bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Hemoconcentration Is Associated With Increased Opioid Use in Hospitalized Patients With Acute Pancreatitis
Authors: Parsa Nasim , Faghih Mahya , Garcia Gonzalez Francisco , Moran Robert A. , Kamal Ayesha , Jalaly Niloofar Y. , Al-Grain Haitham , Akshintala Venkata S. , Makary Martin A. , Khashab Mouen A. , Kalloo Anthony N. , Singh Vikesh K.
Published: January 2019

Objectives

Opioids are commonly required for abdominal pain in hospitalized patients with acute pancreatitis (AP). The factors associated with increased opioid requirements are unknown.

Methods

The medical records of adult inpatients with AP from 2006 to 2016 were reviewed. Patients with chronic pancreatitis, psychiatric comorbidities, intubation, chronic opioid, and illicit drug use were excluded. The total quantity of opioids required during the first 7 days of hospitalization was converted to oral morphine equivalents (OME), divided by the number of days opioids were required to obtain the mean OME per day(s) of treatment (MOME). Multiple regression analysis was performed to identify factors associated with MOME.

Results

A total of 267 patients were included. The mean (standard deviation) age was 46.9 (13.9) years and 56% were males. The most common etiology was alcohol (55.4%). The mean (standard deviation) MOME was 59.1 (54.5) mg. Although age (P= 0.008), black race (P= 0.004), and first episode of AP (P= 0.049) were associated with a lower MOME, early hemoconcentration (hematocrit ≥44%) (P< 0.001) was associated with an increased MOME.

Conclusions

Early hemoconcentration is associated with an increased opioid requirement in hospitalized patients with AP. The impact of fluid therapy in these patients merits prospective study.
Mechanism of Action and Novel IMiD-Based Compounds and Combinations in Multiple Myeloma
Authors: Nooka Ajay K. , Lonial Sagar
Published: January 2019

Over the last 2 decades, thalidomide analogs have induced significant antimyeloma effects via immune-modulation, antiangiogenesis and antiproliferative effects. While the exact molecular mechanism of the targets or the mediators of thalidomide activity were not known, a seminal discovery of cereblon as a thalidomide-binding protein led to explaining the mechanistic basis of antimyeloma activity for this class of agents. Identification of the mechanisms of resistance for immunomodulatory agents (IMiDs), which will have significant clinical implications, remains poorly understood. Newer cereblon modulators with differential effects and improved increased efficacy in cell lines resistant to the current IMiDs are in development with encouraging preclinical data. In this review, we have summarized the mechanisms of action of IMiDs, clinical development, and potential mechanisms of resistance. We also describe novel IMiD-based combinations and the newer cereblon modulators as well.
Collagenase Clostridium Histolyticum for Dupuytren’s Contracture: Comparing Single and Concurrent Injections
Authors: Cook Jonathan , Waughtel Jessica , Andreoni Anthony R. , Sakharpe Aniket , Friedman David W.
Published: January 2019

Background:

The U.S. Food and Drug Administration approved collagenase clostridium histolyticum for treatment of Dupuytren’s contracture in 2010, and for the concurrent treatment of up to two cords in 2014. Although outcomes and adverse events have been well described for single injections, comparative data on concurrent injections are lacking.

Methods:

The authors reviewed 121 concurrent collagenase clostridium histolyticum injections and compared these with 177 single injections over 8 years. All injections were performed by a single surgeon, our senior author (D.F.). A retrospective cohort model was used to compare clinical outcomes and adverse events (i.e., skin tears, spontaneous cord rupture, tendon rupture, lymphadenopathy, blood blisters, and ecchymosis) between groups.

Results:

There were no statistical differences between groups in clinical success rate or change in contracture per joint. The rate of skin tears per joint in concurrent injections (22.3 percent) was not statistically different from that of single injections (18.6 percent; p = 0.46), and was consistent with previously reported rates. The rate of skin tears did not change significantly over time in either group. Concurrent injection did not influence the incidence of skin tears in a dose-dependent manner (relative risk, 1.20). Patients receiving concurrent injections experienced a higher rate of lymphadenopathy compared with those receiving single injections (p = 0.001).

Conclusions:

Concurrent collagenase clostridium histolyticum injections for Dupuytren’s contracture have a similar safety profile and treatment efficacy when compared to single injections. The authors did not find a dose-dependent relationship between skin tears and collagenase clostridium histolyticum injected.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Experimentally Induced Arterial Embolism by Hyaluronic Acid Injection: Clinicopathologic Observations and Treatment
Authors: Chen Yin , Zhang You-liang , Luo Sheng-Kang
Published: January 2019

Background:

Although major complications of hyaluronic acid injection rarely occur, with the rapidly growing number of procedures performed and their expanding applications, such complications warrant greater attention. Our study was designed to explore optimal treatment methods for hyaluronic acid–related vascular occlusion.

Methods:

In the first part of the study, 60 rats were given intraarterial hyaluronic acid injected into the bilateral inferior epigastric arteries to establish an animal model, and were euthanized at different postinjection time points. The inferior epigastric artery was retrieved for pathologic examination. In the second part of the study, bilateral abdominal flaps supplied by the inferior epigastric artery were elevated in six groups of rats, and hyaluronic acid was injected into the right side, with each group receiving a different intervention. The flap survival rate was calculated and analyzed.

