bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing the Volume–Value Relationship in Laminectomy
Authors: Frankel William C. , Navarro Sergio M. , Haeberle Heather S. , Ramanathan Deepak , Ramkumar Prem N.
Published: October 2018

Study Design.

Retrospective cohort study.

Objective.

The objective of the present study was to establish evidence-based volume thresholds for surgeons and hospitals predictive of enhanced value in the setting of laminectomy.

Summary of Background Data.

Previous studies have attempted to characterize the relationship between volume and value; however, none to the authors’ knowledge has employed an evidence-based approach to identify thresholds yielding enhanced value.

Methods.

In total, 67,758 patients from the New York Statewide Planning and Research Cooperative System database undergoing laminectomy in the period 2009 to 2015 were included. We used stratum-specific likelihood ratio analysis of receiver operating characteristic curves to establish volume thresholds predictive of increased length of stay (LOS) and cost for surgeons and hospitals.

Results.

Analysis of LOS by surgeon volume produced strata at: <17 (low), 17 to 40 (medium), 41 to 71 (high), and >71 (very high). Analysis of cost by surgeon volume produced strata at: <17 (low), 17 to 33 (medium), 34 to 86 (high), and >86 (very high). Analysis of LOS by hospital volume produced strata at: <43 (very low), 43 to 96 (low), 97 to 147 (medium), 148 to 172 (high), and >172 (very high). Analysis of cost by hospital volume produced strata at: <43 (very low), 43 to 82 (low), 83 to 115 (medium), 116 to 169 (high), and >169 (very high). LOS and cost decreased significantly (P < 0.05) in progressively higher volume categories for both surgeons and hospitals. For LOS, medium-volume surgeons handle the largest proportion of laminectomies (36%), whereas very high-volume hospitals handle the largest proportion (48%).

Conclusion.

This study supports a direct volume–value relationship for surgeons and hospitals in the setting of laminectomy. These findings provide target-estimated thresholds for which hospitals and surgeons may receive meaningful return on investment in our increasingly value-based system. Further value-based optimization is possible in the finding that while the highest volume hospitals handle the largest proportion of laminectomies, the highest volume surgeons do not.

Level of Evidence: 3
Andexanet Alfa for Reversing Factor Xa Inhibition
Authors: Sible Alexandra M. , Nawarskas James J.
Published: October 2018

The direct oral anticoagulants (DOACs) have gained popularity recently among both patients and providers for their comparable or better efficacy and safety profiles compared with warfarin and the lack of need for routine monitoring of anticoagulant effect. One obstacle for the more widespread use of the DOACs in clinical practice has been the lack of a reversal agent. Most DOACs act by directly binding to and inhibiting the effects of factor Xa. Andexanet alfa (Andexxa, Portola Pharmaceuticals, San Francisco, CA) is a modified form of factor Xa that acts as a decoy binding entity for DOACs, thereby allowing endogenous factor Xa to perform its normal clotting functions. Andexanet has proven efficacious in clinical trials for reversing the anticoagulant effects of apixaban, edoxaban, and rivaroxaban, although its impact on clinical outcomes has not been adequately studied. Andexanet has a boxed warning for thromboembolic risks, ischemic risks, cardiac arrest, and sudden death, with these adverse events occurring in up to 18% of patients in clinical trials. However, the occurrence of these adverse events needs to be considered in relation to the fragile nature of patients who receive this agent. Because the duration of the DOACs is much less than that of warfarin, it is unclear how many patients would actually need andexanet in clinical practice, because cessation of the DOAC may be all that is needed to effectively manage bleeding. Nonetheless, having andexanet available in cases of DOAC-associated severe or life-threatening bleeding represents a therapeutic advance and should provide an added level of comfort with the clinical use of DOACs.
Are there differences in the efficacy of once-weekly GLP-1RAs in patients with type 2 diabetes?
Authors: Strong Jodi
Published: October 2018

Several long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been developed for the treatment of people with type 2 diabetes (T2D). This narrative review compares the relative efficacy of these agents according to glycemic and nonglycemic endpoints in key clinical trials. Primary reports of clinical trials used to support the regulatory applications of once-weekly GLP 1RAs were selected. These articles were critically reviewed for information on efficacy, and comparative assessments were made where possible. The estimated treatment differences for once-weekly GLP-1RAs versus placebo showed that all these agents are effective in reducing glycated hemoglobin (HbA1c). Variations in efficacies of other endpoints were also evident, but no overall pattern emerged. Two head-to-head trials showed that once-weekly semaglutide 1.0 mg was more effective than once-weekly exenatide 2.0 mg (treatment difference: 0.62%; p < .0001) and dulaglutide 1.5 mg (treatment difference: −0.41%; p < 0.0001). Similar trends were evident with bodyweight reductions. Once-weekly GLP-1RAs are a good therapeutic option for patients with T2D. There are differences between the glycemic and nonglycemic efficacies of these agents that, along with adverse event profiles, need to be considered by nurse practitioners when selecting a GLP-1RA for an individual patient.
The mode and mechanism of action of once-weekly glucagon-like peptide-1 receptor agonists in type 2 diabetes
Authors: Ridge Terry
Published: October 2018

