bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionary Divergence of the Genetic Architecture Underlying Photoperiodism in the Pitcher-Plant Mosquito, Wyeomyia smithii
Authors: Lair Kevin P , Bradshaw William E , Holzapfel Christina M
Published: January 2021

We determine the contribution of composite additive, dominance, and epistatic effects to the genetic divergence of photoperiodic response along latitudinal, altitudinal, and longitudinal gradients in the pitcher-plant mosquito, Wyeomyia smithii. Joint scaling tests of crosses between populations showed wide-spread epistasis as well as additive and dominance differences among populations. There were differences due to epistasis between an alpine population in North Carolina and populations in Florida, lowland North Carolina, and Maine. Longitudinal displacement resulted in differences due to epistasis between Florida and Alabama populations separated by 300 km but not between Maine and Wisconsin populations separated by 2000 km. Genetic differences between New Jersey and Ontario did not involve either dominance or epistasis and we estimated the minimum number of effective factors contributing to a difference in mean critical photoperiod of 5 SD between them as nE = 5. We propose that the genetic similarity of populations within a broad northern region is due to their more recent origin since recession of the Laurentide Ice Sheet and that the unique genetic architecture of each population is the result of both mutation and repeated migration-founder-flush episodes during the dispersal of W. smithii in North America. Our results suggest that differences in composite additive and dominance effects arise early in the genetic divergence of populations while differences due to epistasis accumulate after more prolonged isolation.
Germinal Excisions of the Maize Transposon Activator Do Not Stimulate Meiotic Recombination or Homology-Dependent Repair at the bz Locus
Authors: Dooner Hugo K , Martínez-Férez Isabel M
Published: January 2021

Double-strand breaks have been implicated both in the initiation of meiotic recombination in yeast and as intermediates in the transposition process of nonreplicative transposons. Some transposons of this class, notably P of Drosophila and Tc1 of Caenorhabditis elegans, promote a form of homology-dependent premeiotic gene conversion upon excision. In this work, we have looked for evidence of an interaction between Ac transposition and meiotic recombination at the bz locus in maize. We find that the frequency of meiotic recombination between homologues is not enhanced by the presence of Ac in one of the bz heteroalleles and, conversely, that the presence of a homologous sequence in either trans (homologous chromosome) or cis (tandem duplication) does not promote conversion of the Ac insertion site. However, a tandem duplication of the bz locus may be destabilized by the insertion of Ac. We discuss possible reasons for the lack of interaction between Ac excision and homologous meiotic recombination in maize.
2. Funding
Authors: Hodgson Roiya
Published: January 2021

This chapter discusses the changes made to public funding in family cases since The Legal Aid, Sentencing and Punishment of Offenders Act 2012 (LASPO), implemented in April 2013. This includes the evidence of domestic violence required to obtain public funding in family cases. The chapter outlines the availability of public funding for family law proceedings; the levels of funding available to the client; the tests to determine whether a client is eligible for public funding; and the recovery of public funding through the statutory charge. It also considers how a person who is not eligible for public funding may fund proceedings.
7. Defences to Divorce and Dissolution
Authors: Hodgson Roiya
Published: January 2021

This chapter discusses the limited defences that are available in divorce proceedings. It explains that defended divorces or dissolutions of civil partnerships are not very common in practice and that there are limited ‘defences’ available, which may only lead to a delay in proceedings rather that stopping proceedings. It covers petitions after five years’ separation; Section 5 Matrimonial Causes Act 1973; protection in two-year separation cases; Section 10 Matrimonial Causes Act 1973; and section 10A Matrimonial Causes Act 1973, which was passed in the wake of a number of cases of women being refused a religious divorce by their spouse.
12. Financial Orders
Authors: Hodgson Roiya
Published: January 2021

This chapter discusses the principal forms of financial orders under the Matrimonial Causes Act 1973, their scope, and how they are used. It explores the availability of each of the orders, and discusses these in relation to civil partners, spouses, and children. The financial orders discussed, including lump sum orders and property adjustment orders. In relation to property adjustment orders, the transfer of property order, settlement of property, and variation of settlement is outlined. Orders concerning the family home are discussed, such as the sale and division of proceeds, transfer of property, and charges on a property. Periodical payments orders and interim orders are also explained.
13. Pre-Marital Agreements
Authors: Hodgson Roiya
Published: January 2021

This chapter examines the nature of pre-marital agreements (PMAs), advantages and disadvantages of PMAs, and the enforceability of them in proceedings for financial orders, and the potential developments in the enforceability of PMAs. It states that a PMA can sometimes be called an ante-nuptial agreement or pre-nuptial agreement and that it is essentially a contact made between two people before they get married. Various case-laws dealing with the issue of PMAs are presented. The negotiation and drafting of a PMA are outlined following case-law which provided guidance on this, but confirming that even if these steps are taken, it does not guarantee that a PMA will be followed by the courts.
15. Variation, Collection, and Enforcement of Financial Orders
Authors: Hodgson Roiya
Published: January 2021

