bluuebunny/crossref_metadata_2025 huggingface dataset:
Why Are Counterfactual Assessment Methods Not Widespread in Outcome-Based Contracts? A Formal Model Approach
Authors: Lazzarini Sergio G , Cabral Sandro , Firpo Sergio , Teodorovicz Thomaz
Published: December 2021

Counterfactual assessment techniques involving treated and control groups, such as randomized control trials, might be used in outcome-based contracts to avoid rewarding or sanctioning service providers for social outcomes that they did not cause. However, few outcome-based contracts adopt payment rules based on counterfactual assessment techniques. Potential explanations are that these techniques are complex and involve substantial transaction costs. In this paper, we develop a theoretical formal model that integrates the literatures of incentives and policy evaluation to propose the following alternative explanation: counterfactual techniques may lead to counterproductive incentive effects if they reduce the likelihood of payment even if project managers exert sufficient effort to promote the expected interventions. Our model shows that counterfactual assessment may undermine effort when the number of treated subjects is small and there is limited investment per treated subject. Our formal model also suggests that the increased experience of the contract sponsors may inhibit the adoption of counterfactual assessment. Simulations and descriptive evidence from a unique database of 350 outcome-based contracts designed or initiated throughout the world and from linear probability models are aligned with our predictions. By offering additional explanations on why counterfactual assessment methods are not widespread in outcome-based contracts and by identifying the boundary conditions under which these methods are used in incentive contracts, this work informs the literature on cross-sector outcome-based contracts and illustrates the use of formal models to develop novel theories in public administration.
Levels in Biological Organisms: Hierarchy of Production Mechanisms, Heterarchy of Control Mechanisms
Authors: Bechtel William
Published: December 2021

Among the notions of levels invoked in accounts of biological phenomena, I focus on two: levels of production mechanisms and levels of control mechanisms. I argue that these two notions of level exhibit different characteristics: production mechanisms are organized hierarchically while control mechanisms are often organized heterarchically. I illustrate the differences in these modes of organization by examining production and control mechanisms involved in cell division in Escherichia coli and in circulation of blood in mammals. I conclude by exploring how these two notions of levels can be integrated by adopting a perspective in which organisms are autonomous systems maintaining themselves far from equilibrium.
Interactions between species change the uptake of ammonium and nitrate inAbies faxonianaandPicea asperata
Authors: Hu Xuefeng , Li Wanting , Liu Qinghua , Yin Chunying
Published: December 2021

Plant nitrogen (N) uptake is affected by plant–plant interactions, but the mechanisms remain unknown. A 15N-labeled technique was used in a pot experiment to analyze the uptake rate of ammonium (NH4+) and nitrate (NO3−) by Abies faxoniana Rehd. et Wils and Picea asperata Mast. in single-plant mode, intraspecific and interspecific interactions. The results indicated that the effects of plant–plant interactions on N uptake rate depended on plant species and N forms. Picea asperata had a higher N uptake rate of both N forms than A. faxoniana, and both species preferred NO3−. Compared with single-plant mode, intraspecific interaction increased NH4+ uptake for A. faxoniana but reduced that for P. asperata, while it did not change NO3− uptake for the two species. The interspecific interaction enhanced N uptake of both N forms for A. faxoniana but did not affect the P. asperata compared with single-plant mode. NH4+ and NO3− uptake rates for the two species were regulated by root N concentration, root nitrate reductase activity, root vigor, soil pH and soil N availability under plant–plant interactions. Decreased NH4+ uptake rate for P. asperata under intraspecific interaction was induced by lower root N concentration and nitrate reductase activity. The positive effects of interspecific interaction on N uptake for A. faxoniana could be determined mainly by positive rhizosphere effects, such as high soil pH. From the perspective of root–soil interactions, our study provides insight into how plant–plant interactions affect N uptake, which can help to understand species coexistence and biodiversity maintenance in forest ecosystems.
2021: A Year of Hope and Heartbreak
Authors: Kennedy Maureen Shawn
Published: December 2021

Optimism that the pandemic would be over was short lived.
The Top News Stories of 2021: The Climate Crisis
Authors: McSpedon Corinne
Published: December 2021

2021 brought extreme weather and calls to address this global health threat.
Are Impaired Nurses Getting the Help They Need?
Authors: Fauteux Nicole
Published: December 2021

Alternative-to-discipline programs can facilitate a safe return to practice.
Long-Term Anticoagulant Therapy Increases Bleeding Risk in Patients with Unprovoked VTE
Authors: Rosenberg Karen
Published: December 2021

According to this study:

Patients who receive extended anticoagulant therapy after a first unprovoked or weakly provoked venous thromboembolism are at increased risk for major bleeding.
Just One More
Authors: Allen Danielle
Published: December 2021

A nurse gently sets the stage for an impossible goodbye.
Study of the Factors that Influence Low-Level Viremias in Human Immunodeficiency Virus Patients in a Tertiary Hospital
Authors: Pinilla Rello Andrea , Navarro Aznárez Herminia , Magallón Martínez Arantxa , Cazorla Poderoso Lucía , Pérez Moreno María , Martínez-Sapiña Ana , Abad Sazatornil María Reyes
Published: December 2021

Background

Low-level viremias (LLVs) can be associated with age, suboptimal adherence, antiretroviral therapy (ART), and local epidemiology. The objective of the study was to analyze the influence of adherence and ART on the LLVs of human immunodeficiency virus patients in a tertiary hospital.

