bluuebunny/crossref_metadata_2025 huggingface dataset:
Outpatient Fluoroquinolone Use in Children, 2000–2018
Authors: Ross Rachael K , Gerber Jeffrey S , Willis Zachary I , Hersh Adam L , Kinlaw Alan C
Published: November 2020

Background

While fluoroquinolones are commonly used in adults, the use in children has been low. Since 2000, there were 3 US Food and Drug Administration (FDA) Boxed warnings regarding fluoroquinolones (2008, 2013, and 2016). Our objective was to describe the use of fluoroquinolones in children and assess the impact of 3 recent FDA warnings on fluoroquinolone use.

Methods

From 2000 to 2018, we assessed claims for all outpatient prescription fills to measure the use of systemic fluoroquinolones and other broad-spectrum antibiotics in children  less than 18 years old in the MarketScan Commercial Claims and Encounters database. We describe demographics, indication for antibiotic, and clinical characteristics. To assess the impact of FDA warnings on fill rates, we conducted an interrupted time-series analysis.

Results

The cohort included 34.6 million unique beneficiaries less than 18 years old with 441 062 fluoroquinolone fills (5.5 fills per 1000 person-years). The fluoroquinolone fill rate was highest among children > 11 years old. Urinary tract infection was the most common associated diagnosis (21.8%). Since 2008, the fluoroquinolone fill rate has declined. By the end of the study period in December 2018, in the (counterfactual) absence of the FDA warnings, fluoroquinolone fill rate would have been 7.5 (95% confidence interval [CI]: 5.2-9.7); however, the corresponding rate in observed data was 2.8 (95% CI: 1.7-3.9).

Conclusions

Fluoroquinolone use was low compared with other common broad-spectrum antibiotics and declining trends over time were associated with FDA warnings, even though these warnings were not pediatric specific. Future work should assess the adverse events at issue in these warnings in children.
Knocking out NEGATIVE REGULATOR OF PHOTOSYNTHESIS 1 increases rice leaf photosynthesis and biomass production in the field
Authors: Chen Faming , Zheng Guangyong , Qu Mingnan , Wang Yanjie , Lyu Ming-Ju Amy , Zhu Xin-Guang
Published: November 2020

Improving photosynthesis is a major approach to increasing crop yield potential. Here we identify a transcription factor as a negative regulator of photosynthesis, which can be manipulated to increase rice photosynthesis and plant biomass in the field. This transcription factor, named negative regulator of photosynthesis 1 (NRP1; Os07g0471900), was identified through a co-expression analysis using rice leaf RNA sequencing data. NRP1 expression showed significantly negative correlation with the expression of many genes involved in photosynthesis. Knocking out NRP1 led to greater photosynthesis and increased biomass in the field, while overexpression of NRP1 decreased photosynthesis and biomass. Transcriptomic data analysis shows that NRP1 can negatively regulate the expression of photosynthetic genes. Protein transactivation experiments show that NRP1 is a transcription activator, implying that NRP1 may indirectly regulate photosynthetic gene expression through an unknown regulator. This study shows that combination of bioinformatics analysis with transgenic testing can be used to identify new regulators to improve photosynthetic efficiency in crops.
The CIB1 transcription factor regulates light- and heat-inducible cell elongation via a two-step HLH/bHLH system
Authors: Ikeda Miho , Mitsuda Nobutaka , Ishizuka Toru , Satoh Mai , Ohme-Takagi Masaru
Published: November 2020

Light and high temperature promote plant cell elongation. PHYTOCHROME INTERACTING FACTOR4 (PIF4, a typical basic helix-loop-helix [bHLH] transcriptional activator) and the non-DNA binding atypical HLH inhibitors PHYTOCHROME RAPIDLY REGULATED1 (PAR1) and LONG HYPOCOTYL IN FAR-RED 1 (HFR1) competitively regulate cell elongation in response to light conditions and high temperature. However, the underlying mechanisms have not been fully clarified. Here, we show that in Arabidopsis thaliana, the bHLH transcription factor CRYPTOCHROME-INTERACTING BASIC HELIX-LOOP-HELIX 1 (CIB1) positively regulates cell elongation under the control of PIF4, PAR1, and HFR1. Furthermore, PIF4 directly regulates CIB1 expression by interacting with its promoter, and PAR1 and HFR1 interfere with PIF4 binding to the CIB1 promoter. CIB1 activates genes that function in cell elongation, and PAR1 interferes with the DNA binding activity of CIB1, thus suppressing cell elongation. Hence, two antagonistic HLH/bHLH systems, the PIF4–PAR1/HFR1 and CIB1–PAR1 systems, regulate cell elongation in response to light and high temperature. We thus demonstrate the important role of non-DNA binding small HLH proteins in the transcriptional regulation of cell elongation in plants.
TCP5 controls leaf margin development by regulating KNOX and BEL-like transcription factors in Arabidopsis
Authors: Yu Hongyang , Zhang Ling , Wang Weiyao , Tian Peng , Wang Wei , Wang Keyi , Gao Zhong , Liu Shuai , Zhang Yongxia , Irish Vivian F , Huang Tengbo
Published: November 2020