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an efficacious and convenient option for the treatment of type 2 diabetes (T2D). This narrative review assesses the mode and mechanism of action of the GLP-1RA class in general and highlights similarities and differences within the class. Published clinical trials and manuscripts of basic scientific research were collated and critically reviewed for information relating to the mode and mechanism of action of GLP-1RAs. The mode and mechanism of action is consistent across the GLP-1RA class, despite differences in sequence homology, formulation, conjugation and device administration. Within the class there are some differences in efficacy with regard to glycemic control. Crucially, cardiovascular benefit with GLP-1RAs cannot at this time be considered as a class effect. Once-weekly GLP-1RAs are a good therapeutic option for patients with T2D, either as monotherapy or as part of a combination therapy. Differences between these agents in terms of efficacy and safety outcomes, as well as convenience of a particular device and regimen, should be considered as part of individualization of therapy for patients unable to achieve glycemic control with metformin alone.
Among inpatients, ischemic bowel disease predisposes to Clostridium difficile infection with concomitant higher mortality and worse outcomes
Authors: Adejumo Adeyinka C. , Akanbi Olalekan , Pani Lydie
Published: October 2018

Background and aims

Clinical conditions resulting in hypoxia, hypoperfusion, anaerobic milieu within the gut, and intestinal epithelial breakdown, such as seen in heart failure, precipitatesClostridium difficileinfection (CDI). Given that ischemic bowel disease (IB) typically results in similar changes within the gut, we investigated the relationship between CDI and IB, and the impact of CDI on the clinical outcomes of IB.

Patients and methods

We initially performed a cross-sectional analysis on the 2014 Healthcare Cost and Utilization Project – Nationwide Inpatient Sample (NIS) patient’s discharge records of ages 18 years and older, by estimating the crude and adjusted odds ratio (aOR) of CDI and IB as the outcome and predictor respectively. We then pooled data from the 2012–2014 NIS, identified, and compared mortality (and 15 other outcomes) between three groups: IB+CDI, IB-alone, and CDI-alone (Statistical Analysis System 9.4).

Results

In the 2014 NIS, records with IB (n=27 609), had higher rate and odds of CDI [3.95 vs. 1.17%, aOR: 1.89 (1.77–2.02)] than records without IB (n=5 879 943). The 2012–2014 NIS contained 1105 IB+CDI, 30 960 IB-alone, and 60 758 CDI-alone groups. IB+CDI had higher mortality [aOR: 1.44 (1.11–1.86)], length of stay [9.59 (9.03–10.20) vs. 6.12 (5.99–6.26) days], cost [$93 257 (82 892–104 919) vs. $63 257 (61 029–65 567)], unfavorable discharge disposition [aOR: 2.24 (1.91–2.64)] and poorer results across most of the other outcomes than IB-alone. Comparable results were found for IB+CDI versus CDI-alone.

Conclusion

IB is a risk factor for CDI in hospitals. CDI is associated with higher mortality, longer length of stay, higher cost, unfavorable discharge, and many other poorer health outcomes in patients with IB.
End tidal carbon dioxide monitoring in acute asthma: a prospective pilot study in emergency department patients
Authors: Truchot Jennifer , Gayet Albéric-Rembrandt , Philippon Anne-Laure , Chauvin Anthony , Malka Johanna , Vicaut Eric , Plaisance Patrick
Published: October 2018

The peak expiratory flow rate (PEFR) is the gold standard for monitoring asthmatic patients. However, its measurement requires understanding and active participation. End tidal carbon dioxide (EtCO2) may be considered an accurate surrogate for PaCO2, a severity marker in acute asthma. We studied the use of EtCO2 as a monitoring tool in acute asthma.

Patients and methods

This was a prospective study that included consecutive patients admitted to our emergency department for acute asthma exacerbation. Data were collected at first medical contact (T0) and after 1 h of treatment (T60). The primary endpoint was the change in EtCO2; the secondary endpoints included changes in the EtCO2
Q angle value, plateau T time, and change in EtCO2 values for the patients with a PEFR ratio less than 50% after treatment.

Results

Fifty-five patients were included and 36 waveforms were analysed. The mean age was 37 years and 26 (47%) were women. The median initial PEFR was 200 [interquartile range (IQR): 150–240]; the median EtCO2 at T0 and T60 was 35 (IQR: 30–38) and 34 (IQR: 29–37). There was no significant change in EtCO2 after treatment. There was no significant change in the Q angle and the T time after treatment. At T60, 20 (36%) patients had a PEFR ratio less than 50%. Change in EtCO2 from T60 to T0 was associated with a PEFR ratio less than 50%.

Conclusion

After 1 h of treatment, there was no significant change in EtCO2. A decrease in EtCO2 seems to be associated with a higher risk of PEFR ratio less than 50% after treatment.
Declining Sperm Counts… or Rather Not? A Mini Review
Authors: Ravanos Konstantinos , Petousis Stamatios , Margioula-Siarkou Chrysoula , Papatheodorou Achilleas , Panagiotidis Yannis , Prapas Nikos , Prapas Yannis
Published: October 2018

Importance

Temporal global trends of sperm quality remain a matter of debate.

Objective

The aim of this study was to present a comprehensive review of studies reporting on sperm quality counts, summarize the main end points, and assess the main reasons for potential discrepancies.

Evidence Acquisition

An evidence-based review of PubMed and Scopus databases was performed regarding studies reporting on modification of sperm quality counts, independently of study character, study language, or date.