Results:

In the first part of the study, pathologic examination revealed that the composition of the emboli caused by arterial hyaluronic acid–induced occlusion changed from pure hyaluronic acid to a hyaluronic acid–thrombus mixture. In the second part of the study, flap survival rates (mean percentages) were as follows: group A, 43.29 ± 9.28 percent; group B, 54.17 ± 10.86 percent; group C, 59.27 ± 13.40 percent; group D, 64.37 ± 8.61 percent; group E, 71.92 ± 19.06 percent; and group F, 57.47 ± 13.64 percent. Group A differed significantly from groups B, C, D, and E (p < 0.001). No significant difference was observed between groups A and F (p > 0.05).

Conclusions:

The combined use of intravenous or subcutaneous hyaluronidase and urokinase was most effective in treating hyaluronic acid injection-related arterial embolism after 45 minutes and 24 hours. This treatment may be ineffective after 48 hours.
Skin Hydration Level as a Predictor for Diabetic Wound Healing: A Retrospective Study
Authors: Lee Tae-Yul , Kim Ki-Bum , Han Seung-Kyu , Jeong Seong-Ho , Dhong Eun-Sang
Published: January 2019

Background:

In the diabetic foot, the skin may crack and develop fissures, potentially increasing vulnerability to ulceration and infection. Therefore, maintaining adequate skin hydration may be crucial for diabetic wound healing. However, no clinical study has addressed this issue. This study aimed to determine and compare the effect of the skin hydration level on diabetic wound healing with that of the tissue oxygenation level, which is recognized as the most reliable parameter in predicting diabetic wound healing.

Methods:

This retrospective study included 263 diabetic patients with forefoot ulcers. Skin hydration and transcutaneous oxygen pressure data collected before and after percutaneous transluminal angioplasty were analyzed. Skin hydration and tissue oxygenation were graded as poor, moderate, or acceptable. Wound healing outcomes were graded as healed without amputation, minor amputation, or major amputation. Wound healing outcomes were compared using four parameters: skin hydration at baseline, transcutaneous oxygen pressure at baseline, post–percutaneous transluminal angioplasty skin hydration, and post–percutaneous transluminal angioplasty transcutaneous oxygen pressure.

Results:

Each of the four parameters exhibited statistically significant correlations with wound healing outcomes. In the concurrent analysis of both skin hydration and transcutaneous oxygen pressure, skin hydration was a dominant parameter (p = 0.0018) at baseline, whereas transcutaneous oxygen pressure was a dominant parameter (p < 0.0001) following percutaneous transluminal angioplasty.

Conclusions:

Skin hydration level might be a useful predictor for diabetic wound healing. In particular, the skin hydration level before recanalization was found to be superior to transcutaneous oxygen pressure in predicting wound healing.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Reconstruction of Diabetic Foot Defects With the Proximal Lateral Leg Perforator Flap
Authors: Lee Jiunn-Tat , Cheng Li-Fu , Hsu Honda , Wu Meng-Si , Chien Sou-Hsin
Published: January 2019

Background

In patients with diabetic foot ulcers requiring flap reconstruction, the choice of local flaps is limited by the lack of adequate tissue available. Free flaps are often bulky, presenting footwear difficulty due to poor contouring. Here, we present our experience of using the proximal lateral leg perforator flap in the reconstruction of thin diabetic foot ulcers.

Methods

This is a retrospective study of 17 patients with diabetic foot ulcers reconstructed with the proximal lateral leg perforator flap during January 2013 and December 2015.

Results

Nine patients had varying degrees of peripheral arterial disease. The perforator was located 7 to 14 cm (mean, 9.7 cm) from the fibula head. The pedicle length ranged from 5 to 9 cm (mean, 6.9 cm). The arterial diameter of the pedicle measured 0.8 to 1.9 mm (mean, 1.4 mm). There was 1 total flap failure. One other flap complicated by venous thrombosis was successfully salvaged. All donor sites were closed primarily without morbidities. All the wounds were stable without recurrent ulceration during a mean follow-up time of 12 months.

Conclusion

The thin, pliable proximal lateral leg perforator flap is an option for the reconstruction of small to moderate diabetic foot defects especially when it is located over the dorsal foot or the ankle. The flap is simple and quick to harvest without sacrificing a major artery. Although it is limited by the short length and the small diameter of the pedicle, for experienced microsurgeons, the success rate is high.
The Power of Patient Norms
Authors: Rochlin Danielle H. , Leon Daniel Sotelo , Yu Caroline , Long Chao , Nazerali Rahim , Lee Gordon K.
Published: January 2019

Introduction

Enhanced recovery after surgery pathways designed to optimize postoperative care have become increasingly popular across multiple surgical specialties with proven benefits. In this retrospective cohort study, we present a comparative evaluation of the impact of protocol-based postoperative care on free autologous breast reconstruction patients.