Development of leaf margins is an important process in leaf morphogenesis. CIN-clade TCP (TEOSINTE BRANCHED1/CYCLOIDEA/PCF) transcription factors are known to have redundant roles in specifying leaf margins, but the specific mechanisms through which individual TCP genes function remain elusive. In this study, we report that the CIN-TCP gene TCP5 is involved in repressing the initiation and outgrowth of leaf serrations by activating two key regulators of margin development, the Class II KNOX factor KNAT3 and BEL-like SAW1. Specifically, TCP5 directly promotes the transcription of KNAT3 and indirectly activates the expression of SAW1. We also show that TCP5 regulates KNAT3 and SAW1 in a temporal- and spatial- specific manner that is largely in accordance with the progress of formation of serrations. This regulation might serve as a key mechanism in patterning margin morphogenesis and in sculpting the final form of the leaf.
Pseudomonas putida MPE, a manganese-dependent endonuclease of the binuclear metallophosphoesterase superfamily, incises single-strand DNA in two orientations to yield a mixture of 3′-PO4 and 3′-OH termini
Authors: Ghosh Shreya , Ejaz Anam , Repeta Lucas , Shuman Stewart
Published: November 2020

Pseudomonas putida MPE exemplifies a novel clade of manganese-dependent single-strand DNA endonuclease within the binuclear metallophosphoesterase superfamily. MPE is encoded within a widely conserved DNA repair operon. Via structure-guided mutagenesis, we identify His113 and His81 as essential for DNA nuclease activity, albeit inessential for hydrolysis of bis-p-nitrophenylphosphate. We propose that His113 contacts the scissile phosphodiester and serves as a general acid catalyst to expel the OH leaving group of the product strand. We find that MPE cleaves the 3′ and 5′ single-strands of tailed duplex DNAs and that MPE can sense and incise duplexes at sites of short mismatch bulges and opposite a nick. We show that MPE is an ambidextrous phosphodiesterase capable of hydrolyzing the ssDNA backbone in either orientation to generate a mixture of 3′-OH and 3′-PO4 cleavage products. The directionality of phosphodiester hydrolysis is dictated by the orientation of the water nucleophile vis-à-vis the OH leaving group, which must be near apical for the reaction to proceed. We propose that the MPE active site and metal-bound water nucleophile are invariant and the enzyme can bind the ssDNA productively in opposite orientations.
Exposure to Nicotine and Toxicants Among Dual Users of Tobacco Cigarettes and E-Cigarettes: Population Assessment of Tobacco and Health (PATH) Study, 2013–2014
Authors: Smith Danielle M , Christensen Carol , van Bemmel Dana , Borek Nicolette , Ambrose Bridget , Erives Gladys , Niaura Raymond , Edwards Kathryn C , Stanton Cassandra A , Blount Benjamin C , Wang Lanqing , Feng Jun , Jarrett Jeffery M , Ward Cynthia D , Hatsukami Dorothy , Hecht Stephen S , Kimmel Heather L , Travers Mark , Hyland Andrew , Goniewicz Maciej L
Published: November 2020

Introduction

Concurrent use of tobacco cigarettes and e-cigarettes (“dual use”) is common among tobacco users. Little is known about differences in demographics and toxicant exposure among subsets of dual users.

Aims and Methods

We analyzed data from adult dual users (current every/some day users of tobacco cigarettes and e-cigarettes, n = 792) included in the PATH Study Wave 1 (2013–2014) and provided urine samples. Samples were analyzed for biomarkers of exposure to nicotine and selected toxicants (tobacco-specific nitrosamine NNK [NNAL], lead, cadmium, naphthalene [2-naphthol], pyrene [1-hydroxypyrene], acrylonitrile [CYMA], acrolein [CEMA], and acrylamide [AAMA]). Subsets of dual users were compared on demographic, behavioral, and biomarker measures to exclusive cigarette smokers (n = 2411) and exclusive e-cigarette users (n = 247).

Results

Most dual users were predominant cigarette smokers (70%), followed by daily dual users (13%), non-daily concurrent dual users (10%), and predominant vapers (7%). Dual users who smoked daily showed significantly higher biomarker concentrations compared with those who did not smoke daily. Patterns of e-cigarette use had little effect on toxicant exposure. Dual users with high toxicant exposure were generally older, female, and smoked more cigarettes per day. Dual users who had low levels of biomarkers of exposure were generally younger, male, and smoked non-daily.

Conclusions

In 2013–2014, most dual users smoked cigarettes daily and used e-cigarettes occasionally. Cigarette smoking appears to be the primary driver of toxicant exposure among dual users, with little-to-no effect of e-cigarette use on biomarker levels. Results reinforce the need for dual users to stop smoking tobacco cigarettes to reduce toxicant exposure.

Implications

With considerable dual use of tobacco cigarettes and e-cigarettes in the United States, it is important to understand differences in toxicant exposure among subsets of dual users, and how these differences align with user demographics. Findings suggest most dual users smoke daily and use e-cigarettes intermittently. Low exposure to toxicants was most common among younger users, males, and intermittent smokers; high exposure to toxicants was most common among older users, females, and heavier cigarette smokers. Results underscore the heterogeneity occurring within dual users, and the need to quit smoking cigarettes completely in order to reduce toxicant exposure.
Some new maxims of chancery: ‘Explicated for the more facile introduction of such as are studiously addicted to that noble profession’
Authors: Qayyum Sham
Published: November 2020

Over the past half century, the trust has undergone momentous change. A generation of Chancery practitioners reduced it from being a doctrine to a loophole. What, perhaps, many did not realise was that the changes would mostly be for the worse. Before explaining which aspects of the modern express trust trouble my conscience, I divide its history into Three Ages of the Trust. We now live in the Age of the Loophole Trust (1969–). To help us understand this latest stage, I utilise equity’s most venerable teaching aid – the maxim. My remarks are structured around three new (surreptitious) maxims.
Compartment Syndrome in Children With a Supracondylar Fracture: Not Everyone has Risk Factors
Authors: Armstrong Douglas G. , MacNeille Rhett , Lehman Erik B. , Hennrikus William L.
Published: November 2020

Objectives:

To clarify the incidence, associated conditions, and timing of fasciotomy for compartment syndrome (CS) in children with a supracondylar (SC) fracture of the humerus.

