Authors: Punch Patrick R , Irons Eric E , Manhardt Charles T , Marathe Himangi , Lau Joseph T Y
Published: January 2020

High-dose irradiation poses extreme risk of mortality from acute damage to the hematopoietic compartment and gastrointestinal tract. While bone marrow transplantation can reestablish the hematopoietic compartment, a more imminent risk of death is posed by gastrointestinal acute radiation syndrome (GI-ARS), for which there are no FDA-approved medical countermeasures. Although the mechanisms dictating the severity of GI-ARS remain incompletely understood, sialylation by ST6GAL1 has been shown to protect against radiation-induced apoptosis in vitro. Here, we used a C57BL/6 St6gal1-KO mouse model to investigate the contribution of ST6GAL1 to susceptibility to total body irradiation in vivo. Twelve gray total body ionizing γ-irradiation (TBI) followed by bone marrow transplant is not lethal to wild-type mice, but St6gal1-KO counterparts succumbed within 7 d. Both St6gal1-KO and wild-type animals exhibited damage to the GI epithelium, diarrhea and weight loss, but these symptoms became progressively more severe in the St6gal1-KO animals while wild-type counterparts showed signs of recovery by 120 h after TBI. Increased apoptosis in the GI tracts of St6gal1-KO mice and the absence of regenerative crypts were also observed. Together, these observations highlight an important role for ST6GAL1 in protection and recovery from GI-ARS in vivo.
Novel fisheries investigations by Harald Dannevig: some parallels with Johan Hjort on the other side of the world
Authors: Suthers Iain M , Reid Dennis D , Moksness Erlend , Schilling Hayden T
Published: January 2020

Harald Dannevig was Australia’s first Director of fisheries research and Director of Australia’s first ocean-going research vessel. Dannevig’s initial contributions concerned hatchery technology, freshwater fisheries, and impacts of estuarine prawn trawling. Later, he revealed the growth and migration of sea mullet, the spawning of pelagic eggs in the coastal ocean, and he was the first to demonstrate the effect of onshore winds on recruitment to estuarine fisheries. Using plans of the first Norwegian research trawler Michael Sars, he advised on the construction and commissioning of Endeavour. He organized 99 research voyages over 6 years to determine suitable trawling grounds over ∼7000 km, discovering 263 new species, including 96 new fish species and ∼5000 catalogued specimens. Harald Dannevig’s significant achievements in Australia were soon forgotten after his death with the loss of Endeavour in the Southern Ocean at the beginning of World War I. Both Johan Hjort and Dannevig were numerate, loved natural history, and were keenly observant on the deck. As these two scientists did not correspond, their innovative and parallel thinking stems from the shared university environment with G.O. Sars, and the rapport between Sars and Harald’s father Gunder Dannevig, concerning the fish hatchery and stocking of larval cod.
Guidelines for Thrombolytic Therapy for Frostbite
Authors: Hickey Sean , Whitson Amy , Jones Larry , Wibbenmeyer Lucy , Ryan Colleen , Fey Ryan , Litt Jeffrey , Fabia Renata , Cancio Lee , Mohr William , Twomey John , Wagner Anne , Cochran Amalia , Bailey J Kevin
Published: January 2020

The data are insufficient to support standardized treatment of all patients with frostbite with thrombolytic therapy. The following guidelines, however, should be applied to all patients with cyanosis persisting proximal to the distal phalanx (Grade 3 or 4 frostbite injury) and demonstrated loss of perfusion at or proximal to the middle phalanx immediately after rewarming.
The renal replacement therapy landscape in 2030: reducing the global cardiovascular burden in dialysis patients
Authors: Canaud Bernard , Collins Allan , Maddux Frank
Published: January 2020

Despite the significant progress made in understanding chronic kidney disease and uraemic pathophysiology, use of advanced technology and implementation of new strategies in renal replacement therapy, the clinical outcomes of chronic kidney disease 5 dialysis patients remain suboptimal. Considering residual suboptimal medical needs of short intermittent dialysis, it is our medical duty to revisit standards of dialysis practice and propose new therapeutic options for improving the overall effectiveness of dialysis sessions and reduce the burden of stress induced by the therapy. Several themes arise to address the modifiable components of the therapy that are aimed at mitigating some of the cardiovascular risks in patients with end-stage kidney disease. Among them, five are of utmost importance and include: (i) enhancement of treatment efficiency and continuous monitoring of dialysis performances; (ii) prevention of dialysis-induced stress; (iii) precise handling of sodium and fluid balance; (iv) moving towards heparin-free dialysis; and (v) customizing electrolyte prescriptions. In summary, haemodialysis treatment in 2030 will be substantially more personalized to the patient, with a clear focus on cardioprotection, volume management, arrhythmia surveillance, avoidance of anticoagulation and the development of more dynamic systems to align the fluid and electrolyte needs of the patient on the day of the treatment to their particular circumstances.
Evaluating the Effects of a Brief Tobacco Intervention in the US Air Force
Authors: Little Melissa A , Fahey Margaret C , Klesges Robert C , McMurry Timothy , Talcott Gerald W
Published: January 2020