Methods

A descriptive, multidisciplinary, observational, and retrospective study of human immunodeficiency virus–naive patients who started ART between 2013 and 2018, who have not undergone changes in their ART, and who have been on treatment for at least 1 year was conducted. The following are the variables of the study: age, sex, ART, treatment start date, degree of adherence, and existence of LLVs.

Results

The sample included 153 patients (83.7% men) with a median age of 40 years (12–82 years). Of the patients who started with a nonnucleotide analog reverse-transcriptase inhibitor as the third drug, 26.8% (n = 56) presented with LLVs, 62.5% (n = 16) with an enhanced protease inhibitor (PI), and 42.7% (n = 75) with an integrase inhibitor. Fifty-seven patients (37.3%) presented with LLVs, with 48 (84.2%) having high adherence (≥90%). Statistically significant differences were observed in the presence of LLVs in patients who started with nonnucleotide analog reverse-transcriptase inhibitor as the third drug (P = 0.025) and in those patients with PI as the third drug (P = 0.047). In patients with LLVs, statistically significant differences were observed in the adherence of patients with PI (P = 0.041).

Conclusions

A relationship was observed between low adherence, PI as the third drug, and LLVs. In patients with possible poor adherence to ART, a third drug with a high genetic barrier was used, but this did not prevent the presence of LLVs, making it necessary to use other strategies and closely monitor these patients.
Quantifying the Employer Burden of Persistent Musculoskeletal Pain at a Large Employer in the United Kingdom
Authors: Roomes David , Abraham Lucy , Russell Rachel , Beck Craig , Halsby Kate , Wood Robert , O’Brien Megan , Massey Lucy , Burton Kim
Published: December 2021

Objective:

To quantify the burden of work-relevant persistent musculoskeletal (MSK) pain to a large UK employer.

Methods:

A retrospective, longitudinal, analytical cohort study using linked Rolls-Royce data systems. Cases were employees with a MSK-related referral to occupational health; controls were age-, sex-, and job role-matched employees without such a referral. Outcomes were compared during 12 months’ follow-up.

Results:

Overall, 2382 matched case–control pairs were identified (mean age: 46 y; 82% male). Cases took 39,200 MSK-related sickness absence days in total (equating to £50 million in sickness absence costs). Cases took significantly more all-cause sickness absence days than controls (82,341 [£106 million] versus 19,628 [£26 million]; P < 0.0001).

Conclusions:

Despite access to extensive occupational health services, the burden of work-relevant persistent MSK pain remains high in Rolls-Royce. There is a clear need to better understand how to effectively reduce this burden.
Magnesium valproate adjuvant therapy on patients with dementia
Authors: Zhang Chen qi , Zheng ke xin , Sun Ling qi , Sun Hongbin
Published: December 2021

Background:

With the aging population, the prevalence and incidence of dementia disease will continue to rise, and the associated economic burden is increasing as well. However, the available anti-dementia therapeutic arsenal is limited. Meanwhile, magnesium valproate (VPM) as an adjuvant therapy had a general positive effect on the cognitive function and psychiatric symptoms of patient with dementia (PwD). At present, there is lack of meta-analysis focusing on cognitive improvement and disease-modifying about VPM-assisted therapy in the present peer-reviewed literature. Thus, we aimed to likely analyze the efficacy and safety of VPM adjuvant therapy of PwD.

Methods:

We will research MEDLINE via PubMed, Cochrane Library, EBSCO, Embase, China National Knowledge (CNKI) and Wan fang databases to gather relevant data on VPM assistant therapy on the PwD. Meta-analysis will be performed using Stata16.0 software.

Results:

We aim to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD.

Conclusion:

VPM maybe plays an active role in the treatment of dementia patients and this research will provide reliable evidence for clinicians in therapy of PwD.

INPLASY registration number:

INPLASY2021110038 (DOI: 10.37766/inplasy2021.11.0038).
Histopathologic discrepancies between endoscopic forceps biopsy and endoscopic resection specimens in nonampullary duodenal epithelial tumors
Authors: Kim Da Mi , Kim Gwang Ha , Lee Bong Eun , Kim Kyungbin , Choi Kyung Un , Hong Seung Min , Lee Moon Won , Song Geun Am
Published: December 2021

For patients with nonampullary duodenal epithelial tumors (NADETs), endoscopic forceps biopsy results that reflect the final histopathologic results of the entire lesion are indispensable for accurate diagnosis and appropriate treatment modality selection. This study aimed to investigate the histopathologic discrepancies between endoscopic forceps biopsy and endoscopic resection specimens in NADETs and to elucidate the factors contributing to such discrepancies.

This retrospective observational study included 105 patients (105 lesions) who underwent endoscopic resection for NADETs at the Pusan National University Hospital between May 2006 and October 2019. NADETs were classified as low-grade intraepithelial neoplasms (LGINs), high-grade intraepithelial neoplasms (HGINs), or adenocarcinomas. Following slide reviews, the histopathologic concordance between endoscopic forceps biopsy and endoscopic resection specimens was assessed for each case.