Design:

A retrospective trauma system database study.

Setting:

Accredited trauma centers in Pennsylvania.

Patients:

A statewide trauma database was searched for children 2–13 years of age admitted with a SC fracture between January 2001 and December 2015. Four thousand three hundred eight children met inclusion criteria.

Intervention:

Treatment of a SC fracture.

Main Outcome Measurement:

Diagnosis of CS/performance of a fasciotomy.

Results:

During the study period, 21 (0.49%) children admitted with a SC fracture of the humerus were treated with fasciotomy. CS/fasciotomy was more likely in males (P = 0.031), those with a nerve injury (P = 0.049), and/or ipsilateral forearm fracture (P < 0.001). Vascular procedure, performed in 18 (0.42%) children, was strongly associated with CS/fasciotomy (P < 0.001). Closed reduction and fixation of a forearm fracture was associated with CS (P = 0.007). Timing of SC fracture treatment did not influence outcome. Fasciotomy was performed subsequent to reduction in 13 subjects; mean interval between procedures was 23.4 hours (r = 4.5–51.3).

Conclusions:

Risk factors for CS exist; however, they are not required for the condition to develop. CS may develop subsequent to admission and/or SC fracture treatment. In timing of operative management and hospitalization, the results support contemporary practice.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Prevalence and Risk Factors of Problematic Internet Use and Its Relationships to the Self-Esteem and Health-Related Quality of Life
Authors: Cam Hasan Huseyin , Ustuner Top Fadime
Published: November 2020

Purpose

This study aimed to investigate the prevalence of problematic internet use (PIU) among high school students, to evaluate its potential risk factors, and to investigate its relation to self-esteem and health-related quality of life.

Methods

This cross-sectional study included 1,558 high school students in Turkey. Participants completed the Internet Addiction Test as well as the Rosenberg Self-Esteem Scale and 12-item Short Form Health Survey. Demographics and internet usage patterns were also collected. Data analysis was conducted by descriptive and analytical statistics (Pearson chi-square tests, independent-samples t test, and binary logistic regression).

Results

The mean age of the participants was 16.20 ± 1.05 years. Nearly 21.1% of the participants exhibited PIU (Internet Addiction Test score ≥ 50). The findings indicated that PIU was associated with poor self-esteem and poor physical and mental health. The PIU was significantly higher among students using the internet for social networking. The chi-square analysis showed a significant correlation between the severities of PIU and the students' type of school, residence, perceived academic performance, and relationship with parents (p < .05). No significant correlation was found between PIU severity and age group, gender, number of siblings, paternal or maternal educational levels, self-reported family income, sleep duration, or whether or not they resided with parents (p > .05).

Conclusions

PIU was found to be a common problem among high school students, and it was significantly correlated with self-esteem and health-related quality of life. To alleviate this public health problem, at-risk groups should be identified and timely management strategies and effective prevention programs should be established.
Two Nursing Outreach Interventions to Engage Vulnerable Populations in Care
Authors: Doran Kelly , Moen Marik , Doede Megan
Published: November 2020

People experiencing substance use disorders, homelessness, mental health conditions, or poverty often have difficultly engaging in healthcare services particularly prevention services. This brief report describes two nursing interventions implemented by nursing students that aim to empower vulnerable populations and draw them into care using empathetic and patient-centered approaches. The first intervention uses street outreach with naloxone training in an area of Baltimore experiencing a high rate of overdose deaths. The second uses home or street outreach to link people living with HIV to HIV care.
Feasibility and Acceptability of Reiki Therapy for Children Receiving Palliative Care in the Home
Authors: Thrane Susan E. , Maurer Scott H. , Danford Cynthia A.
Published: November 2020

Reiki is often used but not well studied in children. Yet, this gentle, light-touch therapy promotes relaxation and is appropriate for those receiving palliative care. This quasi-experimental pre-post mixed-methods 1-group pilot study examined the feasibility and acceptability of Reiki therapy as a treatment for children aged 7 to 16 years receiving palliative care. During the study, we recorded recruitment, retention, data collection rates, and percent completion of the intervention. Structured interviews with the mothers and verbal children were conducted to elicit their experience. Qualitative data were analyzed using thematic analysis. Twenty-one parent-child dyads agreed to participate and signed consent, whereas 16 completed the study (including verbal [n = 8] and nonverbal [n = 8] children). Themes included “feeling better,” “hard to judge,” and “still going on.” Mothers and children were generally positive regarding the experience of receiving Reiki therapy. Children reported they “felt really relaxed,” and mothers stated, “It was a good experience” and “She was relaxed afterward.” The results of this pilot study show that Reiki was feasible, acceptable, and well-tolerated. Most participants reported it was helpful. Reiki therapy may be a useful adjunct with traditional medical management for symptoms in children receiving palliative care.
Interprofessional Team Approach Using Standardized Patient Simulation to Facilitate Person-Centered Quality Healthcare in Home Hospice Care Setting
Authors: Gurley Lisa , Roberson Jean , York Ashley Burnham , Childress Jennifer
Published: November 2020