Gaining a financial order is sometimes not the end of proceedings. A disgruntled spouse or civil partner may refuse to comply with the terms of an order, even a consent order, and so a family law solicitor must be able to use enforcement mechanisms to enforce the court order. This chapter discusses the circumstances in which a financial order can be varied, including which orders are subject to variation and the applications for variation. It then goes on to discuss the collection of monies due under financial orders, and the enforcement of financial orders such as periodical payments and other orders.
17. Separation and Maintenance Agreements
Authors: Hodgson Roiya
Published: January 2021

This chapter discusses the use of separation and maintenance agreements, the essential features of both types of agreements, and the advantages and disadvantages of separation and maintenance agreements. A separation or maintenance agreement can help parties avoid expensive and drawn-out litigation. Separation agreements essentially record that the parties wish to live apart and can include terms about children, property, and maintenance. Maintenance agreements deal with the payment of maintenance to or for the benefit of spouses, civil partners, or children, but do not deal with the separation of the parties. The form of separation and maintenance agreements is discussed, as well as enforcement.
26. Private Children Law
Authors: Hodgson Roiya
Published: January 2021

Private children law concerns disputes between family members about children. It deals with whom a child shall live, with whom they should have contact, and what steps a parent can take in their exercise of parental responsibility. The Children Act 1989 and the Children and Families Act 2014 have orders that the court can make to help to resolve these disputes. This chapter examines the orders available in private children proceedings, who can apply for them, and the individual considerations of each order. These include child arrangements orders, residence orders, contact orders, specific issues orders, prohibited steps orders, and special guardianship orders.
31. Public Children Procedure
Authors: Hodgson Roiya
Published: January 2021

This chapter examines the procedural issues involved in public children law proceedings. It discusses the public law outline; representation of the child; steps to be taken before proceedings; the issue and allocation of proceedings; and case management hearings. The various court hearings and meetings which take place in public law children proceedings are explained, including first appointment; the case management hearing and advocates’ meeting; the issue resolution hearing; and the final hearing. Changes to the inclusion expert evidence to only when it is ‘necessary’, is explained. The stages of the public law outline are presented in a helpful flow chart and case-law is also used for illustration.
35. Protection under the Family Law Act 1996: Emergency Protection and Enforcement
Authors: Hodgson Roiya
Published: January 2021

This chapter discusses the circumstances in which an order under the Family Law Act 1996 (FLA 1996) will be made without notice to the other party to proceedings; and the availability and methods of enforcement of orders made under the FLA 1996. A client who requires protection urgently is dealt with by applying for an order without notice. The court can only make an order without notice if there is risk of significant harm to the applicant, or the applicant will be deterred from pursuing the application, or the respondent is avoiding service. Duration of a without notice order is explained, as well as enforcing an order.
Pharmacokinetics and target attainment of intravenous posaconazole in critically ill patients during extracorporeal membrane oxygenation
Authors: Van Daele Ruth , Brüggemann Roger J , Dreesen Erwin , Depuydt Pieter , Rijnders Bart , Cotton Frédéric , Fage David , Gijsen Matthias , Van Zwam Kenny , Debaveye Yves , Wauters Joost , Spriet Isabel
Published: January 2021

Background

Posaconazole is an antifungal drug used for prophylaxis and treatment of invasive fungal infections. Severe influenza has been identified as a risk factor for invasive pulmonary aspergillosis in critically ill patients. In this population, extracorporeal membrane oxygenation (ECMO) is used as rescue therapy, although little is known about the pharmacokinetics (PK) of posaconazole during ECMO.

Objectives

To determine the PK and target attainment of six patients treated with IV posaconazole under ECMO and to develop a population PK model that can be used to simulate the PTA.

Methods

Critically ill patients treated with posaconazole and ECMO were included in this study. Plasma samples were collected at several timepoints within one dosing interval on two occasions: an early (Day 2–3) and a late (Day 4–7) sampling day. Daily trough concentrations were measured.

Results

The median (IQR) AUC0–24, CL and Vd were 34.3 (28.3–37.7) mg·h/L, 8.7 (8.0–10.6) L/h and 389 (314–740) L, if calculated with non-compartmental analysis based on the observed concentrations. All measured trough concentrations were ≥0.7 mg/L and 11/16 were ≥1 mg/L, which are the haematological thresholds for prophylaxis and treatment of invasive aspergillosis, respectively. The targeted PTA (>90%) was attained for prophylaxis but not for treatment.

Conclusions

ECMO does not appear to influence posaconazole exposure compared with haematology patients. However, some trough levels were below the lower limit for treatment. An a priori dose adjustment does not appear to be necessary but drug monitoring is recommended.
Molecular characteristics and in vitro effects of antimicrobial combinations on planktonic and biofilm forms of Elizabethkingia anophelis
Authors: Tang Hung-Jen , Lin Yi-Tsung , Chen Chi-Chung , Chen Chih-Wei , Lu Ying-Chen , Ko Wen-Chien , Chen Hung-Jui , Su Bo-An , Chang Ping-Chin , Chuang Yin-Ching , Lai Chih-Cheng
Published: January 2021

Objectives

To investigate the in vitro activity of antibiotics against clinical Elizabethkingia anophelis isolates and to find a suitable antibiotic combination with synergistic effects to combat antibiotic-resistant E. anophelis and its associated biofilm.

