bluuebunny/crossref_metadata_2025 huggingface dataset:
TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly
Authors: Jacquemin Valerie , Antoine Mathieu , Duerinckx Sarah , Massart Annick , Desir Julie , Perazzolo Camille , Cassart Marie , Thomas Dominique , Segers Valérie , Lecomte Sophie , Abramowicz Marc , Pirson Isabelle
Published: November 2020

Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype.
A Legal Black Hole in the Cosmos of Virtue—The Politics of Human Rights Critique Against the World Bank
Authors: Van Den Meerssche Dimitri
Published: November 2020

The World Bank is often portrayed by human rights scholars as a ‘legal black hole’ where the workings of international law have been suspended. In a recognizable routine of human rights activism, consistent attempts are therefore made to throw out the normative net of international law over this institutional domain. A familiar response by the institution is the assertion of its autonomous international legal status and constitutional limitations. Rather than reaffirming a specific position in this deadlocked doctrinal debate, this article enquires into the performative effects of this jousting routine between human rights activists and the World Bank. The account points to the potentially problematic political effects indirectly and unwillingly engendered by repeated enactments of these deeply engrained juridical juxtapositions. This analysis provides an innovative, relational understanding of international law with analytical value beyond the scope of this particular debate.
Congenital diaphragmatic hernia repair in patients requiring extracorporeal membrane oxygenation: are outcomes better with repair on ECMO or after decannulation?
Authors: Low Zhao Kai , Tan Amelia Su May , Nakao Masakazu , Yap Kok Hooi
Published: November 2020

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether congenital diaphragmatic hernia repair outcomes are better before or after decannulation in infants requiring extracorporeal membrane oxygenation (ECMO). A total of 884 papers were found using the reported search, of which 9 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that infants with congenital diaphragmatic hernia requiring ECMO should undergo a trial of weaning and aim for post-decannulation repair, as this has been associated with improved survival, shorter ECMO duration and fewer bleeding complications. However, if weaning of ECMO is unsuccessful, the patient should ideally undergo early on-ECMO repair (within 72 h of cannulation), which has been associated with improved survival, less bleeding, shorter ECMO duration and fewer circuit changes compared to late on-ECMO repair. Anticoagulation protocols including perioperative administration of aminocaproic acid or tranexamic acid, as well as close perioperative monitoring of coagulation parameters have been associated with reduced bleeding risk with on-ECMO repairs.
Evolution from mitral annular dysfunction to severe mitral regurgitation in Barlow’s disease
Authors: Hiemstra Yasmine L , Tomsic Anton , Gripari Paola , van Wijngaarden Aniek L , van der Pas Stéphanie L , Palmen Meindert , Klautz Robert J M , Pepi Mauro , Bax Jeroen J , Delgado Victoria , Marsan Nina Ajmone
Published: November 2020

OBJECTIVES

Barlow’s disease (BD) is characterized by thick, redundant mitral valve (MV) leaflets, which can lead to prolapse and significant mitral regurgitation (MR). MV annular abnormalities are also commonly observed and increasingly recognized as possible primary pathology, with leaflet thickening being secondary to increased stress on the MV apparatus. To provide more insights into this hypothesis, the evolution of MV abnormalities over time in patients with BD was assessed.

METHODS

A total of 64 patients (54 ± 12 years, 72% male) with BD who underwent MV surgery and had multiple transthoracic echocardiograms (TTE) before surgery were included. In total, 186 TTE were analysed (median time interval 4.2, interquartile range 2.2–6.5 years) including specific MV characteristics.

RESULTS

At baseline, MV leaflet length, thickness, billowing height and annular diameter were larger in patients with BD compared to 59 healthy subjects. Systolic outward motion (curling) of the annulus was observed in 77% and severe mitral annular disjunction (≥5 mm) in 38% of patients with BD. Forty (63%) patients had MR grade I–II and 24 (37%) MR grade III–IV; at baseline, the 2 groups only differed in left atrial volume and in thickness and billowing height of the posterior leaflet, showing comparable MV annular abnormalities and dilatation despite different grades of MR. Over time, MV annulus diameter, leaflet length and billowing height increased significantly along with MR grade.

CONCLUSIONS

In patients with BD, MV annulus abnormalities are present at an early stage and precede the development of significant MR, suggesting their substantial role in the pathophysiology of this disease and as an important target for surgical treatment.
Algorithmic prediction of failure modes in healthcare
Authors: Kobo-Greenhut Ayala , Sharlin Ortal , Adler Yael , Peer Nitza , Eisenberg Vered H , Barbi Merav , Levy Talia , Shlomo Izhar Ben , Eyal Zimlichman
Published: November 2020

Background

Preventing medical errors is crucial, especially during crises like the COVID-19 pandemic. Failure Modes and Effects Analysis (FMEA) is the most widely used prospective hazard analysis in healthcare. FMEA relies on brainstorming by multi-disciplinary teams to identify hazards. This approach has two major weaknesses: significant time and human resource investments, and lack of complete and error-free results.

Objectives

To introduce the algorithmic prediction of failure modes in healthcare (APFMH) and to examine whether APFMH is leaner in resource allocation in comparison to the traditional FMEA and whether it ensures the complete identification of hazards.