The histopathologic discrepancy rate between endoscopic forceps biopsy and endoscopic resection specimens was 19.0% (20/105 lesions). Among the 20 diagnostically discordant lesions, up- and downgrade of the histopathologic diagnosis occurred in 17 and 3 lesions, respectively. The predominant discrepancies involved upgrades from LGIN to HGIN (n = 14) and upgrades from LGIN to adenocarcinomas (n = 2). The 3 downgraded cases included 2 from LGIN to inflammation and 1 from HGIN to LGIN. In the multivariate analyses, the old age (>67 years) was the only factor significantly associated with histopathologic upgrade (odds ratio 4.553, 95% confidence interval 1.291–15.939; P = .018).

Considerable histopathologic discrepancies were observed between endoscopic forceps biopsy and endoscopic resection specimens in NADETs. Older age was significantly associated with these discrepancies.
Misplaced emphasis, misunderstood risk: a cultural history of Public Health Service infectious disease guidelines
Authors: Hendele James B. , Limaye Ajit P. , Sibulesky Lena
Published: December 2021

Purpose of review

To review and summarize the evolution of the Public Health Service (PHS) guidelines and Organ Procurement and Transplantation Network (OPTN) regulations for the prevention of blood borne virus transmission in solid organ transplant through the lens of popular culture, scientific evolution, patient and practitioner bias and outcomes research.

Recent findings

The most recent set of guidelines and regulations were released in 2020 and represent a culmination of decades of opinion, research and debate within the scientific and lay communities.

The guidelines were created to address public concern, and the risk of undiagnosed disease transmission in the context of the novel public health crisis of AIDS. We reviewed milestone publications from the scientific and lay press from the first description of AIDS in 1981 to the present to help illustrate the context in which the guidelines were created, the way they changed with subsequent editions, and offer critical consideration of issues with the current set of guidelines and a potential way forward. Further consideration should be given to the way in which the current guidelines identify donors with risk criteria for infectious disease transmission and mandate explanation of donor-specific risk factors to potential recipients, in our era of universal donor screening and recipient surveillance.
Comparison of Same and Different Level Height Falls on Subsequent Midline Shift in Pediatric Traumatic Brain Injury
Authors: Sullivan Brittany G. , Grigorian Areg , Lekawa Michael , Dolich Matthew O. , Schubl Sebastian D. , Barrios Cristobal , Joe Victor C. , Borazjani Boris , Nahmias Jeffry
Published: December 2021

Objectives

Up to 44% of pediatric traumatic brain injury occurs as a result of a fall. We hypothesized that a fall from height is associated with higher risk for subsequent midline shift in pediatric traumatic brain injury compared with a fall from same level.

Methods

The Pediatric Trauma Quality Improvement Program 2016 was queried for kids younger than 16 years with an injury in the abbreviated injury scale for the head after a fall. Patients with midline shift were identified. A logistic regression model was used for analysis.

Results

The risk of a midline shift was lower in those with a fall from a height (odds ratio, 0.64; 95% confidence interval, 0.46–0.91, P = 0.01). In kids older than 4 years, there was no association between the level of height of the fall and subsequent midline shift (P = 0.62). The risk for midline shift in kids younger than 4 years after a fall from same level was lower (odds ratio, 0.40; 95% confidence interval, 0.24–0.67; P = 0.001).

Conclusions

In kids with traumatic brain injury, trauma activations due to falls from the same level are associated with a 2.5-fold higher risk of subsequent midline shift, compared with falling from height.
Computed Tomography Scans in Children With Hemophilia After Minor Head Trauma
Authors: Gardner Alison , McLean Thomas W. , Winslow James E.
Published: December 2021

Objectives

Children with hemophilia have the usual childhood risk of falls and head trauma. Head computed tomographies (HCTs) are fast, detailed, and readily available, but increased radiation exposure in the pediatric population is now recognized as causing increased brain malignancy. By examining the incidence of intracranial cerebral hemorrhage in this population, we will be able to weigh risks and benefits of HCT use more accurately.

Methods

Using a retrospective chart review, we examined past medical records of pediatric patients, aged 0 to 15 years, with hemophilia presenting to 1 academic medical center. Primary outcomes included number of head CTs ordered, total and per patient over the years studied, and the incidence of positive findings, as defined by presence of blood products as documented by radiologist final read/interpretation.

Results

The mean number of head CTs per child was 2.5 (range, 1–10). None of the HCT scans were read as intracranial cerebral hemorrhage, and none of the patients had findings that lead to neurosurgical intervention. In a sensitivity analysis, applying Pediatric Emergency Care Applied Research Network head injury criteria, 11 HCT scans would be ordered for a reduction of 80 HCTs, or a decrease of 2 HCT scans per child. No incidence of intracranial cerebral hemorrhage would have been missed.

Conclusions

Our findings suggest that in the child with hemophilia and a history of minor head trauma, exposure to the radiation of a HCT based on the diagnosis of hemophilia alone may not be necessary but that imaging decisions need to be made in conjunction with clinical examination findings and neurologic status.
Emergency Department Utilization and Serious Bacterial Infection Rates in Children With Renal Transplants
Authors: King Jason , Kannikeswaran Nirupama , Jain Amrish , Farooqi Ahmad , Sethuraman Usha
Published: December 2021

Objectives

Emergency department (ED) visits by children with solid organ transplants have increased significantly. Our objectives were to describe the common complaints, diagnosis, types, and rates of serious bacterial infection (SBI) in children with renal transplant (RT) who present to the hospital.

