bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of Reaction Norms
Authors: Oomen Rebekah A. , Hutchings Jeffrey A.
Published: October 2020

Phenotypic variance is a function of genetic variability, environmental variation, and the ways in which genetic and environmental variation interact, i.e., VG×E. Reaction norms are a means of conceptually, graphically, and mathematically describing this total variance and are a powerful tool for decomposing it into its constituent parts (i.e., nature, nurture, and, critically, their interaction). A reaction norm is defined as the range of phenotypes expressed by a genotype along an environmental gradient. It is represented by a linear or nonlinear function which describes the value of a phenotypic trait for a particular genotype or group of genotypes in different environments. As such, it is closely related to the concept of phenotypic plasticity, which can be represented by a reaction norm with a non-zero slope (i.e., the phenotype varies with respect to the environment). While the term (which originated as Reaktionsnorm) has been in use for over one hundred years, there has been some debate about the most appropriate way to describe it mathematically. Nonetheless, there is general consensus that a reaction norm has multiple properties, each of which can be the target of selection. Reaction norms are typically described as consisting of: (1) an intercept, elevation, or offset, which describes the mean trait value across all environments, (2) a slope, which quantifies the degree of trait plasticity, and (3) shape or curvature (e.g., linear, quadratic, monotonic). Evidence that trait means and plasticities can evolve separately underscores the necessity of applying a reaction norm framework for studying ecological and evolutionary responses to the environment, because measuring phenotypes in a single environmental context does not necessarily reflect their relative values or diversities in a different context. These contextual differences are particularly important in a world of rapid anthropogenic change and increasing environmental variability. Therefore, in addition to being fundamental to ecological and evolutionary phenomena, reaction norm evolution is relevant for diverse biological fields, including behavior and psychology, conservation and natural resource management, global change biology, agriculture and breeding programs, and human health. Given that evolutionary change is defined by genetic change, we focus this article on variation among reaction norms from different genotypes (i.e., reaction norms that have potentially evolved to be divergent from one another) as well as the forces that promote and constrain reaction norm evolution. For an overview of the literature on plasticity itself (keeping in mind that reaction norms need not be plastic), see the separate Oxford Bibliographies in Evolutionary Biology article Phenotypic Plasticity.
Historical migration and contemporary health
Authors: Andersen Thomas Barnebeck , Dalgaard Carl-Johan , Skovsgaard Christian Volmer , Selaya Pablo
Published: October 2020

We argue that migration during the last 500 years induced differences in contemporary health outcomes. The theory behind our analysis builds on three physiological facts. First, vitamin D deficiency is directly associated with higher risk of all-cause mortality. Second, the ability of humans to synthesize vitamin D from sunlight (UV-R) declines with skin pigmentation. Third, skin pigmentation is the result of an evolutionary compromise between higher risk of vitamin D deficiency and lower risk of skin cancer. When individuals from high UV-R regions migrate to low UV-R regions, the risk of vitamin D deficiency rises markedly. We develop a measure that allows us to empirically explore the aggregate health consequences of such migration in a long historical perspective. We find that the potential risk of vitamin D deficiency induced by migration during the last half millennium is a robust predictor of present-day aggregate health indicators.
Neural responses reveal associations between personal values and value-based decisions
Authors: Chuang Yun-Shiuan , Su Yu-Shiang , Goh Joshua O S
Published: October 2020

Personal values are thought to modulate value-based decisions, but the neural mechanisms underlying this influence remain unclear. Using a Lottery Choice Task functional brain imaging experiment, we examined the associations between personal value for hedonism and security (based on the Schwartz Value Survey) and subjective neurocognitive processing of reward and loss probability and magnitude objectively coded in stimuli. Hedonistic individuals accepted more losing stakes and showed increased right dorsolateral prefrontal and striatal and left parietal responses with increasing probability of losing. Individuals prioritizing security rejected more stakes and showed reduced right inferior frontal and amygdala responses with increasing stake magnitude, but increased precuneus responses for high-magnitude high-winning probability. With higher hedonism, task-related functional connectivity with the whole brain was higher in right insula and lower in bilateral habenula. For those with higher security ratings, whole-brain functional connectivity was higher in bilateral insula, supplementary motor areas, right superior frontal gyrus, dorsal anterior cingulate cortex, and lower in right middle occipital gyrus. These findings highlight distinct neural engagement across brain systems involved in reward and affective processing, and cognitive control that subserves how individual differences in personal value for gaining rewards or maintaining status quo modulate value-based decisions
The braincase, brain and palaeobiology of the basal sauropodomorph dinosaurThecodontosaurus antiquus
Authors: Ballell Antonio , King J Logan , Neenan James M , Rayfield Emily J , Benton Michael J
Published: October 2020