Introduction

Military personnel have among the highest rates of tobacco use in the United States. Unfortunately, there are few interventions aimed at reducing tobacco use among this vulnerable population. The current study addresses this need by evaluating the short-term effectiveness of a Brief Tobacco Intervention (BTI), a 40-min group-based intervention designed to reduce contemporary patterns of tobacco use among a sample of US military enlistees during an 11-week period of involuntary tobacco abstinence.

Aims and Methods

Participants were 2999 US Air Force Technical Trainees at Joint Base San Antonio-Lackland Air Force Base in San Antonio, Texas from April 2017 through January 2018. Participants were cluster randomized to three conditions: (1) BTI + Airman’s Guide to Remaining Tobacco Free (AG), (2) AG intervention, or (3) standard smoking cessation intervention. The primary analysis was a comparison of the interventions’ efficacies in preventing tobacco use during Technical Training, conducted using a generalized estimating equations logistic regression model controlling for covariates. Multiple imputation was used to account for loss to follow-up.

Results

There was not a significant difference by condition in the use of tobacco products at follow-up (p = .454). The BTI + AG condition did produce short-term changes in perceived harm, intentions to use tobacco, knowledge about tobacco products, and normative beliefs.

Conclusions

These findings suggest that while the intervention was effective in the short term, it was not potent enough over a 12-week period to prevent Airmen from initiating tobacco use. Future studies should examine whether adding a booster session or media campaign enhances the effectiveness of the intervention.

Implications

Despite the fact that most Airmen believe they will remain tobacco free following the ban in Technical Training, a large percentage of these Airmen resume and initiate tobacco use during this high-risk period. As a result, there is a need for interventions targeting the range of tobacco available to military trainees during a teachable moment when they report intentions to remain tobacco free. The current study shows that a BTI has promise in reducing long-term tobacco use, when coupled with additional interventions, such as a booster session or a media campaign.
Petrologic Insights into Rift Zone Magmatic Interactions from the 2011 Eruption of Kīlauea Volcano, Hawaiʻi
Authors: Walker Brett H , Garcia Michael O , Orr Tim R
Published: January 2020

The high frequency of historical eruptions at Kīlauea Volcano presents an exceptional opportunity to address fundamental questions related to the transport, storage, and interaction of magmas within rift zones. The Nāpau Crater area on Kīlauea’s East Rift Zone (ERZ) experienced nine fissure eruptions within 50 years (1961–2011). Most of the magma intruded during these frequent eruptions remained stored within the rift zone, creating a potential magma mixing depot within the ERZ. The superbly monitored and sampled 2011 eruption (Puʻu ʻŌʻō episode 59) presents an extraordinary opportunity to evaluate magma mixing processes within the ERZ. Whole-rock, glass, and olivine compositions were determined, not only for lava from the 2011 eruption, but also for a new suite of Nāpau Crater area samples from the 1963, 1965, 1968, 1983, and 1997 eruptions, as well as the previously undocumented 1922 eruption. Whole-rock XRF data revealed two geochemically distinct magma batches for episode 59: one less evolved (∼6·6 wt % MgO, 0·46 wt % K2O) than the other (∼6·2 wt % MgO, 0·58 wt % K2O). Episode 59 lava is remarkably aphyric (∼0·1 vol. % phenocrysts), making use of mineralogy to identify parent magma affinities problematic. Linear compositional trends of whole-rock major and trace elements, and reversely zoned olivine crystals indicate episode 59 lavas underwent magma mixing. Least squares regression calculations and plots of major and trace element data, were used to evaluate whether the episode 59 samples are products of mixing summit-derived magma with residual magma from previous Nāpau Crater area eruptions. The regression results and trace element ratios are inconsistent with previously proposed mixing scenarios, but they do support mixing between summit-derived magma and residual magma from the 1983 and 1997 Nāpau Crater area eruptions. These magmas were stored in physically and chemically distinct pods at depths of 1·6–3·0 km prior to mixing with new magma intruded from the summit to produce the episode 59 lava. One pod contained a fractionated equivalent of 1983 lava, and the other a hybrid of compositions similar to 1983 and 1997 lavas. The petrology of episode 59 lava demonstrates that magmas from two previous eruptions (1983 and 1997) were available to mix with magma intruded from the summit region. This study clarifies the pre-eruptive history of the mixed episode 59 lava, and elucidates the evolution of the volcano's magmatic system in a region of frequent eruptions.
Molecular phylogeny of freshwater snails and limpets (Panpulmonata: Hygrophila)
Authors: Saadi Ahmed J , Davison Angus , Wade Christopher M
Published: January 2020