Methods

We conducted a retrospective study from 2012 to 2016 of RT children up to 18 years who presented to the ED or were directly admitted. We excluded patients who presented for a procedure. We collected demographics, transplant type, immunosuppressive data, chief complaints, diagnostic testing with results, interventions performed, and final diagnosis.

Results

We analyzed 131 visits in 29 patients during the study period. Most common chief complaints were infectious (34.4%) and gastrointestinal (26%). Infection was proven in 42.0% of visits with only 3.1% being organ rejection. Serious bacterial infection was diagnosed in 34 visits (26.0%) with urinary tract infection (UTI) being the most common (20.6%). Of the 33 visits for fever, SBI occurred in 16 (48.5%) patients with the most common SBI being UTI 10 (30.3%). Bacteremia occurred in 1 patient and hypotension in 4 patients. Antibiotic administration was the most common intervention performed (78; 59.5%). Significant interventions were uncommon (2 patients). Logistic regression revealed no factors to be associated with SBI.

Conclusions

Our cohort of children with RT presented most commonly with infections to the hospital with UTI being the most common SBI. Bacteremia and significant interventions were rare. Future studies are needed to identify subgroups of low-risk pediatric RT patients who can possibly be safely discharged home from the ED.
An Insidious Cause of Abdominal Pain in a Preschooler Girl
Authors: Raffaldi Irene , Guidi Carla , Di Gianni Valeria Rita , Cosentino Valentina , Personnettaz Eraldo , Brach del Prever Adalberto
Published: December 2021

The ovarian torsion (OT) represents one of the most misleading and challenging diagnoses for the pediatrician. Symptoms are often nonspecific, including sudden, piercing localized lower abdominal pain and tenderness associated with a palpable mass and peritoneal signs. Although the adnexal torsion is most frequently unilateral, cases of bilateral synchronous or asynchronous have been recorded; in the latter, the OT involved both ovaries at different settings. We reported the case of a 6-year-old girl who presented an asynchronous bilateral OT.
The Toddler's Fracture
Authors: Wang Yiqiao , Doyle Meagan , Smit Kevin , Varshney Terry , Carsen Sasha
Published: December 2021

Objective

The tibial toddler's fracture is an important diagnosis in both emergency and urgent care, presenting as acute onset lower extremity pain or limping in a young child. Diagnosis and management may be challenging because of an extensive differential diagnosis. The objectives of this study were to provide an overview of the toddler's fracture and to guide clinicians by summarizing up to date literature for both diagnosis and management this common condition.

Methods

This study analyzed literature from the PubMed database from the years of 1964 to 2018. The main focus was on the diagnosis and management of the toddler's fracture.

Results

This review demonstrates that diagnosis is primarily made through history and physical examination, as radiographs are often negative at initial presentation. Treatment involves a short period of immobilization, which can be facilitated through the use of a cast, a splint, or no external support. Successful healing and a full return to normal activities and development are near universal.

Conclusions

Although a stable fracture with an excellent prognosis, opportunities exist to improve toddler's fractures diagnosis and treatment protocols, to optimize clinical management.
Comparison Between Physicians' and Nurse Practitioners' Resource Utilization in the Diagnosis and Management of Bronchiolitis in the Pediatric Emergency Department
Authors: Bouchibti Salma , Maul Timothy , Rivera-Sepulveda Andrea
Published: December 2021

Objective

This study aimed to describe the resource utilization of nurse practitioners (NPs) in the pediatric emergency department (ED) and compare among physicians.

Methods

A retrospective cross-sectional study of secondary data analysis in a level 1 academic pediatric trauma center was conducted. Patients were aged 1 to 24 months, evaluated in the ED between January 1, 2014, and November 30, 2018, with a diagnosis of bronchiolitis or wheezing. Data included age group, length of stay, disposition, diagnostic tests (chest radiography [CXR], viral testing, respiratory syncytial virus test), treatment (bronchodilator, corticosteroid, antibiotic), and medical provider (physician, NP, combination of both). Resources were evaluated before (early era) and after (late era) the implementation of an institutional clinical practice guideline.

Comparisons between groups were done through χ2, Fisher exact, or Kruskal-Wallis test, as appropriate.

Results

A total of 5311 cases were treated by a physician (65.3%), an NP (30.3%), or a combination of both (4.3%). The was a difference in the use of CXR, respiratory syncytial virus testing, bronchodilators, and corticosteroids among providers (P = 0.001). In the late era, NPs were less likely to order a bronchodilator (odds ratio [OR], 0.390 [95% confidence interval, 0.318–0.478; P < 0.001]), whereas physicians were less likely to order a CXR (OR, 0.772 [0.667–0.894, P = 0.001]), bronchodilator (OR, 0.518 [0.449–0.596, P < 0.001]), or a corticosteroid (OR, 0.630 [0.531–0.749, P < 0.001]).