Methods

The patient identification during imaging process at the emergency department of Sheba Medical Center was analyzed by FMEA and APFMH, independently and separately. We compared between the hazards predicted by APFMH method and the hazards predicted by FMEA method; the total participants’ working hours invested in each process and the adverse events, categorized as ‘patient identification’, before and after the recommendations resulted from the above processes were implemented.

Results

APFMH is more effective in identifying hazards (P < 0.0001) and is leaner in resources than the traditional FMEA: the former used 21 h whereas the latter required 63 h. Following the implementation of the recommendations, the adverse events decreased by 44% annually (P = 0.0026). Most adverse events were preventable, had all recommendations been fully implemented.

Conclusion

In light of our initial and limited-size study, APFMH is more effective in identifying hazards (P < 0.0001) and is leaner in resources than the traditional FMEA. APFMH is suggested as an alternative to FMEA since it is leaner in time and human resources, ensures more complete hazard identification and is especially valuable during crisis time, when new protocols are often adopted, such as in the current days of the COVID-19 pandemic.
The emergence of azithromycin-resistant Salmonella Typhi in Nepal
Authors: Duy Pham Thanh , Dongol Sabina , Giri Abhishek , Nguyen To Nguyen Thi , Dan Thanh Ho Ngoc , Nhu Quynh Nguyen Pham , Duc Trung Pham , Thwaites Guy E , Basnyat Buddha , Baker Stephen , Rabaa Maia A , Karkey Abhilasha
Published: November 2020

Background

Typhoid fever remains a significant cause of morbidity and mortality in Asia and Africa. The emergence of azithromycin resistance in South Asia is concerning, as azithromycin is one of the last effective oral drugs for treating typhoid.

Objectives

To describe the molecular mechanism and phylogenetics of azithromycin-resistant (AzithR) Salmonella Typhi isolates from Patan Hospital, Kathmandu, Nepal.

Methods

Whole-genome sequences of three AzithR  S. Typhi isolates (MIC >256 mg/L) were analysed and compared with a global collection to investigate the azithromycin resistance mechanism and phylogenetic structure. Clinical information is reported for one of the three patients infected with AzithR  S. Typhi.

Results

The three AzithR isolates belonged to the H58 lineage and were genetically identical; they were distantly related to contemporaneous S. Typhi from Nepal and AzithR  S. Typhi recently described in Bangladesh. Azithromycin resistance was mediated by a non-synonymous mutation in the acrB gene (R717L). The three AzithR isolates showed reduced susceptibility to ciprofloxacin (double mutation in the gyrA: S83F and D87G), and were susceptible to ampicillin, chloramphenicol and co-trimoxazole. Clinical information from one patient suggested non-response to azithromycin treatment.

Conclusions

This is the first molecular description of AzithR  S. Typhi in Nepal. These organisms showed no phylogenetic link to AzithR  S. Typhi in Bangladesh. Our data suggest that increasing use of azithromycin may pose a strong selective pressure driving the emergence of AzithR  S. Typhi in South Asia. Further investigations are needed to evaluate treatment responses to azithromycin, predict evolutionary trajectories, and track the transmission of these organisms.
The volume effect in cartel cases—a special challenge for damage quantification?
Authors: Weber Franziska
Published: November 2020

Cartel damage occurs in many different shapes. Actors that are beyond doubt heavily affected by a cartel agreement are the purchasers of the cartel—the direct same as the indirect ones. Economic insights teach us that they do not only suffer damage in the form of the overcharge they paid or of shares of this overcharge that are passed-on to lower levels in the supply chain, but also in the form of the volume effect: a price increase as induced by a cartel agreement leads to a reduction in quantities sold, the consequence of which is typically lost profit—ie the volume effect. Whereas this effect is firmly established in economics, on the legal side it is so far discussed only on a superficial level with legal practice lacking behind in its recognition altogether. This is particularly surprising in the German and Spanish legal order where the highest courts many years ago did recognize the relevance of this damage component in pass-on situations. This article thoroughly analyses the economic and legal perspectives in respect of volume effects.
Ensuring full participation of people with disabilities in an era of telehealth
Authors: Valdez Rupa S , Rogers Courtney C , Claypool Henry , Trieshmann Lucy , Frye Olivia , Wellbeloved-Stone Claire , Kushalnagar Poorna
Published: November 2020

The widespread use of telehealth resulting from the COVID-19 pandemic has the potential to further exacerbate inequities faced by people with disabilities. Although, for some members of the disability community, the option to engage with telehealth may result in reduced barriers to care, for others, inadequate attention to the design, implementation, and policy dimensions may be detrimental. Addressing such considerations is imperative to mitigate health inequities faced by the disability community.
Long-run analysis of regional inequalities in the US
Authors: Logan Trevon , Hardy Bradley , Parman John
Published: November 2020

We consider the regional differences in economic development across the United States, which have been a unique feature of American economic history. The paths of both convergence and divergence by region have been driven by a complex mix of differences in resource endowments, demographic differences, international and internal migration patterns, and variation in the scope and impact of government policies at the local, state, and federal level. We show that the development of a national and fully integrated economy have accelerated and decelerated over time, and these features are driven by unique sets of historical circumstances and policy choices.
Regional growth and inequality in the long-run: Europe, 1900–2015
Authors: Rosés Joan R , Wolf Nikolaus
Published: November 2020