Sauropodomorph dinosaurs underwent drastic changes in their anatomy and ecology throughout their evolution. The Late Triassic Thecodontosaurus antiquus occupies a basal position within Sauropodomorpha, being a key taxon for documenting how those morphofunctional transitions occurred. Here, we redescribe the braincase osteology and reconstruct the neuroanatomy of Thecodontosaurus, based on computed tomography data. The braincase of Thecodontosaurus shares the presence of medial basioccipital components of the basal tubera and a U-shaped basioccipital–parabasisphenoid suture with other basal sauropodomorphs and shows a distinct combination of characters: a straight outline of the braincase floor, an undivided metotic foramen, an unossified gap, large floccular fossae, basipterygoid processes perpendicular to the cultriform process in lateral view and a rhomboid foramen magnum. We reinterpret these braincase features in the light of new discoveries in dinosaur anatomy. Our endocranial reconstruction reveals important aspects of the palaeobiology of Thecodontosaurus, supporting a bipedal stance and cursorial habits, with adaptations to retain a steady head and gaze while moving. We also estimate its hearing frequency and range based on endosseous labyrinth morphology. Our study provides new information on the pattern of braincase and endocranial evolution in Sauropodomorpha.
An Evaluation of Faculty Development Programs for Clinician–Educators: A Scoping Review
Authors: Alexandraki Irene , Rosasco Robyn E. , Mooradian Arshag D.
Published: October 2020

Purpose

Faculty development (FD) has become increasingly important for clinician–educators. An array of FD programs has been developed, but the impact of these programs on clinician–educators and their learners and workplace is less known. The authors conducted a scoping review to explore the status of program evaluation in FD for clinician–educators to inform future planning and research.

Method

Five databases were searched for articles published from January 1998 to August 2018 using Arksey and O’Malley’s framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. Studies that described evaluation methods and outcomes of FD programs for clinician–educators were included. Data were collected and organized according to program domain (teaching, research/scholarship, leadership, or a combination of skills). A modified version of the Kirkpatrick model was used to compare results among studies.

Results

From a total of 2,091 articles, 1,095 were eligible for full review, and 31 met the inclusion criteria. Seven programs targeted only teaching skills, 3 research/scholarship skills, 7 leadership skills, and 14 a combination of skills. Eighteen programs required the completion of a project; fewer offered fellowships, master’s degrees, or certificates. Participant surveys were the most common evaluation method across all domains. Often used metrics included participant satisfaction and self-reported knowledge, skills, behavior changes, scholarly output, and leadership positions. Less common evaluation methods included learner and peer evaluations, interviews, and focus groups. Change at the institutional level was evaluated in 11 programs.

Conclusions

Program evaluation remains an underdeveloped area in FD for clinician–educators. Developers expend significant effort on program design and implementation but approach evaluation less purposefully. Rigorous metrics that align with program goals and are used longitudinally are needed to accurately assess the impact of FD programs on participants and their learners, workplace, and institutions at large.
Unexpectedly High Frequency of Enterococcal Bloodstream Infections in Coronavirus Disease 2019 Patients Admitted to an Italian ICU: An Observational Study
Authors: Bonazzetti Cecilia , Morena Valentina , Giacomelli Andrea , Oreni Letizia , Casalini Giacomo , Galimberti Laura Rina , Bolis Matteo , Rimoldi Matteo , Ballone Elisabetta , Colombo Riccardo , Ridolfo Anna Lisa , Antinori Spinello
Published: October 2020

OBJECTIVES:

We aimed to assess the frequency of ICU-acquired bloodstream infections in coronavirus disease 2019 patients.

DESIGN:

Retrospective observational study.

SETTING:

The emergency expansion of an ICU from eight general beds to 30 coronavirus disease 2019 beds.

PARTICIPANTS:

Patients with coronavirus disease 2019 admitted to the ICU of Luigi Sacco Hospital (Milan, Italy) for greater than or equal to 48 hours between February 21, 2020, and April 30, 2020.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

The frequency of bloodstream infections per 1,000 days of ICU stay was calculated in 89 coronavirus disease 2019 patients, and the cumulative probability of bloodstream infection was estimated using death and ICU discharge as competing events. Sixty patients (67.4%) experienced at least one of the 93 recorded episodes of bloodstream infection, a frequency of 87 per 1,000 days of ICU stay (95% CI, 67–112).The patients who experienced a bloodstream infection had a higher Sequential Organ Failure Assessment score upon ICU admission (9.5; interquartile range, 8–12 vs 8, interquartile range, 5–10; p = 0.042), a longer median ICU stay (15 d; interquartile range, 11–23 vs 8, interquartile range, 5–12; p < 0.001), and more frequently required invasive mechanical ventilation (98.3% vs 82.8%; p = 0.013) than those who did not. The median time from ICU admission to the first bloodstream infection episode was 10 days. Gram-positive bacteria accounted for 74 episodes (79.6%), with Enterococcus species being the most prevalent (53 episodes, 55.8%). Thirty-two isolates (27.3%) showed multidrug resistance.