Conclusions

Nurse practitioners made fewer diagnostic and therapeutic orders. A clinical practice guideline on the diagnosis and management of children with bronchiolitis successfully decreased the use of nonrecommended tests and therapies among NP and physicians.
Towards equitable diagnoses for autism and attention-deficit/hyperactivity disorder across sexes and genders
Authors: Lai Meng-Chuan , Lin Hsiang-Yuan , Ameis Stephanie H.
Published: December 2021

Purpose of review

Sex/gender-related factors contribute to contextual issues influencing the recognition of autism and attention-deficit/hyperactivity disorder (ADHD), and modulate how neurodevelopmental characteristics are manifested. This review summarizes the empirical literature to provide directions for improving clinical diagnostic practices.

Recent findings

Timing of autism and/or ADHD diagnosis, particularly in girls/women, is related to the individual's developmental characteristics and co-occurring diagnoses, and expectancy, alongside gender stereotype biases, of referral sources and clinicians. This is further compounded by sex and gender modulations of behavioural presentations. The emerging ’female autism phenotype’ concept may serve as a helpful illustration of nuanced autism phenotypes, but should not be viewed as essential features of autism in a particular sex or gender. These nuanced phenotypes that can present across sexes and genders include heightened attention to socially salient stimuli, friendship and social groups, richness in language expression, and more reciprocal behaviours. The nuanced female-predominant ADHD phenotypes are characterized by subtle expressions in hyperactivity-impulsivity (e.g., hyper-verbal behaviours). Optimizing neurodevelopmental diagnoses across sexes and genders also requires an understanding of sex-related and gender-related variations in developmental trajectories, including compensation/masking efforts, and the influences of co-occurring conditions on clinical presentations.

Equitable diagnoses across sexes and genders for autism and ADHD require understanding of the nuanced presentations and the Gestalt clinical-developmental profiles, and addressing contextual biases that influence diagnostic practices.
Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein
Authors: Boer Elke de , Ockeloen Charlotte W. , Kampen Rosalie A. , Hampstead Juliet E. , Dingemans Alexander J.M. , Rots Dmitrijs , Lütje Lukas , Ashraf Tazeen , Baker Rachel , Barat-Houari Mouna , Angle Brad , Chatron Nicolas ,   The DDD study, Denommé-Pichon Anne-Sophie , Devinsky Orrin , Dubourg Christèle , Elmslie Frances , Elloumi Houda Zghal , Faivre Laurence , Fitzgerald-Butt Sarah , Geneviève David , Goos Jacqueline A.C. , Helm Benjamin M. , van de Kamp Jiddeke M. , Kini Usha , Lasa-Aranzasti Amaia , Lesca Gaetan , Lynch Sally A. , Mathijssen Irene M.J. , McGowan Ruth , Monaghan Kristin G. , Odent Sylvie , Pfundt Rolph , Putoux Audrey , van Reeuwijk Jeroen , Santen Gijs W.E. , Sasaki Erina , Sivanathan Jesitha , Sorlin Arthur , van der Spek Peter J. , Stegmann Alexander P.A. , Swagemakers Sigrid M.A. , Valenzuela Irene , Viora-Dupont Eléonore , Vitobello Antonio , Ware Stephanie M. , Wéber Mathys , Gilissen Christian , Low Karen J. , Fisher Simon E. , Vissers Lisenka E.L.M. , Wong Maggie M.K. , Kleefstra Tjitske
Published: December 2021

Purpose

Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized the clinical, molecular and functional spectra of ANKRD11 missense variants.

Methods

We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants by in silico analyses and cell-based experiments.

Results

We identified 29 individuals with (mostly de novo) ANKRD11 missense variants, who presented with syndromic neurodevelopmental disorders and were phenotypically similar to individuals with KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in Repression Domain 2. Cellularly, most variants caused reduced ANKRD11 stability. One variant resulted in decreased proteasome degradation and loss of ANKRD11 transcriptional activity.

Conclusion

Our study indicates that pathogenic heterozygous missense variants in ANKRD11 cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges, as the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.
Paralog editing tunes rice stomatal density to maintain photosynthesis and improve drought tolerance
Authors: Karavolias Nicholas G. , Patel-Tupper Dhruv , Seong Kyungyong , Tjahjadi Michelle , Gueorguieva Gloria-Alexandra , Tanaka Jaclyn , Cruz Ana Gallegos , Liebermann Samantha , Litvak Lillian , Dahlbeck Douglas , Cho Myeong-Je , Niyogi Krishna K. , Staskawicz Brian J.
Published: December 2021

Rice (Oryza sativa) is of paramount importance for global nutrition, supplying at least 20% of global calories. However, water scarcity and increased drought severity are anticipated to reduce rice yields globally. Rice stomatal developmental genetics were explored as a mechanism to improve drought resilience while maintaining yield under climate stress. CRISPR/Cas9-mediated knockouts of EPFL10 and STOMAGEN yielded lines with c. 80% and 25% of wild-type stomatal density, respectively.epfl10lines with moderate reductions in stomatal densities are able to conserve water to similar extents asstomagenlines, but do not suffer from the concomitant reductions in stomatal conductance, carbon assimilation, or thermoregulation observed instomagenknockouts. Moderate reductions in stomatal densities achieved by editing EPFL10 may be a climate-adaptive approach in rice that can safeguard yield. Editing the paralog of STOMAGEN in other species may provide a means to tune stomatal density in agriculturally important crops beyond rice.
Hydrogen properties and charges in a sub-1.2 Å resolution cryo-EM structure revealed by a cold field emission beam
Authors: Maki-Yonekura Saori , Kawakami Keisuke , Hamaguchi Tasuku , Takaba Kiyofumi , Yonekura Koji
Published: December 2021