In this paper we discuss regional income growth and inequality based on a new set of long-run data. The data cover 173 European regions in 16 countries, from 1900 to 2015. These data allow us to compare regions over time, among each other, and to other parts of the world. After some brief notes on methodology, we describe the basic patterns in the data in terms of some key dimensions: variation in the density of population and economic activity, structural change with a declining role of agriculture, the rise and fall of industry, and the long rise of services. We show how ‘fundamentals’ of institutions and geography affected income levels over the twentieth century, and describe how regional growth after 1945 turned from convergence and adjustment to shocks to divergence. In the long run we observe a U-shaped pattern of regional convergence followed by divergence, not unlike recent observations on personal income and wealth distributions.
Increased risk of rheumatoid arthritis among patients with endometriosis: a nationwide population-based cohort study
Authors: Xue Yu-Hao , You Liang-Tian , Ting Hsin-Fu , Chen Yu-Wen , Sheng Zi-Yun , Xie Yi-Dong , Wang Yu-Hsun , Chiou Jeng-Yuan , Wei James Cheng-Chung
Published: November 2020

Objectives

Autoimmunity may play a role in endometriosis. The association between endometriosis and RA remains unknown. This study was conducted to identify any evidence for this relationship.

Methods

This 13-year, nationwide, population-based, retrospective cohort study analysed the risk of RA in a cohort of individuals with endometriosis. We investigated the incidence of RA among patients with endometriosis using data from the Longitudinal Health Insurance Database 2000, which is maintained by the Taiwan National Health Research Institutes. We used propensity scores to match comorbidities in the two cohorts. Kaplan–Meier analysis and Cox proportional hazard model were employed to analyse the association between endometriosis and RA among patients with different potential risks.

Results

Patients with endometriosis [adjusted hazard ratio (HR) 1.75, 95% CI 1.27, 2.41], aged ≥45 years (adjusted HR 1.50, 95% CI 1.06–2.13) and with autoimmune disease (adjusted HR 6.99, 95% CI 2.84–17.21) had a significantly higher risk of RA. The analyses also showed that when stratified by age, comorbidities and medication use, the risk of RA in patients with endometriosis was also higher than in those without endometriosis.

Conclusions

This 14-year, nationwide, population-based retrospective cohort study revealed that patients with endometriosis have a higher risk of RA. In the clinical management of patients with RA, rheumatologists should be especially mindful of the possibility of underlying endometriosis.
Collision of Solid Pseudopapillary Tumor and Neuroendocrine Tumor of the Pancreas on 18F-FDG PET/CT
Authors: Yin Hongyan , Lv Jing , Chen Lingli , Xiu Yan , Shi Hongcheng
Published: November 2020

We report a rare case of pancreatic collision tumor of solid pseudopapillary tumor and neuroendocrine tumor in a 43-year-old woman. A pancreatic mass was found by abdominal ultrasound. A mainly cystic mass with solid component progressive enhancement was revealed using abdominal enhanced CT. Staging 18F-FDG PET/CT demonstrated a pancreatic tail mass with an increased uneven 18F-FDG uptake. Distal pancreatectomy was performed. Postoperatively, the mass was diagnosed as pancreatic collision tumor of solid pseudopapillary tumor and neuroendocrine tumor.
Calcified Adrenal Metastasis of High-Grade Osteosarcoma on FDG PET/CT
Authors: Filizoglu Nuh , Engur Ceren Ozge , Turkoz Huseyin Kemal , Ones Tunc , Erdil Tanju Yusuf
Published: November 2020

Classic type of high-grade osteosarcoma is the most common type of skeletal malignancy in children and adolescents. Metastasis of osteosarcoma frequently occurs in the lung. Adrenal metastasis of osteosarcoma is extremely rare, with only few reported case in the literature. Herein, we present the case of a 13-year-old boy with adrenal metastasis of high-grade osteosarcoma, which was seen as a solitary calcified hypermetabolic adrenal lesion on FDG PET/CT.
Sinus Tarsi Syndrome on Bone Scintigraphy With SPECT/CT
Authors: Martineau Patrick , Pelletier-Galarneau Matthieu
Published: November 2020

Sinus tarsi syndrome is a common cause of hindfoot pain in adults; however, diagnosis on planar bone scintigraphy can be challenging. We present 3 cases of sinus tarsi syndrome, review the spectrum of imaging findings associated with sinus tarsi syndrome, and show the key role that SPECT/CT can play in its diagnosis.
Brain Connectomics and Severity of Internalizing Symptoms in Early Adolescence Predict Severity of Suicidal Ideation in Later Adolescence
Authors: Kirshenbaum Jaclyn S. , Chahal Rajpreet , Ho Tiffany C. , King Lucy S. , Gifuni Anthony J. , Mastrovito Dana , Coury Saché M. , Weisenburger Rachel L. , Gotlib Ian H.
Published: November 2020

Background

Suicidal ideation (SI) typically emerges during adolescence but is challenging to predict. Given the consequences of SI, it is important to identify neurobiological and psychological predictors of SI in adolescents in order to improve strategies to prevent suicide.