Methods

With institutional review board approval, we performed a chart review of patients who underwent breast reconstruction with free autologous tissue transfer by a single surgeon from 2006 to 2017. Patients were managed according to a postoperative protocol since 2006 that initially called for discharge home on postoperative day (POD) 4 for unilateral cases and POD 5 for bilateral cases. In May 2015, the protocol was revised to discharge home on POD 3 for all cases. Patients who underwent reconstruction before (2006 to April 2015) and after (May 2015 to 2017) the change in postoperative protocol were compared.

Results

A total of 432 patients (647 breasts) underwent free autologous breast reconstruction during the study period. Flaps were predominantly muscle-sparing transverse rectus abdominis myocutaneous (56.3%) or deep inferior epigastric perforator (30.3%) flaps. Average patient age was 51.6 years (range, 29.7–80.3 years). Unilateral reconstructions were performed for 167 patients before and 50 patients after the protocol change; average hospital length of stay (LOS) was 4.5 and 3.4 days, respectively (P < 0.001). Bilateral reconstructions were performed for 153 patients before and 62 patients after the protocol change; average hospital LOS was 5.1 and 3.5 days, respectively (P < 0.001). There was no significant increase in patients with major or minor complications.

Conclusions

Revising our postoperative protocol to reduce expected LOS was associated with an overall faster time to discharge without negative consequences in patients who underwent unilateral and bilateral free autologous breast reconstruction. Use of protocols to guide behavior not only can improve the patient experience by promoting a quicker return home, but may also have the added benefit of decreasing healthcare expenditures through reduced inpatient utilization.
Colorectal Surgical Site Infection Prevention Kits Prior to Elective Colectomy Improve Outcomes
Authors: Deery Sarah E. , Cavallaro Paul M. , McWalters Sean T. , Reilly Syrene R. , Bonnette Holly M. , Rattner David W. , Mort Elizabeth A. , Hooper David C. , del Carmen Marcela G. , Bordeianou Liliana G.
Published: January 2019

Introduction:

Patient compliance with preoperative mechanical and antibiotic bowel preparation, skin washes, carbohydrate loading, and avoidance of fasting are key components of successful colorectal ERAS and surgical site infection (SSI)-reduction programs. In July 2016, we began a quality improvement project distributing a free SSI Prevention Kit (SSIPK) containing patient instructions, mechanical and oral bowel preparation, chlorhexidine washes, and carbohydrate drink to all patients scheduled for elective colectomy, with the goal of improving patient compliance and rates of SSI.

Methods:

This was a prospective data audit of our first 221 SSIPK+ patients, who were compared to historical controls (SSIPK−) of 1760 patients undergoing elective colectomy from January 2013 to March 2017. A 1:1 propensity score system accounted for nonrandom treatment assignment. Matched patients’ complications, particularly postoperative infection and ileus, were compared.

Results:

SSIPK+ (n = 219) and SSIPK− (n = 219) matched patients were statistically identical on demographics, comorbidities, BMI, surgical indication, and procedure. SSIPK+ patients had higher compliance with mechanical (95% vs 71%, P < 0.001) and oral antibiotic (94% vs 27%, P < 0.001) bowel preparation. This translated into lower overall SSI rates (5.9% vs 11.4%, P = 0.04). SSIPK+ patients also had lower rates of anastomotic leak (2.7% vs 6.8%, P = 0.04), prolonged postoperative ileus (5.9% vs 14.2%, P < 0.01), and unplanned intubation (0% vs 2.3%, P = 0.02). Furthermore, SSIPK+ patients had shorter mean hospital length of stay (3.1 vs 5.4 d, P < 0.01) and had fewer unplanned readmissions (5.9% vs 14.6%, P < 0.001). There were no differences in rates of postoperative pneumonia, urinary tract infection, Clostridium difficile colitis, sepsis, or death.

Conclusion:

Provision of a free-of-charge SSIPK is associated with higher patient compliance with preoperative instructions and significantly lower rates of surgical site infections, lower rates of prolonged postoperative ileus, and shorter hospital stays with fewer readmissions. Widespread utilization of such a bundle could therefore lead to significantly improved outcomes.
Automated noninvasive evaluation of blood flow and oxygenation in rats integrated with systemic physiological monitoring
Authors: Torres Filho Ivo P. , Barraza David , Williams Charnae , Hildreth Kim , Dubick Michael A.
Published: January 2019

BACKGROUND

Many studies evaluating blood flow and oxygen partial pressure (Po
2) do not directly measure both parameters, are confined to few locations/microvessels, and depend on investigator's selection of measuring sites. Moreover, clinically/physiologically relevant systemic parameters are not simultaneously recorded. We implemented an automated system for prolonged blood flow/Po
2 acquisition in large areas while collecting relevant systemic information.

METHODS

In anesthetized animals, cardiorespiratory parameters were continuously recorded. Other data were collected at baseline and hourly after 4 hours of hemorrhagic shock. A cremaster muscle was spread over a pedestal fixed to a motorized stage. One 2-dimensional tissue scan allowed 16 noninvasive Po
2 measurements using oxygen-dependent phosphorescence quenching and fiber optics. Blood flow was estimated using laser speckle contrast imaging in the same areas used for Po
2 measurements. At each timepoint, blood was sampled for extensive biochemistry/coagulation profile.

RESULTS

The system was used successfully by different operators. A set of flow/Po
2 measurements was completed in less than 90 seconds. Muscle flow and Po
2 correlated with some but not several systemic parameters, emphasizing the importance of performing both local and systemic evaluations.