Methods

E. anophelis isolates were identified by 16S rRNA sequencing; 30 strains with different pulsotypes were identified and the MIC, antibiotic resistance mechanism, antibiotic combination activity and killing effects of antimicrobial agents on biofilms of these strains were determined.

Results

All E. anophelis isolates were susceptible to minocycline and cefoperazone/sulbactam (1:1). More than 90% of clinical isolates were susceptible to cefoperazone/sulbactam (1:0.5), piperacillin/tazobactam and rifampicin. Some novel mutations, such as gyrA G81D, parE D585N and parC P134T, that have never been reported before, were identified. The synergistic effect was most prominent for the combination of minocycline and rifampicin, with 93.3% of their FIC index values ≤0.5, and no antagonism was observed using the chequerboard method. This synergistic effect between minocycline and rifampicin was also observed using time–killing methods for clinical E. anophelis isolates at both normal inoculum and high inoculum. Twenty-nine isolates tested positive for biofilm formation. Minocycline remained active against biofilm-embedded and biofilm-released planktonic E. anophelis cells; however, the enhanced effect of minocycline by adding rifampicin was only observed at 24 h (not at 72 and 120 h).

Conclusions

Although E. anophelis was resistant to many antibiotics and could exhibit biofilm formation, minocycline showed potent in vitro activity against this pathogen and its associated biofilm.
Clinical outcomes of temocillin use for invasive Enterobacterales infections: a single-centre retrospective analysis
Authors: Heard Katie L , Killington Kieran , Mughal Nabeela , Moore Luke S P , Hughes Stephen
Published: January 2021

Background

With increasing frequency of resistant Gram-negative bacteria, temocillin has potential utility in reducing carbapenem use. The 2020 EUCAST guideline changes temocillin breakpoints and reclassifies isolates with an MIC of 0.001–16 mg/L as ‘susceptible, increased exposure’ necessitating 6 g/day rather than the previous 4 g/day, associated with significant cost implications.

Objectives

We explore the clinical utility and treatment failure rate of temocillin at 4 g/day dosing.

Methods

All adult inpatient electronic prescriptions of temocillin (3 days or greater) from March 2016 to October 2019 were retrieved using a clinical decision support system (ICNET®). Treatment success was defined as survival, no switch to broad-spectrum agent for the same indication and no subsequent recrudescence of infection, occurring within 30 days.

Results

Temocillin was used in 205 eligible patient-episodes, median age 79 years (IQR : 71–87 years), 42.4% female. Median temocillin course length was 5.9 days (IQR : 4.6–7.8 days). Indications for use: urinary tract infection (UTI) (n = 141), pneumonia (n = 53), other (n = 11). In total, 144 (70.2%) patients had targeted treatment; 74 (36.1%) against Escherichia coli, 70 (34.4%) other Enterobacterales. A total of 130 (63%) patients received 4 g/day; the remaining patients had reduced renal function with dosing in accordance with guidance. Overall temocillin treatment success was 79.5%; highest when used to treat UTI 85.8% (versus 67.9% in respiratory infections, P = 0.008). Empirical treatment demonstrated 82.0% (50/61) success [versus 78.5% (113/144) among targeted treatment, P = 0. 71].

Conclusions

Temocillin at 4 g/day is an effective and safe alternative in treating patients with Gram-negative infections, but should be considered in the context of patient age and comorbidities. Increased dosing or alternate strategies may be indicated when the infection is not of a urinary source.
Healthcare Process Modeling to Phenotype Clinician Behaviors for Exploiting the Signal Gain of Clinical Expertise (HPM-ExpertSignals): Development and evaluation of a conceptual framework
Authors: Rossetti Sarah Collins , Knaplund Chris , Albers Dave , Dykes Patricia C , Kang Min Jeoung , Korach Tom Z , Zhou Li , Schnock Kumiko , Garcia Jose , Schwartz Jessica , Fu Li-Heng , Klann Jeffrey G , Lowenthal Graham , Cato Kenrick
Published: January 2021

Objective

There are signals of clinicians’ expert and knowledge-driven behaviors within clinical information systems (CIS) that can be exploited to support clinical prediction. Describe development of the Healthcare Process Modeling Framework to Phenotype Clinician Behaviors for Exploiting the Signal Gain of Clinical Expertise (HPM-ExpertSignals).

Materials and Methods

We employed an iterative framework development approach that combined data-driven modeling and simulation testing to define and refine a process for phenotyping clinician behaviors. Our framework was developed and evaluated based on the Communicating Narrative Concerns Entered by Registered Nurses (CONCERN) predictive model to detect and leverage signals of clinician expertise for prediction of patient trajectories.

Results

Seven themes—identified during development and simulation testing of the CONCERN model—informed framework development. The HPM-ExpertSignals conceptual framework includes a 3-step modeling technique: (1) identify patterns of clinical behaviors from user interaction with CIS; (2) interpret patterns as proxies of an individual’s decisions, knowledge, and expertise; and (3) use patterns in predictive models for associations with outcomes. The CONCERN model differentiated at risk patients earlier than other early warning scores, lending confidence to the HPM-ExpertSignals framework.