Methods

In 109 participants (61 female), we assessed psychological characteristics and obtained resting-state fMRI data in early adolescence (ages 9-13). Using graph theoretical methods, we assessed local network properties across 250 brain regions by computing measures of nodal interconnectedness: local efficiency, eigenvector centrality, nodal degree, within-module z-score, and participation coefficient. Four years later (ages 13-17), participants self-reported their SI severity. We used LASSO regression to identify a linear combination of the most important psychological, environmental, and brain-based predictors of future SI severity.

Results

The LASSO analysis identified a combination of 10 predictors of future SI severity (R2=0.23). Severity of internalizing symptoms at baseline was the strongest predictor; the remaining 9 predictors were brain-based, including nodal degree of the inferior frontal gyrus, precentral gyrus, fusiform gyrus, and inferior temporal gyrus; within-module degree of the substantia nigra and inferior parietal lobe; eigenvector centrality of the subgenual cingulate gyrus; participation coefficient of the caudal cingulate gyrus and medial amygdala.

Conclusions

Our findings suggest that combining network properties and earlier internalizing symptoms may improve prediction of later SI, compared to prior symptoms and other sociodemographic variables alone. Research should validate the clinical utility of these markers as predictors of suicidal thoughts.
Altered cerebellar white matter in sensory processing dysfunction is associated with impaired multisensory integration and attention
Authors: Narayan Anisha , Rowe Mikaela A. , Palacios Eva M. , Wren-Jarvis Jamie , Bourla Ioanna , Gerdes Molly , Brandes-Aitken Annie , Desai Shivani , Marco Elysa J. , Mukherjee Pratik
Published: November 2020

Sensory processing dysfunction (SPD) is characterized by a behaviorally observed difference in the response to sensory information from the environment. While the cerebellum is involved in normal sensory processing, it has not yet been examined in SPD. Diffusion tensor imaging scans of children with SPD (n=42) and typically developing controls (TDC; n=39) were compared for fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) across the following cerebellar tracts: the middle cerebellar peduncles (MCP), superior cerebellar peduncles (SCP), and cerebral peduncles (CP). Compared to TDC, children with SPD show reduced microstructural integrity of the SCP and MCP, which correlates with abnormal auditory behavior, multisensory integration, and attention, but not tactile behavior or direct measures of auditory discrimination. In contradistinction, decreased CP microstructural integrity in SPD correlates with abnormal tactile and auditory behavior and direct measures of auditory discrimination, but not multisensory integration or attention. Hence, altered cerebellar white matter organization is associated with complex sensory behavior and attention in SPD, which prompts further consideration of diagnostic measures and treatments to better serve affected individuals.
COVID-19 COGNITIVE DEFICITS AFTER RESPIRATORY ASSISTANCE IN THE SUBACUTE PHASE: A COVID-REHABILITATION UNIT EXPERIENCE
Authors: Alemanno Federica , Houdayer Elise , Parma Anna , Spina Alfio , Forno Alessandra Del , Scatolini Alessandra , Angelone Sara , Brugliera Luigia , Tettamanti Andrea , Beretta Luigi , Iannaccone Sandro
Published: November 2020

Introduction

COVID-19 complications can include neurological, psychiatric, psychological, and psychosocial impairments. Little is known on the consequences of SARS-COV-2 on cognitive functions of patients in the sub-acute phase of the disease. We aimed to investigate the impact of COVID-19 on cognitive functions of patients admitted to the COVID-19 Rehabilitation Unit of the San Raffaele Hospital (Milan, Italy).

Material and Methods

87 patients admitted to the COVID-19 Rehabilitation Unit from March 27th to June 20th 2020 were included. Patients underwent Mini Mental State Evaluation (MMSE), Montreal Cognitive Assessment (MoCA), Hamilton Rating Scale for Depression, and Functional Independence Measure (FIM). Data were divided in 4 groups according to the respiratory assistance in the acute phase: Group1 (orotracheal intubation), Group2 (non-invasive ventilation using Biphasic Positive Airway Pressure), Group3 (Venturi Masks), Group4 (no oxygen therapy). Follow-ups were performed at one month after home-discharge.

Results

Out of the 87 patients (62 Male, mean age 67.23 ± 12.89 years), 80% had neuropsychological deficits (MoCA and MMSE) and 40% showed mild-to-moderate depression. Group1 had higher scores than Group3 for visuospatial/executive functions (p=0.016), naming (p=0.024), short- and long-term memory (p=0.010, p=0.005), abstraction (p=0.024), and orientation (p=0.034). Group1 was younger than Groups2 and 3. Cognitive impairments correlated with patients’ age. Only 18 patients presented with anosmia. Their data did not differ from the other patients. FIM (<100) did not differ between groups. Patients partly recovered at one-month follow-up and 43% showed signs of post-traumatic stress disorder.