CONCLUSION

System advantages include integration between local and over 40 systemic parameters, unbiased data collection/analysis, improved performance/sampled area, easy expansion, implementation and maintenance, no customized programming, and simplified training. Combining this system with trauma/prolonged HS models will enhance our ability to investigate tissue stability and select better resuscitation strategies to improve outcomes and survival.

LEVEL OF EVIDENCE

Diagnostic test, level V.
Somatosensory Evoked Potentials as a Stand-Alone Tool During Spine Surgery: An Egyptian Preliminary Report
Authors: Abdelkader Ann Ali , Zohdi Ahmed , El Gohary Amira M. , El-Hadidy Reem Atef , AlMahdy Rania A.
Published: January 2019

Purpose:

Monitoring of somatosensory evoked potentials (SSEPs) serves as an early warning system to detect spinal cord injury and is correlated with postoperative sensory findings. It is an indirect indicator of motor function. This study aimed to evaluate the usefulness of intraoperative SSEPs monitoring as a stand-alone tool during spinal surgeries when motor evoked potentials are not available, to prevent and predict new postoperative neurologic deficits. Motor evoked potentials were not used as the equipment needed to record them was not available at the time of this study.

Methods:

This study included 50 patients, aged 14 to 67 years, undergoing extramedullary manipulations, decompression of an epidural abscess or neoplasm, removal of intramedullary tumor, or arteriovenous malformation or spine correction procedures. Somatosensory evoked potentials were analyzed for latency and peak-to-peak amplitude. Critical SSEP changes were defined as a 50% decrease in amplitude or a 10% increase in latency.

Results:

Somatosensory evoked potentials had an overall sensitivity of 81.8%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 91.3%.

Conclusions:

Intraoperative SSEPs have proved to be highly sensitive and specific for iatrogenic injury, mechanical stress caused by cord traction/compression, dural traction, lowered systemic blood pressure, and cord hypothermia. The reversibility of intraoperative SSEP changes showed a highly significant relation to the number of cases with new postoperative deficits as well as type and site of pathologic study (P = 0.00, P = 0.01, and P = 0.00, respectively) but not with the level of pathologic study (P = 0.49).
Ocean warming and acidification may challenge the riverward migration of glass eels
Authors: Borges Francisco O. , Santos Catarina P. , Sampaio Eduardo , Figueiredo Cátia , Paula José Ricardo , Antunes Carlos , Rosa Rui , Grilo Tiago F.
Published: January 2019

The dramatic decline of European eel (
Anguilla anguilla
) populations over recent decades has attracted considerable attention and concern. Furthermore, little is known about the sensitivity of the early stages of eels to projected future environmental change. Here, we investigated, for the first time, the potential combined effects of ocean warming (OW; Δ + 4°C; 18°C) and acidification (OA; Δ − 0.4 pH units) on the survival and migratory behaviour of
A. anguilla
glass eels, namely their preference towards riverine cues (freshwater and geosmin). Recently arrived individuals were exposed to isolated and combined OW and OA conditions for 100 days, adjusting for the salinity gradients associated with upstream migration. A two-choice test was used to investigate migratory activity and shifts in preference towards freshwater environments. While OW decreased survival and increased migratory activity, OA appears to hinder migratory response, reducing the preference for riverine cues. Our results suggest that future conditions could potentially favour an early settlement of glass eels, reducing the proportion of fully migratory individuals. Further research into the effects of climate change on eel migration and habitat selection is needed to implement efficient conservation plans for this critically endangered species.
Maternal corticosterone increases thermal sensitivity of heart rate in lizard embryos
Authors: Owen Dustin A. S. , Sheriff Michael J. , Heppner Jennifer J. , Gerke Hannah , Ensminger David C. , MacLeod Kirsty J. , Langkilde Tracy
Published: January 2019

While it is well established that maternal stress hormones, such as corticosterone (CORT), can induce transgenerational phenotypic plasticity, few studies have addressed the influence of maternal CORT on pre-natal life stages. We tested the hypothesis that experimentally increased CORT levels of gravid female eastern fence lizards (
Sceloporus undulatus
) would alter within-egg embryonic phenotype, particularly heart rates. We found that embryos from CORT-treated mothers had heart rates that increased faster with increasing temperature, resulting in higher heart rates at developmentally relevant temperatures but similar heart rates at maintenance relevant temperatures, compared with embryos of control mothers. Thus, maternal CORT appears to alter the physiology of pre-natal offspring. This may speed development and decrease the amount of time spent in eggs, the most vulnerable stage of life.
Effect of restoration on saltmarsh carbon accumulation in Eastern England
Authors: Burden A. , Garbutt A. , Evans C. D.
Published: January 2019