Results

Since the meta-analysis of Carlsen et al in 1992 (Br Med J1992;305:609–613) that suggested an annual decline in sperm count of 1%, several reports confirmed the decline in sperm quality, whereas others disproved them, suggesting a slight increase or absence of change in sperm count. Such controversies may be attributed to geographical and time-related variability in sperm values and also to several confounding factors that influence the semen parameters. Intrinsic weaknesses of the studies include heterogeneity of subjects recruited, lack of adjustment for confounding factors, and samples that do not always represent the general population.

Conclusions

No consensus exists on whether sperm counts actually decrease because studies' results are often controversial or inconclusive with methodological deficiencies. More prospective, large-scale, population based studies are needed in order to provide sound evidence of possible global trends in sperm count.

Target Audience

Obstetricians and gynecologists, family physicians.

Learning Objectives

After completing this activity, the learner should be better able to examine the modern trends about modification of sperm quality parameters, critique several reports revealing a decline in sperm quality, and demonstrate the necessity of performing more prospective, large-scale studies.
Reimagining Health Communication: A Noninferiority Randomized Controlled Trial of Crowdsourced Intervention in China
Authors: Tang Weiming , Mao Jessica , Liu Chuncheng , Mollan Katie , Zhang Ye , Tang Songyuan , Hudgens Michael , Ma Wei , Kang Dianmin , Wei Chongyi , Tucker Joseph D.
Published: October 2018

Background

Crowdsourcing, the process of shifting individual tasks to a large group, may be useful for health communication, making it more people-centered. We aimed to evaluate whether a crowdsourced video is noninferior to a social marketing video in promoting condom use.

Methods

Men who have sex with men (≥16 years old, had condomless sex within 3 months) were recruited and randomly assigned to watch 1 of the 2 videos in 2015. The crowdsourced video was developed through an open contest, and the social marketing video was designed by using social marketing principles. Participants completed a baseline survey and follow-up surveys at 3 weeks and 3 months postintervention. The outcome was compared with a noninferiority margin of +10%.

Results

Among the 1173 participants, 907 (77%) and 791 (67%) completed the 3-week and 3-month follow-ups. At 3 weeks, condomless sex was reported by 146 (33.6%) of 434 participants and 153 (32.3%) 473 participants in the crowdsourced and social marketing arms, respectively. The crowdsourced intervention achieved noninferiority (estimated difference, +1.3%; 95% confidence interval, −4.8% to 7.4%). At 3 months, 196 (52.1%) of 376 individuals and 206 (49.6%) of 415 individuals reported condomless sex in the crowdsourced and social-marketing arms (estimated difference: +2.5%, 95% confidence interval, −4.5 to 9.5%). The 2 arms also had similar human immunodeficiency virus testing rates and other condom-related secondary outcomes.

Conclusions

Our study demonstrates that crowdsourced message is noninferior to a social marketing intervention in promoting condom use among Chinese men who have sex with men. Crowdsourcing contests could have a wider reach than other approaches and create more people-centered intervention tools for human immunodeficiency virus control.
Using an Email Alert to Improve Identification of Pregnancy Status for Women With Syphilis—Florida, 2017–2018
Authors: Matthias James M. , Keller Gayle , George Daniel , Wilson Craig , Peterman Thomas A.
Published: October 2018

Background

Congenital syphilis can be prevented if syphilis is treated early in pregnancy. Identifying women with syphilis who are pregnant facilitates prioritization for follow-up. In 2016, Florida reported 1062 female syphilis cases, aged 15 to 44 years, and 160 (15%) cases were missing pregnancy status. The Florida Department of Health developed a system-generated weekly email notification sent to local program staff for all female syphilis investigations with unknown pregnancy status. We describe the outcome of these efforts to reduce unknown pregnancy status among women with syphilis.

Methods

Review of the frequency and outcomes (reduction in investigations flagged and change in pregnancy status variable) of the first email notification (October 2, 2017) were compared with subsequent notifications through June 25, 2018. In addition, we reviewed pregnancy status of reported female syphilis cases (age, 15–44 years) from 2013 to 2018.

Results

The first email notification listed 76 investigations with unknown pregnancy status. This number decreased to 40 in 1 week and to 22 by 1 month. The decreased volume continued through June 2018 (n = 13). Of the original 76 investigations, 3 women were pregnant, and 38 (50%) were determined to meet the syphilis case definition (including 1 who was pregnant). In 2017, pregnancy ascertainment for female syphilis cases reached 98%.

Conclusions

Focused efforts using email notification to obtain pregnancy status improved ascertainment in large sexually transmitted disease (STD) programs with minimal effort. Most but not all women with unknown pregnancy status were identified as not pregnant.
Exsanguination From an Ulcerated, Atypical, Superficial Venous Malformation
Authors: Ma Li , Milne Nathan , Strutton Geoffrey , Ong Beng Beng
Published: October 2018

Venous malformations (VMs) are the most common vascular malformations, and their diagnosis can be challenging. They may develop in any region of the body, with highly variable clinical presentations. Although they typically present early in life, many case reports have documented the sudden appearance of a previously unrecognized venous malformation in adulthood. Pain is the major complaint in most of the cases, and other complications include phlebolith formation and bleeding. To our knowledge, fatal hemorrhage from a VM has not previously been reported in the medical literature. We present a case of exsanguination from a previously undiagnosed lower limb superficial VM. This case stresses the importance of proper diagnosis and management of VM.
Diagnostic Rate of Autoinflammatory Diseases Evaluated by Fever Patterns in Pediatric- and Adult-Onset Patients
Authors: Miyamae Takako , Hanaya Aki , Kawamoto Manabu , Tani Yumi , Kawaguchi Yasushi , Yamanaka Hisashi
Published: October 2018

Objectives

This is a noncomparative study performed to determine if fever pattern is related to a diagnosis of autoinflammatory disease (AID) in pediatric- and adult-onset patients.