The cold field emission (CFE) beam produces the less-attenuated contrast transfer function of electron microscopy, thereby enhancing high-resolution signals and this particularly benefits higher-resolution single particle cryogenic electron microscopy. Here, we present a sub-1.2 Å resolution structure of a standard protein sample, apoferritin. Image data were collected with the CFE beam in a high-throughput scheme while minimizing beam tilt deviations from the coma-free axis. A difference map reveals positive densities for most hydrogen atoms in the core region of the protein complex including those in water molecules, while negative densities around acidic amino-acid side chains likely represent negative charges. The position of the hydrogen densities depends on parent bonded-atom type, which is validated by an estimated level of coordinate errors.
Epi-MEIF, a flexible and efficient method for detection of high order epistatic interactions from complex phenotypic traits
Authors: Saha Saswati , Perrin Laurent , Röder Laurence , Brun Christine , Spinelli Lionel
Published: December 2021

Understanding the relationship between genetic variations and variations in complex and quantitative phenotypes remains an ongoing challenge. While Genome-wide association studies (GWAS) have become a vital tool for identifying single-locus associations, we lack methods for identifying epistatic interactions. In this article, we propose a novel method for high-order epistasis detection using mixed effect conditional inference forest (epiMEIF). The epiMEIF model is fitted on a group of potential causal SNPs and the tree structure in the forest facilitates the identification of n-way interactions between the SNPs. Additional testing strategies further improve the robustness of the method. We demonstrate its ability to detect true n-way interactions via extensive simulations in both cross-sectional and longitudinal synthetic datasets. This is further illustrated in an application to reveal epistatic interactions from natural variations of cardiac traits in flies (Drosophila). Overall, the method provides a generalized way to identify high order interactions from any GWAS data, thereby greatly improving the detection of the genetic architecture of complex phenotypes.
Visual, delay and oculomotor timing and tuning in macaque dorsal pulvinar during instructed and free choice memory saccades
Authors: Schneider Lukas , Dominguez-Vargas Adan-Ulises , Gibson Lydia , Wilke Melanie , Kagan Igor
Published: December 2021

Causal perturbations suggest that the primate dorsal pulvinar (dPul) plays a crucial role in target selection and saccade planning, but its basic visuomotor neuronal properties are unclear. While some functional aspects of dPul and interconnected frontoparietal areas – e.g. ipsilesional choice bias after inactivation – are similar, it is unknown if dPul shares oculomotor properties of the cortical circuitry, in particular the delay and choice-related activity. We investigated such properties in macaque dPul during instructed and free-choice memory saccades. Most recorded units showed visual (16%), visuomotor (29%) or motor-related (35%) responses. Visual responses were mainly contralateral; motor-related responses were predominantly post-saccadic (64%) and showed weak contralateral bias. Pre-saccadic enhancement was infrequent (9-15%) – instead, activity was often suppressed during saccade planning (30%) and execution (19%). Surprisingly, only few units exhibited classical visuomotor patterns combining cue and continuous delay activity until the saccade or pre-saccadic ramping, and most spatially-selective neurons did not encode the upcoming decision during free-choice delay. Thus, in absence of a visible goal, the dorsal pulvinar has a limited role in prospective saccade planning, with patterns partially complementing its frontoparietal partners. Conversely, prevalent cue and post-saccadic responses imply the participation in integrating spatial goals with processing across saccades.
Immune escape of SARS-CoV-2 Omicron variant from mRNA vaccination-elicited RBD-specific memory B cells
Authors: Sokal Aurélien , Broketa Matteo , Meola Annalisa , Barba-Spaeth Giovanna , Fernández Ignacio , Fourati Slim , Azzaoui Imane , de La Selle Andrea , Vandenberghe Alexis , Roeser Anais , Bouvier-Alias Magali , Crickx Etienne , Languille Laetitia , Michel Marc , Godeau Bertrand , Gallien Sébastien , Melica Giovanna , Nguyen Yann , Zarrouk Virginie , Canoui-Poitrine Florence , Noizat-Pirenne France , Megret Jérôme , Pawlotsky Jean-Michel , Fillatreau Simon , Simon-Lorière Etienne , Weill Jean-Claude , Reynaud Claude-Agnès , Rey Félix A. , Bruhns Pierre , Chappert Pascal , Mahévas Matthieu
Published: December 2021

Memory B cells (MBCs) represent a second layer of immune protection against SARS-CoV-2. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant is of major concern. We used bio-layer interferometry to assess the affinity against the receptor-binding-domain (RBD) of Omicron spike of 313 naturally expressed monoclonal IgG that were previously tested for affinity and neutralization against VOC prior to Omicron. We report here that Omicron evades recognition from a larger fraction of these antibodies than any of the previous VOCs. Additionally, whereas 30% of these antibodies retained high affinity against Omicron-RBD, our analysis suggest that Omicron specifically evades antibodies displaying potent neutralizing activity against the D614G and Beta variant viruses. Further studies are warranted to understand the consequences of a lower memory B cell potency on the overall protection associated with current vaccines.
Antagonism of Saxitoxin and Tetrodotoxin Block by Internal Monovalent Cations in Squid Axon
Authors: Oxford Gerry S. , Forscher Paul , Wagoner P. Kay , Adams David J.
Published: December 2021