Wetland soils are globally important carbon stores, and natural wetlands provide a sink for atmospheric carbon dioxide (CO
2
) through ongoing carbon accumulation. Recognition of coastal wetlands as a significant contributor to carbon storage (blue carbon) has generated interest into the climate change mitigation benefits of restoring or recreating saltmarsh habitat. However, the length of time a re-created marsh will take to become functionally equivalent to a natural (reference) system, or indeed, whether reference conditions are attainable, is largely unknown. Here, we describe a combined field chronosequence and modelling study of saltmarsh carbon accumulation and provide empirically based predictions of changes in the carbon sequestration rate over time following saltmarsh restoration. Carbon accumulation was initially rapid (average 1.04 t C ha
−1
yr
−1
during the first 20 years), slowing to a steady rate of around 0.65 t C ha
−1
yr
−1
thereafter. The resulting increase in C stock gave an estimated total C accumulation of 74 t C ha
−1
in the century following restoration. This is approximately the same as our observations of natural marsh C content (69 t C ha
−1
), suggesting that it takes approximately 100 years for restored saltmarsh to obtain the same carbon stock as natural sites.
Dennis James Greenland. 13 June 1930—23 December 2012
Authors: Gregory Peter J.
Published: January 2019

Dennis Greenland was an outstanding soil scientist who combined the analytical rigour of a chemist with the practical application of an agricultural scientist. His early research employed X-ray diffraction and other emerging analytical techniques to determine the surface properties of clay minerals and their interactions with organic components of soils. This, in turn, led to research to understand the forces leading to aggregate and structural stability (and instability) in soils of the UK, Australia, Nigeria and the tropics generally. Simultaneously, Dennis engaged with the practical problems faced by farmers in the tropics to maintain the fertility of their soils and ensure long-term crop production; his early work (with Peter Nye) on shifting cultivation is regarded as a classic of the soil science literature. These two elements of his research came together during his periods as deputy director general, with responsibility for research, at the International Institute for Tropical Agriculture (IITA) in Nigeria (1974–1976) and the International Rice Research Institute (IRRI) in The Philippines (1979–1987). At both institutions he sought to improve the research in natural resources so that the genetic gains delivered by crop breeding could be achieved by farmers on their fields. At IRRI he encouraged research on rice-growing environments and improved water management taking account of catchment uses, and he promoted integrated approaches to nutrient management that combined organic and inorganic sources. This passion for integrated approaches to soil management led to his championing, and eventually chairing, the International Board for Soil Research and Management (IBSRAM), in which he played a major role in forming networks of multi-location experiments with many institutions.
Extending statistical models for source attribution of zoonotic diseases: a study of campylobacteriosis
Authors: Liao Sih-Jing , Marshall Jonathan , Hazelton Martin L. , French Nigel P.
Published: January 2019

Preventing and controlling zoonoses through the design and implementation of public health policies requires a thorough understanding of transmission pathways. Modelling jointly the epidemiological data and genetic information of microbial isolates derived from cases provides a methodology for tracing back the source of infection. In this paper, the attribution probability for human cases of campylobacteriosis for each source, conditional on the extent to which each case resides in a rural compared to urban environment, is estimated. A model that incorporates genetic data and evolutionary processes is applied alongside a newly developed genetic-free model. We show that inference from each model is comparable except for rare microbial genotypes. Further, the effect of ‘rurality’ may be modelled linearly on the logit scale, with increasing rurality leading to the increasing likelihood of ruminant-sourced campylobacteriosis.
Analysing diffusion and flow-driven instability using semidefinite programming
Authors: Hori Yutaka , Miyazako Hiroki
Published: January 2019

Diffusion and flow-driven instability, or transport-driven instability, is one of the central mechanisms to generate inhomogeneous gradient of concentrations in spatially distributed chemical systems. However, verifying the transport-driven instability of reaction–diffusion–advection systems requires checking the Jacobian eigenvalues of infinitely many Fourier modes, which is computationally intractable. To overcome this limitation, this paper proposes mathematical optimization algorithms that determine the stability/instability of reaction–diffusion–advection systems by finite steps of algebraic calculations. Specifically, the stability/instability analysis of Fourier modes is formulated as a sum-of-squares optimization program, which is a class of convex optimization whose solvers are widely available as software packages. The optimization program is further extended for facile computation of the destabilizing spatial modes. This extension allows for predicting and designing the shape of the concentration gradient without simulating the governing equations. The streamlined analysis process of self-organized pattern formation is demonstrated with a simple illustrative reaction model with diffusion and advection.
An insect-inspired collapsible wing hinge dampens collision-induced body rotation rates in a microrobot
Authors: Mountcastle Andrew M. , Helbling E. Farrell , Wood Robert J.
Published: January 2019

Some flying insects frequently collide their wingtips with obstacles, and the next generation of insect-inspired micro air vehicles will inevitably face similar wing collision risks when they are deployed in real-world environments. Wasp wings feature a flexible resilin joint called a ‘costal break’ that allows the wingtip to reversibly collapse upon collision, helping to mitigate wing damage over repeated collisions. However, the costal break may provide additional benefits beyond reducing wing wear. We tested the hypothesis that a collapsible wing tip can also dampen sudden and unpredictable body rotations caused by collisions. We designed a wing buckle hinge for an insect-scale microrobot, inspired by the costal break in wasp wings, and performed wing collision tests in a yaw-based magnetic tether system. We found that a collapsible wing tip reduced collision-induced airframe yaw rates by approximately 40% compared to a stiff wing, and that the effect was most pronounced for collisions that occurred early in the wing stroke. Our results suggest that a collapsible wingtip may simplify flight control requirements in both insects and insect-scale microrobots. We also introduce a scalable hinge design for engineering applications that recreates the nonlinear strain-weakening behaviour of a costal break.
Quantifying the mechanics of locomotion of the schistosome pathogen with respect to changes in its physical environment
Authors: Zhang Shun , Skinner Danielle , Joshi Prateek , Criado-Hidalgo Ernesto , Yeh Yi-Ting , Lasheras Juan C. , Caffrey Conor R. , del Alamo Juan C.
Published: January 2019