Discussion

The HPM-ExpertSignals framework moves beyond transactional data analytics to model clinical knowledge, decision making, and CIS interactions, which can support predictive modeling with a focus on the rapid and frequent patient surveillance cycle.

Conclusions

We propose this framework as an approach to embed clinicians’ knowledge-driven behaviors in predictions and inferences to facilitate capture of healthcare processes that are activated independently, and sometimes well before, physiological changes are apparent.
Cost-Effectiveness of Smoking Cessation Interventions in the Lung Cancer Screening Setting: A Simulation Study
Authors: Cadham Christopher J , Cao Pianpian , Jayasekera Jinani , Taylor Kathryn L , Levy David T , Jeon Jihyoun , Elkin Elena B , Foley Kristie L , Joseph Anne , Kong Chung Yin , Minnix Jennifer A , Rigotti Nancy A , Toll Benjamin A , Zeliadt Steven B , Meza Rafael , Mandelblatt Jeanne ,   the CISNET-SCALE Collaboration, Cadham Christopher J , Cao Pianpian , Jayasekera Jinani , Taylor Kathryn L , Levy David T , Jeon Jihyoun , Meza Rafael , Mandelblatt Jeanne
Published: January 2021

Background

Guidelines recommend offering cessation interventions to smokers eligible for lung cancer screening, but there is little data comparing specific cessation approaches in this setting. We compared the benefits and costs of different smoking cessation interventions to help screening programs select specific cessation approaches.

Methods

We conducted a societal-perspective cost-effectiveness analysis using a Cancer Intervention and Surveillance Modeling Network model simulating individuals born in 1960 over their lifetimes. Model inputs were derived from Medicare, national cancer registries, published studies, and micro-costing of cessation interventions. We modeled annual lung cancer screening following 2014 US Preventive Services Task Force guidelines plus cessation interventions offered to current smokers at first screen, including pharmacotherapy only or pharmacotherapy with electronic and/or web-based, telephone, individual, or group counseling. Outcomes included lung cancer cases and deaths, life-years saved, quality-adjusted life-years (QALYs) saved, costs, and incremental cost-effectiveness ratios.

Results

Compared with screening alone, all cessation interventions decreased cases of and deaths from lung cancer. Compared incrementally, efficient cessation strategies included pharmacotherapy with either web-based cessation ($555 per QALY), telephone counseling ($7562 per QALY), or individual counseling ($35 531 per QALY). Cessation interventions continued to have costs per QALY well below accepted willingness to pay thresholds even with the lowest intervention effects and was more cost-effective in cohorts with higher smoking prevalence.

Conclusion

All smoking cessation interventions delivered with lung cancer screening are likely to provide benefits at reasonable costs. Because the differences between approaches were small, the choice of intervention should be guided by practical concerns such as staff training and availability.
In nomen omen: the effect of flower distance on female reproductive success of the lax-flowered orchidAnacamptis laxiflora(Orchidaceae)
Authors: Scopece Giovanni , Criscuolo Nicola , Cozzolino Salvatore
Published: January 2021

Aims

In multiflowered species, the architecture of inflorescences is of primary importance in shaping plant attractiveness. The aim of this study was to disentangle the role of inflorescence traits in plant female reproductive success and pollination patterns along the inflorescence in the lax-flowered orchid Anacamptis laxiflora, a terrestrial species exploiting a deceptive pollination strategy. We also evaluated whether the relationship between inflorescence traits and female reproductive success was modified by the height of surrounding vegetation and/or by population density.

Methods

We delimited experimental plots in a natural population of A. laxiflora. We tallied the individuals within each plot and categorized low-density plots and high-density plots; then, in part of the plots we manually removed surrounding grass thus producing an equal number of plots with high grass and low grass. Within these plots, we recorded inflorescence traits and female reproductive success (i.e. the number of fruit and their position along the inflorescence). We analyzed these data using generalized linear mixed-effects models (GLMMs) and calculated selection gradients.

Important Findings

We found that all the investigated inflorescence traits influenced female reproductive success. In particular, our GLMMs showed that ‘average flower distance’ was the best predictor for shaping reproductive success patterns. We detected significant positive selection on the investigated inflorescence traits, but these selective trends were strictly linked to both the height of the surrounding vegetation and the population density, suggesting a significant influence of local environmental context in shaping selective patterns. Female reproductive success was not linked to the position of flowers along the inflorescence, suggesting that pollinators visit flowers randomly along the inflorescence without a detectable preference for a specific part. This study highlights the importance of inflorescence traits in shaping female reproductive success of multiflowered deceptive orchids, and confirms a primary role for the environmental context in modifying pollinator-mediated selection patterns.
Sleep and Psychological Difficulties in Italian School-Age Children During COVID-19 Lockdown
Authors: Cellini Nicola , Di Giorgio Elisa , Mioni Giovanna , Di Riso Daniela
Published: January 2021

Objective

On March 10, 2020, the Italian Government ordered a national lockdown to limit the viral transmission of coronavirus disease 2019 infections. This study investigated how these restrictive measures have impacted sleep quality, timing, and psychological difficulties in school-age children and their mothers during the lockdown.