The block of voltage-dependent sodium channels by saxitoxin (STX) and tetrodotoxin (TTX) was investigated in voltage-clamped squid giant axons internally perfused with a variety of permeant monovalent cations. Substitution of internal Na+by either NH4+or N2H5+resulted in a reduction of outward current through sodium channels under control conditions. In contrast, anomalous increases in both inward and outward currents were seen for the same ions if some of the channels were blocked by STX or TTX, suggesting a relief of block by these internal cations. External NH4+was without effect on the apparent magnitude of toxin block. Likewise, internal inorganic monovalent cations were without effect, suggesting that proton donation by NH4+might be involved in reducing toxin block. Consistent with this hypothesis, decreases in internal pH mimicked internal perfusion with NH4+in reducing toxin block. The interaction between internally applied protons and externally applied toxin molecules appears to be competitive, as transient increases in sodium channel current were observed during step increases in intracellular pH in the presence of a fixed STX concentration. In addition to these effects on toxin block, low internal pH produced a voltage-dependent block of sodium channels and enhanced steady-state inactivation. Elevation of external buffer capacity only marginally diminished the modulation of STX block by internal NH4+, suggesting that alkalinization of the periaxonal space and a resultant decrease in the cationic STX concentration during NH4+perfusion may play only a minor role in the effect. These observations indicate that internal monovalent cations can exert trans-channel influences on external toxin binding sites on sodium channels.
The origins of placental mesenchymal stromal cells: Full spectrum flow cytometry reveals mesenchymal heterogeneity in first trimester placentae, and phenotypic convergence in culture
Authors: Boss A.L. , Damani T. , Chamley L.W. , James J.L. , Brooks A.E.S.
Published: December 2021

Single-cell technologies (RNA-sequencing, flow cytometry) are critical tools to reveal how cell heterogeneity impacts developmental pathways. The placenta is a fetal exchange organ, containing a heterogeneous mix of mesenchymal cells (fibroblasts, myofibroblasts, perivascular, and progenitor cells). Placental mesenchymal stromal cells (pMSC) are also routinely isolated, for therapeutic and research purposes. However, our understanding of the diverse phenotypes of placental mesenchymal lineages, and their relationships remain unclear. We designed a 23-colour flow cytometry panel to assess mesenchymal heterogeneity in first-trimester human placentae.. Four distinct mesenchymal subsets were identified; CD73+CD90+mesenchymal cells, CD146+CD271+perivascular cells, podoplanin+CD36+stromal cells, and CD26+CD90+myofibroblasts. CD73+CD90+and podoplanin+CD36+ cells expressed markers consistent with cultured pMSCs, and were explored further. Despite their distinct ex-vivo phenotype, in culture CD73+CD90+cells and podoplanin+CD36+cells underwent phenotypic convergence, losing CD271 or CD36 expression respectively, and homogenously exhibiting a basic MSC phenotype (CD73+CD90+CD31-CD144-CD45-). However, some markers (CD26, CD146) were not impacted, or differentially impacted by culture in different populations. Comparisons of cultured phenotypes to pMSCs further suggested cultured pMSCs originate from podoplanin+CD36+cells. This highlights the importance of detailed cell phenotyping to optimise therapeutic capacity, and ensure use of relevant cells in functional assays.
Accumulation of TERT in Mitochondria Shows Two Opposing Effects on Apoptosis
Authors: Ebata Hiroshi , Shima Tomohiro , Iizuka Ryo , Uemura Sotaro
Published: December 2021

Telomerase reverse transcriptase (TERT) is a protein that catalyzes the reverse transcription of telomere elongation. TERT is also expected to play a noncanonical role beyond telomere lengthening since it localizes not only in the nucleus but also in mitochondria, where telomeres do not exist. Several studies have reported that mitochondrial TERT regulates apoptosis induced by oxidative stress. However, there remains controversy about whether mitochondrial TERT promotes or inhibits apoptosis, mainly due to the lack of information on changes in the TERT distribution in individual cells over time. Here we simultaneously detected apoptosis and TERT localization after oxidative stress in individual HeLa cells by live-cell tracking. This tracking revealed that the stress-induced accumulation of TERT in mitochondria caused apoptosis but that the accumulation positively correlated with the time until cell death. The results suggest a new model in which mitochondrial TERT has two opposing effects at different stages of apoptosis: it predetermines apoptosis at the first stage of cell-fate determination but also delays apoptosis at the second stage. Because these distinct effects respectively support both sides of the controversy regarding the role of mitochondrial TERT in apoptosis, our model integrates two opposing hypotheses. Furthermore, detailed statistical analysis of TERT mutations, which have been predicted to inhibit TERT transport to mitochondria, revealed that these mutations suppress apoptosis independent of the mitochondrial localization of TERT. Together, these results indicate that the non-canonical functions of TERT affect a wide range of pathways.
Construction of a potent pan-vaccine based on the evolutionary tendency of SARS-CoV-2 spike protein
Authors: Zhao Yongliang , Ni Wenjia , Liang Simeng , Dong Lianghui , Xiang Min , Cai Zeng , Niu Danping , Zhang Qiuhan , Wang Dehe , Zheng Yucheng , Zhang Zhen , Zhou Dan , Guo Wenhua , Pan Yongbing , Wu Xiaoli , Yang Yimin , Jing Zhaofei , Jiang Yongzhong ,   SARS-CoV-2 Vaccine Task Force Group, Chen Yu , Yan Huan , Zhou Yu , Xu Ke , Lan Ke
Published: December 2021