CONCLUSIONS:

Coronavirus disease 2019 seemed to increase the frequency of bloodstream infections (particularly Enterococcus-related bloodstream infection) after ICU admission. This may have been due to enteric involvement in patients with severe coronavirus disease 2019 and/or limitations in controlling the patient-to-patient transmission of infectious agents in extremely challenging circumstances.
Bilateral vertebral artery dissection complicated by posterior circulation stroke in a young man
Authors: Li Zhichao , Liu Junni , Wang Xiang , Liu Xiaohui , Sun Qinjian , Du Yifeng , Yin Ling
Published: October 2020

Introduction:

Vertebral artery dissection (VAD) is a common cause of stroke in young and mid-aged adults without predisposing risk factors for vascular disease. It can be induced by a particular head or neck posture; its early signs often include headache and neck pain. Improved imaging techniques can be used to detect VAD, whose current treatment options are limited.

Patient concerns:

The patient presented with neck and shoulder pain for a week after sleeping against the wall with cervical proneness for 1 night. He had sudden headache, slurred speech, and left side weakness for 1.5 hours on admission.

Diagnosis:

The patient had VAD complicated by posterior circulation stroke.

Interventions:

Acute stroke was treated with intravenous thrombolytic therapy. Then, the patient was administered follow-up anticoagulants.

Outcomes:

The patient's condition improved after thrombolytic therapy. He recovered well, with no recurrence during a 4-year follow-up.

Conclusion:

VAD should be taken into consideration in differential diagnosis of posterior circulation stroke or transient ischemic attack in young patients. Intravenous thrombolytic therapy may be safe and effective for stroke-complicated cases. This case report demonstrates that expanded diagnostic protocol for acute ischemic stroke assures rapid and correct diagnosis.
Central nervous system aspergillosis in immunocompetent patients
Authors: Ma Yubao , Li Wanjun , Ao Ran , Lan Xiaoyang , Li Yang , Zhang Jiatang , Yu Shengyuan
Published: October 2020

The aim of this study was to investigate the clinical characteristics of central nervous system (CNS) aspergillosis in immunocompetent patients.

This study enrolled six immunocompetent patients diagnosed with CNS aspergillosis. Additionally, we reviewed the clinical profiles for 28 cases reported in the literature. The age, gender, etiology of Aspergillus infection, clinical manifestations, location of the lesion, treatment, and prognosis were analyzed.

There were 19 men (average age, 54.6 ± 14.3 years) and 15 women (average age, 47.0 ± 19.4 years). The clinical manifestations included headache (55.9%; n = 19), visual impairment (32.4%; n = 11), diplopia (32.4%; n = 11), hemiplegia (20.6%; n = 7), fever (17.6%; n = 6), and epilepsy (8.8%; n = 3). According to the radiological features, CNS aspergillosis lesions were divided into two subtypes: parenchymal lesions in the cerebral lobes (n = 11), and meningeal lesions in the meninges (n = 23). The patients with meningeal lesions are easy to be complicated with more serious cerebrovascular diseases, such as subarachnoid hemorrhage and massive infarction. Most of the lesions in brain parenchyma were abscess formation, and magnetic resonance imaging showed ring enhancement. The clinical diagnosis of Aspergillus infection was mainly based on brain biopsy (n = 14), autopsy (n = 8), pathological examination of adjacent brain tissues (n = 7), cerebrospinal fluid (CSF) or tissue culture (n = 3), and second-generation sequencing analysis of the CSF (n = 3). Clinical improvement was achieved in 23 cases, and 11 patients succumbed to the disease. Voriconazole treatment was effective in 24 (70.6%) cases.

Immunocompetent subjects are also at risk for Aspergillus infections. Concomitant cerebrovascular diseases are common in patients with CNS aspergillosis, especially in patients with meningeal aspergillosis. Parenchymal aspergillosis lesions are usually localized and manifest as brain abscesses with annular enhancement on magnetic resonance imaging. Biopsy, CSF culture, and next-generation sequencing are mainstream diagnostic modalities. Voriconazole is an effective treatment for Aspergillus infection, and early diagnosis and treatment should be highlighted.
Two cases of imported pneumonic plague in Beijing, China
Authors: Zhou Haijiang , Guo Shubin
Published: October 2020

Introduction:

Plague is an acute, often fulminating infectious disease caused by Yersinia Pestis transmitted by rodents. It is rarely encountered in clinics, although natural plague foci are widely distributed around the world.

Patient Concerns:

A couple who are cattle and sheep herdsmen from the Inner Mongolia Autonomous Region presented with cough, expectoration and fever. The husband developed sudden onset of fever and bloody sputum after working the soil on his farm. The wife also developed fever after nursing his husband. Both patients were preliminarily diagnosed with severe pneumonia, but antimicrobial treatments in the local hospital were unsuccessful. Their conditions deteriorated and they were transferred to our center.

