bluuebunny/crossref_metadata_2025 huggingface dataset:
Liver resection for metastatic uveal melanoma: experience from a supra-regional centre and review of literature
Authors: Trivedi Dharmadev B. , Aldulaimi Natasha , Karydis Ioannis , Wheater Matthew , Modi Sachin , Stedman Brian , Karavias Dimitrios , Primrose John , Pearce Neil , Takhar Arjun S.
Published: November 2022

Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study describes evolution of liver resection for LMUM, reviewing current literature and institutional outcomes. Records of patients referred to the Melanoma Multi-Disciplinary Team between February 2005 and August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar. Thirty-one of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. Nineteen liver resections were performed locally [7 major (≥3 seg), 14 laparoscopic] without major complications or mortality. Overall survival positively correlated with the time from uveal melanoma to LMUM (Spearman’s rho r
s = 0.859, P < 0.0001). Overall and recurrence-free survivals were comparable following R1 or R0 resections (OS 25 vs. 28 months, P = 0.404; RFS 13 vs. 6 months, P = 0.596). R1 resection cohort had longer lead-time (median 100 vs. 24 months, P = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of uveal melanoma to LMUM remains a key factor affecting survival after liver resection.
Genvoya-Associated and Simvastatin-Associated Noninflammatory and Nonautoimmune Myopathy: A Case Report and Literature Review
Authors: Huang Merry , Prayson Richard A. , Li Yuebing
Published: November 2022

Patients with HIV have a higher incidence of rhabdomyolysis compared with the HIV negative population because of medication-related myotoxicity and drug–drug interactions. Statins and antiretroviral therapy have been previously reported to cause myopathy in patients with HIV when used alone or in combination. In this study, we describe a case of biopsy-proven noninflammatory and nonautoimmune myopathy associated with the use of simvastatin and Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate) and review 3 previously reported similar cases. Our patient presented with acute proximal limb weakness and significantly elevated serum creatine kinase. Muscle biopsy revealed scattered degenerating and regenerating muscle fibers without evidence for an inflammatory process. She did not respond to empiric treatment with high-dose intravenous steroids and intravenous immunoglobulin. Her creatine kinase only began to downtrend after discontinuation of both simvastatin and Genvoya, and she returned to baseline function at 2-month follow-up. Our case highlights the importance of recognizing drug–drug interactions between HIV and statin medications in causing significant noninflammatory myopathy. In these patients, both categories of medications need to be discontinued for recovery.
Nitrofurantoin and Minocycline–Associated Vasculitic Neuropathy: Case Reports and Literature Review
Authors: Aladawi Mohammad , Shelly Shahar , Dyck P. James B. , Koster Matthew , Engelstad JaNean , Piccione Ezequiel A. , Naddaf Elie
Published: November 2022

Background:

Vasculitic neuropathies usually present acutely to subacutely, with an asymmetric pattern, involving multiple peripheral nerve territories. Drug-induced vasculitis is an often overlooked etiology of vasculitic neuropathy.

Methods:

We present the first reported case of nitrofurantoin-associated and an illustrative case of minocycline-associated vasculitic neuropathy, with a review of the literature.

Results:

The first patient is a 60-year-old woman who developed axonal sensorimotor peripheral neuropathy after nitrofurantoin use, with a superficial radial nerve biopsy confirming vasculitis. The second patient is a 23-year-old woman, with a history of acne vulgaris treated with minocycline, who presented with a subacute right common peroneal mononeuropathy followed by a left deep peroneal mononeuropathy, with elevated antinuclear, perinuclear-antineutrophil cytoplasmic, and myleoperoxidase antibodies, and MPO titers, and a sural nerve biopsy showing large arteriole vasculitis. Finally, we provide a comprehensive review of previously published cases.

Conclusions:

Medications should be considered as a trigger for medication-induced vasculitic neuropathy. Accurate diagnosis would ensure timely treatment.
A world of choices: preference elicitation methods for improving the delivery and uptake of HIV prevention and treatment
Authors: Kerkhoff Andrew D. , Muiruri Charles , Geng Elvin H. , Hickey Matthew D.
Published: November 2022

Purpose of review

Despite the growing availability of effective HIV prevention and treatment interventions, there are large gaps in their uptake and sustained use across settings. It is crucial to elicit and apply patients’ and stakeholders’ preferences to maximize the impact of existing and future interventions. This review summarizes quantitative preference elicitation methods (PEM) and how they can be applied to improve the delivery and uptake of HIV prevention and treatment interventions.

Recent findings

PEM are increasingly applied in HIV implementation research; however, discrete choice experiments (DCEs) have predominated. Beyond DCEs, there are other underutilized PEM that may improve the reach and effectiveness of HIV prevention and treatment interventions among individuals by prioritizing their barriers to engagement and determining which attributes of interventions and delivery strategies are most valued. PEM can also enhance the adoption and sustained implementation of strategies to deliver HIV prevention and treatment interventions by assessing which attributes are the most acceptable and appropriate to key stakeholders.

