bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimates of Healthcare Spending for Preterm and Low-Birthweight Infants in a Commercially Insured Population: 2008–2016
Authors: Beam Andrew L. , Fried Inbar , Palmer Nathan , Agniel Denis , Brat Gabriel , Fox Kathe , Kohane Isaac , Sinaiko Anna , Zupancic John A. F. , Armstrong Joanne
Published: December 2020

(Abstracted from J Perinatol 2020;40:1091–1099)

Preterm birth and low birthweight incur large medical, social, and economic costs on affected families and the US health care system. A 2007 study from the Institute of Medicine estimated that the total cost associated with preterm delivery in the United States was at least $26.2 billion annually or $51,600 per infant born preterm.
Convergent dental adaptations in the serrations of hypercarnivorous synapsids and dinosaurs
Authors: Whitney M. R. , LeBlanc A. R. H. , Reynolds A. R. , Brink K. S.
Published: December 2020

Theropod dinosaurs are well known for having a ziphodont dentition: serrated, blade-shaped teeth that they used for cutting through prey. Serrations along the carinae of theropod teeth are composed of true denticles, a complex arrangement of dentine, enamel, and interdental folds. This structure would have supported individual denticles and dissipated the stresses associated with feeding. These particular serrations were previously thought to be unique to theropod dinosaurs and some other archosaurs. Here, we identify the same denticles and interdental folds forming the cutting edges in the teeth of a Permian gorgonopsian synapsid, extending the temporal and phylogenetic distribution of this dental morphology. This remarkable instance of convergence not only represents the earliest record of this adaptation to hypercarnivory but also demonstrates that the first iteration of this feature appeared in non-mammalian synapsids. Comparisons of tooth serrations in gorgonopsians with those of earlier synapsids and hypercarnivorous mammals reveal some gorgonopsians acquired a complex tissue arrangement that differed from other synapsids.
Foistar(Camostat mesylate) associated with the significant decrease in CRP levels compared to Kaletra(Lopinavir/Ritonavir) treatment in Korean mild COVID-19 pneumonic patients.
Authors: Choi Jae-Phil , Choi Jae-Phil , Kim Hyoung-Jun , Han Jumi , Park Sujung , Han JinJoo
Published: December 2020

Background
There is limited information due to absence of virus titer and symptom related changes. Nonetheless, this is the first comparative study between the use of Foistar (Camostat mesilate) and Kaletra (lopinavir/ritonavir) on COVID-19 infection.

Methods
Patients with confirmed SARS-CoV-2 infection by positive polymerase chain reaction (PCR) testing that were admitted to Seoul Medical Center (Seoul, South Korea) where is the largest public medical center in South Korea between August 1 and September 20, 2020 were included
The data of the patients with pneumonia who received Foistar (Foistar group) during their hospitalization period were primarily collected, and the patients who received Kaletra (Kaletra group) during their hospitalization period were matched to have a similar age group to that of Foistar group so that three times the number of Foistar group patients were randomly selected into Kaletra group and their body temperature, CRP level, WBC count, and event of diarrhea were collected, accordingly.

Results
A total of 29 patients (7 Foistar group and 22 Kaletra group) was included. The median age was 69, and all had mild COVID-19 (WHO ordinal scale 3 or 4) on admission. 6 patients out of 7 patients (85.71%) from Foistar group who exhibited elevated CRP levels (CRP >0.4mg/dL) on admission have controlled their CRP levels to the normal range. In Kaletra group, 11 out of 18 patients (61.11%) have controlled their CRP levels to the normal range, and only 1 of 2 patients (50.00%) who had normal CRP level has maintained his or her normal CRP level. The difference in the white blood cell counts was not significant between two groups. None of the patients in the study had hyperkalemia.

Conclusion
This study has found a probable association of controlling inflammatory reactions and fever in COVID-19 patients with Foistar (camostat mesilate) use. In addition, there was no significant adverse drug event found from this study upon the Foistar use. These results may encourage the use of Foistar as a treatment option for the patients with mild to moderate COVID-19.
Does Contact Tracing Work? Quasi-Experimental Evidence from an Excel Error in England
Authors: Fetzer Thiemo , Graeber Thomas
Published: December 2020