Diagnosis:

Preliminary etiological examinations were unremarkable, while blood and sputum specimens were found to be positive by RT-PCR and colloidal gold-immunochromatography assay targeting the F1 antigen and by reverse indirect hemagglutination assay. Pneumonic plague was confirmed.

Interventions:

Both patients were transferred to special infectious disease hospital for further treatment.

Outcomes:

The condition of the female patient deteriorated. The male recovered after treatment, while the female patient finally died.

Conclusion:

There are 3 main forms of plague: bubonic, pneumonic and septicemic. Humans can be infected by the bites of bacterium-bearing fleas or direct contact of wild animals that died from plague. Human plague can be transmitted by close contact through coughing droplet. Neglected diagnosis of plague could cause severe consequences. Strict surveillance and protection measures should be taken and the public should be alerted about potential risks when epizootic plague is detected.
Iodine-125 radioactive particles antagonize hyperprogressive disease following immunotherapy
Authors: Yang Ning , Zhang Pin-Liang , Liu Zeng-Jun
Published: October 2020

Rationale:

Increasing evidence has shown that immune checkpoint inhibitors are associated with hyperprogressive disease (HPD). HPD usually resulted in dramatically reduced survival duration, which limited the opportunity to administer other therapies.

Patient concerns:

A heavily pretreated lung adenocarcinoma patient experienced rapid progression of rib metastasis soon after immune checkpoint inhibitor -based combination therapy.

Diagnoses:

On the basis of radiographic and pathological findings, the patient was diagnosed with HPD.

Interventions:

We treated the patient with iodine-125 radioactive particle implantation to the metastatic lesions in the chest wall.

Outcomes:

The metastatic lesions shrank significantly 1 month later.

Lessons:

Early detection and adequate treatment are essential for prolonged survival when HPD occurs.
Effects of Laser Photobiomodulation Therapy at 808 nm on Muscle Performance and Perceived Exertion in Elderly Women
Authors: Rodrigues Claudiane Pedro , Jacinto Jeferson Lucas , Roveratti Mirela Casonato , Nunes João Pedro , Pacagnelli Francis Lopes , Andraus Rodrigo Antonio Carvalho , Soares-Caldeira Lúcio Flávio , Ribeiro Alex Silva , Buzzachera Cosme Franklim , Aguiar Andreo Fernando
Published: October 2020

Objective:

This study aimed to investigate the acute effects of laser photobiomodulation (λ: 808 nm) therapy on muscle performance and perceived exertion in physically active elderly women.

Methods:

Seventeen physically active elderly women (72.6 ± 4.1 years) participated in a crossover study in which they received active or placebo laser therapy on the rectus femoris muscle on 2 occasions, separated by a 7-day washout period. On each occasion, the following performance outcomes were assessed: functional capacity by short physical performance battery, knee extensor strength by maximum voluntary isometric contraction, muscle endurance by repetitions-to-failure test and blood lactate levels, and perceived exertion.

Results:

No statistical (P > .05) differences were observed between active and placebo laser conditions for all muscle performance outcome (ie, short physical performance battery, maximum voluntary isometric contraction, repetitions-to-failure, and lactate) and perceived exertion.

Conclusions:

Acute laser photobiomodulation therapy at 808 nm does not improve muscle performance (functional capacity, strength, and endurance) and perceived exertion in physically active elderly women.

Trial registration: NCT04241991.
Perceived and actual fighting ability: determinants of success by decision, knockout or submission in human combat sports
Authors: Lane Sarah M. , Briffa Mark
Published: October 2020

Animal contest theory assumes individuals to possess accurate information about their own fighting ability or resource-holding potential (RHP) and, under some models, that of their opponent. However, owing to the difficulty of disentangling perceived and actual RHP in animals, how accurately individuals are able to assess RHP remains relatively unknown. Furthermore, it is not just individuals within a fight that evaluate RHP. Third-party observers evaluate the fight performance of conspecifics in order to make behavioural decisions. In human combat sports, when fights remain unresolved at the end of the allotted time, bystanders take a more active role, with judges assigning victory based on their assessment of each fighter's performance. Here, we use fight data from mixed martial arts in order to investigate whether perceived fighting performance (judges' decisions) and actual fighting success (fights ending in knockout or submission) are based on the same performance traits, specifically striking skill and vigour. Our results indicate that both performance traits are important for victory, but that vigour is more important for fights resolved via decision, even though the effect of vigour is enhanced by skill. These results suggest that while similar traits are important for fighting success across the board, vigour is overvalued in judges' perceptions of RHP.
Dynamical Ising model of spatially coupled ecological oscillators
Authors: Nareddy Vahini Reddy , Machta Jonathan , Abbott Karen C. , Esmaeili Shadisadat , Hastings Alan
Published: October 2020