Greater attention to and incorporation of patient's and stakeholders’ preferences for HIV prevention and treatment interventions and their delivery has the potential to increase the number of persons accessing and retained in HIV prevention and treatment services.
Plasma alkaline phosphatase is associated with mortality risk in patients with aortic valve stenosis
Authors: Nunes José Pedro L.
Published: November 2022

Background: Aortic valve stenosis is an important clinical condition, with a significant mortality rate in the elderly. Plasma values of alkaline phosphatase (ALP) have been shown to act as a marker of prognosis in different clinical conditions and in the general population.

Methods: Plasma levels of ALP were studied in a cohort of patients with aortic valve stenosis, and a 5-year survival evaluation was performed.

Results: Twenty-four patients were under study, of whom 12 were dead at the 5-year follow-up. The median age at baseline evaluation was 79 years (interquartile range, 72–85 years), and 11 patients were female (13 were male). The median value of ALP, of 83 IU/L, was used to separate patients into two groups: 2 patients who died in the group with low ALP values versus 10 patients who died in the group with high ALP values. Using ALP with the same cutoff level, the Kaplan–Meier study with log-rank analysis showed a significance level <0.01. Cox regression analysis showed an overall significant result, with a significant level for plasma ALP (significance level 0.03), but not for age, sex, or transvalvular gradient (assessed by echocardiography).

Conclusions: Elevated plasma ALP is associated with increased mortality risk in patients with aortic valve stenosis. This finding may merit evaluation in studies with a larger number of patients.
Evaluation of the quality of life and associated factors of a group of children and adolescents with cystic fibrosis in the northern region of Portugal: a cross-sectional pilot study
Authors: Pita Olívia , Teixeira Beatriz , Dias Cláudia Camila , Almeida Paulo , Azevedo Inês , e Silva Diana
Published: November 2022

Introduction:

Children/adolescents with cystic fibrosis (CF) have psychological and physical difficulties that have a severe impact on their health-related quality of life (HRQoL).

Aim:

To evaluate the impact of CF on HRQoL in a pediatric age sample by identifying major determinants and comparing the HRQoL reports of children and their parents.

Methods:

A sample of 27 children/adolescents was included in a cross-sectional observational study. Inclusion criteria were age between 4 and 18 years, diagnosis of CF, and the attendance of a caregiver in patients younger than 14 years. A questionnaire was applied to assess sociodemographic data and nutritional status. HRQoL was evaluated using the Portuguese revised version of the CF questionnaire (CFQ-R). Spearman correlations were calculated to analyze the agreement between children's and parents' reports. Spearman correlations and Mann–Whitney U tests were performed to identify associations between HRQoL domains and determinants.

Results:

The scores of CFQ-R domains were high, with the lowest median value being 66.67. It was found positive moderate associations between children's and parents' reports in 3 domains (P < .05): eating disturbances, body image, and respiratory symptoms. The median scores were similar in the eating disturbances (approximately 80.00) and in the respiratory symptoms (83.33). However, there is a consistent difference of 14.07 in the body image domain. Current age, physical activity, and iron were positively associated with HRQoL, whereas age at diagnosis was negatively associated.

Conclusion:

These findings reinforce the importance to evaluate HRQoL during childhood and adolescence and to invest in this public health theme.
Physician Assistants’ Training and Self-Perceived Competencies to Work with Survivors of Intimate Partner Violence
Authors: Smith Noël E. , Thompson Katherine M. , McCall Timothy C.
Published: November 2022

Introduction

The purpose of this research was to assess physician assistant (PA) education and training on the diagnosis, management, and treatment of survivors of intimate partner violence (IPV), as well as perceived current vs. desired skills in tasks related to the management and treatment of IPV.

Methods

Participants in 2 studies included a convenience sample of attendees at an annual PA conference (study 1) and PAs in the United States who were randomly selected to be administered an online survey related to their PA practice (study 2).

Results

In 2 studies, PAs reported low perceived competence to treat and manage patients who are survivors of IPV. More than half of the respondents (51.2%) had received training to work with survivors of IPV. Almost 3 in 5 indicated that they felt adequately prepared, and almost 3 in 10 regularly asked patients about IPV. Gaps between current and desired perceived skills to treat and manage survivors of IPV were larger among PAs who had previous training related to IPV compared with PAs with no prior training.

Discussion

Guidance for PA educators may improve PA education and increase competencies among new PAs. Without more substantial guidance from an accrediting body, PA programs are left responsible for implementing IPV curriculum. Professional associations as well as constituent and specialty organizations that provide continuing medical education have an equally important role in strengthening skills and abilities among PAs.
An Examination of Predictors of Attrition in Physician Assistant Programs
Authors: Quincy Brenda , Snyder Jennifer , Brown Darwin
Published: November 2022

Introduction

The purpose of this study was to explore the relationship between program characteristics and attrition rates.

Methods

Program graduation rates, attrition rates, and Physician Assistant National Certifying Examination (PANCE) pass rates were extracted from program websites from February-March 2021 and summarized for 2018, 2019, and 2020. Means were compared across categories of independent variables. Attrition rates and PANCE pass rates were correlated. Prerequisites and attrition rate were evaluated with multiple regression.