We have undertaken a comprehensive molecular phylogenetic analysis of the Hygrophila based on 3112 sites of the large subunit and 5.8S ribosomal RNA genes. A clear basal division between Chilinoidea and Lymnaeoidea is observed. The monophyly of Acroloxidae, Lymnaeidae and Physidae is also well established. However, Planorbidae are not supported as a monophyletic group, because the Bulinidae cluster within Planorbidae. The Amphipepleinae within Lymnaeidae and both Planorbinae and Ancylinae within Planorbidae are strongly supported as monophyletic subfamilies. However, the Aplexinae within Physidae and the Lymnaeinae within Lymnaeidae are not recovered. A new taxonomic revision of the Hygrophila is proposed based on the findings of this molecular phylogeny, and the implications for the evolution of chirality are discussed.
A Simple Intervention to Decrease Nutrient Losses in Continuous Feeds With Human Milk
Authors: Davidson Jennifer , Elabiad Mohamad T.
Published: January 2020

Objectives:

Current evidence suggests that a significant amount of human milk fat is lost because of tubing adsorption. The objective was to evaluate the effect of reintroducing tubing leftover milk on the quality of macronutrient content of delivered milk.

Methods:

This was an in vitro study. The standard method of preparing and delivering fortified human milk includes preparing a small extra volume that would be used for priming the connection tubes. At the end of the infusion, the tubes and any milk leftover would be discarded. This method was compared with a new method where by the exact milk volume was prepared and used to prime the connection tubes. Leftover tubing milk was pushed with air.

Results:

The standard method was associated with significant losses in fat, protein, and calories of 16.7%, 3.4%, and 9.2% compared with the new method of 8.2%, 0%, and 3.3%, respectively. These losses in the standard method were predominantly explained by the significant gains in the left over milk contents of fat 6.3 ± 1.1 g/dL, protein 3.5 ± 0.4 g/dL, and calories 28 ± 2.6 kcal/oz as compared with prepared milk of 4.8 ± 0.3, 2.9 ± 0.3 g/dL, and 24.0 ± 0.8 kcal/oz respectively, P = 0.002.

Conclusions:

Traditional continuous delivery methods of human milk are associated with significant losses of fat and protein. By preparing the exact amount of ordered milk and then pushing through the residual milk left in the tubing with a small amount of air, this study offers a simple intervention that would significantly decrease these losses.
Altered Gut Microbiota Is Present in Newly Diagnosed Pediatric Patients With Inflammatory Bowel Disease
Authors: Sila Sara , Jelić Marko , Trivić Ivana , Tambić Andrašević Arjana , Hojsak Iva , Kolaček Sanja
Published: January 2020

Background and aims:

Clinical and experimental data suggest that gut microbiota plays an important role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to determine intestinal microbiota in newly diagnosed patients with IBD and to compare it with patients’ healthy siblings who share same genetic and environmental background and to healthy unrelated controls.

Methods:

Molecular approach targeting 16S ribosomal RNA was employed for analyzing the gut microbiota of participants’ stool samples. Terminal restriction fragment length polymorphphism analysis was performed.

Results:

Newly diagnosed pediatric patients with IBD (n = 19, 68.4% Crohn disease [CD], mean age 14.8 ± 0.65 years), their unaffected healthy siblings (n = 20, mean age 12.8 ± 0.85 years), and unrelated healthy controls (n = 19, mean age 10.7 ± 0.8 years) were included. Microbial diversity differed significantly between IBD patients, healthy siblings, and healthy controls (P = 0.018 for MspI digestion, P = 0.013 for HhaI digestion). No significant difference in microbial diversity was found between healthy siblings and healthy controls. In patients reduced presence of genus Eubacterium, Lactobacillus, Enterobacter and Clostridium, and increased presence of genus Streptococcus, Prevotella and Escherichia, compared with healthy siblings and healthy controls, was found.