Long-range synchrony from short-range interactions is a familiar pattern in biological and physical systems, many of which share a common set of ‘universal’ properties at the point of synchronization. Common biological systems of coupled oscillators have been shown to be members of the Ising universality class, meaning that the very simple Ising model replicates certain spatial statistics of these systems at stationarity. This observation is useful because it reveals which aspects of spatial pattern arise independently of the details governing local dynamics, resulting in both deeper understanding of and a simpler baseline model for biological synchrony. However, in many situations a system’s dynamics are of greater interest than their static spatial properties. Here, we ask whether a dynamical Ising model can replicate universal and non-universal features of ecological systems, using noisy coupled metapopulation models with two-cycle dynamics as a case study. The standard Ising model makes unrealistic dynamical predictions, but the Ising model with memory corrects this by using an additional parameter to reflect the tendency for local dynamics to maintain their phase of oscillation. By fitting the two parameters of the Ising model with memory to simulated ecological dynamics, we assess the correspondence between the Ising and ecological models in several of their features (location of the critical boundary in parameter space between synchronous and asynchronous dynamics, probability of local phase changes and ability to predict future dynamics). We find that the Ising model with memory is reasonably good at representing these properties of ecological metapopulations. The correspondence between these models creates the potential for the simple and well-known Ising class of models to become a valuable tool for understanding complex biological systems.
Extraordinary attention, ordinary neglect: the high cost of disaster preparedness and response
Authors: Hahn Robert A.
Published: October 2020

Background

Funds allocated to disaster preparedness and response in the U.S. have grown rapidly in recent decades. This analysis examines the ratio of cost per outcome of public health events classified as disasters and those not classified as disasters, e.g., smoking-related morbidity and mortality.

Methods

Mortality is taken as an outcome metric; the validity of this measure is assessed by examination of ratios of tangible and intangible costs of disaster and non-disaster outcomes to mortality from two conditions, using available data. The relative allocation of CDC funding to disaster and non-disaster events is assumed to conservatively represent the U.S. overall relative funding allocation.

Results

Non-disaster deaths are 2,500 more likely than disaster deaths; we allocate 370 times more funding per disaster death than we do per non-disaster death.

Conclusion

The rationality of this implicit decision be reconsidered.
A multiagent coronavirus model with territorial vulnerability parameters
Authors: Magalhães Patrícia , Pinto José Paulo Guedes , Segura Angel Diana Maritza
Published: October 2020

We developed a simple and user-friendly simulator called MD Corona that is based on a multiagent model and describes the transmission dynamics of coronavirus for a given location considering three setting parameters: population density, social-isolation rate, and effective transmission probability. The latter is represented by the Coronavirus Protection Index (CPI) - a measurement of a given territory’s vulnerability to the coronavirus that includes characteristics of the health system and socioeconomic development as well as infrastructure. The dynamic model also relies on other real epidemiological parameters. The model is calibrated by using immunity surveys and provides accurate predictions and indications of the different spread dynamic mechanisms. Our simulation studies clearly demonstrate the existence of multiple epidemic curves in the same city due to different vulnerabilities to the virus across regions. And it elucidates the phenomenon of the epidemic slowing despite a reduction in social-distancing policies, understood as a consequence of “local protection bubbles.” The simulator can be used for scientific outreach purposes, bringing science closer to the general public in order to raise awareness and increase engagement about the effectiveness of social distancing in reducing the transmissibility of the virus, but also to support effective actions to mitigate the spread of the virus.
Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features
Authors: Li Dong , Wang Qin , Gong Naihua N. , Kurolap Alina , Feldman Hagit Baris , Boy Nikolas , Brugger Melanie , Grand Katheryn , McWalter Kirsty , Guillen Sacoto Maria J. , Wakeling Emma , Hurst Jane , March Michael E. , Bhoj Elizabeth J. , Nowaczyk Małgorzata J.M. , Gonzaga-Jauregui Claudia , Mathew Mariam , Dava-Wala Ashita , Siemon Amy , Bartholomew Dennis , Huang Yue , Lee Hane , Martinez Julian A , Schwaibold Eva M.C. , Brunet Theresa , Choukair Daniela , Pais Lynn S. , White Susan M , Christodoulou John , Brown Dana , Lindstrom Kristin , Grebe Theresa , Tiosano Dov , Kayser Matthew S. , Tan Tiong Yang , Deardorff Matthew A. , Song Yuanquan , Hakonarson Hakon
Published: October 2020

Intellectual disability (ID) encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for over 50% of the patients remains elusive. We describe mutations inSMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a novel neurodevelopmental disorder, identifying twelve individuals withde novoor dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature, and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5DrosophilaorthologIswiled to smaller body size, reduced dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology and abnormal locomotor function.Iswiloss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate thatSMARCA5pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.
Causal factors affecting gross motor function in children diagnosed with cerebral palsy
Authors: MacWilliams Bruce A. , Prasad Sarada , Shuckra Amy L. , Schwartz Michael H.
Published: October 2020