Results

Mean attrition rates varied little across years. Significant differences in mean attrition were limited to a few US Census Bureau regions or divisions. No significant correlation between the total number of prerequisite courses or total prerequisite credits and attrition existed. In 2020, mean attrition rate was statistically significantly greater when biochemistry was required (M = 6.89, SD = 7.04) than when not required (M = 4.91, SD = 4.75) and was statistically significantly lower when an additional chemistry course was required (M = 3.65, SD = 4.00) than when not required (M = 5.93, SD = 5.82). No significant predictors of attrition were found with regression.

Discussion

The mean attrition rates have been relatively stable from 2018–2020, suggesting that the presence of prerequisite coursework has no significant impact on attrition rates. This suggests that specific prerequisites may not predict success in a program, supporting the idea of decreasing or eliminating prerequisites. Additional studies are needed to understand the factors, including specific combinations of prerequisites, that predict completion of a physician assistant program.
A Qualitative Evaluation of Medical Students' Perspectives Regarding Collaboration with Physician Assistants
Authors: Shachar Ben , Rubin Serena , Kazevman Gill , Leung Fok-Han
Published: November 2022

Introduction

Physician assistant (PA) is a burgeoning profession in Canada, with several accredited training programs. Because the scope of practice for PAs in Ontario, as delineated by the province, stipulates that all tasks they perform must be delegated by a supervising physician, it is expected that medical students will increasingly encounter and work alongside PAs in clinical environments. There has been a paucity of research to date investigating how medical students experience this professional relationship. This current study aimed to investigate the attitudes and perspectives that medical students have about working with PAs.

Methods

Medical students from the University of Toronto (n = 11) in various stages of training participated in 3 focus groups. The focus groups used a semi-structured interview guide to explore medical students’ general opinions of the profession, their understanding of the interprofessional relationship, and their experiences working with PAs. Qualitative methods with a phenomenological underpinning were used to analyze the focus groups.

Results

The findings show that medical students have observed or collaborated with PAs in clinical environments but are generally unaware of the profession’s scope of practice and responsibilities. Medical students also viewed PAs as beneficial to patient care and expressed a desire to discover more about the profession through formal education.

Discussion

This call for interprofessional education should be heeded by medical faculty to better prepare medical students for future collaboration with PAs.
Pediatric Testicular Cavernous Hemangioma With Acute Onset Mimicking Testicular Torsion: Case Report and Review of the Literature
Authors: Escolino Maria , Cerulo Mariapina , Insabato Luigi , Puccio Francesca , Borgogni Rachele , Chiodi Annalisa , Lepore Benedetta , Califano Gianluigi , Esposito Ciro
Published: November 2022

Testicular cavernous hemangioma is a rare benign vascular tumor that typically occurs in childhood and adolescence. The clinical presentation may be variable and lead to diagnostic difficulties. We report an atypical presentation of intratesticular cavernous hemangioma with acute onset mimicking testicular torsion in a teenager. Inadvertent minor scrotal injury may have probably triggered the rupture of the hemangioma, leading to hemorrhage and infarction of the testicle. Although ultrasonography findings and serum tumor markers may be helpful in differential diagnosis, surgical exploration, and pathology examination are essential for definitive diagnosis.
American Organization for Nursing Leadership Nurse Leader Core Competencies
Authors: Hughes Ronda , Meadows M.T. , Begley Robyn
Published: November 2022

Leadership competencies represent the knowledge, skills, and abilities associated with effective leadership. This fall, the American Organization for Nursing Leadership published its core nursing leadership competencies that are intended to be measurable and translatable across the care continuum and throughout all levels of nursing leadership. In this column, the authors discuss these updated competencies and the relevance to practice, academia, and industry.
Partnering With Patients
Authors: Hoke Linda M. , Zekany Rachel T.
Published: November 2022

A fall prevention agreement was developed in a cardiac progressive care unit to engage patients and families on admission as partners in fall prevention. The postimplementation of the fall prevention agreement showed significant decreases in falls on this unit.
Factors Influencing Nurse Intent to Leave Acute Care Hospitals
Authors: Skillman Debi , Toms Robin
Published: November 2022

Professional nurses are leaving their current positions in acute care hospitals and, in some cases, the profession in greater numbers than ever. Nurse leaders must understand factors surrounding nurses' intent to leave to develop strategies to mitigate this phenomenon and retain nurses. This review of the literature seeks to synthesize studies on nurses' intent to leave. Themes include job satisfaction, resources and staffing impacting workloads, leadership, and burnout.
Beyond a Clinical Ladder
Authors: Tucci Roseann , McClain Brittany , Peyton Lauren
Published: November 2022

Nurses at this Magnet®-recognized, National Cancer Institute–designated comprehensive cancer center restructured an existing clinical ladder program based on Benner's model and implemented an evidence-based progressive career development program for staff nurses. The revised program defines structured performance expectations and requirements for promotion and role maintenance, which encourage individual engagement and accountability. This article describes the creation and implementation of the clinical advancement program as well as outcomes of the 1st 10 years of the program.
PEARL
Authors: Kapu April
Published: November 2022

This column highlights 5 key categories in which nurse practitioners continually strive for excellence: practice, education, advocacy, research, and leadership, also known as “PEARL.”
Intraindividual Tumor Heterogeneity of Mismatch Repair Status in Metastatic Colorectal Cancer
Authors: Huang Qianpeng , Yu Tao , Li Lei , Zhang Qi , Zhang Shiyao , Li Baosong , Li Xiaoping , Xiao Wanyi , Liu Gang
Published: November 2022