Conclusion:

Newly diagnosed pediatric patients with IBD show significantly less diverse microbiota and microbial composition compared with healthy siblings and healthy controls.
Reliability of Visual Analog Scale and Numeric Rating Scale for the Assessment of Disease Activity in Systemic Lupus Erythematosus
Authors: Elera-Fitzcarrald Claudia , Vega Karen , Gamboa-Cárdenas Rocío V. , Zúñiga Katiuska , Zevallos Francisco , Reátegui-Sokolova Cristina , Pastor-Asurza César , Perich-Campos Risto , Rodríguez Bellido Zoila , Aranow Cynthia , Alarcón Graciela S. , Calvo Armando , Ugarte-Gil Manuel F.
Published: January 2020

Objective

To determine the reliability of SLE patients' disease activity measurements.

Methods

This was a cross-sectional study conducted (August 2016–December 2017) at 2 main public Peruvian hospitals, 1 with a comprehensive lupus care program. Patients assessed their disease activity with a visual analog scale (VAS) (0–100 mm) or a numerical rating scale (NRS) (0–4) before and after their physician's (MD's) assessment. Demographic and disease-related characteristics were recorded. Reliability of patients' disease activity before and after MD's assessment was determined using Spearman rank correlation. Factors possibly associated with this variability were examined with Spearman rank correlation and Mann-Whitney U test.

Results

Two hundred forty, mostly Mestizo, SLE patients were included; mean (SD) age and disease duration (diagnosis) were 34.9 (12.9) years and 10.1 (7.0) years, respectively. The Mexican version of the Systemic Lupus Erythematosus Disease Activity Index was 1.9 (2.7), and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index was 1.2 (1.5). The correlations between NRS and VAS before and after the MD's assessment were ρ = 0.839; p < 0.001; and ρ = 0.872; p < 0.001, respectively. Visual analog scale and NRS were higher before than after the MD's assessment (VAS 29.3 [26.5] and 26.5 [24.9], p = 0.052; and NRS (1.5 [1.2] and 1.3 [1.1], p = 0.003); only the comprehensive program explained this variability (p = 0.043). The reliability of VAS and NRS was ρ = 0.917 and ρ = 0.861, p < 0.001, before and after for the comprehensive program and ρ = 0.710 and ρ = 0.785, p < 0.001, for before and after for the regular program.

Conclusions

Both VAS an NRS are highly reliable. Patients scored higher before than after their physicians' assessment but that these differences were smaller for the patients in the comprehensive care program than in the regular one.
Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival
Authors: Barcia Giulia , Rio Marlène , Assouline Zahra , Zangarelli Coralie , Roux Charles-Joris , de Lonlay Pascale , Steffann Julie , Desguerre Isabelle , Munnich Arnold , Bonnefont Jean-Paul , Boddaert Nathalie , Rötig Agnès , Metodiev Metodi D. , Ruzzenente Benedetta
Published: January 2020

Mitochondrial translation is essential for the biogenesis of the mitochondrial oxidative phosphorylation system (OXPHOS) that synthesizes the bulk of ATP for the cell. Hypomorphic and loss-of-function variants in either mitochondrial DNA or in nuclear genes that encode mitochondrial translation factors can result in impaired OXPHOS biogenesis and mitochondrial diseases with variable clinical presentations.

Compound heterozygous or homozygous missense and frameshift variants in the FARS2 gene, that encodes the mitochondrial phenylalanyl-tRNA synthetase, are commonly linked to either early-onset epileptic mitochondrial encephalopathy or spastic paraplegia. Here, we expand the genetic spectrum of FARS2-linked disease with three patients carrying novel compound heterozygous variants in the FARS2 gene and presenting with spastic tetraparesis, axial hypotonia and myoclonic epilepsy in two cases.
Surgical candidacy and treatment uptake among women with cervical cancer at public referral hospitals in Kampala, Uganda
Authors: Swanson Megan L , Nakalembe Miriam , Chen Lee-may , Ueda Stefanie M , Namugga Jane , Nakisige Carol , Huchko Megan J
Published: January 2020

Purpose

Cervical cancer is the most common malignancy among women in Uganda. Most present with advanced disease, when hysterectomy is not possible and cure is less likely. This study reports the proportion recommended for hysterectomy and associated factors, recommended treatments by stage, and treatment uptake.