Methods

In an online survey, 299 mothers reported their sleep habits, experience of time, and psychological difficulties as well as those of their children (6–10 years old) during and, retrospectively, before the lockdown.

Results

During the lockdown, children showed a marked delay in sleep timing—that is, later bedtime and rise time—and a mild worsening in sleep quality. They were less prone to respect daily routines or to keep track of the passage of time. They showed increased emotional, conduct, and hyperactive symptoms, and the increase in these psychological difficulties was predicted by the change in sleep quality, boredom, and mothers’ psychological difficulties. In addition, mothers showed a delayed sleep timing and worsening of sleep quality during the lockdown, in varying degrees depending on their working conditions. Mothers who kept working regularly outside their homes during lockdown reported more regular sleep patterns, whereas mothers who stopped working showed more emotional symptoms and relevant changes in their perception of time.

Conclusions

Overall, given the evidence of the adverse behavioral and psychological impact of home confinement and social restrictions, effective measures needed to be in place to mitigate long-term effects on children and their mothers, especially those who have had to stop working during lockdown.
A case of hereditary metachronous bilateral triple-negative breast cancer that was highly sensitive to carboplatin
Authors: Wu Rongrong , Adachi Kayo , Koyama Yoichi , Orimoto Kyoko , Okazaki Miki , Asaoka Mariko , Teraoka Saeko , Ueda Ai , Miyahara Kana , Kawate Takahiko , Kaise Hiroshi , Yamada Kimito , Sato Eichi , Ishikawa Takashi
Published: January 2021

A 52-year-old woman with a strong family history of breast cancer was diagnosed as having triple-negative breast cancer (TNBC) in her right breast. Neoadjuvant chemotherapy (NAC; four cycles of epirubicin/cyclophosphamide/5-fluorouracil) was performed, followed by breast-conserving surgery and axillary lymph node dissection. Histopathological analysis of the surgical specimens demonstrated a few focal tumor cells remaining in the stroma, but not a pathological complete response (pCR). Weekly paclitaxel was subsequently added to the treatment regimen. A total of 17 months after the adjuvant treatments, TNBC recurred in her left breast with massive lymph node metastasis. Because of the early recurrence after standard treatment, NAC was administered together with carboplatin and paclitaxel. Histopathological analysis of the partially resected breast and axillary lymph nodes demonstrated a pCR. No recurrent disease was found 2 years after the second TNBC treatment. This case underlines the importance of platinum-based chemotherapy and prophylactic mastectomy for patients with BRCA dysfunction.
Ageing beautifully: can the benefits of seed priming be separated from a reduced lifespan trade-off?
Authors: Fabrissin Isabelle , Sano Naoto , Seo Mitsunori , North Helen M
Published: January 2021

Germination performance is affected following seed exposure to a combination of temperature fluctuations and cycles of hydration and dehydration. This has long been exploited in a seed technology termed priming, which increases germination speed and seedling vigour, but these benefits have often been associated with effects on seed lifespan, or longevity, with conflicting evidence for positive and negative effects. Seed longevity is a key seed trait influencing not only the storage of commercial stocks but also in situ and ex situ seed conservation. In the context of increasingly variable environmental conditions faced by both crops and wild species, this has led to renewed interest in understanding the molecular factors that underlie priming. Here, we provide an overview of the literature relating to the effect of priming on seed lifespan, and catalogue the different parameters used for priming treatments and their consequences on longevity for a range of species. Our current limited understanding of the molecular basis for priming effects is also outlined, with an emphasis on recent advances and promising approaches that should lead towards the application and monitoring of the priming process in a less empirical manner.
Maintenance of Adaptive Dynamics and No Detectable Load in a Range-Edge Outcrossing Plant Population
Authors: Takou Margarita , Hämälä Tuomas , Koch Evan M , Steige Kim A , Dittberner Hannes , Yant Levi , Genete Mathieu , Sunyaev Shamil , Castric Vincent , Vekemans Xavier , Savolainen Outi , Meaux Juliette de
Published: January 2021

During range expansion, edge populations are expected to face increased genetic drift, which in turn can alter and potentially compromise adaptive dynamics, preventing the removal of deleterious mutations and slowing down adaptation. Here, we contrast populations of the European subspecies Arabidopsis lyrata ssp. petraea, which expanded its Northern range after the last glaciation. We document a sharp decline in effective population size in the range-edge population and observe that nonsynonymous variants segregate at higher frequencies. We detect a 4.9% excess of derived nonsynonymous variants per individual in the range-edge population, suggesting an increase of the genomic burden of deleterious mutations. Inference of the fitness effects of mutations and modeling of allele frequencies under the explicit demographic history of each population predicts a depletion of rare deleterious variants in the range-edge population, but an enrichment for fixed ones, consistent with the bottleneck effect. However, the demographic history of the range-edge population predicts a small net decrease in per-individual fitness. Consistent with this prediction, the range-edge population is not impaired in its growth and survival measured in a common garden experiment. We further observe that the allelic diversity at the self-incompatibility locus, which ensures strict outcrossing and evolves under negative frequency-dependent selection, has remained unchanged. Genomic footprints indicative of selective sweeps are broader in the Northern population but not less frequent. We conclude that the outcrossing species A. lyrata ssp. petraea shows a strong resilience to the effect of range expansion.
Compatibility of Evolutionary Responses to Constituent Antibiotics Drive Resistance Evolution to Drug Pairs
Authors: Jahn Leonie Johanna , Simon Daniel , Jensen Mia , Bradshaw Charles , Ellabaan Mostafa Mostafa Hashim , Sommer Morten Otto Alexander
Published: January 2021