Conclusion

Patients with severe functional impairments had important cognitive and emotional deficits which might have been influenced by the choice of ventilatory therapy, but mostly appeared to be related to aging, independently of FIM scores. These findings should be integrated for decision-making in respiratory and neuropsychiatric assistance of COVID-19 patients in the subacute phase of the disease, and show the need for long-term support and psychological treatment of post-COVID-19 patients.
The implementation of remote home monitoring models during the COVID-19 pandemic in England
Authors: Vindrola-Padros Cecilia , Sidhu Manbinder S , Georghiou Theo , Sherlaw-Johnson Chris , Singh Kelly E , Tomini Sonila M , Ellins Jo , Morris Steve , Fulop Naomi J
Published: November 2020

Background

There is a paucity of evidence for the implementation of remote home monitoring for COVID-19 infection. The aims of this study were to identify the key characteristics of remote home monitoring models for COVID-19 infection, explore the experiences of staff implementing these models, understand the use of data for monitoring progress against outcomes, and document variability in staffing and resource allocation.

Methods

This was a multi-site mixed methods study that combined qualitative and quantitative approaches to analyse the implementation and impact of remote home monitoring models during the first wave of the COVID-19 pandemic (July to September 2020) in England. The study combined interviews (n=22) with staff delivering these models across eight sites in England with the collection and analysis of data on staffing models and resource allocation.

Findings

The models varied in relation to the healthcare settings and mechanisms used for patient triage, monitoring and escalation. Implementation was embedded in existing staff workloads and budgets. Good communication within clinical teams, culturally-appropriate information for patients/carers and the combination of multiple approaches for patient monitoring (app and paper-based) were considered facilitators in implementation. The mean cost per monitored patient varied from £400 to £553, depending on the model.

Interpretation

It is necessary to provide the means for evaluating the effectiveness of these models, for example, by establishing comparator data. Future research should also focus on the sustainability of the models and patient experience (considering the extent to which some of the models exacerbate existing inequalities in access to care).

Funding

The study was funded by the National Institute for Health Research-NIHR (Health Services and Delivery Research, 16/138/17 – Rapid Service Evaluation Research Team; or The Birmingham, RAND and Cambridge Evaluation (BRACE) Centre Team (HSDR16/138/31).
Rapid feedback on hospital onset SARS-CoV-2 infections combining epidemiological and sequencing data
Authors: Stirrup Oliver T , Hughes Joseph , Parker Matthew , Partridge David G , Shepherd James G , Blackstone James , Coll Francesc , Keeley Alexander J , Lindsey Benjamin B , Marek Aleksandra , Peters Christine , Singer Joshua B ,   The COVID-19 Genomics UK (COG-UK) consortium, Tamuri Asif , de Silva Thushan I , Thomson Emma C , Breuer Judith
Published: November 2020

Background

Rapid identification and investigation of healthcare-associated infections (HCAIs) is important for suppression of SARS-CoV-2, but the infection source for hospital onset COVID-19 infections (HOCIs) cannot always be readily identified based only on epidemiological data. Viral sequencing data provides additional information regarding potential transmission clusters, but the low mutation rate of SARS-CoV-2 can make interpretation using standard phylogenetic methods difficult.

Methods

We developed a novel statistical method and sequence reporting tool (SRT) that combines epidemiological and sequence data in order to provide a rapid assessment of the probability of HCAI among HOCI cases (defined as first positive test >48 hours following admission) and to identify infections that could plausibly constitute outbreak events. The method is designed for prospective use, but was validated using retrospective datasets from hospitals in Glasgow and Sheffield collected February-May 2020.

Results

We analysed data from 326 HOCIs. Among HOCIs with time-from-admission ≥8 days the SRT algorithm identified close sequence matches from the same ward for 160/244 (65.6%) and in the remainder 68/84 (81.0%) had at least one similar sequence elsewhere in the hospital, resulting in high estimated probabilities of within-ward and within-hospital transmission. For HOCIs with time-from-admission 3-7 days, the SRT probability of healthcare acquisition was >0.5 in 33/82 (40.2%).

Conclusions

The methodology developed can provide rapid feedback on HOCIs that could be useful for infection prevention and control teams, and warrants further prospective evaluation. The integration of epidemiological and sequence data is important given the low mutation rate of SARS-CoV-2 and its variable incubation period.
Sex differences in the decline of neutralizing antibodies to SARS-CoV-2
Authors: Grzelak Ludivine , Velay Aurélie , Madec Yoann , Gallais Floriane , Staropoli Isabelle , Schmidt-Mutter Catherine , Wendling Marie-Josée , Meyer Nicolas , Planchais Cyril , Rey David , Mouquet Hugo , Glady Ludovic , Hansmann Yves , Bruel Timothée , De Sèze Jérome , Fontanet Arnaud , Gonzalez Maria , Schwartz Olivier , Fafi-Kremer Samira
Published: November 2020

The evolution of SARS-CoV-2 humoral response in infected individuals remains poorly characterized. Here, we performed a longitudinal study of sera from 308 RT-qPCR+ individuals with mild disease, collected at two time-points, up to 6 months post-onset of symptoms (POS). We performed two anti-S and one anti-N serology assays and quantified neutralizing antibodies (NAbs). At month 1 (M1), males, individuals > 50 years of age or with a body mass index (BMI) > 25 exhibited higher levels of antibodies. Antibody levels decreased over time. At M3-6, anti-S antibodies persisted in 99% of individuals while anti-N IgG were measurable in only 59% of individuals. The decline in anti-S and NAbs was faster in males than in females, independently of age and BMI. Our results show that some serology tests are less reliable overtime and suggest that the duration of protection after SARS-CoV-2 infection or vaccination will be different in women and men.
Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies
Authors: Dufloo Jérémy , Grzelak Ludivine , Staropoli Isabelle , Madec Yoann , Tondeur Laura , Anna François , Pelleau Stéphane , Wiedemann Aurélie , Planchais Cyril , Buchrieser Julian , Robinot Rémy , Ungeheuer Marie-Noëlle , Mouquet Hugo , Charneau Pierre , White Michael , Lévy Yves , Hoen Bruno , Fontanet Arnaud , Schwartz Olivier , Bruel Timothée
Published: November 2020