Methods

We conducted a prospective study among patients seeking care for cervical cancer at public referral hospitals in Uganda. In-person surveys were followed by a phone call. Descriptive and multivariate statistical analyses examined associations between predictors and outcomes.

Results

Among 268 participants, 76% were diagnosed at an advanced stage (IIB-IVB). In total, 12% were recommended for hysterectomy. In adjusted analysis, living within 15 kilometers of Kampala (OR 3.10, 95% CI 1.20-8.03) and prior screening (OR 2.89, 95% CI 1.22-6.83) were significantly associated with surgical candidacy. Radiotherapy availability was not significantly associated with treatment recommendations for early-stage (IA-IIA) disease, but was associated with recommended treatment modality (chemo-radiation versus primary chemotherapy) for locally advanced stage (IIB-IIIB). Most (67%) had started treatment. No demographic or health factor, treatment recommendation, or radiation availability was associated with treatment initiation. Among those recommended for hysterectomy, 55% underwent surgery. Among those who had initiated treatment, 82% started the modality that was actually recommended.

Conclusion

Women presented to public referral centers in Kampala with mostly advanced-stage cervical cancer and few were recommended for surgery. Lack of access to radiation did not significantly increase the proportion of early-stage cancers recommended for hysterectomy.
Non-canonical glutamate signaling in a genetic model of migraine with aura
Authors: Parker Patrick D. , Suryavanshi Pratyush , Melone Marcello , Reinhart Katelyn M. , Sawant-Pokam Punam M. , Kaufmann Dan , Theriot Jeremy J. , Pugliese Arianna , Conti Fiorenzo , Shuttleworth C. William , Pietrobon Daniela , Brennan K.C.
Published: January 2020

Migraine with aura is an extremely common but poorly understood sensory circuit disorder. Monogenic models allow an opportunity to understand its mechanisms, in particular because the migraine aura is associated with spreading depolarizations that can be measured physiologically. Using fluorescent glutamate imaging in awake mice carrying a familial hemiplegic migraine type 2 mutation, we recorded previously undescribed spontaneous ‘plumes’ of glutamate signaling that anatomically overlapped with reduced density of GLT-1a positive astrocyte processes. These events could be mimicked in wild-type animals by inhibition of glutamate clearance, which we show to be slower during sensory processing in FHM2 carriers. Plumes depended on calcium mediated vesicular release from neurons, but not action potentials. Importantly, a rise in both basal glutamate and plume frequency predicted the onset of spreading depolarization in WT and FHM2 animals, providing a novel mechanism in migraine with aura and by extension the many other neurological disorders where spreading depolarizations occur.
VolPy: automated and scalable analysis pipelines for voltage imaging datasets
Authors: Cai Changjia , Friedrich Johannes , Pnevmatikakis Eftychios A , Podgorski Kaspar , Giovannucci Andrea
Published: January 2020

Voltage imaging enables monitoring neural activity at sub-millisecond and sub-compartment scale, and therefore opens the path to studying sub-threshold activity, synchrony, and network dynamics with unprecedented spatio-temporal resolution. However, high data rates (>800MB/s) and low signal-to-noise ratios have created a severe bottleneck for analysis of such datasets. Here we presentVolPy, the first turn-key, automated and scalable pipeline to pre-process voltage imaging datasets.VolPyfeatures fast motion correction, memory mapping, segmentation, and spike inference, all built on a highly parallelized and computationally efficient framework that optimizes memory and speed. Given the lack of single cell voltage imaging ground truth examples, we introduce a corpus of 24 manually annotated datasets from different preparations and voltage indicators. We benchmarkVolPyagainst this corpus and electrophysiology recordings, demonstrating excellent performance in neuron localization, spike extraction, and scalability.
AMPKα1 is essential for Glucocorticoid Receptor triggered anti-inflammatory macrophage activation
Authors: Caratti Giorgio , Desgeorges Thibaut , Juban Gaëtan , Koenen Mascha , Kozak Bozhena , Théret Marine , Chazaud Bénédicte , Tuckermann Jan P , Mounier Rémi
Published: January 2020