Antibiotic combinations are considered a relevant strategy to tackle the global antibiotic resistance crisis since they are believed to increase treatment efficacy and reduce resistance evolution (WHO treatment guidelines for drug-resistant tuberculosis: 2016 update.). However, studies of the evolution of bacterial resistance to combination therapy have focused on a limited number of drugs and have provided contradictory results (Lipsitch, Levin BR. 1997; Hegreness et al. 2008; Munck et al. 2014). To address this gap in our understanding, we performed a large-scale laboratory evolution experiment, adapting eight replicate lineages of Escherichia coli to a diverse set of 22 different antibiotics and 33 antibiotic pairs. We found that combination therapy significantly limits the evolution of de novode novo resistance in E. coli, yet different drug combinations vary substantially in their propensity to select for resistance. In contrast to current theories, the phenotypic features of drug pairs are weak predictors of resistance evolution. Instead, the resistance evolution is driven by the relationship between the evolutionary trajectories that lead to resistance to a drug combination and those that lead to resistance to the component drugs. Drug combinations requiring a novel genetic response from target bacteria compared with the individual component drugs significantly reduce resistance evolution. These data support combination therapy as a treatment option to decelerate resistance evolution and provide a novel framework for selecting optimized drug combinations based on bacterial evolutionary responses.
Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome
Authors: Guiblet Wilfried M , Cremona Marzia A , Harris Robert S , Chen Di , Eckert Kristin A , Chiaromonte Francesca , Huang Yi-Fei , Makova Kateryna D
Published: January 2021

Approximately 13% of the human genome can fold into non-canonical (non-B) DNA structures (e.g. G-quadruplexes, Z-DNA, etc.), which have been implicated in vital cellular processes. Non-B DNA also hinders replication, increasing errors and facilitating mutagenesis, yet its contribution to genome-wide variation in mutation rates remains unexplored. Here, we conducted a comprehensive analysis of nucleotide substitution frequencies at non-B DNA loci within noncoding, non-repetitive genome regions, their ±2 kb flanking regions, and 1-Megabase windows, using human-orangutan divergence and human single-nucleotide polymorphisms. Functional data analysis at single-base resolution demonstrated that substitution frequencies are usually elevated at non-B DNA, with patterns specific to each non-B DNA type. Mirror, direct and inverted repeats have higher substitution frequencies in spacers than in repeat arms, whereas G-quadruplexes, particularly stable ones, have higher substitution frequencies in loops than in stems. Several non-B DNA types also affect substitution frequencies in their flanking regions. Finally, non-B DNA explains more variation than any other predictor in multiple regression models for diversity or divergence at 1-Megabase scale. Thus, non-B DNA substantially contributes to variation in substitution frequencies at small and large scales. Our results highlight the role of non-B DNA in germline mutagenesis with implications to evolution and genetic diseases.
Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections
Authors: Morrisette Taylor , Alosaimy Sara , Philley Julie V , Wadle Carly , Howard Catessa , Webb Andrew J , Veve Michael P , Barger Melissa L , Bouchard Jeannette , Gore Tristan W , Lagnf Abdalhamid M , Ansari Iman , Mejia-Chew Carlos , Cohen Keira A , Rybak Michael J
Published: January 2021

Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2–11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
Pain and fatigue are longitudinally and bi-directionally associated with more sedentary time and less standing time in rheumatoid arthritis
Authors: O’Brien Ciara M , Ntoumanis Nikos , Duda Joan L , Kitas George D , Veldhuijzen van Zanten Jet J C S , Metsios George S , Fenton Sally A M
Published: January 2021

Objectives

The aims of this study were to examine the longitudinal and bi-directional associations of pain and fatigue with sedentary, standing and stepping time in RA.

Methods

People living with RA undertook identical assessments at baseline (T1, n = 104) and 6-month follow-up (T2, n = 54). Participants completed physical measures (e.g. height, weight, BMI) and routine clinical assessments to characterize RA disease activity (DAS-28). Participants also completed questionnaires to assess physical function (HAQ), pain (McGill Pain Questionnaire) and fatigue (Multidimensional Assessment of Fatigue Scale). Participants’ free-living sedentary, standing and stepping time (min/day) were assessed over 7 days using the activPAL3µ™. For the statistical analysis, hierarchical regression analysis was employed to inform the construction of path models, which were subsequently used to examine bi-directional associations of pain and fatigue with sedentary, standing and stepping time. Specifically, where significant associations were observed in longitudinal regression analysis, the bi-directionality of these associations was further investigated via path analysis. For regression analysis, bootstrapping was applied to regression models to account for non-normally distributed data, with significance confirmed using 95% CIs. Where variables were normally distributed, parametric, non-bootstrapped statistics were also examined (significance confirmed via β coefficients, with P < 0.05) to ensure all plausible bi-directional associations were examined in path analysis.