Methods

The final diagnosis of patients suspected to have AID was evaluated against gene polymorphisms known to be responsible for AID, clinical manifestations, and fever pattern, in our institute from 2005 to 2016. Genomic DNA was isolated from patients' peripheral blood, and polymerase chain reaction was used to amplify the indicated exons of 12 genes: MEFV, TNFRSF1A, MVK, NLRP3, NOD2, LI1RN, IL36RN, PSMB8, NALP12, PSTPIP1, TNFAIP3, and NLRC4. Genetic polymorphisms of the above genes were examined.

Results

All 210 individuals (135 pediatric onset and 75 adult onset) were classified into the following 3 subgroups: (1) periodic fever (n = 74 and 25 for pediatric and adult onset, respectively), (2) recurrent fever lacking a regular period (n = 47 and 41), and (3) persistent fever (n = 14 and 9). Diagnosis of AID was highest in subgroup 1 (70.2% and 36.0% for pediatric and adult onset, respectively), followed by subgroup 2(29.8% and 17.1%), including PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) (n = 34 and 1), familial Mediterranean fever (n = 22 and 13), cryopyrin-associated periodic syndrome (n = 6 and 1), and tumor necrosis factor receptor–associated periodic syndrome (n = 3 and 1 for pediatric and adult onset, respectively). None were diagnosed with AID in subgroup 3.

Conclusions

Autoinflammatory disease was more likely to be diagnosed in pediatric-onset patients compared with adult-onset patients. In both age-onset groups, AID was primarily identified in patients with periodic fever and never diagnosed in patients with persistent fever. Our findings indicate that fever pattern is a useful factor to estimate the probability of AID.
Prostate-Specific Membrane Antigen–Positive Manifestations of Chronic Beryllium Lung Disease
Authors: Huang Kai , Baur Alexander DJ , Furth Christian
Published: October 2018

Three years after prostatectomy, a 78-year-old man with initial high-risk prostate cancer and new increasing prostate-specific antigen levels underwent 68Ga-prostate-specific membrane antigen (PSMA) PET/CT. Imaging revealed PSMA-positive pelvic, ascending retroperitoneal and left supraclavicular lymph nodes consistent with metastases. Additionally, there was PSMA-positive lymphadenopathy (hilar and mediastinal) and pulmonary changes (fibrotic and nodular) in which histopathology excluded metastases. A lymphocyte proliferation test was indicative of beryllium sensitization. Chronic beryllium lung disease—a multisystem granulomatous inflammatory disease mainly affecting the lungs—could be established in this patient with occupational exposure to beryllium. This case shows that manifestations of berylliosis can also be PSMA positive.
Is the Neutrophil-to-Lymphocyte Ratio Associated With Increased Morbidity After Colorectal Surgery?
Authors: Benlice Cigdem , Onder Akin , Babazade Rovnat , Hrabe Jennifer , Stocchi Luca , Steele Scott , Gorgun Emre
Published: October 2018

Purpose:

We aimed to evaluate the association between preoperative and postoperative neutrophil-to-lymphocyte ratio (NLR) and 30-day postoperative complications after colorectal surgery.

Methods:

Patients undergoing elective colorectal surgery between January, 2010 and December, 2014 were identified. Patients who had preoperative and postoperative days 1 and 2 (Postoperative day [POD]-1, POD-2) NLR were included in the study. Primary study outcomes were optimal NLR cutoff values at preop, POD-1, and POD-2.

Results:

A total of 1328 patients met the inclusion criteria. Of those, 518 (39%) patients experienced at least one postoperative complication. Sex (P<0.001), diabetes mellitus (DM) (P<0.001), diagnosis (P=0.001), operation type (P=0.03), and open surgery (P<0.001) were statistically associated with higher NLR (POD-1, P=0.02; POD2, P=0.01). DM (OR, 1.97; 95%CI, 1.27-3.08; P=0.003] and NLR on POD-2≥9.2 (OR, 1.43; 95%CI, 1.03-1.98; P=0.02) were significantly related to postoperative complications.

Conclusions:

NLR may provide clinicians with an additional tool for identifying patients at high risk for postoperative complications after elective colorectal surgery. Routine use of NLR may lead to early intervention and potentially improve the management of complications after colorectal surgery.
Suitability of hepatocyte cell lines HepG2, AML12 and THLE-2 for investigation of insulin signalling and hepatokine gene expression
Authors: Sefried Stephanie , Häring Hans-Ulrich , Weigert Cora , Eckstein Sabine S.
Published: October 2018