Macrophages are key immune cells which mediate both the acute inflammatory phase and the repair phase after tissue damage. Macrophages switch from pro-inflammatory to anti-inflammatory cells that sustain repair and return to tissue homeostasis. We show that the metabolic sensor, AMP-activated protein kinase (AMPK) is essential for glucocorticoid induction of an anti-inflammatory macrophage phenotype. While canonical gene regulation by glucocorticoids was not affected by loss of AMPK, we identified AMPK-dependent glucocorticoid-regulated genes in macrophages, related to efferocytosis. AMPK-deficient macrophages do not acquire phenotypic and functional anti-inflammatory features upon glucocorticoid exposure. We identified FOXO3 as an AMPK-dependent regulator of glucocorticoid activity in macrophages. Loss of AMPK in macrophagesin vivoabrogates glucocorticoid anti-inflammatory actions during post-injury muscle regeneration and endotoxin induced acute lung injury. These data highlight that the glucocorticoid receptor is dependent on AMPK for its immunomodulatory actions in macrophages, linking their metabolic status to transcriptional control in resolving inflammation.
Near-chromosome level genome assembly of the fruit pestDrosophila suzukiiusing long-read sequencing
Authors: Paris Mathilde , Boyer Roxane , Jaenichen Rita , Wolf Jochen , Karageorgi Marianthi , Green Jack , Cagnon Mathilde , Parinello Hugues , Estoup Arnaud , Gautier Mathieu , Gompel Nicolas , Prud’homme Benjamin
Published: January 2020

Over the past decade, the spotted wing Drosophila, Drosophila suzukii, has invaded Europe and America and has become a major agricultural pest in these areas, thereby prompting intense research activities to better understand its biology. Two draft genome assemblies based on short-read sequencing were released in 2013 for this species. Although valuable, these resources contain pervasive assembly errors and are highly fragmented, two features limiting their values. Our purpose here was to improve the assembly of theD. suzukiigenome. For this, we generated PacBio long-read sequencing data at 160X sequence coverage and assembled a novel, contiguousD. suzukiigenome. We obtained a high-quality assembly of 270 Mb (with 546 contigs, a N50 of 2.6Mb, a L50 of 15, and a BUSCO score of 95%) that we called WT3-2.0. We found that despite 16 rounds of full-sib crossings theD. suzukiistrain that we sequenced has maintained high levels of polymorphism in some regions of its genome (ca. 19Mb). As a consequence, the quality of the assembly of these regions was reduced. We explored possible origins of this high residual diversity, including the presence of structural variants and a possible heterogeneous admixture pattern of North American and Asian ancestry. Overall, our WT3-2.0 assembly provides a higher quality genomic resource compared to the previous one in terms of general assembly statistics, sequence quality and gene annotation. This newD. suzukiigenome assembly is therefore an improved resource for high-throughput sequencing approaches, as well as manipulative genetic technologies to studyD. suzukii.
Human Genes AreIn SilicoPotential Targets For Rice miRNA
Authors: Rakhmetullina Aizhan , Pyrkova Anna , Aisina Dana , Ivashchenko Anatoliy
Published: January 2020

Exogenous miRNAs enter the human body through food, and their effects on metabolic processes can be considerable. It is important to determine which miRNAs from plants affect the expression of human genes and the extent of their influence. The binding sites of 738 osa-miRNAs that interact with 17508 mRNAs of human genes were determined using the MirTarget program. The characteristics of the binding of 46 single osa-miRNAs to 86 mRNAs of human genes with a value of free energy (ΔG) interaction equal 94% to 100% from maximum ΔG were established. The findings showed that osa-miR2102-5p, osa-miR5075-3p, osa-miR2097-5p, osa-miR2919 targeted the largest number of genes at 38, 36, 23, 19 sites, respectively. mRNAs of 86 human genes were identified as targets for 93 osa-miRNAs of all family osa-miRNAs with ΔG values equal 94% to 98% from maximum ΔG. Each miRNA of the osa-miR156-5p, osa-miR164-5p, osa-miR168-5p, osa-miR395-3p, osa-miR396-3p, osa-miR396-5p, osa-miR444-3p, osa-miR529-3p, osa-miR1846-3p, osa-miR2907-3p families had binding sites in mRNAs of several human target genes. The binding sites of osa-miRNAs in mRNAs of the target genes for each family of osa-miRNAs were conserved when compared to flanking nucleotide sequences. mRNA human genes of osa-miRNAs are candidate genes of cancer, cardiovascular and neurodegenerative diseases.
Light Sheet Fluorescence Microscopy as a New Method for Unbiased Three-Dimensional Analysis of Vascular Injury
Authors: Buglak Nicholas E. , Lucitti Jennifer , Ariel Pablo , Maiocchi Sophie , Miller Francis J. , Bahnson Edward S. M.
Published: January 2020

Aims

Assessment of preclinical models of vascular disease are paramount in the successful translation of novel treatments. The results of these models have traditionally relied on 2-D histological methodologies. Light sheet fluorescence microscopy (LSFM) is an imaging platform that allows for 3-D visualization of whole organs and tissues. In this study, we describe an improved methodological approach utilizing LSFM for imaging of preclinical vascular injury models while minimizing analysis bias.