A large proportion of SARS-CoV-2 infected individuals remains asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyzed antibody functions in 52 asymptomatic infected individuals, 119 mild and 21 hospitalized COVID-19 patients. We measured anti-Spike antibody levels with the S-Flow assay and mapped SARS-CoV-2 Spike- and N-targeted regions by Luminex. Neutralization, complement deposition and Antibody-Dependent Cellular Cytotoxicity (ADCC) were evaluated using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC and trigger complement deposition. Antibody levels and activities are slightly lower in asymptomatic individuals. The different functions of the antibodies are correlated, independently of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction, with minor variations. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells.

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Sera from convalescent COVID-19 patients activate the complement and kill infected cells by ADCC.

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Asymptomatic and symptomatic SARS-CoV-2-infected individuals harbor polyfunctional antibodies.

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Antibody levels and functions are slightly lower in asymptomatic individuals

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The different antiviral activities of anti-Spike antibodies are correlated regardless of disease severity.

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Functions of anti-Spike antibodies have similar kinetics of induction and contraction.
SensitizingStaphylococcus aureusto antibacterial host defense by decoding and blocking the lipid flippase MprF
Authors: Slavetinsky Christoph J. , Hauser Janna N. , Gekeler Cordula , Slavetinsky Jessica , Geyer André , Kraus Alexandra , Heilingbrunner Doris , Wagner Samuel , Tesar Michael , Krismer Bernhard , Kuhn Sebastian , Ernst Christoph M. , Peschel Andreas
Published: November 2020

The pandemic of antibiotic resistance represents a major human health threat demanding new antimicrobial strategies. MprF is the synthase and flippase of the phospholipid lysyl-phosphatidylglycerol that increases virulence and resistance of methicillin-resistantStaphylococcus aureus(MRSA) and other pathogens to cationic host defense peptides and antibiotics. With the aim to design MprF inhibitors that could sensitize MRSA to both, human antimicrobials and antibiotics and support the clearance of staphylococcal infections with minimal selection pressure, we developed MprF-targeting monoclonal antibodies, which bound and blocked the MprF flippase subunit. Antibody M-C7.1 targeted a specific loop in the flippase domain that proved to be exposed at both sides of the bacterial membrane, thereby enhancing the mechanistic understanding into bacterial lipid translocation. M-C7.1 rendered MRSA susceptible to host antimicrobial peptides and antibiotics such as daptomycin. Moreover, it impaired MRSA survival in human phagocytes, which recommends MprF inhibitors for new anti-MRSA approaches. MprF-directed monoclonal antibodies provide a proof of concept for development of precisely targeted anti-virulence approaches, which block bacterial antimicrobial resistance mechanisms.
Sex-specific stress-related behavioral phenotypes and central amygdala dysfunction in a mouse model of 16p11.2 microdeletion
Authors: Giovanniello Jacqueline , Ahrens Sandra , Yu Kai , Li Bo
Published: November 2020

Substantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders including autism spectrum disorders (ASD). Carriers of this deletion show divergent symptoms besides the core features of ASD, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. Here we report mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., the ‘16p11.2 del/+ mice’) have sex-specific anxiety-related behavioral and neural circuit changes. We found that female, but not male16p11.2 del/+ mice showed enhanced fear generalization – a hallmark of anxiety disorders – after auditory fear conditioning, and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male16p11.2 del/+ mice. Together, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome, and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.
Using the novel priority index in prioritizing the selection of inland water bodies for site-based fish species conservation
Authors: Basooma Anthony , Nakiyende Herbert , Olokotum Mark , Nkalubo Winnie , Musinguzi Laban , Natugonza Vianny
Published: November 2020

Freshwater ecosystems occupy <1% of the Earth’s total surface area but provide an array of ecosystem services. However, these ecosystems are threatened by multiple stressors, including overexploitation, infrastructure developments, habitat alteration, and alien species introductions. The magnitude of these threats varies in different water bodies, requiring site-based conservation actions. In this paper, we aimed at developing a priority index (CPIw) that can be used to inform conservation managers in prioritizing the selection of a waterbody for site-based fish conservation purposes. We used data on distribution, diversity, and conservation status of fishes of Uganda, which were retrieved from the Global Biodiversity Information Facility (GBIF) and International Union Conservation for Nature (IUCN) databases. In the index, we incorporated the species richness, surface area of a waterbody, species rarity, and species IUCN status. A total of 288 fish species were recorded in 81 waterbodies (7 large lakes, 37 small lakes, and 37 rivers). Of these species, 110 were only found in large lakes, followed by rivers (19) and small lakes (6). Despite the higher species richness in large lakes relative to small lakes, the latter recorded significantly higher CPIw compared with the former (t = −2.8, df = 30, p-value = 0.008, d=0.7). This observation is consistent with the expectation, given the low ecological substitutability for the species and higher levels of exposure to human-induced threats in small water bodies compared with large systems. Therefore, we suggest that in situations where resources are limiting, small water bodies need to be given much attention, although we do not suggest ignoring water bodies with low CPIw values.
A comparison of DNA/RNA extraction protocols for high-throughput sequencing of microbial communities
Authors: Shaffer Justin P. , Marotz Clarisse , Belda-Ferre Pedro , Martino Cameron , Wandro Stephen , Estaki Mehrbod , Salido Rodolfo A. , Carpenter Carolina S. , Zaramela Livia S. , Minich Jeremiah J. , Bryant MacKenzie , Sanders Karenina , Fraraccio Serena , Ackermann Gail , Humphrey Gregory , Swafford Austin D. , Miller-Montgomery Sandrine , Knight Rob
Published: November 2020