Schistosomiasis is a chronic and morbid disease of poverty affecting approximately 200 million people worldwide. Mature schistosome flatworms wander in the host's hepatic portal and mesenteric venous system where they encounter a range of blood flow conditions and geometrical confinement. However, the mechanisms that support schistosome locomotion and underlie the pathogen's adaptation to its physical environment are largely unknown. By combining microfabrication and traction force microscopy, we developed variousin vitroassays to quantify the mechanics of locomotion of adult maleSchistosoma mansoniin different physiologically relevant conditions. We show that in unconfined settings, the parasite undergoes two-anchor marching mediated by the coordinated action of its oral and ventral suckers. This mode of locomotion is maintained when the worm faces an external flow, to which it responds by adjusting the strength of its suckers. In geometrically confined conditions,S. mansoniswitches to a different crawling modality by generating retrograde peristaltic waves along its body, a mechanism shared with terrestrial and marine worms. However, while the surface of most worms has backward-pointing bristles that rectify peristaltic waves and facilitate forward locomotion,S. mansonihas isotropically oriented tubercles. This requires tight coordination between muscle contraction and substrate friction but givesS. mansonithe ability to reverse its direction of locomotion without turning its body, which is likely advantageous to manoeuvre in narrow-bore vessels. We show that the parasite can also coordinate the action of its suckers with its peristaltic body contractions to increase crawling speed. Throughout this study, we report on a number of biomechanical parameters to quantify the motility of adult schistosomes (e.g. sucker grabbing strength, the rate of detachment under flow, peristaltic wave properties and traction stresses). The new series ofin vitroassays make it possible to quantify key phenotypical aspects ofS. mansonimotility that could guide the discovery of new drugs to treat schistosomiasis.
Reflexive witnessing: Boyle, the Royal Society and scientific style
Authors: Hogarth Alan James , Witmore Michael
Published: January 2019

This article uses quantitative methods to analyse the language of Royal Society prose. Historians of science such as Barbara Shapiro have argued that specific linguistic features are detectable in the Royal Society's experimental reports, including first-person reporting and expressions of modesty. Moreover, Steven Shapin and Simon Schaffer's influential study of Royal Society writing suggests that such linguistic strategies are designed to establish trust in the reporter and enable readers to become ‘virtual witnesses’ to experimental activities. While previous scholarship has persuasively identified distinct modes of rhetorical appeal in Royal Society texts, our corpus-based linguistic approach offers a more fine-grained description of the rhetoric of modesty and witnessing identified by other scholars. Our analysis further suggests that Royal Society writers had a self-reflexive and temporally complex relationship with the process of inquiry that is not fully captured by these qualitative studies; we call this linguistic structure ‘reflexive witnessing’. Having defined that structure linguistically and surveyed it across a broader range of early modern texts, we demonstrate that ‘reflexive witnessing’ was not exclusive to the community of the Royal Society.
Experimental evolution of parasitic host manipulation
Authors: Hafer-Hahmann Nina
Published: January 2019

Host manipulation is a parasite-induced alteration of a host's phenotype that increases parasite fitness. However, if genetically encoded in the parasite, it should be under selection in the parasite. Such host manipulation has often been assumed to be energetically costly, which should restrict its evolution. Evidence of such costs, however, remains elusive. The trophically transmitted cestodeSchistocephalus solidusmanipulates the activity of its first intermediate copepod host to reduce its predation susceptibility before the parasite is ready for transmission. Thereafter,S. solidusincreases host activity to facilitate transmission to its subsequent fish host. I selectedS. solidusfor or against host manipulation over three generations to investigate the evolvability of manipulation and identify potential trade-offs. Host manipulation responded to selection, confirming that this trait is heritable in the parasite and hence can present an extended phenotype. Changes in host manipulation were not restrained by any obvious costs.
Interactions between cardiac activity and conscious somatosensory perception
Authors: Motyka Paweł , Grund Martin , Forschack Norman , Al Esra , Villringer Arno , Gaebler Michael
Published: January 2019

Fluctuations in the heart’s activity can modulate the access of external stimuli to consciousness. The link between perceptual awareness and cardiac signals has been investigated mainly in the visual and auditory domain. We here investigated whether the phase of the cardiac cycle and the pre-stimulus heart rate influence conscious somatosensory perception. We also tested how conscious detection of somatosensory stimuli affects the heart rate. Electrocardiograms (ECG) of 33 healthy volunteers were recorded while applying near-threshold electrical pulses at a fixed intensity to the left index finger. Conscious detection was not uniformly distributed across the cardiac cycle but significantly higher in diastole than in systole. We found no evidence that the heart rate before a stimulus influenced its detection but hits (correctly detected somatosensory stimuli) led to a more pronounced cardiac deceleration than misses. Our findings demonstrate interactions between cardiac activity and conscious somatosensory perception, which highlights the importance of internal bodily states for sensory processing beyond the auditory and visual domain.