Heterogeneous mismatch repair (MMR) status in metastatic colorectal cancer (mCRC) may associate with refractoriness to immunotherapy. We aimed here to study the concordance in MMR status between primary and paired metastasis in mCRC. Our study included 84 patients diagnosed with mCRC with primary and matched metastatic cancers. Immunohistochemistry was used to determine the MMR status of primary lesions and matched metastases. Pooled analysis of 913 cases was used to evaluate the prevalence and organ specificity of MMR status heterogeneity. The correlations between MMR pattern heterogeneity and clinical outcomes were analyzed. MMR status heterogeneity between primary and corresponding metastatic sites was exhibited by 10 (11.9%) patients. The prevalence of the heterogeneous MMR phenotype was significantly higher in primary tumors with deficient MMR (dMMR) than with proficient MMR (pMMR), which was verified in the pooled analysis (P<0.001). Among patients with a dMMR primary tumor, the discrepancy was detected in liver, lung, ovary, peritoneum, and distant lymph node metastases. However, the discrepancy was confined to liver (26/440) or peritoneum (7/112) (P=0.02) in patients with a pMMR primary tumor. Patients with or without MMR status heterogeneity experienced comparable overall survival (P=0.452). Heterogeneous MMR patterns generally existed in a subset of patients with mCRC, particularly those with dMMR primary tumors. Testing the metastatic site may be valuable because the discordance of MMR status may potentially affect immune surveillance and immunotherapy.
Primary cleft rhinoplasty: A systematic review of results, growth restriction, and avoiding secondary rhinoplasty
Authors: Zelko Ian , Zielinski Eric , Santiago Chiara N , Alkureishi Lee WT , Purnell Chad A
Published: November 2022

Background:

Primary rhinoplasty (PR) during correction of unilateral cleft lip continues to be a topic of debate due to concerns that early nasal intervention affects nasal and maxillary development long-term. This study aims to determine the volume and quality of evidence for and against primary unilateral cleft rhinoplasty.

Methods:

A systematic review was performed adhering to the PRISMA Guidelines. Articles were pulled from PubMed and EMBASE and screened by title and abstract. Studies with human subjects undergoing rhinoplasty at the time of unilateral cleft lip repair and some evaluation of the nasal outcome were included. Studies with a large proportion of syndromic patients, case reports, editorials, letters, reviews, studies exclusive to bilateral clefts, and studies not available in English were excluded. Those that met criteria were then systematically reviewed.

Results:

Twenty-five articles were included. Ten articles that assessed the results of PR subjectively all supported cleft lip repair with PR. Sixteen articles assessed the results of PR objectively, with fifteen supporting PR during cleft lip repair. Eight of nine studies that evaluated nasal growth and development over time found no restriction in nasal development. Five studies with a follow-up period of at least six years found the percentage of patients that avoided revision rhinoplasty ranged from 43% to 100%. There were significant risks of bias in a majority of studies.

Conclusion:

The vast majority studies reviewed support that primary rhinoplasty during unilateral cleft lip repair results in good outcomes with limited or no effect on nasal growth.
Peripheral visual field loss and activities of daily living
Authors: Okrent Smolar Avital Lily , Gagrani Meghal , Ghate Deepta
Published: November 2022

Purpose of review

Peripheral visual field (VF) loss affects 13% of the population over 65. Its effect on activities of daily living and higher order visual processing is as important as it is inadequately understood. The purpose of this review is to summarize available literature on the impact of peripheral vision loss on driving, reading, face recognition, scene recognition and scene navigation.

Recent findings

In this review, glaucoma and retrochiasmal cortical damage are utilized as examples of peripheral field loss which typically spare central vision and have patterns respecting the horizontal and vertical meridians, respectively. In both glaucoma and retrochiasmal damage, peripheral field loss causes driving difficulty – especially with lane maintenance – leading to driving cessation, loss of independence, and depression. Likewise, peripheral field loss can lead to slower reading speeds and decreased enjoyment from reading, and anxiety. In glaucoma and retrochiasmal field loss, face processing is impaired which impacts social functioning. Finally, scene recognition and navigation are also adversely affected, impacting wayfinding and hazard detection leading to decreased independence as well as more frequent injury.

Peripheral VF loss is an under-recognized cause of patient distress and disability. All peripheral field loss is not the same, differential patterns of loss affect parameters of activities of daily living (ADL) and visual processing in particular ways. Future research should aim to further characterize patterns of deranged ADL and visual processing, their correlation with types of field loss, and associated mechanisms.
Strain development of A/H1N1pdm09 candidate vaccine viruses for the 2021–22 northern hemisphere influenza season
Authors: Dempsey Rachael , Ritter Lydia , Parker Lauren
Published: November 2022

The vaccine effectiveness (VE) of the A/H1N1pdm09 component of the 2017–18 quadrivalent live attenuated influenza vaccine (QLAIV) was improved by performing rational haemagglutinin (HA) mutagenesis. Introducing N125D, D127E, D222G and R223Q substitutions into the HA protein of A/Slovenia/2903/2015 (A/SLOV15) enhanced replicative fitness in primary human nasal epithelial cells (hNECs). This allowed A/SLOV15 to overcome inter-strain competition in QLAIV, resulting in improved VE.