Immortal hepatocyte cell lines are widely used to elucidate insulin-dependent signalling pathways and regulation of hepatic metabolism, although the often tumorigenic origin might not represent the metabolic state of healthy hepatocytes. We aimed to investigate if murine cell line AML12 and human cell line THLE-2, which are derived from healthy liver cells, are comparable to hepatoma cell line HepG2 for studying acute insulin signalling and expression of gluconeogenic enzymes and hepatokines. Insulin responsiveness of AML12 and THLE-2 cells was impaired when cells were cultured in the recommended growth medium, but comparable with HepG2 cells by using insulin-deficient medium. THLE-2 cells showed low abundance of insulin receptor, while protein levels in HepG2 and AML12 were comparable. AML12 and THLE-2 cells showed only low or non-detectable transcript levels of
G6PC
and
PCK1
. Expression of
ANGPTL4
was regulated similarly in HepG2 and AML12 cells upon peroxisome proliferator-activated receptor δ activation but only HepG2 cells resemble the
in vivo
regulation of hepatic
ANGPTL4
by cAMP. Composition of the culture medium and protein expression levels of key signalling proteins should be considered when AML12 and THLE-2 are used to study insulin signalling. With regard to gluconeogenesis and hepatokine expression, HepG2 cells appear to be closer to the
in vivo
situation despite the tumorigenic origin.
Wild jackdaws are wary of objects that violate expectations of animacy
Authors: Greggor Alison L. , McIvor Guillam E. , Clayton Nicola S. , Thornton Alex
Published: October 2018

Nature is composed of self-propelled, animate agents and inanimate objects. Laboratory studies have shown that human infants and a few species discriminate between animate and inanimate objects. This ability is assumed to have evolved to support social cognition and filial imprinting, but its ecological role for wild animals has never been examined. An alternative, functional explanation is that discriminating stimuli based on their potential for animacy helps animals distinguish between harmless and threatening stimuli. Using remote-controlled experimental stimulus presentations, we tested if wild jackdaws (
Corvus monedula
) respond fearfully to stimuli that violate expectations for movement. Breeding pairs (
N
= 27) were presented at their nests with moving and non-moving models of ecologically relevant stimuli (birds, snakes and sticks) that differed in threat level and propensity for independent motion. Jackdaws were startled by movement regardless of stimulus type and produced more alarm calls when faced with animate objects. However, they delayed longest in entering their nest-box after encountering a stimulus that should not move independently, suggesting they recognized the movement as unexpected. How jackdaws develop expectations about object movement is not clear, but our results suggest that discriminating between animate and inanimate stimuli may trigger information gathering about potential threats.
Effect of components on the curing of glycidyl azide polymer spherical propellant through rheological method
Authors: He Liming , He Wei , Ma Zhongliang
Published: October 2018

We have conducted a novel study of the influence of energy components (RDX, AP and CL-20) on curing kinetics of glycidyl azide polymer (GAP) spherical propellant based on rheological method. The autocatalytic model was used to describe curing kinetics and the parameters were determined by the model-fitting method. It was found that the incorporation of components hinders the cross-linking reaction of GAP spherical propellant. Integral isoconversional method was used on rheological kinetics to investigate the changes of the activation energy and we confirmed that the incorporation of components increased the activation energy. It was also found that such components had no effect on the trend of activation energy curves but shrank the peak value at
a
= 0.2. Dynamic mechanical analysis (DMA) showed the differences between pure curing system and its components. These findings are potentially helpful to control the curing effectively and optimize the processing schedules. The addition of components decreased
α
translation temperature which means the reduction in cross-links. The differences in the values of loss factor tan
δ
and
β
translation showed that pure curing system has lower resistance for side chain to motion.
Disarrangements and instabilities in augmented one-dimensional hyperelasticity
Authors: Palumbo Stefania , Deseri Luca , Owen David R. , Fraldi Massimiliano
Published: October 2018

In the present work, the overall nonlinear elastic behaviour of a one-dimensional multi-modular structure incorporating possible imperfections at the discrete (microscale) level is derived with respect to both tensile and compressive applied loads. The model is built up through the repetition of
n
units, each one comprising two rigid rods having equal lengths, linked by means of pointwise constraints capable of elastically limiting motions in terms of relative translations (sliders) and rotations (hinges). The mechanical response of the structure is analysed by varying the number
n
of the elemental moduli, as well as in the limit case of an infinite number of infinitesimal constituents, in light of the theory of (first-order) structured deformations (SDs), which interprets the deformation of any continuum body as the projection, at the macroscopic scale, of geometrical changes occurring at the level of its sub-macroscopic elements. In this way, a wide family of nonlinear elastic behaviours is generated by tuning internal microstructural parameters, the tensile buckling and the classical Euler's elastica under compressive loads resulting as special cases in the so-called
continuum limit
—say when

n
→
∞

. Finally, by plotting the results in terms of the first Piola–Kirchhoff stress versus macroscopic stretch, it is for the first time demonstrated that such SD-based one-dimensional models can be used to generalize some standard hyperelastic behaviours by additionally taking into account instability phenomena and concealed defects.
Modelling determinants of extinction across two Mesozoic hyperthermal events
Authors: Dunhill Alexander M. , Foster William J. , Azaele Sandro , Sciberras James , Twitchett Richard J.
Published: October 2018