SARS-CoV-2 continued to spread globally along with different variants. Here, we systemically analyzed viral infectivity and immune-resistance of SARS-CoV-2 variants to explore the underlying rationale of viral mutagenesis. We found that the Beta variant harbors both high infectivity and strong immune resistance, while the Delta variant is the most infectious with only a mild immune-escape ability. Remarkably, the Omicron variant is even more immune-resistant than the Beta variant, but its infectivity increases only in Vero E6 cells implying a probable preference for the endocytic pathway. A comprehensive analysis revealed that SARS-CoV-2 spike protein evolved into distinct evolutionary paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance, resulting in a narrow spectrum of the current single-strain vaccine. In light of these findings and the phylogenetic analysis of 2674 SARS-CoV-2 S-protein sequences, we generated a consensus antigen (S6) taking the most frequent mutations as a pan-vaccine against heterogeneous variants. As compared to the ancestry SWT vaccine with significantly declined neutralizations to emerging variants, the S6 vaccine elicits broadly neutralizing antibodies and full protections to a wide range of variants. Our work highlights the importance and feasibility of a universal vaccine strategy to fight against antigen drift of SARS-CoV-2.
Scars of hope and forewarn of a bleak future: Post-mortem findings of dugongs (Dugong dugon) belonging to a relict population in the Gulf of Kachchh, India
Authors: Pathan Sameeha , Pande Anant , Johnson J.A. , Sivakumar Kuppusamy
Published: December 2021

A relict dugong population resides in the Gulf of Kachchh in Gujarat state of India. Very little is known on this population stemming from lack of focused studies and inadequate examinations of previous strandings. In this study, crucial ecological information is gathered through a systematic necropsy on stranded dugongs in the gulf. As indicated through dorsal tusk-rake scars on both the carcasses, this study presents first records of derivative physical evidence to the presence of a socially interacting population. Progressive healing and differences in width of the scars indicated more than two individuals had participated in a sexual agnostic or courtship event. Conversely, our findings report that both the animals suffered relative effects of asphyxiation after fishing net entanglement. An implication of a prior pathological condition(s) in the form of dermal cysts, swollen mesenteric lymph nodes, and endoparasites are also reported. Stomach content was examined for a qualitative dietary characterization. Other potential threats along with fishing net microfilaments found in the stomach contents of both dugongs are discussed in brief.
Molecular and morphological analyses support recognition ofProstanthera volucris(Lamiaceae), a new species from the Central Tablelands of New South Wales
Authors: O’Donnell Ryan P. , Bruhl Jeremy J. , Telford Ian R.H. , Wilson Trevor C. , Zimmer Heidi C. , Taseski Guy M. , Andrew Rose L.
Published: December 2021

Research into the systematics ofProstantherahas recently revealed a close evolutionary relationship amongP. phylicifolia s. str., the critically endangeredP. gilesii, and a population of uncertain identity from the Central Tablelands of New South Wales, Australia. Previous analyses were unable to establish whether genetic boundaries separated these taxa. This study aimed to assess the species boundaries among these three taxa using a combination of single-nucleotide polymorphisms (SNP) sampled at the population-scale and multivariate analysis of morphological characters. Non-parametric and parametric statistics, neighbour-network analysis, phylogenetic analysis, and ancestry coefficient estimates all provided support for discrete genetic differences between the three taxa. Morphological phenetic analysis identified a suite of characters that distinguished each of these taxa. This corroboration of evidence supports the presence of three independently evolving lineages.Prostanthera gilesiiandP. phylicifolia s. str.are distinct species independent from the third taxon which is described here asP. volucrisR.P.O’Donnell. A detailed description, diagnostic line drawings and photographs are provided. We evaluateP. volucrisas satisfying criteria to be considered Critically Endangered.
Single spikes drive sequential propagation and routing of activity in a cortical network
Authors: Riquelme Juan Luis , Hemberger Mike , Laurent Gilles , Gjorgjieva Julijana
Published: December 2021

Single spikes can trigger repeatable firing sequences in cortical networks. The mechanisms that support reliable propagation of activity from such small events and their functional consequences remain unclear. By constraining a recurrent network model with experimental statistics from turtle cortex, we generate reliable and temporally precise sequences from single spike triggers. We find that rare strong connections support sequence propagation, while dense weak connections modulate propagation reliability. We identify sections of sequences corresponding to divergent branches of strongly connected neurons which can be selectively gated. Applying eternal inputs to specific neurons in the sparse backbone of strong connections can effectively control propagation and route activity within the network. Finally, we demonstrate that concurrent sequences interact reliably, generating a highly combinatorial space of sequence activations. Our results reveal the impact of individual spikes in cortical circuits, detailing how repeatable sequences of activity can be triggered, sustained, and controlled during cortical computations.