During strain development for the 2021–22 QLAIV formulation, A/H1N1pdm09 LAIV viruses containing wild-type (WT) HA and neuraminidase (NA) sequences were found to replicate poorly in embryonated eggs and hNECs. We aimed to enhance replicative fitness via the HA mutagenesis approach that was performed previously for A/SLOV15. Therefore, combinations of these four mutations were introduced into the HA protein of representative 6B.1A-5a.2 viruses, A/Victoria/2570/2019 and A/Victoria/1/2020 (A/VIC1). Replicative fitness of A/VIC1 V7 was improved ~30-fold in eggs and ~300-fold in hNECs relative to its parent, without compromising other critical LAIV characteristics.
Kinetic model derivation for design, building and operation of solid waste treatment unit based on system dynamics and computer simulation
Authors: Hu Dawei , Li Shuaishuai , Liu Xiaolei , Liu Hong , Liu Guanghui
Published: November 2022

Solid waste disposal is significantly important to maintain normal operation of both natural and artificial ecosystems. In this study, a kinetic model of solid waste treatment unit (SWTU) was upfront developed based on microbial ecology, system dynamics, cybernetics and digital simulation, which accurately described the relationships and interactions between solid waste decomposition (SWD) processes and biotic/abiotic factors. Then a specific SWTU prototype was designed and built from this kinetic model. A 370-day experiment demonstrated that SWTU maintained normal operation with robust stability and desired dynamic behaviors, and effectively disposed the solid waste. Therefore, this kinetic model was highly valid due to its high structural and behavioral similarity with the prototype. This research could lay a strong theoretical foundation for further closed-loop control and optimization of SWTU, and provide scientific guidance to environmental management and sustainable development.
Computational structure prediction methods enable the systematic identification of oncogenic mutations
Authors: Fu Xi , Reglero Clara , Swamy Vinay , Loh Jui Wan , Khiabanian Hossein , Albero Robert , Forouhar Farhad , AlQuraishi Mohammed , Ferrando Adolfo A. , Rabadan Raul
Published: November 2022

Oncogenic mutations are associated with the activation of key pathways necessary for the initiation, progression and treatment-evasion of tumors. While large genomic studies provide the opportunity of identifying these mutations, the vast majority of variants have unclear functional roles presenting a challenge for the use of genomic studies in the clinical/therapeutic setting. Recent developments in predicting protein structures enable the systematic large-scale characterization of structures providing a link from genomic data to functional impact. Here, we observed that most oncogenic mutations tend to occur in protein regions that undergo conformation changes in the presence of the activating mutation or when interacting with a protein partner. By combining evolutionary information and protein structure prediction, we introduce the Evolutionary and Structure (ES) score, a computational approach that enables the systematic identification of hotspot somatic mutations in cancer. The predicted sites tend to occur in Short Linear Motifs and protein-protein interfaces. We test the use of ES-scores in genomic studies in pediatric leukemias that easily recapitulates the main mechanisms of resistance to targeted and chemotherapy drugs. To experimentally test the functional role of the predictions, we performed saturated mutagenesis in NT5C2, a protein commonly mutated in relapsed pediatric lymphocytic leukemias. The approach was able to capture both commonly mutated sites and identify previously uncharacterized functionally relevant regions that are not frequently mutated in these cancers. This work shows that the characterization of protein structures provides a link between large genomic studies, with mostly variants of unknown significance, to functional systematic characterization, prioritizing variants of interest in the therapeutic setting and informing on their possible mechanisms of action.
Protected area planning to conserve biodiversity in an uncertain future
Authors: Schuster Richard , Buxton Rachel , Hanson Jeffrey O. , Binley Allison D. , Pittman Jeremy , Tulloch Vivitskaia , La Sorte Frank A. , Roehrdanz Patrick R. , Verburg Peter H. , Rodewald Amanda D. , Wilson Scott , Possingham Hugh P. , Bennett Joseph R.
Published: November 2022

Protected areas are a key instrument for conservation. Despite this, they are vulnerable to risks associated with weak governance, land use intensification, and climate change. Using a novel hierarchical optimization approach, we identified priority areas for expanding the global protected area system to explicitly account for such risks whilst maximizing protection of all known terrestrial vertebrate species. We illustrate how reducing exposure to these risks requires expanding the area of the global protected area system by 1.6% while still meeting conservation targets. Incorporating risks from weak governance drove the greatest changes in spatial priorities for protection, while incorporating risks from climate change required the largest increase in global protected area. Conserving wide-ranging species required countries with relatively strong governance to protect more land when bordering nations with comparatively weak governance. Our results underscore the need for cross-jurisdictional coordination and demonstrate how risk can be efficiently incorporated into conservation planning.