Methods and Results

The rat carotid artery segmental pressure-controlled balloon injury and mouse carotid artery ligation injury were performed. Arteries were harvested and processed for LSFM imaging and 3-D analysis, as well as for 2-D area histological analysis. Artery processing for LSFM imaging did not induce vessel shrinkage or expansion, and was reversible by rehydrating the artery, allowing for subsequent sectioning and histological staininga posteriori. By generating a volumetric visualization along the length of the arteries, LSFM imaging provided different analysis modalities including volumetric, area, and radial parameters. Thus, LSFM-imaged arteries provided more precise measurements compared to classic histological analysis. Furthermore, LSFM provided additional information as compared to 2-D analysis in demonstrating remodeling of the arterial media in regions of hyperplasia and periadventitial neovascularization around the ligated mouse artery.

Conclusions

LSFM provides a novel and robust 3-D imaging platform for visualizing and quantifying arterial injury in preclinical models. When compared with classic histology, LSFM outperformed traditional methods in precision and quantitative capabilities. LSFM allows for more comprehensive quantitation as compared to traditional histological methodologies, while minimizing user bias associated with area analysis of alternating, 2-D histological artery cross-sections.

Translational Perspective

A more reproducible and robust quantitation of vascular pathology in preclinical models is necessary to accelerate translational discovery. Current methodology to assess vascular disease has significant limitations. The methodology described herein employs a modern imaging modality, light sheet fluorescence microscopy (LSFM), to improve assessment of established preclinical vascular injury models. LSFM provides more comprehensive and precise analysis capabilities than classical histological approaches. Hence, LSFM applied to vascular research has the potential to drive new basic discoveries, and ultimately translation of novel therapies.
Plant Trans-Golgi Network/Early Endosome pH regulation requires Cation Chloride Cotransporter (CCC1)
Authors: McKay Daniel W , Qu Yue , McFarlane Heather E , Situmorang Apriadi , Gilliham Matthew , Wege Stefanie
Published: January 2020

Plant cells maintain a low luminal pH in the Trans-Golgi-Network/Early Endosome (TGN/EE), the organelle in which the secretory and endocytic pathways intersect. Impaired TGN/EE pH regulation translates into severe plant growth defects. The identity of the proton pump and proton/ion antiporters that regulate TGN/EE pH have been determined, but an essential component required to complete the TGN/EE membrane transport circuit remains unidentified − a pathway for cation and anion efflux. Here, we have used complementation, genetically encoded fluorescent sensors, and pharmacological treatments to demonstrate that the TGN/EE localised Arabidopsis Cation Chloride Cotransporter (CCC1) is this missing component necessary for regulating TGN/EE pH and function. Loss of CCC1 function leads to alterations in TGN/EE-mediated processes including endo- and exocytosis, and trafficking to the vacuole, and response to abiotic stress, consistent with the multitude of phenotypes observed in ccc1 knockout plants. This discovery places CCC1 as a central component of plant cellular function.
Cellular identity and Ca2+signaling activity of the non-reproductive GnRH system in theCionalarva
Authors: Okawa Nanako , Shimai Kotaro , Ohnishi Kohei , Ohkura Masamichi , Nakai Junichi , Horie Takeo , Kuhara Atsushi , Kusakabe Takehiro G.
Published: January 2020

Tunicate larvae have a non-reproductive gonadotropin-releasing hormone (GnRH) system with multiple ligands and receptor heterodimerization enabling complex regulation. In theCionalarva, one of thegnrhgenes,gnrh2, is conspicuously expressed in the motor ganglion and nerve cord, which are homologous structures to the hindbrain and spinal cord, respectively, of vertebrates. Thegnrh2gene is also expressed in the proto-placodal sensory neurons, which are the proposed homologue of vertebrate olfactory neurons. The tunicate larvae occupy a non-reproductive dispersal stage, yet the role of their GnRH system remains elusive. In this study, we investigated neuronal types ofgnrh2-expressing cells inCionalarvae and visualized the activity of these cells by fluorescence imaging using a calcium sensor protein. Some cholinergic neurons and dopaminergic cells expressgnrh2, suggesting that GnRH plays a role in controlling swimming behavior. However, none of thegnrh2-expressing cells overlap with glycinergic or GABAergic neurons. A role in motor control is also suggested by the correlation between the activity of somegnrh2-expressing cells and tail movements. Interestingly,gnrh2-positive ependymal cells in the nerve cord, known as a kind of glia cells, actively produced Ca2+transients, suggesting that neuroendocrine signaling occurs in the glia cells of the nerve cord.
Temporal and spatial changes in phyllosphere microbiome of acacia trees growing in super arid environments
Authors: Al-Ashhab Ashraf , Meshner Shiri , Alexander-Shani Rivka , Brandwein Michael , Lavan Yael Bar , Winters Gidon
Published: January 2020