One goal among microbial ecology researchers is to capture the maximum amount of information from all organisms in a sample. The recent COVID-19 pandemic, caused by the RNA virus SARS-CoV-2, has highlighted a gap in traditional DNA-based protocols, including the high-throughput methods we previously established as field standards. To enable simultaneous SARS-CoV-2 and microbial community profiling, we compare the relative performance of two total nucleic acid extraction protocols and our previously benchmarked protocol. We included a diverse panel of environmental and host-associated sample types, including body sites commonly swabbed for COVID-19 testing. Here we present results comparing the cost, processing time, DNA and RNA yield, microbial community composition, limit of detection, and well-to-well contamination, between these protocols.

Accession numbers

Raw sequence data were deposited at the European Nucleotide Archive (accession#: ERP124610) and raw and processed data are available at Qiita (Study ID: 12201). All processing and analysis code is available on GitHub (github.com/justinshaffer/Extraction_test_MagMAX).

Methods summary

To allow for downstream applications involving RNA-based organisms such as SARS-CoV-2, we compared the two extraction protocols designed to extract DNA and RNA against our previously established protocol for extracting only DNA for microbial community analyses. Across 10 diverse sample types, one of the two protocols was equivalent or better than our established DNA-based protocol. Our conclusion is based on per-sample comparisons of DNA and RNA yield, the number of quality sequences generated, microbial community alpha- and beta-diversity and taxonomic composition, the limit of detection, and extent of well-to-well contamination.
X-ray Irradiation activates immune response in human T-lymphocytes by eliciting a Ca2+signaling cascade
Authors: Tandl Dominique , Sponagel Tim , Fuck Sebastian , Smit Timo , Hehlgans Stephanie , Jakob Burkhard , Fournier Claudia , Rödel Franz , Roth Bastian , Moroni Anna , Thiel Gerhard
Published: November 2020

Radiation therapy is efficiently employed for eliminating cancer cells and reducing tumor growth. To further improving its therapeutic application it is mandatory to unravel the molecular effects of ionizing irradiation and to understand whether they support or counteract tumor therapy. Here we examine the impact of X-ray irradiation on immune activation of human T cells with single doses typically employed in tumor therapy. We discover that exposing cells to radiation triggers in a population of leukemic Jurkat T cells and in peripheral blood mononuclear cells (PBMCs) a canonical Ca2+signaling cascade, which elicits immune activation of these cells. An early step in the signaling cascade is the initiation of sustained oscillations of the cytosolic Ca2+concentration, an event mediated by store operated Ca2+entry (SOCE) via an X-ray induced clustering of the Calcium Release-Activated Calcium Modulator 1 with the stromal interaction molecule 1 (Oari1/STIM1). A functional consequence of the Ca2+signaling cascade is the translocation of the transcription factor nuclear factor of activated T cells (NFAT) from the cytosol into the nucleus where it elicits the expression of genes required for immune activation. These data imply that a direct activation of blood immune cells by ionizing irradiation has an impact on toxicity and therapeutic effects of radiation therapy.
The cell fate controlling CLE40 peptide requires CNGC9 to trigger highly localized Ca2+transients inArabidopsis thalianaroot meristems
Authors: Breiden Maike , Olsson Vilde , Gustavo-Pinto Karine , Schultz Patrick , Denay Gregoire , Schlegel Jenia , Dietrich Petra , Butenko Melinka A. , Simon Rüdiger
Published: November 2020