Article Impact Statement

Accounting for governance, land use and climate risks will result in more resilient and effective conservation effort for biodiversity.
A novel method revealing animal evolutionary relationships based on milk Mid-infrared
Authors: Fan Yikai , Han Jiazheng , Wang Haitong , Nan Liangkang , Luo Xuelu , Chu Chu , Wang Liang , Liu Li , Li Yongqing , Li Chunfang , Ren Xiaoli , Ding Lei , Liu Wenju , Hao Xingjie , Chen Yansen , Liu George E. , Zhou Yang , Zhang Shujun
Published: November 2022

Mid-infrared spectra (MIRS) can effectively reflect the chemical bonds in milk, which has been widely used in dairy herd improvement. However, the relationship between MIRS and animal evolution remains largely unclear. This study firstly found great differences in MIRS and the components of milk by analyzing MIRS information of 12 different mammal species. A five-level discriminant model of evolutionary level based on MIRS was established with a test set kappa coefficient >0.97. In addition, a regression model of genetic distance was also established to estimate the genetic distance of different animal species with a correlation coefficient of R >0.94. These results showed that this method could be used for accurate mammalian evolutionary relationship assessment. We further clarified the potential relationship between MIRS and genes, such as PPP3CA and SCD that could change MIRS by regulating specific milk components. In conclusion, we expand the application of MIRS in animal species identification and evolution research and provide new perspectives for the research on the formation mechanism of different animal milk special components.
CAGEE: computational analysis of gene expression evolution
Authors: Bertram Jason , Fulton Ben , Tourigny Jason P , Pena-Garcia Yadira , Moyle Leonie C , Hahn Matthew W.
Published: November 2022

Despite the increasing abundance of whole transcriptome data, few methods are available to analyze global gene expression across phylogenies. Here, we present a new software package (CAGEE) for inferring patterns of increases and decreases in gene expression across a phylogenetic tree, as well as the rate at which these changes occur. In contrast to previous methods that treat each gene independently, CAGEE can calculate genome-wide rates of gene expression, along with ancestral states for each gene. The statistical approach developed here makes it possible to infer lineage-specific shifts in rates of evolution across the genome, in addition to possible differences in rates among multiple tissues sampled from the same species. We demonstrate the accuracy and robustness of our method on simulated data, and apply it to a dataset of ovule gene expression collected from multiple self-compatible and self-incompatible species in the genus Solanum to test hypotheses about the evolutionary forces acting during mating system shifts. These comparisons allow us to highlight the power of CAGEE, demonstrating its utility for use in any empirical system and for the analysis of most morphological traits. Our software is available at https://github.com/hahnlab/CAGEE/.
Evolution, Expansion and Characterization of Cannabinoid Synthase Gene Family inCannabis Sativa
Authors: Allen Keith D , Torres Anthony , De Cesare Kymron , Gaudino Reginald
Published: November 2022

We are working toward a complete functional and genomic characterization of the cannabinoid synthase family inCannabis(itself part of the larger Berberine Bridge Enzyme family). This clade, which is unique toCannabis, includes four main subclades that appear to have arisen by a series of gene duplications. We have functionally characterized three cannabinoid synthases, in addition to the three already characterized, so that now all four subclades contain at least one characterized enzyme. The previously uncharacterized Clade C enzymes have relatively low activity and produce CBCA as their primary product. In addition, we report genomic characterization to better understand the structure and high level of copy number variation in this family. We report a pattern of shared regions immediately upstream of the cannabinoid synthase genes that suggests a specific sequence of breakpoints, and hence gene duplication events. We present a model of gene family expansion to account for the observed data, along with evidence that this expansion occurred under selective pressure. This work adds to our understanding of both the high level of variability in this family and the origin of THCA in type III plants lacking a functional THCAS gene.
Characterisation and automated quantification of induced seizure-related behaviours inXenopus laevistadpoles
Authors: Panthi Sandesh , Chapman Phoebe A. , Szyszka Paul , Beck Caroline W.
Published: November 2022

Epilepsy, a clinical diagnosis characterized by paroxysmal episodes known as seizures, affects 1% of people worldwide. Safe and patient-specific treatment is vital and can be achieved by the development of rapid pre-clinical models of for identified epilepsy genes. Epilepsy can result from either brain injury or gene mutations, and can also be induced chemically.Xenopus laevistadpoles could be a useful model for confirmation of variants of unknown significance found in epilepsy patients, and for drug re-purposing screens that could eventually lead to benefits for patients. Here, we characterise and quantify seizure-related behaviours inX. laevistadpoles arrayed in 24-well plates. To provoke acute seizure behaviours, tadpoles were chemically induced with either pentylenetetrazole (PTZ) or 4-aminopyridine (4-AP). To test the capacity to adapt this method for drug testing, we also exposed induced tadpoles to the anti-seizure drug valproate (VPA). Four induced seizure-like behaviours were described and manually quantified, and two of these (darting, circling) could be accurately detected automatically, using the video analysis software TopScan. Additionally, we recorded swimming trajectories and mean swimming velocity. Automatic detection showed that either PTZ or 4-AP induced darting behaviour and increased mean swimming velocity compared to untreated controls. Both parameters were significantly reduced in the presence of VPA. In particular, darting behaviour was a shown to be a sensitive measure of epileptic seizure activity. While we could not automatically detect the full range of seizure behaviours, this method shows promise for future studies, sinceX. laevisis a well-characterised and genetically tractable model organism.
Serologic Responses to COVID-19 Vaccination in Children with History of Multisystem Inflammatory Syndrome (MIS-C)
Authors: Perez Maria A. , Hsiao Hui-Mien , Chen Xuemin , Kunkel Amber , Baida Nadine , Hussaini Laila , Lu Austin T. , Kao Carol M. , Laham Federico R. , Hunstad David A. , Beltran Yajira , Hammett Teresa A. , Godfred-Cato Shana , Chahroudi Ann , Anderson Evan J. , Belay Ermias , Rostad Christina A.
Published: November 2022