The Late Triassic and Early Toarcian extinction events are both associated with greenhouse warming events triggered by massive volcanism. These Mesozoic hyperthermals were responsible for the mass extinction of marine organisms and resulted in significant ecological upheaval. It has, however, been suggested that these events merely involved intensification of background extinction rates rather than significant shifts in the macroevolutionary regime and extinction selectivity. Here, we apply a multivariate modelling approach to a vast global database of marine organisms to test whether extinction selectivity varied through the Late Triassic and Early Jurassic. We show that these hyperthermals do represent shifts in the macroevolutionary regime and record different extinction selectivity compared to background intervals of the Late Triassic and Early Jurassic. The Late Triassic mass extinction represents a more profound change in selectivity than the Early Toarcian extinction but both events show a common pattern of selecting against pelagic predators and benthic photosymbiotic and suspension-feeding organisms, suggesting that these groups of organisms may be particularly vulnerable during episodes of global warming. In particular, the Late Triassic extinction represents a macroevolutionary regime change that is characterized by (i) the change in extinction selectivity between Triassic background intervals and the extinction event itself; and (ii) the differences in extinction selectivity between the Late Triassic and Early Jurassic as a whole.
El Niño/Southern Oscillation-driven rainfall pulse amplifies predation by owls on seabirds via apparent competition with mice
Authors: Thomsen Sarah K. , Mazurkiewicz David M. , Stanley Thomas R. , Green David J.
Published: October 2018

Most approaches for assessing species vulnerability to climate change have focused on direct impacts via abiotic changes rather than indirect impacts mediated by changes in species interactions. Changes in rainfall regimes may influence species interactions from the bottom-up by increasing primary productivity in arid environments, but subsequently lead to less predictable top-down effects. Our study demonstrates how the effects of an EL Niño/Southern Oscillation (ENSO)-driven rainfall pulse ricochets along a chain of interactions between marine and terrestrial food webs, leading to enhanced predation of a vulnerable marine predator on its island breeding grounds. On Santa Barbara Island, barn owls (
Tyto alba
) are the main predator of a nocturnal seabird, the Scripps's murrelet (
Synthliboramphus scrippsi
), as well as an endemic deer mouse. We followed the links between rainfall, normalized difference vegetation index and subsequent peaks in mouse and owl abundance. After the mouse population declined steeply, there was approximately 15-fold increase in the number of murrelets killed by owls. We also simulated these dynamics with a mathematical model and demonstrate that bottom-up resource pulses can lead to subsequent declines in alternative prey. Our study highlights the need for understanding how species interactions will change with shifting rainfall patterns through the effects of ENSO under global change.
A test of the European Pleistocene refugial paradigm, using a Western Palaearctic endemic bird species
Authors: Drovetski Sergei V. , Fadeev Igor V. , Raković Marko , Lopes Ricardo J. , Boano Giovanni , Pavia Marco , Koblik Evgeniy A. , Lohman Yuriy V. , Red'kin Yaroslav A. , Aghayan Sargis A. , Reis Sandra , Drovetskaya Sofya S. , Voelker Gary
Published: October 2018

Hewitt's paradigm for effects of Pleistocene glaciations on European populations assumes their isolation in peninsular refugia during glacial maxima, followed by re-colonization of broader Europe during interstadials. This paradigm is well supported by studies of poorly dispersing taxa, but highly dispersive birds have not been included. To test this paradigm, we use the dunnock (
Prunella modularis
), a Western Palaearctic endemic whose range includes all major European refugia. MtDNA gene tree, multilocus species tree and species delimitation analyses indicate the presence of three distinct lineages: one in the Iberian refugium, one in the Caucasus refugium, and one comprising the Italian and Balkan refugia and broader Europe. Our gene flow analysis suggests isolation of both the Iberian and Caucasus lineages but extensive exchange between Italy, the Balkans and broader Europe. Demographic stability could not be rejected for any refugial population, except the very recent expansion in the Caucasus. By contrast, northern European populations may have experienced two expansion periods. Iberia and Caucasus had much smaller historical populations than other populations. Although our results support the paradigm, in general, they also suggest that in highly dispersive taxa, isolation of neighbouring refugia was incomplete, resulting in large super-refugial populations.
Human variation in the shape of the birth canal is significant and geographically structured
Authors: Betti Lia , Manica Andrea
Published: October 2018

The human birth canal shows a tight fit with the size of the neonate, which can lead to obstetric complications. This is not the case in other apes, and has been explained as the outcome of conflicting evolutionary pressures for bipedal locomotion and parturition of a highly encephalized fetus. Despite the suggested evolutionary constraints on the female pelvis, we show that women are, in fact, extremely variable in the shape of the bony birth canal, with human populations having differently shaped pelvic canals. Neutral evolution through genetic drift and differential migration are largely responsible for the observed pattern of morphological diversity, which correlates well with neutral genetic diversity. Climatic adaptation might have played a role, albeit a minor one, with populations from colder regions showing a more transversally oval shape of the canal inlet. The significant extent of canal shape variation among women from different regions of the world has important implications for modern obstetric practice in multi-ethnic societies, as modern medical understanding has been largely developed on studies of European women.
Microglial SIRPα regulates the emergence of CD11c+ microglia and demyelination damage in white matter
Authors: Sato-Hashimoto Miho , Nozu Tomomi , Toriba Riho , Horikoshi Ayano , Akaike Miho , Kawamoto Kyoko , Hirose Ayaka , Hayashi Yuriko , Nagai Hiromi , Shimizu Wakana , Saiki Ayaka , Ishikawa Tatsuya , Elhanbaly Ruwaida , Kotani Takenori , Murata Yoji , Saito Yasuyuki , Naruse Masae , Shibasaki Koji , Oldenborg Pre-Arne , Jung Steffen , Matozaki Takashi , Fukazawa Yugo , Ohnishi Hiroshi
Published: October 2018