Results

Longitudinal bootstrapped regression analysis indicated that from T1 to T2, change in pain, but not fatigue, was positively associated with change in sedentary time. In addition, change in pain and fatigue were negatively related to change in standing time. Longitudinal non-bootstrapped regression analysis demonstrated a significant positive association between change in fatigue with change in sedentary time. Path analysis supported the hypothesized bi-directionality of associations between change in pain and fatigue with change in sedentary time (pain, β = 0.38; fatigue, β = 0.44) and standing time (pain, β = –0.39; fatigue, β = –0.50).

Conclusion

Findings suggest pain and fatigue are longitudinally and bi-directionally associated with sedentary and standing time in RA.
The distribution of indirect cost recovery in academic research
Authors: Graddy-Reed Alexandra , Feldman Maryann , Bercovitz Janet , Langford W. Scott
Published: January 2021

Research universities rely heavily on external funding to advance knowledge and generate economic growth. In the USA, tens of billions of dollars are spent each year on research and development with the federal government contributing over half of these funds. Yet a decline in relative federal funding highlights the role of other funders and their varying contractual terms. Specifically, nonfederal funders provide lower recovery of indirect costs. Using project-level university-sponsored research administrative records from four institutions, we examine indirect cost recovery. We find significant variation in the amount of indirect funding recovered—both across and within funders, as well as to different academic fields within a university. The distribution of sponsors in the overall research funding portfolio also impacts indirect cost recovery. The recovery variation has important implications for the sustainability and cross-subsidization of the university research enterprise. Together, our results show where universities are under-recovering indirect costs.
A Total-Group Phylogenetic Metatree for Cetacea and the Importance of Fossil Data in Diversification Analyses
Authors: Lloyd Graeme T , Slater Graham J
Published: January 2021

Phylogenetic trees provide a powerful framework for testing macroevolutionary hypotheses, but it is becoming increasingly apparent that inferences derived from extant species alone can be highly misleading. Trees incorporating living and extinct taxa are needed to address fundamental questions about the origins of diversity and disparity but it has proved challenging to generate robust, species-rich phylogenies that include large numbers of fossil taxa. As a result, most studies of diversification dynamics continue to rely on molecular phylogenies. Here, we extend and apply a recently developed meta-analytic approach for synthesizing previously published phylogenetic studies to infer a well-resolved set of species level, time-scaled phylogenetic hypotheses for extinct and extant cetaceans (whales, dolphins, and allies). Our trees extend sampling from the $\sim 90$ extant species to over 500 living and extinct species, and therefore allow for more robust inference of macroevolutionary dynamics. While the diversification scenarios, we recover are broadly concordant with those inferred from molecular phylogenies they differ in critical ways, notably in the relative contributions of extinction and speciation rate shifts in driving rapid radiations. The metatree approach provides the most immediate route for generating higher level phylogenies of extinct taxa and opens the door to re-evaluation of macroevolutionary hypotheses derived only from extant taxa.[Extinction; macroevolution; matrix representation with parsimony; morphology; supertree.]
It’s more than climate change and active transport—physical activity’s role in sustainable behavior
Authors: Nigg Carina , Nigg Claudio R
Published: January 2021

Considering the interdependence of human’s and nature’s health within the planetary health concept, we evaluated how physical activity (PA) can be conceptualized as sustainable behavior (SuB) and how PA relates to other types of SuBs within the United Nations’ sustainable development goal (SDG) framework. Regarding social SDGs, PA contributes to improving malnutrition (SDG 2), health behaviors (SDG 3), education (SDG 4), reducing inequalities (SDG 10), sustainable cities (SDG 12), and peace (SDG 16). For ecological SDGs, PA contributes to sustainable consumption (SDG 11) and combating climate change (SDG 13). Therefore, PA is more than a health behavior, it contributes to planetary health and sustainable development. However, caution is warranted as PA also has the potential to contribute and reinforce unsustainability. Thus, PA as a SuB requires an own research agenda, investigating (a) PA as social and ecological SuB, (b) sustainable PA promotion, (c) sustainable PA measurement, (d) common underlying constructs of PA and SuB, and (e) technology’s role to assess and promote PA and SuB.
Return to Play Guidelines After Cervical Spine Injuries in American Football Athletes
Authors: Swiatek Peter R. , Nandurkar Tejas S. , Maroon Joseph C. , Cantu Robert C. , Feuer Henry , Bailes Julian E. , Hsu Wellington K.
Published: January 2021

Study Design

Literature-based review.

Objective

We sought to evaluate clinical and case studies related to return to play (RTP) after cervical spine injuries in elite American football athletes and to formulate guidelines to help health care practitioners manage these conditions.

Summary of Background Data

American football athletes are at unique risk of cervical spine injury and appropriate case-by-case management of cervical spine injuries is necessary for these athletes. Despite this need, no standardized guidelines exist for RTP after cervical spine injury.