Understanding the serological responses to COVID-19 vaccination in children with history of MIS-C could inform vaccination recommendations. We prospectively enrolled five children hospitalized with MIS-C and measured SARS-CoV-2 binding IgG antibodies to spike protein variants longitudinally pre- and post-Pfizer-BioNTech BNT162b2 primary series COVID-19 vaccination. We found that SARS-CoV-2 variant cross-reactive IgG antibodies waned following acute MIS-C, but were significantly boosted with vaccination and maintained for at least 3 months. We then compared post-vaccination binding, pseudovirus neutralizing, and functional antibody-dependent cell-mediated cytotoxicity (ADCC) titers to the reference strain (Wuhan-hu-1) and Omicron variant (B.1.1.529) among previously healthy children (n=6) and children with history of MIS-C (n=5) or COVID-19 (n=5). Despite the breadth of binding antibodies elicited by vaccination in all three groups, pseudovirus neutralizing and ADCC titers were reduced to the Omicron variant. Vaccination after MIS-C or COVID-19 (hybrid immunity) conferred advantage in generating pseudovirus neutralizing and functional ADCC antibodies to Omicron.
Angle-dependence and auxin asymmetry: towards the formulation of a universal theory of root gravitropism
Authors: Sageman-Furnas K. , Del Bianco M. , Friml J. , Wolverton C. , Kepinski S.
Published: November 2022

Gravitropism has been conceptualized through three main theories: the starch-statolith model for sensing, the Cholodny-Went model of growth control via auxin asymmetry, and the law of angle-dependence for behavior, in which the magnitude of gravitropic response increases with displacement from the vertical. While experimental data show that the generation of both Cholodny-Went-type auxin gradients and angle-dependent behavior requires statolith sedimentation, a link between auxin asymmetry and angle-dependence has not been demonstrated. Here, we use large scale reorientation assays of Arabidopsis roots, epidermal length measurements, and confocal microscopy to quantify auxin distribution and PIN localization during graviresponse. We show angle-dependence in auxin asymmetry and growth response, even at low stimulation angles. As such, our work integrates the three theories sensing, signal transduction and behavior into a single unified model of gravitropism and provides an important framework for exploring major outstanding questions in the field.
A shared neural code for the physics of actions and object events
Authors: Akbiyik Seda , Caramazza Alfonso , Wurm Moritz
Published: November 2022

Observing others’ actions recruits frontoparietal and posterior temporal brain regions – also called the action observation network. It is typically assumed that these regions support recognizing actions of animate entities (e.g., person jumping over a box). However, objects can also participate in events with rich meaning and structure (e.g., ball bouncing over a box). So far, it has not been clarified which brain regions encode information specific to goal-directed actions or more general information that also defines object events. Here, we show a shared neural code for visually presented actions and object events throughout the action observation network. We argue that this neural representation captures the structure and physics of events regardless of animacy. We find that lateral occipitotemporal cortex encodes information about events that is also invariant to stimulus modality. Our results shed light onto the representational profiles of posterior temporal and frontoparietal cortices, and their roles in encoding event information.
Maresin 1 Repletion Improves Muscle Regeneration After Volumetric Muscle Loss
Authors: Castor-Macias Jesus A. , Larouche Jacqueline A. , Wallace Emily C. , Spence Bonnie D. , Eames Alec , Yang Benjamin A. , Davis Carol , Brooks Susan V. , Maddipati Krishna Rao , Markworth James F. , Aguilar Carlos A.
Published: November 2022

The acute traumatic or surgical loss of skeletal muscle, known as volumetric muscle loss (VML), is a devastating type of injury that results in exacerbated and persistent inflammation followed by fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied and as such, the development of regenerative therapies has been limited. To address this need, we profiled how lipid mediators, which are potent regulators of the immune response after injury, varied with VML injuries that heal or result in fibrosis. We observed that non-healing VML injuries displayed increased pro-inflammatory eicosanoids and a lack of pro-resolving lipid mediators. Treatment of VML with a pro-resolving lipid mediator synthesized from docosahexaenoic acid, called Maresin 1, ameliorated fibrosis through reduction of neutrophils and macrophages and improved myogenesis, leading to enhanced recovery of muscle strength. These results expand our knowledge of the dysregulated immune response that develops after VML and identify a novel immuno-regenerative therapeutic modality in Maresin 1.
GBMdeconvoluteR accurately infers proportions of neoplastic and immune cell populations from bulk glioblastoma transcriptomics data
Authors: Ajaib Shoaib , Lodha Disha , Pollock Steven , Hemmings Gemma , Finetti Martina A. , Gusnanto Arief , Chakrabarty Aruna , Ismail Azzam , Wilson Erica , Varn Frederick S , Hunter Bethany , Filby Andrew , Brockman Asa A. , McDonald David , Verhaak Roel GW , Ihrie Rebecca A. , Stead Lucy F.
Published: November 2022