Hospice care requires person-centered holistic approaches from interprofessional health care teams. Traditional curricular models include teaching hospice care in discipline-specific didactic settings. There are limited opportunities for prelicensure students to engage in real-life and hands-on hospice care. Students are often observers and lack meaningful interactions with patients, families, and interprofessional teams. Using “IPEC Core Competencies for Interprofessional Collaborative Practice” and “AACN CARES” as the framework, nursing and social work faculty collaborated to develop, implement, and evaluate an interprofessional home hospice simulation incorporating standardized patients. The purpose of this interprofessional simulation was to facilitate hands-on application of complex health care concepts in an authentic home hospice setting. Twenty-three Bachelor of Science in Nursing students and 10 Master of Social Work students participated as interprofessional teams to provide home hospice care for patients and families. Faculty evaluated the simulation experience through analysis of presimulation and postsimulation guided reflections, intrasimulation observations, and postsimulation debriefing. Evaluation indicated students gained a greater understanding of how to provide quality person-centered end-of-life care, increased comfort with assessing spiritual needs, increased confidence in initiating sensitive interactions, and greater appreciation for working in an interprofessional health care team. This interprofessional simulation provided a robust learning environment paving the way for future simulations incorporating additional members of the health care team.
Understanding the role of gut microbiota in the pathogenesis of schizophrenia
Authors: Ghorbani Mahin , Rajandas Heera , Parimannan Sivachandran , Stephen Joseph Gerard Benedict , Tew Mei Mei , Ramly Siti Salwa , Muhamad Rasat Muhammad Arif , Lee Su Yin
Published: November 2020

Schizophrenia is a chronic mental disorder with marked symptoms of hallucination, delusion, and impaired cognitive behaviors. Although multidimensional factors have been associated with the development of schizophrenia, the principal cause of the disorder remains debatable. Microbiome involvement in the etiology of schizophrenia has been widely researched due to the advancement in sequencing technologies. This review describes the contribution of the gut microbiome in the development of schizophrenia that is facilitated by the gut-brain axis. The gut microbiota is connected to the gut-brain axis via several pathways and mechanisms, that are discussed in this review. The role of the oral microbiota, probiotics and prebiotics in shaping the gut microbiota are also highlighted. Lastly, future perspectives for microbiome research in schizophrenia are addressed.
Did pre-Columbian populations of the Amazonian biome reach carrying capacity during the Late Holocene?
Authors: Arroyo-Kalin Manuel , Riris Philip
Published: November 2020

The increasingly better-known archaeological record of the Amazon basin, the Orinoco basin and the Guianas both questions the long-standing premise of a pristine tropical rainforest environment and also provides evidence for major biome-scale cultural and technological transitions prior to European colonization. Associated changes in pre-Columbian human population size and density, however, are poorly known and often estimated on the basis of unreliable assumptions and guesswork. Drawing on recent developments in the aggregate analysis of large radiocarbon databases, here we present and examine different proxies for relative population change between 1050 BC and AD 1500 within this broad region. By using a robust model testing approach, our analyses document that the growth of pre-Columbian human population over the 1700 years prior to European colonization adheres to a logistic model of demographic growth. This suggests that, at an aggregate level, these pre-Columbian populations had potentially reached carrying capacity (however high) before the onset of European colonization. Our analyses also demonstrate that this aggregate scenario shows considerable variability when projected geographically, highlighting significant gaps in archaeological knowledge yet also providing important insights into the resilience of past human food procurement strategies. By offering a new understanding of biome-wide pre-Columbian demographic trends based on empirical evidence, our analysis hopes to unfetter novel perspectives on demic expansions, language diversification trajectories and subsistence intensification processes in the Amazonian biome during the late Holocene.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Directly modelling population dynamics in the South American Arid Diagonal using
14
C dates
Authors: Timpson Adrian , Barberena Ramiro , Thomas Mark G. , Méndez César , Manning Katie
Published: November 2020

Large anthropogenic
14
C datasets are widely used to generate summed probability distributions (SPDs) as a proxy for past human population levels. However, SPDs are a poor proxy when datasets are small, bearing little relationship to true population dynamics. Instead, more robust inferences can be achieved by directly modelling the population and assessing the model likelihood given the data. We introduce the R package ADMUR which uses a continuous piecewise linear (CPL) model of population change, calculates the model likelihood given a
14
C dataset, estimates credible intervals using Markov chain Monte Carlo, applies a goodness-of-fit test, and uses the Schwarz Criterion to compare CPL models. We demonstrate the efficacy of this method using toy data, showing that spurious dynamics are avoided when sample sizes are small, and true population dynamics are recovered as sample sizes increase. Finally, we use an improved
14
C dataset for the South American Arid Diagonal to compare CPL modelling to current simulation methods, and identify three Holocene phases when population trajectory estimates changed from rapid initial growth of 4.15% per generation to a decline of 0.05% per generation between 10 821 and 7055 yr BP, then gently grew at 0.58% per generation until 2500 yr BP.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Population density and size facilitate interactive capacity and the rise of the state
Authors: Roscoe Paul , Sandweiss Daniel H. , Robinson Erick
Published: November 2020