Along the arid Arava, southern Israel, acacia trees (Acacia raddianaandAcacia tortilis) are considered keystone species. In this study, we investigated the ecological effects of plant species, microclimate (different areas within the tree canopies) and seasonality on the endophytic and epiphytic microbiome associated with these two tree species. 186 leaf samples were collected along different seasons throughout the year and their microbial communities were studied using the diversity of the 16S rDNA gene sequenced on the 150-PE Illumina sequencing platform. Results show that endophytic, but not epiphytic, microbiome communities were different between the two acacia species. Endophytic, but not epiphytic, microbiome was affected by temporal changes (seasons) in air temperature. Acacia canopy microclimate was also found to have a significant effect on exosphere microbiome, withA. tortilishaving a higher microbial diversity thanA. raddianawith significantly different community compositions in different seasons.

Importance

The evolutionary relationships and interactions between plants and their microbiome are of high importance to the survival of plants in extreme conditions. Changes in microbiome of plants can affect plant development, growth and health. In this study, we explored the relationship between keystone desert trees and their microbiome along seasonal variation. These results shed light on the importance and uniqueness of desert phyllosphere microbiome. Although acacia trees are considered keystone species in many arid regions, to the best of our knowledge, this is the first time that microbial descriptors have been applied in these systems. This work constitutes a new approach to the assessment of these important trees and a stepping stone in the application of microbial communities as a putative marker in a changing environment.
A novel toxin-antitoxin module SlvT–SlvA governs megaplasmid stability and incites solvent tolerance inPseudomonas putidaS12
Authors: Kusumawardhani Hadiastri , van Dijk David , Hosseini Rohola , de Winde Johannes H.
Published: January 2020

Pseudomonas putidaS12 is highly tolerant towards organic solvents in saturating concentrations, rendering this microorganism suitable for the industrial production of various aromatic compounds. Previous studies reveal thatP. putidaS12 contains a single-copy 583 kbp megaplasmid pTTS12. This pTTS12 encodes several important operons and gene clusters facilitatingP. putidaS12 to survive and grow in the presence of toxic compounds or other environmental stresses. We wished to revisit and further scrutinize the role of pTTS12 in conferring solvent tolerance. To this end, we cured the megaplasmid fromP. putidaS12 and conclusively confirmed that the SrpABC efflux pump is the major contributor of solvent tolerance on the megaplasmid pTTS12. Importantly, we identified a novel toxin-antitoxin module (proposed gene namesslvTandslvArespectively) encoded on pTTS12 which contributes to the solvent tolerant phenotype and is essential in conferring genetic stability to the megaplasmid. Chromosomal introduction of thesrpoperon in combination withslvAT gene pair created a solvent tolerance phenotype in non-solvent tolerant strains such asP. putidaKT2440,E. coliTG1, andE. coliBL21(DE3).

Importance

Sustainable alternatives for high-value chemicals can be achieved by using renewable feedstocks in bacterial biocatalysis. However, during bioproduction of such chemicals and biopolymers, aromatic compounds that function as products, substrates or intermediates in the production process may exert toxicity to microbial host cells and limit the production yield. Therefore, solvent-tolerance is a highly preferable trait for microbial hosts in the biobased production of aromatic chemicals and biopolymers. In this study, we revisit the essential role of megaplasmid pTTS12 from solvent-tolerantP. putidaS12 for molecular adaptation to organic solvent. In addition to the RND efflux pump (SrpABC), we identified a novel toxin-antitoxin module (SlvAT) which contributes to tolerance in low solvent concentration as well as to genetic stability of pTTS12. These two gene clusters were successfully transferred to non-solvent tolerant strains ofP. putidaand toE. colistrains to confer and enhance solvent tolerance.