Cerebral palsy (CP) is a complex neuromuscular condition which may negatively impact gross motor function. Children diagnosed with CP often exhibit spasticity, weakness, reduced motor control, contracture, and bony malalignment. Despite many previous association studies, the causal impact of these impairments on motor function is unknown. In this study, we propose a causal model for motor function as measured by the 66-item Gross Motor Function Measure (GMFM-66), and estimate the direct and total effect sizes of these common impairments using linear regression based on covariate adjustment sets implied by the causal model. We evaluated 300/314 consecutive subjects with cerebral palsy who underwent routine clinical gait analysis. The largest effect sizes, as measured by standardized regression coefficients (standard error), were for static motor control (direct = 0.35 (0.04), total = = 0.40 (0.04)) and dynamic motor control (direct = 0.26 (0.04), total = 0.31 (0.04)), followed by strength (direct = 0.23 (0.04), total = 0.26 (0.04)). The next largest effect was found for gait deviations (direct = total = 0.15 (0.04)). In contrast, common treatment targets, such as spasticity (direct = 0.05 (0.03), total = 0.08 (0.03)) and orthopedic deformity (direct = 0.00 (0.03) to 0.08 (0.03), total = −0.01 (0.03) to 0.11 (0.03)), had relatively small effects. We also show that effect sizes estimated from bivariate models, which fail to appropriately adjust for other causal factors dramatically overestimate the total effect of spasticity (510%), strength (271%), and orthopedic deformity (192% to -2017%). Understanding the relative influences of impairments on gross motor function will allow clinicians to direct treatments at those impairments with the greatest influence on gross motor function and provide realistic expectations of the anticipated functional changes.
Sex-specific classification of drug-induced Torsade de Pointes susceptibility using cardiac simulations and machine learning
Authors: Iseppe Alex Fogli , Ni Haibo , Zhu Sicheng , Zhang Xianwei , Coppini Raffaele , Yang Pei-Chi , Srivatsa Uma , Clancy Colleen E. , Edwards Andrew G. , Morotti Stefano , Grandi Eleonora
Published: October 2020

Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel blockin vitroand QT interval prolongationin vivofor all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. While this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly underrepresented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (1) TdP classifiers require different features in females vs. males; (2) malebased classifiers perform more poorly when applied to female data; (3) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially lifethreatening consequences for the female population.
Deep Neural Network Models of Object Recognition Exhibit Human-Like Limitations when Performing Visual Search Tasks
Authors: Nicholson David A. , Prinz Astrid A.
Published: October 2020

To find an object we are looking for, we must recognize it. Prevailing models of visual search neglect recognition, focusing instead on selective attention mechanisms. These models account for performance limitations that participants exhibit when searching highly simplified stimuli often used in laboratory tasks. However, it is unclear how to apply these models to complex natural images of real-world objects. Deep neural networks (DNN) can be applied to any image, and recently have emerged as state-of-the-art models of object recognition in the primate ventral visual pathway. Using these DNN models, we ask whether object recognition explains limitations on performance across visual search tasks. First, we show that DNNs exhibit a hallmark effect seen when participants search simplified stimuli. Further experiments show this effect results from optimizing for object recognition: DNNs trained from randomly-initialized weights do not exhibit the same performance limitations. Next, we test DNN models of object recognition with natural images, using a dataset where each image has a visual search difficulty score, derived from human reaction times. We find DNN accuracy is inversely correlated with visual search difficulty score. Our findings suggest that to a large extent visual search performance is explained by object recognition.
Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome
Authors: Mazumder Aloran , Jimenez Athena , Ellsworth Rachel E , Freedland Stephen J , George Sophia , Bainbridge Matthew , Haricharan Svasti
Published: October 2020

IMPORTANCE

African American (AA) breast cancer patients have worse outcomes than Caucasian Americans (CAs). DNA damage repair (DDR) genes drive poor outcome in CA estrogen receptor (ER)+ breast cancer patients. Whether DDR genes similarly impact survival in AAs is unknown. Identifying AA-specific patterns of DDR dysregulation could change how we tailor predictive/prognostic biomarkers.

OBJECTIVE

To characterize DDR dysregulation in ER+ AA patient tumors and test associations with clinical outcome.

DESIGN SETTINGS AND PARTICIPANTS

Three independent tumor, and two normal breast datasets were analyzed. Tumor datasets: (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA). Normal datasets: (4) GSE43973 (5) GSE50939.

MAIN OUTCOME AND MEASURES

Up/down-regulation of 104 DDR genes was assessed in AA samples vs CAs. Survival associations were assessed for genes dysregulated in multiple datasets.