Radiocarbon summed probability distribution (SPD) methods promise to illuminate the role of demography in shaping prehistoric social processes, but theories linking population indices to social organization are still uncommon. Here, we develop Power Theory, a formal model of political centralization that casts population density and size as key variables modulating the interactive capacity of political agents to construct power over others. To evaluate this argument, we generated an SPD from 755 radiocarbon dates for 10 000–1000 BP from Central, North Central and North Coast Peru, a period when Peruvian political form developed from ‘quasi-egalitarianism’ to state levels of political centralization. These data are congruent with theoretical expectations of the model but also point to an artefactual distortion previously unremarked in SPD research.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Demographic estimates from the Palaeolithic–Mesolithic boundary in Scandinavia: comparative benchmarks and novel insights
Authors: Lundström Victor , Peters Robin , Riede Felix
Published: November 2020

Prehistoric demography has recently risen to prominence as a potentially explanatory variable for episodes of cultural change as documented in the archaeological and ethnographic record. While this has resulted in a veritable boom in methodological developments seeking to address temporal changes in the relative size of prehistoric populations, little work has focused on the manner in which population dynamics manifests across a spatial dimension. Most recently, the so-called Cologne Protocol has led the way in this endeavour. However, strict requirements of raw-material exchange data as analytical inputs have prevented further applications of the protocol to regions outside of continental Europe. We apply an adjusted approach of the protocol that makes it transferable to cases in other parts of the world, while demonstrating its use by providing comparative benchmarks of previous research on the Late Glacial Final Palaeolithic of southern Scandinavia, and novel insights from the early Holocene pioneer colonization of coastal Norway. We demonstrate again that population size and densities remained fairly low throughout the Late Glacial, and well into the early Holocene. We suggest that such low population densities have played a significant role in shaping what may have been episodes of cultural loss, as well as potentially longer periods of only relatively minor degrees of cultural change.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Dispersals as demographic processes: testing and describing the spread of the Neolithic in the Balkans
Authors: Vander Linden Marc , Silva Fabio
Published: November 2020

Although population history and dispersal are back at the forefront of the archaeological agenda, they are often studied in relative isolation. This contribution aims at combining both dimensions, as population dispersal is, by definition, a demographic process. Using a case study drawn from the Early Neolithic of South-Eastern Europe, we use radiocarbon dates to jointly investigate changes in speed and population size linked to the new food production economy and demonstrate that the spread of farming in this region corresponds to a density-dependent dispersal process. The implications of this characterization are evaluated in the discussion.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Effect of antifungal agents, lysozyme and human antimicrobial peptide LL-37 on clinical Candida isolates with high biofilm production
Authors: Chen Yi-Chun , Chen Fang-Ju , Lee Chen-Hsiang
Published: November 2020

Introduction.
Candida species can form biofilms on tissues and medical devices, making them less susceptible to antifungal agents.

Hypothesis/Gap Statement. Antifungal combination may be an effective strategy to fight against Candida biofilm.

Aim. In this study, we investigated the in vitro activity of fluconazole, caspofungin and amphotericin B, alone and in combination, against 17 clinical Candida tropicalis and 6 Candida parapsilosis isolates with high biofilm formation. We also tested LL-37 and lysozyme for anti-biofilm activity against a selected C. tropicalis isolate.

Methodology.
Candida biofilms were prepared using the 96-well plate-based method. The minimum biofilm eradication concentrations were determined for single and combined antifungal drugs. The activity of LL-37 and lysozyme was determined by visual reading for planktonic cells and using the XTT assay for biofilms.

Results. Under biofilm conditions, fluconazole plus caspofungin showed synergistic effects against 60.9% (14 of 23) of the tested isolates, including 70.6% of C. tropicalis [fractional inhibitory concentration index (FICI), 0.26–1.03] and 33.3% of C. parapsilosis (FICI, 0.04–2.03) isolates. Using this combination, no antagonism was observed. Amphotericin B plus caspofungin showed no effects against 78.3% (18 of 23) of the tested isolates. Amphotericin B plus fluconazole showed no effects against 65.2% (15 of 23) of the tested isolates and may have led to antagonism against 2 C. tropicalis and 2 C. parapsilosis isolates. LL-37 and lysozyme had no effect on biofilms of the selected C. tropicalis isolate.

Conclusions. We found that fluconazole plus caspofungin led to a synergistic effect against C. tropicalis and C. parapsilosis biofilms. The efficacy of the antifungal combination therapies of the proposed schemes against biofilm-associated Candida infections requires careful and constant evaluation.
Perceived Implications of Current Conflict of Interest Policy in Individuals Accepted or Rejected for Participation in Food and Drug Administration Advisory Committee
Authors: Shimada Yuichi J. , Hair Kyle , Faerber Adrienne , Zimmerman Christian G. , Houchin Timothy , Hart Robert A. , Gibb Matthew D. , Homma Shunichi
Published: November 2020

Background and Objective

The Food and Drug Administration (FDA) relies on advice from scientific and medical experts to make approval decisions about new prescription medications and medical devices. Therefore, it is crucial that FDA Advisory Committees (ACs) include the most knowledgeable scientists and clinicians in the decision-making process. However, to ensure that the advice is free from biases, current FDA policy often excludes those most qualified from participating in ACs due to perceived conflicts of interest (COI). The objective of the present study is to elicit opinion among subject matter experts regarding current FDA COI rules and regulations.