Impact Statement

It is highly debated to what extent cardiac activity modulates the access of external stimuli to consciousness. The evidence is inconsistent across sensory modalities and previous research focused at specific intervals within the cardiac cycle. Here, we examined the perception of near-threshold electrical pulses across the entire cardiac cycle. Our results show that conscious somatosensory perception is enhanced during the late phase of the cardiac cycle (at diastole) and associated with a more pronounced cardiac deceleration (as compared to non-detected stimuli). This strengthens the evidence that the physiological state of the body influences how we perceive the world.
Dedifferentiation orchestrated through remodeling of the chromatin landscape defines PSEN1 mutation-induced Alzheimer’s Disease
Authors: Caldwell Andrew B. , Liu Qing , Schroth Gary P. , Tanzi Rudolph E. , Galasko Douglas R. , Yuan Shauna H. , Wagner Steven L. , Subramaniam Shankar
Published: January 2019

Early-Onset Familial Alzheimer’s Disease (EOFAD) is a dominantly inherited neurodegenerative disorder elicited by mutations in the PSEN1, PSEN2, and APP genes1. Hallmark pathological changes and symptoms observed, namely the accumulation of misfolded Amyloid-β (Aβ) in plaques and Tau aggregates in neurofibrillary tangles associated with memory loss and cognitive decline, are understood to be temporally accelerated manifestations of the more common sporadic Late-Onset Alzheimer’s Disease. The complete penetrance of EOFAD-causing mutations has allowed for experimental models which have proven integral to the overall understanding of AD2. However, the failure of pathology-targeting therapeutic development suggests that the formation of plaques and tangles may be symptomatic and not describe the etiology of the disease3,4. Here, we use an integrative, multi-omics approach and systems-level analysis in hiPSC-derived neurons to generate a mechanistic disease model for EOFAD. Using patient-specific cells from donors harboring mutations in PSEN1 differentiated into neurons, we characterize the disease-related gene expression and chromatin accessibility changes by RNA- Seq, ATAC-Seq, and histone methylation ChIP-Seq. We show that the defining disease-causing mechanism of EOFAD is dedifferentiation, primarily through the REST-mediated repression of neuronal lineage specification gene programs and the activation of non-specific germ layer precursor gene programs concomitant with modifications in chromatin accessibility. These gene signature profiles and changes in chromatin topology illustrate that EOFAD neurons traverse the chromatin landscape from an ectodermal origin to a mixed germ lineage state. Further, a reanalysis of existing transcriptomic data from PSEN1 patient brain samples demonstrates that the mechanisms identified in our experimental system recapitulate EOFAD in the human brain. Our results comprise a disease model which describes the mechanisms culminating in dedifferentiation that precede amyloid and tau pathology formation and engender neurodegeneration.
Consecutive signaling pathways are activated in progression of Duchenne muscular dystrophy inC. elegans
Authors: Hrach Heather C , Steber Hannah S , Newbern Jason , Rawls Alan , Mangone Marco
Published: January 2019

Background:

Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease characterized by progressive muscle degeneration. The condition is driven by nonsense and missense mutations in the dystrophin gene, but the resulting changes in muscle-specific gene expression that take place in dystrophin’s absence remain uncharacterized, as they are potentially obscured by the chronic inflammation elicited by muscle damage in humans.C. eleganspossess a mild inflammatory response that allows for the characterization of the transcriptome rearrangements affecting disease progression independently of inflammation.

Results:

In effort to better understand these dynamics we have isolated and sequenced body muscle-specific transcriptomes fromC. eleganslacking functional dystrophin at distinct stages of disease progression. We have identified two consecutively altered gene networks, which are also disrupted in the dystrophin deficientmdxmouse model. We found an upregulation of genes involved in mitochondrial function early in disease progression, and an upregulation of genes related to muscle fibre repair in later stages. This suggests that dystrophin may have a signaling role early in development, and its absence may activate compensatory mechanisms that counteract muscle degradation caused by loss of dystrophin. We have also developed a temperature-based screening method for synthetic paralysis that can be used to rapidly identify genetic partners of dystrophin.

Conclusions:

Our results allow for the comprehensive identification of transcriptome rearrangements that potentially serve as independent drivers of disease progression and may in turn allow for the identification of new therapeutic targets for the treatment of DMD.