RESULTS

Overall, RNA levels of single strand break repair (SSBR) genes were downregulated in AA tumors and double strand break repair (DSBR) genes were upregulated compared to CAs. While SSBR downregulation was mainly detected in tumors, DSBR upregulation was detectable in both tumor and normal breast AA samples. Seven specific DDR genes identified as dysregulated in AAs vs CAs in multiple datasets associated with poor survival. A subset of tumors with simultaneous dysregulation of homologous recombination and single strand break repair genes was enriched in AAs and had associated consistently with poor survival.

CONCLUSION AND RELEVANCE

Overall, these results constitute the first systematic analysis of differences in DDR regulation in AA ER+ tumors and normal tissue vs CAs. We identify a profile of DDR dysregulation enriched in AA patients, which associates with poor outcome. These results suggest a distinct molecular mechanism of DDR regulation in AAs that lays the groundwork for refining biomarker profiles by race and improving precision medicine for underserved populations.
ISG15-dependent Activation of the RNA Sensor MDA5 and its Antagonism by the SARS-CoV-2 papain-like protease
Authors: Liu GuanQun , Lee Jung-Hyun , Parker Zachary M. , Acharya Dhiraj , Chiang Jessica J. , van Gent Michiel , Riedl William , Davis-Gardner Meredith E. , Wies Effi , Chiang Cindy , Gack Michaela U.
Published: October 2020

Activation of the RIG-I-like receptors, RIG-I and MDA5, establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15 whose mechanistic roles in innate immunity still remain enigmatic. Here we report that ISGylation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISG15 conjugation to the caspase activation and recruitment domains of MDA5 promotes the formation of higher-order assemblies of MDA5 and thereby triggers activation of innate immunity against a range of viruses including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease (PLpro) of SARS-CoV-2, a recently emerged coronavirus that causes the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a novel immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19.
Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens
Authors: Jiang Wei , Yang Ailing , Ma Jingchuan , Lv Dawei , Liu Mingxian , Xu Liang , Wang Chao , He Zhengjin , Chen Shuo , Zhao Jie , Chen Shishuang , Jiang Qi , Chu Yankai , Shan Lin , Zhou Zhaocai , Zhao Yun , Long Gang , Jiang Hai
Published: October 2020

Immunomodulatory agents dexamethasone and colchicine, antiviral drugs remdesivir, favipiravir and ribavirin, as well as antimalarial drugs chloroquine phosphate and hydroxychloroquine are currently used in the combat against COVID-191–16. However, whether some of these drugs have clinical efficacy for COVID-19 is under debate. Moreover, these drugs are applied in COVID-19 patients with little knowledge of genetic biomarkers, which will hurt patient outcome. To answer these questions, we designed a screen approach that could employ genome-wide sgRNA libraries to systematically uncover genes crucial for these drugs’ action. Here we present our findings, including genes crucial for the import, export, metabolic activation and inactivation of remdesivir, as well as genes that regulate colchicine and dexamethasone’s immunosuppressive effects. Our findings provide preliminary information for developing urgently needed genetic biomarkers for these drugs. Such biomarkers will help better interpret COVID-19 clinical trial data and point to how to stratify COVID-19 patients for proper treatment with these drugs.
Exact Matching of Trabectome-Mediated Ab Interno Trabeculectomy to Conventional Trabeculectomy with Mitomycin C Followed for Two Years
Authors: Strzalkowska A. , Strzalkowski P. , Al Yousef Y. , Grehn F. , Hillenkamp J. , Loewen N. A.
Published: October 2020

Purpose

We used exact matching for a highly balanced comparison of ab interno trabeculectomy (AIT) with the trabectome to trabeculectomy with mitomycin C (TRAB).

Methods

5485 patients who underwent AIT were exact-matched to 196 TRAB patients by baseline intraocular pressure (IOP), number of glaucoma medications, and glaucoma type. Nearest-neighbor-matching was applied to age. Success was defined as a final IOP of less than 21 mmHg, IOP reduction of at least 20% reduction from baseline, and no secondary surgical interventions. Outcomes were measured at 1, 3, 6, 12, 18, and 24 months.

Results

165 AIT could be matched to 165 TRAB. The mean baseline IOP was 22.3±5.6 mmHg, and the baseline number of glaucoma medications was 2.7±1.1 in both groups. At 24 months, IOP was reduced to 15.8±5.2 mmHg in AIT and 12.4±4.7 mmHg in TRAB. IOP was lower than baseline at all visits (p<0.01) and lower in TRAB than AIT (p<0.01). Glaucoma medications were reduced to 2.1 ± 1.3 in AIT and 0.2 ± 0.8 in TRAB. Compared to baseline, patients used fewer drops postoperatively (p<0.01) and more infrequently in TRAB than in AIT (p>0.01). Secondary surgical interventions had the highest impact on success and became necessary in 15 AIT and 59 TRAB patients. Thirty-two challenging events occurred in TRAB and none in AIT.

Conclusion

Both AIT and TRAB reduced IOP and medications. This reduction was more significant in TRAB but at the expense of four times as many secondary interventions.