Methods

We conducted a cross-sectional study using formal, self-administered online survey consisting of 14 questions, 3 of which addressed perceived implications of current FDA COI policy. We send a formal online survey to study subjects via Qualtrics. Study subjects were 1) individuals who participated in FDA ACs and 2) those who were interested in participating in ACs and had completed FDA COI paperwork but rejected by the FDA due to COI. The outcome measure is response to the 3 questions about the perceived implications of current FDA COI policy. Responses were scored on a 5-point Likert-type scale.

Results

Among 403 study subjects (200 AC members and 203 individuals who were rejected due to COI), 145 (36%) responded to the survey including 90 AC members and 55 rejected individuals. Respondents included 41 (28%) females. 97% were holding MD or PhD degrees. 88% were age 46 and over, and 66% had more than 25 years in practice. The primary findings were that 49% of respondents agreed that the current FDA regulations lead to a lower quality of experts on ACs, 72% agreed that current policies exclude qualified experts from serving on ACs, and 48% agreed that FDA policy lowers the overall quality of AC input, to at least a “moderate” extent (19%-37% to a “high” or “very high” extent).

Conclusions

The prevailing opinion among respondents to the formal survey is that current FDA COI policy has the potential effects to lowering quality of experts, excluding qualified experts, and lowering overall quality of AC input. The present report elucidates a potential need for the FDA to discuss the benefit and risk of the current AC COI policies.
Perceived Health Benefits of Using Non-Electrical Water Filters under ‘Clean India Mission’ Programme in a Village of Bhopal
Authors: Rana Sindhuprava , Dhiman Vikas , Banerjee Nalok , Prakash Anil , Tiwari Rajnarayan R
Published: November 2020

In India, the access to clean and safe drinking water to rural population is very limited, hence the Government of India has initiated multiple schemes to tackle the problem of huge health burden due to poor quality of water in rural areas. Under ‘Clean India Mission’ cost-effective, non-electric water filters were distributed (n=144 households) in Barkheda Bondar village of Bhopal district in Central India and after one year of usage, a questionnaire based door-to-door survey was conducted to assess the usage and perceived health benefits of water filters by the users. The study showed that the acceptance of water filter among rural population was about 82% and 69.4% of the population reported reduction in the frequency of various water-related diseases. The present study shows that the use of non-electric water filters on mass basis in rural India is efficacious for providing safe drinking water.
Characteristics of COVID-19 patients admitted to a tertiary care hospital in Pune, India, and cost-effective predictors of intensive care treatment requirement
Authors: Shukla Urvi Bhooshan , Shukla Sharvari Rahul , Palve Sachin Bhaskar , Yeravdekar Rajiv Chintaman , Natarajan Vijay Madhusoothan , Tiwari Pradeep , Yajnik Chittaranjan Sakerlal
Published: November 2020

Background

Maharashtra is one of the worst affected states in this pandemic.2 As of 30th September, Maharashtra has in total 1.4 million cases with 38,000 deaths. Objective was to study associations of severity of disease and need for ICU treatment in COVID-19 patients.

Methods

A retrospective study of clinical course in 800 hospitalized COVID-19 patients, and a predictive model of need for ICU treatment. Eight hundred consecutive patients admitted with confirmed COVID-19 disease.

Results

Average age was 41 years, 16% were <20 years of age, 55% were male, 50% were asymptomatic and 16% had at least one comorbidity. Using MoHFW India severity guidelines, 73% patients had mild, 6% moderate and 20% severe disease. Severity was associated with higher age, symptomatic presentation, elevated neutrophil and reduced lymphocyte counts and elevated inflammatory markers. Seventy-seven patients needed ICU treatment: they were older (56 years), more symptomatic and had lower SpO2 and abnormal chest X-ray and deranged hematology and biochemistry at admission. A model trained on the first 500 patients, using above variables predicted need for ICU treatment with sensitivity 80%, specificity 88% in subsequent 300 patients; exclusion of expensive laboratory tests did not affect accuracy.

Conclusion

In the early phase of COVID- 19 epidemic, a significant proportion of hospitalized patients were young and asymptomatic. Need for ICU treatment was predicted by simple measures including higher age, symptomatic onset, low SpO2 and abnormal chest X-ray. We propose a cost-effective model for referring patients for treatment at specialized COVID-19 hospitals.

Key Messages

Of 800 patients, 73% had mild, 6% moderate and 20% had severe disease.

Seventy-seven patients (9.6%) required ICU treatment, 25 (3%) died.

ICU treatment was predicted by higher age, more symptomatic presentation, lower SpO2 and pneumonia on chest X-ray at admission.

A machine learning model features in first 500 patients accurately predicted ICU treatment in subsequent 300 patients.

A good clinical protocol, SpO2 and chest X-ray are adequate to predict and triage COVID-19 patients for hospital admissions in resource poor environments.
Failure of the New Kidney Allocation System in a Specific Ethnic Group
Authors: Longoria-Dubocq Texell , Pizarro-Gonzalez Yaritza , Mayorga-Perez Isabel , Javier-Gonzalez Mariel , Hernandez-Rivera Pedro
Published: November 2020

Introduction

The Kidney Allocation System (KAS) implemented on December 4, 2014, was expected to improve kidney transplant list wait-time and allocate more kidney to high cPRA patients. This study aims to demonstrate outcomes after the implementation of the KAS in a Hispanic transplant center.