Communication between plant cells and their biotic environment is largely dependent on the function of plasma membrane localized receptor-like kinases (RLKs). Major players in this communication within root meristems are secreted peptides, including CLAVATA3/EMBRYO SURROUNDING REGION40 (CLE40). In the distal root meristem, CLE40 acts through the receptor like kinase (RLK) ARABIDOPSIS CRINKLY4 (ACR4) and the leucine-rich repeat (LRR) RLK CLAVATA1 (CLV1) to promote cell differentiation. In the proximal meristem, CLE40 signalling requires the LRR receptor-like protein (RLP) CLAVATA2 (CLV2) and the membrane localized pseudokinase CORYNE (CRN), and serves to inhibit cell differentiation. The molecular components that act immediately downstream of the CLE40-activated receptors are not yet known. Here we show that active CLE40 signalling triggers the release of intracellular Ca2+leading to increased cytosolic Ca2+concentration ([Ca2+]cyt) in a subset of proximal root meristem cells. This rise in [Ca2+]cytdepends on the CYCLIC NUCLEOTIDE GATED CHANNEL 9 (CNGC9), CLV1, the CLV1-related BARELY ANY MERISTEM1 (BAM1), CLV2 and CRN. The precise function of changes in [Ca2+]cytare not yet known, but might form a central part of a fine-tuned response to CLE40 peptide that serves to integrate root meristem growth with stem cell fate decisions and initiation of lateral root primordia.
Template-independent genome editing and repairing correct frameshift diseasein vivo
Authors: Liu Lian , Li Kuan , Zou Linzhi , Hou Hanqing , Hu Qun , Liu Shuang , Wang Shufeng , Wang Yangzhen , Li Jie , Song Chenmeng , Chen Jiaofeng , Li Changri , Du Haibo , Li Jun-Liszt , Chen Fangyi , Xu Zhigang , Sun Wenzhi , Sun Qianwen , Xiong Wei
Published: November 2020

Frameshift mutation caused by small insertions/deletions (indels) often generate truncated and non-functional proteins, which underlies 22% inherited Mendelian disorders in humans. However, there is no efficientin vivogene therapy strategies available to date, especially in postmitotic systems. Here, we leveraged the non-homologous end joining (NHEJ) mediated non-random editing profiles to compensate the frameshift mutation in a USH1F mouse model –av3j. After treatment by the selected gRNA, about 50% editing products showed reading-frame restoration, and more than 70% targeted hair cells recovered mechanotransduction.In vivotreatment ameliorated the hearing and balance symptoms in homozygous mutant mice. Furthermore, a scale-up analysis of 114 gRNAs targeting 40 frameshift deafness mutations reveals that 65% loci have at least one gRNA with predicted therapeutic potential. Together, our study demonstrates that the NHEJ-mediated frame restoration is a simple and highly efficient therapeutic strategy for small-indel induced frameshift mutations.
Analysis of the Dynamics and Distribution of SARS-CoV-2 Mutations and its Possible Structural and Functional Implications
Authors: Arévalo Santiago Justo , Sifuentes Daniela Zapata , Robles César Huallpa , Bianchi Gianfranco Landa , Chávez Adriana Castillo , Casas Romina Garavito-Salini , Chavarría Roberto Pineda , Uceda-Campos Guillermo
Published: November 2020

After eight months of the pandemic declaration, COVID-19 has not been globally controlled. Several efforts to control SARS-CoV-2 dissemination are still running including vaccines and drug treatments. The effectiveness of these procedures depends, in part, that the regions to which these treatments are directed do not vary considerably. Although, it is known that the mutation rate of SARS-CoV-2 is relatively low it is necessary to monitor the adaptation and evolution of the virus in the different stages of the pandemic. Thus, identification, analysis of the dynamics, and possible functional and structural implication of mutations are relevant. Here, we first estimate the number of COVID-19 cases with a virus with a specific mutation and then calculate its global relative frequency (NRFp). Using this approach in a dataset of 100 924 genomes from GISAID, we identified 41 mutations to be present in viruses in an estimated number of 750 000 global COVID-19 cases (0.03 NRFp). We classified these mutations into three groups: high-frequent, low-frequent non-synonymous, and low-frequent synonymous. Analysis of the dynamics of these mutations by month and continent showed that high-frequent mutations appeared early in the pandemic, all are present in all continents and some of them are almost fixed in the global population. On the other hand, low-frequent mutations (non-synonymous and synonymous) appear late in the pandemic and seems to be at least partially continent-specific. This could be due to that high-frequent mutation appeared early when lockdown policies had not yet been applied and low-frequent mutations appeared after lockdown policies. Thus, preventing global dissemination of them. Finally, we present a brief structural and functional review of the analyzed ORFs and the possible implications of the 25 identified non-synonymous mutations.
A zero inflated log-normal model for inference of sparse microbial association networks
Authors: Prost Vincent , Gazut Stéphane , Brüls Thomas
Published: November 2020

The advent of high-throughput metagenomic sequencing has prompted the development of efficient taxonomic profiling methods allowing to measure the presence, abundance and phylogeny of organisms in a wide range of environmental samples. Multivariate sequence-derived abundance data further has the potential to enable inference of ecological associations between microbial populations, but several technical issues need to be accounted for, like the compositional nature of the data, its extreme sparsity and overdispersion, as well as the frequent need to operate in under-determined regimes.

The ecological network reconstruction problem is frequently cast into the paradigm of Gaussian Graphical Models (GGMs) for which efficient structure inference algorithms are available, like the graphical lasso and neighborhood selection. Unfortunately, GGMs or variants thereof can not properly account for the extremely sparse patterns occurring in real-world metagenomic taxonomic profiles. In particular, structural zeros (as opposed to sampling zeros) corresponding to true absences of biological signals fail to be properly handled by most statistical methods.

We present here a zero-inflated log-normal graphical model (available athttps://github.com/vincentprost/Zi-LN) specifically aimed at handling such “biological” zeros, and demonstrate significant performance gains over state-of-the-art statistical methods for the inference of microbial association networks, with most notable gains obtained when analyzing taxonomic profiles displaying sparsity levels on par with real-world metagenomic datasets.