Contact tracing has been a central pillar of the public health response to the COVID-19 pandemic. Yet, contact tracing measures face substantive challenges in practice and well-identified evidence about their effectiveness remains scarce. This paper exploits quasi-random variation in COVID-19 contact tracing. Between September 25 and October 2, 2020, a total of 15,841 COVID-19 cases in England (around 15 to 20% of all cases) were not immediately referred to the contact tracing system due to a data processing error. Case information had been truncated from an Excel spreadsheet due to a row limit, which was discovered on October 3. There is substantial variation in the degree to which different parts of England areas were exposed - by chance - to delayed referrals of COVID-19 cases to to the contact tracing system. We show that more affected areas subsequently experienced a drastic rise in new COVID-19 infections and deaths alongside an increase in the positivity rate and the number of test performed, as well as a decline in the performance of the contact tracing system. Conservative estimates suggest that the failure of timely contact tracing due to the data glitch is associated with more than 125,000 additional infections and over 1,500 additional COVID-19-related deaths. Our findings provide strong quasi-experimental evidence for the effectiveness of contact tracing.
Towards achieving a vaccine-derived herd immunity threshold for COVID-19 in the U.S.
Authors: Gumel Abba B. , Iboi Enahoro A. , Ngonghala Calistus N. , Ngwa Gideon A.
Published: December 2020

A novel coronavirus emerged in December of 2019 (COVID-19), causing a pandemic that continues to inflict unprecedented public health and economic burden in all nooks and corners of the world. Although the control of COVID-19 has largely focused on the use of basic public health measures (primarily based on using non-pharmaceutical interventions, such as quarantine, isolation, social-distancing, face mask usage and community lockdowns), three safe and highly-effective vaccines (by AstraZeneca Inc., Moderna Inc. and Pfizer Inc., with protective efficacy of 70%, 94.1% and 95%, respectively) have been approved for use in humans since December 2020. We present a new mathematical model for assessing the population-level impact of the three currently-available anti-COVID vaccines that are administered in humans. The model stratifies the total population into two subgroups, based on whether or not they habitually wear face mask in public. The resulting multigroup model, which takes the form of a deterministic system of nonlinear differential equations, is fitted and parametrized using COVID-19 cumulative mortality data for the third wave of the COVID-19 pandemic in the U.S. Conditions for the asymptotic stability of the associated disease-free equilibrium, as well as expression for the vaccine-derived herd immunity threshold, are rigorously derived. Numerical simulations of the model show that the size of the initial proportion of individuals in the masks-wearing group, together with positive change in behaviour from the non-masks wearing group (as well as those in masks-wearing group do not abandon their masks-wearing habit) play a crucial role in effectively curtailing the COVID-19 pandemic in the U.S. This study further shows that the prospect of achieving herd immunity (required for COVID-19 elimination) in the U.S., using any of the three currently-available vaccines, is quite promising. In particular, while the use of the AstraZeneca vaccine will lead to herd immunity in the U.S. if at least 80% of the populace is vaccinated, such herd immunity can be achieved using either the Moderna or Pfizer vaccine if about 60% of the U.S. population is vaccinated. Furthermore, the prospect of eliminating the pandemic in the US in the year 2021 is significantly enhanced if the vaccination program is complemented with nonpharmaceutical interventions at moderate increased levels of compliance (in relation to their baseline compliance). The study further suggests that, while the waning of natural and vaccine-derived immunity against COVID-19 induces only a marginal increase in the burden and projected time-to-elimination of the pandemic, adding the impacts of the therapeutic benefits of the vaccines into the model resulted in a dramatic reduction in the burden and time-to-elimination of the pandemic.
COVID-19 TARRACO Cohort Study: Development of a predictive prognostic rule for early assessment of COVID-19 patients in primary care settings
Authors: Vila-Corcoles Angel , Satue-Gracia Eva , Vila-Rovira Angel , de Diego-Cabanes Cinta , Forcadell-Peris Maria Jose , Hospital-Guardiola Imma , Ochoa-Gondar Olga
Published: December 2020

PURPOSE

Clinical course in COVID-19 patients is uncertain. This study investigated possible early prognostic factors among middle-aged and older adult and explored prognostic rules stratifying risk of patients.

METHODS

Community-based retrospective cohort study that included 282 community-dwelling symptomatic patients ≥50 years with laboratory-confirmed COVID-19 (hospitalised and/or outpatient) during March-June 2020 in Tarragona (Southern Catalonia, Spain). Relationship between demographics, pre-existing comorbidities and early symptomatology (first 5-days) and risk of suffering critical outcome (ICU-admission/death) across clinical course was evaluated by logistic regression analyses, and simple predictive models were developed.