Methods

Retrospective study from a prospectively maintained database from a single-transplant center. Included all DDKT from July 2013 to June 2016. Compare and analyze DDKT selection and outcomes before and after KAS implementation.

Results

The overall number of kidney transplants performed during this period was 220. All of the patients were Hispanic. Included 50.5% Pre-KAS and 49.5% Post-KAS. Pre-KAS group had a significantly shorter waiting-time list than the post-KAS group, 900.05 vs 1126.75 respectively. EPTS less than 20% significantly improved in the Post-KAS group compared to the Pre-KAS group, 41.3% vs 20.9% respectively. No differences observed in KDPI, 1-year graft failure, or 1-year mortality rates.

Conclusion

This might be the first Hispanic only cohort evaluating the effects of KAS on a moderate volume kidney transplant center. The new system increased the wait-time list by approximately 25%, and it did not improve graft quality, graft failure, or mortality rates.
Quantifying superspreading for COVID-19 using Poisson mixture distributions
Authors: Kremer Cécile , Torneri Andrea , Boesmans Sien , Meuwissen Hanne , Verdonschot Selina , Driessche Koen Vanden , Althaus Christian L. , Faes Christel , Hens Niel
Published: November 2020

The number of secondary cases is an important parameter for the control of infectious diseases. When individual variation in disease transmission is present, like for COVID-19, the number of secondary cases is often modelled using a negative binomial distribution. However, this may not be the best distribution to describe the underlying transmission process. We propose the use of three other offspring distributions to quantify heterogeneity in transmission, and we assess the possible bias in estimates of the offspring mean and its overdispersion when the data generating distribution is different from the one used for inference. We find that overdispersion estimates may be biased when there is a substantial amount of heterogeneity, and that the use of other distributions besides the negative binomial should be considered. We revisit three previously analysed COVID-19 datasets and quantify the proportion of cases responsible for 80% of transmission,p80%, while acknowledging the variation arising from the assumed offspring distribution. We find that the number of secondary cases for these datasets is better described by a Poisson-lognormal distribution.
The reversion variant (p.Arg90Leu) at the evolutionarily adaptive p.Arg90 site in CELA3B predisposes to chronic pancreatitis
Authors: Masson Emmanuelle , Rebours Vinciane , Buscail Louis , Frete Frédérique , Pagenault Mael , Lachaux Alain , Chevaux Jean-Baptiste , Génin Emmanuelle , Cooper David N. , Férec Claude , Chen Jian-Min
Published: November 2020

A gain-of-function missense variant in the CELA3B gene, p.Arg90Cys (c.268C>T), has recently been reported to cause pancreatitis in an extended pedigree. Herein, we sequenced the CELA3B gene in 644 genetically unexplained French chronic pancreatitis (CP) patients (all unrelated) and 566 controls. No predicted loss-of-function variants were identified. None of the six low frequency or common missense variants detected showed significant association with CP. Nor did the aggregate rare/very rare missense variants (n=14) show any significant association with CP. However, p.Arg90Leu (c.269G>T), which was found in 4 patients but no controls and affects the same amino acid as p.Arg90Cys, serves to revert p.Arg90 to the human elastase ancestral allele. Since p.Arg90Leu has previously been shown to exert a similar functional effect to p.Arg90Cys, our findings not only confirm the involvement of CELA3B in the etiology of CP but also pinpoint a new evolutionarily adaptive site in the human genome.
Global architecture of the nucleus in single cells by DNA seqFISH+ and multiplexed immunofluorescence
Authors: Takei Yodai , Yun Jina , Ollikainen Noah , Zheng Shiwei , Pierson Nico , White Jonathan , Shah Sheel , Thomassie Julian , Eng Chee-Huat Linus , Guttman Mitchell , Yuan Guo-cheng , Cai Long
Published: November 2020

Identifying the relationships between chromosome structures, chromatin states, and gene expression is an overarching goal of nuclear organization studies. Because individual cells are highly variable at all three levels, it is essential to map all three modalities in the same single cell, a task that has been difficult to accomplish with existing tools. Here, we report the direct super-resolution imaging of over 3,660 chromosomal loci in single mouse embryonic stem cells (mESCs) by DNA seqFISH+, along with 17 chromatin marks by sequential immunofluorescence (IF) and the expression profile of 70 RNAs, in the same cells. We discovered that the nucleus is separated into zones defined by distinct combinatorial chromatin marks. DNA loci and nascent transcripts are enriched at the interfaces between specific nuclear zones, and the level of gene expression correlates with an association between active or nuclear speckle zones. Our analysis also uncovered several distinct mESCs subpopulations with characteristic combinatorial chromatin states that extend beyond known transcriptional states, suggesting that the metastable states of mESCs are more complex than previously appreciated. Using clonal analysis, we show that the global levels of some chromatin marks, such as H3K27me3 and macroH2A1 (mH2A1), are heritable over at least 3-4 generations, whereas other marks fluctuate on a faster time scale. The long-lived chromatin states may represent “hidden variables” that explain the observed functional heterogeneity in differentiation decisions in single mESCs. Our integrated spatial genomics approach can be used to further explore the existence and biological relevance of molecular heterogeneity within cell populations in diverse biological systems.
Bidirectional Control of Parathyroid Hormone and Bone Mass by Subfornical Organ
Authors: Zhang Lu , Liu Nian , Shao Jie , Gao Dashuang , Liu Yunhui , Chen Di , Wang Liping , Lu William Weijia , Yang Fan
Published: November 2020