A characteristic subset of microglia expressing CD11c appears in response to brain damage. However, the functional role of CD11c+ microglia, as well as the mechanism of its induction, are poorly understood. Here we report that the genetic ablation of signal regulatory protein α (SIRPα), a membrane protein, induced CD11c+ microglia in the brain white matter. Mice lacking CD47, a physiological ligand of SIRPα, and microglia-specific SIRPα knockout mice exhibited the same phenotype, suggesting the interaction between microglial SIRPα and CD47 on neighbouring cells suppressed the emergence of CD11c+ microglia. A lack of SIRPα did not cause detectable damage in the white matter, but resulted in the increased expression of genes characteristic of the repair phase after demyelination. In addition, cuprizone-induced demyelination was alleviated by the microglia-specific ablation of SIRPα. Thus, microglial SIRPα suppresses the induction of CD11c+ microglia that have the potential to accelerate the repair of damaged white matter.
Variation in tolerance to parasites in natural Asian tiger mosquito populations and its effect on vectorial capacity
Authors: Dharmarajan Guha , Walker Kathryne D. , Lehmann Tovi
Published: October 2018

The vectorial capacity of mosquitoes depends upon the magnitude of reduction of parasite load upon infection through resistance mechanisms (e.g., immune-mediated killing) and the ability of mosquitoes to offset infection-mediated costs through tolerance mechanisms (e.g., tissue repair). Here we use a common-garden experimental framework to measure variation in resistance and tolerance to dog heartworm (Dirofilaria immitis) between natural Aedes albopictus mosquito populations representing areas of low and high transmission intensity. Our data revealed that survival to the extrinsic incubation period, the earliest time point at which infective L3 larvae develop, significantly differed between populations (ranging from 10-60%) when mosquitoes infected with D. immitis at both the low (15 microfilaria/μl blood) and high (30 microfilaria/μl blood) infection dose (Dose: χ2 = 191.473; P < 0.001; Population: χ2 = 24.485; P = 0.001; Dose × Population: χ2 = 35.566; P = 0.001). Contrary to expectations, we found that mosquito populations with highest resistance (i.e., greatest reduction in parasite load) also exhibited highest mortality upon infection (F1,12 = 6.781, P = 0.023; Dose: F1,12 = 6.747; P = 0.023; Mortality × Dose: F1,12 = 0.111, P = 0.744). Expressing the effect of the number of killed (NKILLED) and live (NLIVE) parasite on survival of mosquitoes from the different population, we document a significant inter-population variation in the survival cost of additional parasite (i.e., tolerance to infection (NLIVE × Population: χ2 = 22.845; P = 0.002; NKILLED × Population: χ2 = 31.959; P = < 0.001; NLIVE × NKILLED × Population: χ2 = 22.266; P = 0.002), in conjunction with negative relationship between tolerance and resistance (Resistance: F1,12 = 11.870, P = 0.005; Dose: F1,12 = 16.0170, P = 0.002; Resistance × Dose: F1,12 = 9.699, P =0.009). Importantly, populations from areas with high transmission intensity (as measured by parasite prevalence in dogs) showed elevated tolerance (Prevalence: F1,12 = 9.5, P = 0.012; Prevalence2: F1,12 = 4.353, P = 0.064; Dose: F1,12 = 38.855, P = <0.001), and these populations were also associated with increased vectorial capacity (Tolerance: F1,12 = 8.175, P = 0.014; Dose: F1,12 = 0.005, P = 0.946; Tolerance × Dose: F1,12 = 0.920, P = 0.356). Consequently, our data indicate that spatial variation in disease transmission intensity is linked to the evolution of tolerance in natural mosquito populations, which in turn can feedback to impact disease risk.
Immigration from the metacommunity affects bdelloid rotifer community dynamics most
Authors: Debortoli Nicolas , De Laender Frederik , Van Doninck Karine
Published: October 2018

Dispersal is an important driver of local community dynamics. It has been proposed that, for communities composed of microscopic organisms, dispersal could well be the dominant process, outpacing local processes driven by environmental conditions and species interactions. This is because microscopic organisms often reproduce asexually, fostering rapid colonization, and are easily dispersed by water or air current. We studied the case of bdelloid rotifers belonging to the genus Adineta, microscopic asexual animals with dried stages that are easily dispersed by wind to investigate the relative effects of dispersal and local processes on their community dynamics. To this end, we constructed a classic competition model to theoretically examine how spatial and local biodiversity dynamics varied with fitness and dispersal characteristics of bdelloid Adineta species. Next, we compared our predictions with an experimental dataset containing spatio-temporal Adineta community dynamics from the wild. This comparison suggested that immigration from the local meta-community was the most critical parameter under the conditions tested. One Adineta vaga species, abundant in the surrounding area, rapidly colonized our experimental habitats and dominated most of the communities. We also ran the model under different levels of environmental conditions (permissive, intermediate and harsh) to simulate seasonal community variability and found that communities experience important bottlenecks yearly in winter but that the same community re-established. The dissimilarities observed between roof communities suggest differences in adaptation or immigration capacities. Besides their asexual reproduction and extreme desiccation tolerance, a key characteristic of bdelloid ecology identified here, is the spatio-temporal dynamic of abundant bdelloid clones present in the meta-community that rapidly colonize empty patches to establish new populations.
A physiology-based model of bile acid metabolism shows altered tissue concentrations after drug administration and in specific genotype subgroups
Authors: Baier V. , Cordes H. , Thiel C. , Neumann U. , Blank L.M. , Kuepfer L.
Published: October 2018