Key messages

Despite vastly different IOP reduction and safety profile, ab interno trabeculectomy with the Trabectome and trabeculectomy with mitomycin C are both used as primary glaucoma surgeries. Exact matching allowed us to strictly focus on identical IOP and medications to create highly similar patient pairs for a balanced comparison that cannot be accomplished short of a randomized controlled trial. We found that trabeculectomy could achieve low IOPs and independence from drops, but trabeculectomies often required postoperative interventions. Trabectome patients had a lesser reduction of IOP and drops but needed far fewer interventions.
Knowledge, attitudes, and perceptions of long-acting reversible contraceptive (LARC) methods among healthcare workers in sub-Saharan Africa: a systematic review and meta-analysis
Authors: Rouncivell Laura , Takuva Simbarashe , Ledibane Neo , Musekiwa Alfred , Leong Trudy D
Published: October 2020

Objective

To assess the knowledge, attitudes, and perceptions (KAP) of long-acting reversible contraceptive (LARC) methods among healthcare workers (HCWs) in sub-Saharan Africa (SSA).

Methods

A systematic review and meta-analysis were conducted following the PRISMA methodology. Two authors independently searched three electronic databases for studies published between 2000 and January 2020 reporting on the KAP of LARC methods among HCWs in SSA. Titles and abstracts were screened against eligibility criteria, data were extracted and the included studies were assessed for risk of bias. A meta-analysis of proportions for 11 pre-determined questions relating to LARC KAP was performed. Heterogeneity was explored using the I2-statistic and publication bias investigated using funnel plots and Egger’s tests.

Results

Twenty-two studies comprising of 11 272 HCWs from 11 SSA countries were included. Forty-one percent (95% CI: 20%, 61%) of HCWs had received intrauterine contraceptive device (IUCD) insertion training while 63% (95% CI: 44%, 81%) expressed a desire for training. Only 27% (95% CI: 18%, 36%) deemed IUCD appropriate for HIV-infected women. Restrictions for IUCD and injectables based on a minimum age were imposed by 56% (95% CI: 33%, 78%) and 60% (95% CI: 36%, 84%), respectively. Minimum parity restrictions were observed among 29% (95% CI: 9%, 50%) of HCWs for IUCDs and 36% (95% CI: 16%, 56%) for injectable contraceptives. Heterogeneity was high and publication bias was present in two of the 11 questions.

Conclusion

The systematic review and meta-analysis indicate that unnecessary provider-imposed restrictions may hinder the uptake of LARC methods by women in SSA.

Conflicts of Interest

None.

Ethics approval

Ethical approval was received from the Faculty of Health Sciences Research Ethics Committee (REC) at the University of Pretoria, School of Health Systems and Public Health. Reference Number: 640/2019

Authors Contributions

All authors contributed to the design of the study and the preparation of the manuscript. LR, ST and AM contributed toward the statistical analysis. All authors read and approved the content of the manuscript.
Corona-Independent Excess Mortality Due to Reduced Use of Emergency Medical Care in the Corona Pandemic: A Population-Based Observational Study
Authors: Kortüm S. , Frey P. , Becker D. , Ott H.-J. , Schlaudt H-P.
Published: October 2020

Background

A significant decrease in the number of cases of emergency medical care during the first phase of the Corona pandemic has been reported from various regions of the world. Due to the lack of or delayed use of medical assistance, particularly in the case of time-critical clinical pictures (myocardial infarction, stroke), a corona collateral damage syndrome is postulated regarding possible health consequences. The present study investigates changes in the use of preclinical and clinical emergency care and effects on overall mortality in a rural area.

Methods

The number of patients in the emergency department at the Klinikum Hochrhein and the ambulance service were retrospectively aggregated and analyzed regarding the total number and selected tracer diagnoses and alarm keywords. The investigation period was the 9th to 22nd calendar week 2020 compared to the identical period of the previous year. In addition, the death rates in the district were collected directly from the registries and related to the number of patients in emergency care.

Results

Overall, the number of patients in clinical and preclinical emergency care declined significantly during the investigation period. This concerned in particular emergency inpatient treatment of patients with exacerbations or complications of severe chronic diseases. At the same time, excess mortality occurred in April 2020, which was still highly significant even after excluding deaths on or with COVID-19.

Discussion

Only about 55 % of the excess mortality in April 2020 can be attributed to COVID-19 and is associated with the decline in inpatient emergency treatment, especially of chronically ill patients. Since a drift of patients with the use of other service providers is unlikely, we assume that fears of infection in overburdened hospitals, one-sided public communication and reporting, and the extent of contact restrictions have contributed significantly to the decline in case numbers and to excess mortality (collateral damage).

Conclusion

For similar situations in the future, it is strongly recommended to make crisis communication and media coverage more balanced so as not to prevent people with acute health problems from receiving medical assistance. Contact restrictions should be critically reviewed and limited to the objectively necessary minimum.