Parathyroid hormone (PTH) is one of the most important hormones responsible for bone turnover and calcium homeostasis. In mammals, PTH is secreted through the parathyroid glands, unlike in fishes, which are secreted through central nervous system. Studies indicated that a variety of peripheral nerve regulates serum PTH level, however, the mechanism underlying central neural regulation of PTH in mammals remains largely unknown. With an approach including neural-specific retrograde tracing, PTH-Biotin binding assay, and cFos staining, we identified the subfornical organ (SFO) and the paraventricular nucleus (PVN) as two important brain nuclei that responded to serum PTH and calcium changes. Using chemogenetics, we found that serum PTH was suppressed by stimulation of GABAergic neurons in SFO followed by a decrease in trabecular bone mass. Conversely, stimulation of glutamatergic neurons in SFO promoted serum PTH and bone mass. Moreover, we found that the majority of neurons expressing parathyroid hormone 1 receptor (PTH1R) were GABAergic neurons and the majority of neurons expressing parathyroid hormone 2 receptor (PTH2R) were glutamatergic neurons. The paraventricular nucleus (PVN) is downstream of the SFO, and chemogenetic activation of glutamatergic neurons in PVN induced an increase in serum PTH. In summary, our study demonstrates for the first time that distinct neuronal subtypes in the SFO are responsible for bidirectional regulation of serum PTH and bone metabolism, which is mediated through the PVN and the peripheral nervous system. These findings reveal important central neural nodes and will advance our understanding of the central neural regulation of PTH at the molecular, cellular and circuit level.
Nanoscale imaging of shale fragments with coherent X-ray diffraction
Authors: Chattopadhyay Basab , Madathiparambil Aldritt S. , Mürer Fredrik K. , Cerasi Pierre , Chushkin Yuriy , Zontone Federico , Gibaud Alain , Breiby Dag W.
Published: November 2020

Despite the abundance of shales in the Earth's crust and their industrial and environmental importance, their microscale physical properties are poorly understood, owing to the presence of many structurally related mineral phases and a porous network structure spanning several length scales. Here, the use of coherent X-ray diffraction imaging (CXDI) to study the internal structure of microscopic shale fragments is demonstrated. Simultaneous wide-angle X-ray diffraction (WAXD) measurement facilitated the study of the mineralogy of the shale microparticles. It was possible to identify pyrite nanocrystals as inclusions in the quartz–clay matrix and the volume of closed unconnected pores was estimated. The combined CXDI–WAXD analysis enabled the establishment of a correlation between sample morphology and crystallite shape and size. The results highlight the potential of the combined CXDI–WAXD approach as an upcoming imaging modality for 3D nanoscale studies of shales and other geological formations via serial measurements of microscopic fragments.
Fruitzone India Limited (C): Data Collection & Analysis
Authors: Tripathi Sanjeev
Published: November 2020

Fruitzone India Limited (FIL) was the Indian subsidiary of the multinational company Gypsy Inc., the global leader in the beverages industry. The company had conducted market research to identify a new flavour of fruit juice that it could launch. The case discusses how the data collected in confirmatory research using primary research is analysed and interpreted. This case is useful for participants in the Business Research Methods, Market Research and Qualitative Research courses.
MakeMyTrip: 2013(B): Research Design for Redesigning the Home Page
Authors: Jain Abhinandan Kumar , Misra Kaveri
Published: November 2020

One week since the first meeting, Mr. Deepak Kumar, Chairman and Group CEO of MakeMyTrip (MMT), called a second meeting of the homepage website redesign team for redesigning the Home Page (see Exhibit 1 for the current Home Page)1. This team comprised of the CBO, Analytics Head, User Experience (UX) Head, Product Head and the Tech Head (CTO). The second meeting was called to discuss and finalise the options of the Home Page design to be tested, the criteria to be used for choosing the best option, and the testing methodology.
MakeMyTrip: 2013(C): Redesigning the Home Page
Authors: Jain Abhinandan Kumar , Misra Kaveri
Published: November 2020

In mid-2013 Deepak Kumar, Chairman and Group CEO of MakeMyTrip (MMT), was headed to the Hindustan conference room of the company's head office in Gurgaon, India, for deciding the new homepage design. A day earlier, Ajay, Product Head, had shared the consolidated results of the trials of different options (see Exhibit 1 for the results of testing the options) with the homepage website redesign team, responsible for the entire project. The team consisted of the head of business (CBO), the Analytics Head, the user experience (UX)head, the Product Head and the Tech Head (CTO).

Looking at the results, Deepak Kumar reflected that there were a lot of surprises in how the different options had performed. While the tracking tools in online businesses had a huge advantage over traditional businesses in that almost every customer interaction could be measured, there was still a lot of reading between the numbers that had to be done. Deepak was looking forward to a fruitful discussion to evaluate the options and finalise the new homepage design to be rolled out. As he opened the door to the conference room, he heard an excited chatter.