The biological and clinical impact of neoplastic and immune cell type ratios in the glioblastoma (GBM) tumour microenvironment is being realised. Characterising and quantifying cell types within GBMs at scale will facilitate a better understanding of the association between the cellular landscape and tumour phenotypes or clinical correlates. This study aimed to develop a tool that can deconvolute immune and neoplastic cells within the GBM tumour microenvironment from bulk RNA sequencing data. We developed an IDH wild-type (IDHwt) GBM specific single immune cell reference dataset, from four independent studies, consisting of B cells, T cells, NK cells, microglia, tumour associated macrophages, monocytes, mast and DC cells. We used this alongside an existing neoplastic single cell-type dataset consisting of astrocyte-like, oligodendrocyte- and neuronal-progenitor like and mesenchymal GBM cancer cells to create both marker and gene signature matrix-based deconvolution tools. We then applied single-cell resolution imaging mass cytometry (IMC) to ten IDHwt GBM samples, five paired primary and recurrent tumours, in parallel with these tools to determine which performed best. Marker based gene expression deconvolution using GBM tissue specific markers, which we have packaged as GBMdeconvoluteR, gave the most accurate results. The correlation between immune cell quantification by IMC and by GBMdeconvoluteR for primary IDHwt GBM samples was 0.52 (Pearson’s P=7.8×10−3) and between neoplastic cell quantification by IMC and by GBMdeconvoluteR was 0.75 (Pearson’s P=1.2×10−3). We applied GBMdeconvoluteR to bulk GBM RNAseq data from The Cancer Genome Atlas (TCGA) and were able to recapitulate recent findings from multi-omics single cell studies with regards associations between mesenchymal GBM cancer cells and both lymphoid and myeloid cells. Furthermore, we were able to expand upon this to show that these associations are stronger in patients with worse prognosis. GBMdeconvoluteR is accessible online athttps://gbmdeconvoluter.leeds.ac.uk.

Key points

GBMdeconvoluteR is a glioblastoma-specific cellular deconvolution tool. When applied to bulk GBM RNAseq data, it accurately quantifies the neoplastic and immune cells in that tumour. It is available online athttps://gbmdeconvoluter.leeds.ac.uk
Evolution of the SARS-CoV-2 mutational spectrum
Authors: Bloom Jesse D , Beichman Annabel C , Neher Richard A , Harris Kelley
Published: November 2022

SARS-CoV-2 evolves rapidly in part because of its high mutation rate. Here we examine whether this mutational process itself has changed during viral evolution. To do this, we quantify the relative rates of different types of single nucleotide mutations at four-fold degenerate sites in the viral genome across millions of human SARS-CoV-2 sequences. We find clear shifts in the relative rates of several types of mutations during SARS-CoV-2 evolution. The most striking trend is a roughly two-fold decrease in the relative rate of G→T mutations in Omicron versus early clades, as was recently noted by Ruis et al (2022). There is also a decrease in the relative rate of C→T mutations in Delta, and other subtle changes in the mutation spectrum along the phylogeny. We speculate that these changes in the mutation spectrum could arise from viral mutations that affect genome replication, packaging, and antagonization of host innate-immune factors—although environmental factors could also play a role. Interestingly, the mutation spectrum of Omicron is more similar than that of earlier SARS-CoV-2 clades to the spectrum that shaped the long-term evolution of sarbecoviruses. Overall, our work shows that the mutation process is itself a dynamic variable during SARS-CoV-2 evolution, and suggests that human SARS-CoV-2 may be trending towards a mutation spectrum more similar to that of other animal sarbecoviruses.
TheRuminococcus bromiiamylosome protein Sas6 binds single and double helical α-glucan structures in starch
Authors: Photenhauer Amanda L. , Cerqueira Filipe M. , Villafuerte-Vega Rosendo , Armbruster Krista M. , Mareček Filip , Chen Tiantian , Wawrzak Zdzislaw , Hopkins Jesse B. , Vander Kooi Craig W. , Janeček Štefan , Ruotolo Brandon T. , Koropatkin Nicole M.
Published: November 2022

Resistant starch is a prebiotic with breakdown by gut bacteria requiring the action of specialized amylases and starch-binding proteins. The human gut symbiontRuminococcus bromiiexpresses granular starch-binding protein Sas6 (Starch Adherence System member 6) that consists of two starch-specific carbohydrate binding modules from family 26 (RbCBM26) and family 74 (RbCBM74). Here we present the crystal structures of Sas6 andRbCBM74 with a double helical dimer of maltodecaose bound along an extended surface groove. Binding data combined with native mass spectrometry suggest that RbCBM26 binds short maltooligosaccharides while RbCBM74 can bind single and double helical α-glucans. Our results support a model by which RbCBM74 and RbCBM26 bind neighboring α-glucan chains at the granule surface. CBM74s are conserved among starch granule-degrading bacteria and our work provides molecular insight into how this structure is accommodated by select gut species.