Methods

Observational or case-based articles relating to RTP after cervical spine injury in American football athletes were curated from PubMed/EMBASE databases. Primary literature published before December 1, 2019 involving National Football League (NFL) or National Collegiate Athletic Association (NCAA) athletes met inclusion criteria.

Results

The data acquisition process yielded 28 studies addressing cervical spine injuries and RTP in American football athletes. Stingers/burners were the most common injury and placed athletes at higher risk of a more severe re-injury. Transient quadriplegia, cervical stenosis, cervical disc herniation (CDH), and cervical fractures have a more significant impact on the long-term health and career longevity of the American football athlete. As such, the literature offers some guidance for management of these athletes, including average time for RTP in patients treated nonoperatively, thresholds involving cervical stenosis, and postoperative recommendations after spinal decompression and/or fusion surgery.

Conclusion

Elite American football athletes are at high risk for cervical spine injury due to the nature of their sport. The decision to allow these athletes to return to play should involve an understanding of the average RTP time, the potential risks of recurrence or re-injury, and individual characteristics such as position played and pathology on imaging.

Level of Evidence: 3
Diagnostic Yield of Axial Computed Tomography Scans for Pediatric Axial Skeletal Injuries
Authors: Maqsoodi Noorullah , Louis Clauden , Botros Mina , Baldwin Avionna , Jefferson Jamal , Moses Jalea T. , Wakeman Derek , Mesfin Addisu
Published: January 2021

Study Design

Retrospective cohort study.

Objective

To evaluate the diagnostic yield of computed tomography (CT) imaging of the axial skeleton in pediatric patients evaluated a level I trauma center.

Summary of Background Data

CT imaging has become ubiquitous in the assessment of axial skeletal injuries in trauma patients.

Methods

This is a retrospective study from one Level I trauma center of patients undergoing CT imaging during pediatric trauma assessment. Medical records of pediatric trauma patients 18-year old and younger who underwent axial skeletal CT imaging from 2013 to 2015 were evaluated. The following were assessed: mechanism of injury, age, sex, race/ethnicity, presence of fracture, management of fracture.

Results

A total of 831 patients were assessed, there were 355 (42.7%) females and 476 males (57.3%) with an average age of 15.4 (2 mo–18 yrs). 588 (70.8%) were White, 164 (19.7%) were African-American, 12 (1.4%) were Asians, 67 (8.1%) other, and 46 (5.5%) identified as Hispanic. There were 45 patients (5.4%) who sustained 52 fractures. Common mechanisms were motor vehicle accidents (MVA) 28%, sports injuries (18%), and fall from height (15%). 35.9% of fractures were identified on plain radiographs. Nine injuries were treated surgically (one cervical, two thoracic, two lumbar, and four pelvic); three of these were identified on radiographs. From the 14 patients with cervical spine fractures none were detected on radiographs.

Conclusion

In this large series of 831 pediatric patients undergoing axial CT imaging, the rate of axial fractures was 5.4%. The majority of these fractures were managed non-surgically. Only 35.9% of fractures were identified on radiographs.

Level of Evidence: 3
Cardiac Troponin I and T in Checkpoint Inhibitor–associated Myositis and Myocarditis
Authors: Ang Edmond , Mweempwa Angela , Heron Campbell , Ahn Yeri , Rivalland Gareth , Ha Leah Y. , Deva Sanjeev
Published: January 2021

Checkpoint inhibitor–associated myocarditis (ir-myocarditis) and myositis (ir-myositis) may occur concurrently among patients on checkpoint inhibitor immunotherapy. While cardiac-specific troponin I (cTnI) and troponin T (cTnT) are regarded to have similar sensitivities and specificities in conditions such as acute coronary syndrome, the cardiac specificity of cTnT has been challenged following observation that patients with neuromuscular diseases, including myositis, may have elevated cTnT without apparent clinical evidence of myocardial injury. Consequently, in the context of concurrent ir-myositis, cTnI may be a more appropriate biomarker for diagnosing and monitoring ir-myocarditis. To illustrate this point, we report a case of a patient with severe ir-myositis while on adjuvant programmed cell death protein 1 inhibitor immunotherapy for stage III melanoma, with accompanying elevation in cTnT.
Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer
Authors: Mendonça Gorgulho Carolina , Krishnamurthy Anuradha , Lanzi Anastasia , Galon Jérôme , Housseau Franck , Kaneno Ramon , Lotze Michael T.
Published: January 2021

Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%–6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to this modality of treatment, even though colorectal tumors are frequently infiltrated with T cells. Tumor cells limit apoptosis and survive following intensive chemotherapy leading to drug resistance and induction of autophagy. Pharmacological or molecular inhibition of autophagy improves the efficacy of cytotoxic chemotherapy in murine models. The microbiome clearly plays an etiologic role, in some or most colon tumors, realized by elegant findings in murine models and now investigated in human clinical trials. Recent results have suggested that cancer vaccines may be beneficial, perhaps best as preventive strategies. The search for therapies that can be combined with current approaches to increase their efficacy, and new knowledge of the biology of CRC are pivotal to improve the care of patients suffering from this disease. Here, we review the basic immunobiology of CRC, current “state-of-the-art” immunotherapies and define those areas with greatest therapeutic promise for the future.