Drug-induced liver injuries (DILI) are an important issue in drug development and patient safety and often lead to termination of drug-development programs or late withdrawals of drugs. Since DILI events are hard to diagnose in preclinical settings, a need for alternative prediction methods such as computational modeling emerges. Impairment of bile acid (BA) metabolism, known as cholestasis, is a frequent form of DILI. Being rather a systemic then a single organ related disease, whole-body physiology-based modeling is a predestined approach for cholestasis modeling. The objectives of the presented study were 1) the development of a physiology-based model for human bile acid metabolism, 2) model validation and characterization for a virtual population, and 3) prediction and quantification of the effects of genetic predispositions and drug interaction on bile acid metabolism. The developed physiology-based bile acid (PBBA) model is based on the standard PBPK model of PKSim® and describes the bile acid circulation in a healthy reference individual. Active processes such as the hepatic synthesis, gallbladder emptying upon meal intake, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the body, and excretion are included. The kinetics of active processes for the surrogate BA glycochenodeoxycholic acid were fitted to time-concentration profiles of blood BA levels reported in literature. The robustness of our PBBA model is underlined by the comparison of simulated plasma BA concentrations in a virtual population of 1,000 healthy individuals with reported data. In addition to plasma concentrations, the PBBA model allows simulations of BA exposure in relevant tissues like the liver and can therefore enhance the mechanistic understanding of cholestasis. This feature was used to analyse the reported increased risk of cholestatic DILI in Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients. Simulations of the PBBA model suggest a higher susceptibility of BRIC2 patients towards cholestatic DILI due to BA accumulation in hepatocytes. Apart from these intrinsic effects, drug-interactions and their effect on the systemic bile acid metabolism were simulated by combining the PBBA model with a drug PBPK model of cyclosporine A (CsA). The results of which confirmed the reported higher risk of developing DILI as a consequence of CsA intake. Altogether, the presented model enhances our mechanistic understanding of cholestasis, allows the identification of drug-interactions leading to altered BA levels in blood and organs, and could be used to prevent clinical cases of cholestasis and enhance patient safety.
MeShClust2: Application of alignment-free identity scores in clustering long DNA sequences
Authors: James Benjamin T. , Girgis Hani Z.
Published: October 2018

Grouping sequences into similar clusters is an important part of sequence analysis. Widely used clustering tools sacrifice quality for speed. Previously, we developed MeShClust, which utilizes k-mer counts in an alignment-assisted classifier and the mean-shift algorithm for clustering DNA sequences. Although MeShClust outperformed related tools in terms of cluster quality, the alignment algorithm used for generating training data for the classifier was not scalable to longer sequences. In contrast, MeShClust2 generates semi-synthetic sequence pairs with known mutation rates, avoiding alignment algorithms. MeShClust2clustered 3600 bacterial genomes, providing a utility for clustering long sequences using identity scores for the first time.
Crossover recombination and synapsis are linked by adjacent regions within the N terminus of the Zip1 synaptonemal complex protein
Authors: Voelkel-Meiman Karen , Cheng Shun-Yun , Parziale Melanie , Morehouse Savannah J. , Feil Arden , Davies Owen R. , Muyt Arnaud de , Borde Valérie , MacQueen Amy J.
Published: October 2018

Accurate chromosome segregation during meiosis relies on the prior establishment of at least one crossover recombination event between homologous chromosomes, which is often associated with the meiosis-specific MutSγ complex. The recombination intermediates that give rise to MutSγ interhomolog crossovers are embedded within a hallmark meiotic prophase structure called the synaptonemal complex (SC), but the mechanisms that coordinate the processes of SC assembly (synapsis) and crossover recombination remain poorly understood. Among known central region building blocks of the budding yeast SC, the Zip1 protein is unique for its SC-independent role in promoting MutSγ crossovers. Here we report that adjacent regions within Zip1’s unstructured N terminus encompass its crossover and SC assembly functions. We previously showed that deletion of Zip1 residues 21-163 abolishes tripartite SC assembly and prevents the robust SUMOylation of the SC central element component, Ecm11, but allows excess MutSγ crossover recombination. We find the reciprocal phenotype when Zip1 residues 2-9 or 10-14 are deleted; in these mutants SC assembles and Ecm11 is hyperSUMOylated, but MutSγ crossovers are strongly diminished. Interestingly, Zip1 residues 2-9 or 2-14 are required for the normal localization of Zip3, a putative E3 SUMO ligase and pro-MutSγ crossover factor, to Zip1 polycomplex structures and to recombination initiation sites. By contrast, deletion of Zip1 residues 15-20 does not detectably prevent Zip3’s localization at Zip1 polycomplex and supports some MutSγ crossing over but prevents normal SC assembly and robust Ecm11 SUMOylation. These results highlight distinct N terminal regions that are differentially critical for Zip1’s roles in crossover recombination and SC assembly; we speculate that the adjacency of these regions enables Zip1 to serve as a liaison, facilitating crosstalk between the two processes by bringing crossover recombination and synapsis factors in close proximity to one another.