One Sentence Summary:

A tissue specific transcriptome analysis of dystrophin deficient muscle inC. elegansreveals that dystrophin has distinct, dynamic signaling roles in early and late stage progression of Duchenne muscular dystrophy.
Comparative ChIP-seq (Comp-ChIP-seq): a practical guideline for experimental design and a novel computational methodology
Authors: Blanco Enrique , Croce Luciano Di , Aranda Sergi
Published: January 2019

Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is a pivotal technique for understanding the functionality of the chromatin-bound factors and for mapping the functional elements of the genome. In order to evaluate cell- and disease-specific changes in the interacting strength of chromatin targets, ChIP-seq signal across multiple conditions must undergo robust normalization. However, this is not possible using the standard ChIP-seq scheme, which lacks a reference for the control of biological and experimental variabilities. While several studies have recently proposed different solutions to circumvent this problem, substantial technical and analytical differences among methodologies could hamper the experimental reproducibility. Here we provide a practical binary decision-making process to experimentally implement a normalizing method for comparative ChIP-seq across different samples. In addition, we evaluate side-by-side the current computational approaches for normalizing using a reference internal genome. Finally, we propose a local regression strategy to accurately normalize ChIP-seq data in a genome-wide manner. Overall, our proposed experimental and computational standard for comparative ChIP-seq (Comp-ChIP-seq) will increase experimental reproducibility, thereby reducing this major confounding factor in interpreting ChIP-seq results.
Thioridazine as an Anticancer Therapeutic: Interplay with the Isoprenoid Biosynthetic Pathway
Authors: Weissenrieder Jillian S. , Reed Jessie L. , Neighbors Jeffrey D. , Hohl Raymond J.
Published: January 2019

Glioblastoma multiforme is a form of cancer with poor survival prognosis and few treatment options. The cerebrovascular barrier complicates the delivery of chemotherapeutic agents and contributes to poor treatment response in patients with this disease. Recently, dopamine D2 receptor antagonizing compounds, including the FDA-approved phenothiazine, thioridazine, were identified as potential anticancer therapeutics, but their mechanism of action is as yet poorly understood. We investigated the hypothesis that the cytotoxicity of thioridazine may be tied to disruption of lipid metabolism, specifically the synthesis of isoprenoids and cholesterol by the isoprenoid biosynthetic pathway. We show that, while pathway inhibitors lovastatin and zoledronate can sensitize U87MG and U251MG cells to thioridazine treatment, the addition of pathway intermediates cannot prevent thioridazine’s cytotoxic effects. Treatment with methyl-schweinfurthin G, which is known to disrupt lipid trafficking, is able to sensitize these cell lines as well, suggesting that cholesterol availability or localization may be involved in these effects. However, all measured effects were of very small, biologically insignificant magnitude and thus findings are of limited utility.
Defining tissue- and disease-associated macrophages using a transcriptome-based classification model
Authors: Chen Hung-Jen , Li Yim Andrew Y.F. , Griffith Guillermo R. , de Jonge Wouter J. , Mannens Marcel M.A.M. , Ferrero Enrico , Henneman Peter , de Winther Menno P.J.
Published: January 2019

Macrophages are heterogeneous multifunctional leukocytes which are regulated in a tissue-and disease-specific context. Many different studies have been published using in vitro macrophage models to study disease. Here, we aggregated public expression data to define consensus expression profiles for eight commonly-used in vitro macrophage models. Altogether, we observed well-known but also novel markers for different macrophage subtypes. Using these data we subsequently built the classifier macIDR, capable of distinguishing macrophage subsets with high accuracy (>0.95). This classifier was subsequently applied to transcriptional profiles of tissue-isolated and disease-associated macrophages to specifically define macrophage characteristics in vivo. Classification of these in vivo macrophages showed that alveolar macrophages displayed high resemblance to interleukin-10 activated macrophages, whereas macrophages from patients with chronic obstructive pulmonary disease patients displayed a drop in interferon-γ signature. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but resembled LPS-activated macrophages more in diabetic-obese patients. Finally, rheumatoid arthritic synovial macrophages showed characteristics of both interleukin-10 or interferon-γ signatures. Altogether, our results suggest that macIDR is capable of identifying macrophage-specific changes as a result of tissue-and disease-specific stimuli and thereby can be used to better define and model populations of macrophages that contribute to disease.
Identification of transgene-free CRISPR edited plants of rice and tomato by monitoring DsRED fluorescence in dry seeds
Authors: Aliaga Norma , Zhang Cunjin , Presa Silvia , Granell Antonio , Alabadi David , Sadanandom Ari , Blazquez Miguel A. , Minguet Eugenio G.
Published: January 2019

CRISPR/Cas technology for specific and precise modification of genomes has transformed molecular biology. However, quick elimination of the transgene remains a challenge in plant biotechnology after genome edition, especially for crops due to their long life cycle and multiploidy, not only to avoid transgene position effects and to minimize the probability of off-target mutation appearance, but also to deliver end users with edited plants free of the recombinant gene editing machinery. Counter selection based on resistance marker genes are inconvenient in the case of CRISPR/Cas applications because plants lacking the transgene cannot survive the selection, and thus two more generations must be screened to evaluate the presence of the transgene. In the case of some crops, generations can last between 6 months and a few years, and the workload may be a limiting factor because transgene detection by PCR requires germination of seeds, and selected plants must be grown until a new generation can be harvested. The expression of fluorescent proteins as selective marker has been successfully used in Arabidopsis thaliana (Stuitje et al., 2003) as a fast method for transgene presence detection prior to seed germination. Despite this clear advantage, it has not been tested in other species yet, because of the special requirements of in vitro transformation protocols. To overcome the above mentioned inconvenient, we have adapted fluorescence-dependent monitoring of transgene to genome editing approaches in tomato and rice with the goal of obtaining transgene-free homozygous edited crop plants in two generations.