RESULTS

Of the 282 cases (mean age: 65.9 years; 140 men), 154 (54.6%) were hospitalised (30 ICU-admitted) and 45 (16%) deceased. In crude analyses, increasing age, male sex, some comorbidities (renal, respiratory or cardiac disease, diabetes and hypertension) and symptoms (confusion, dyspnea) were associated with an increased risk to suffer critical outcome, whereas other symptoms (rinorrhea, myalgias, headache, anosmia/disgeusia) were related with reduced risk. After multivariable-adjustment only age/years (OR: 1.04; 95% CI: 1.01-1.07; p=0.004), confusion (OR: 5.33; 95% CI: 1.54-18.48; p=0.008), dyspnea (OR: 5.41; 95% CI: 2.74-10.69; p<0.001) and myalgias (OR: 0.30; 95% CI: 0.10-0.93; p=0.038) remained significantly associated with increased or reduced risk. A proposed CD65-M prognostic rule (including the above mentioned 4 variables) showed a good correlation with the risk of suffering critical outcome (area under ROC curve: 0.828; 95% CI: 0.774-0.882).

CONCLUSION

Clinical course of COVID-19 is early unpredictable, but simple clinical tools as the proposed CD65-M rule (pending external validation) may be helpful assessing these patients in primary care settings.
Maintenance therapy with infliximab or vedolizumab in inflammatory bowel disease is not associated with increased SARS-CoV-2 seroprevalence: UK experience in the 2020 pandemic
Authors: McGregor Colleen G C , Adams Alex , Sadler Ross , Arancibia-Cárcamo Carolina V , Palmer Rebecca , Ambrose Tim , Brain Oliver , Walsh Alissa , Klenerman Paul , Travis Simon , Croft Nicholas M , Lindsay James O , Satsangi Jack
Published: December 2020

Background

There has been great concern amongst clinicians and patients that immunomodulatory treatments for IBD may increase risk of SARS-CoV-2 susceptibility or progression to severe disease.

Methods

Sera from 640 patients attending for maintenance infliximab or vedolizumab infusions between April and June 2020 at the John Radcliffe Hospital (Oxford, UK) and Royal London Hospital (London, UK) were tested using the Abbott SARS-CoV-2 IgG assay. Demographic and clinical data were collated from electronic patient records and research databases.

Results

Seropositivity rates of 3.0% (12/404), 7.2% (13/180), and 12.5% (7/56) were found in the Oxford and London adult IBD cohorts and London paediatric IBD cohorts respectively. Seroprevalence rates in the Oxford adult IBD cohort were lower than that seen in non-patient facing health-care workers within the same hospital (7.2%). Seroprevalence rates of the London paediatric IBD cohort were comparable to a contemporary healthy cohort collected at the same hospital (54/396, 13.6%).

Conclusions

SARS-CoV-2 seropositivity rates are not elevated in patients with IBD receiving maintenance infliximab or vedolizumab infusions. There is no rationale based on these data for elective interruption of maintenance therapy, and we recommend continuation of maintenance therapy. These data do not address the efficacy of vaccination in these patients.
Computational Analysis of Dynamic Allostery and Control in the three SARS-CoV-2 non-structural proteins
Authors: Dubanevics Igors , Heaton Charles , Riechmann Carlos , McLeish Tom C.B.
Published: December 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic, has no vaccine or antiviral drugs available to the public, at the time of writing. The virus’ non-structural proteins are promising drug targets because of their vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which covalently and competitively bind the active site of the non-structural proteins, but little has been done to address regions other than the active site, i.e. for non-competitive inhibition. Here we extend previous work on the SARS-CoV-2 Mpro (nsp5) to three other SARS-CoV-2 proteins: host shutoff factor (nsp1), papain-like protease (nsp3, also known as PLpro) and RNA-dependent RNA-polymerase (nsp12, also known as RdRp) in complex with nsp7 and nsp8 cofactors. Using open-source software (DDPT) to construct Elastic Network Models (ENM) of the chosen proteins we analyse their fluctuation dynamics and thermodynamics, as well as using this protein family to study convergence and robustness of the ENM. Exhaustive 2-point mutational scans of the ENM and their effect on fluctuation free energies suggest several new candidate regions, distant from the active site, for control of the proteins’ function, which may assist the drug development based on the current small molecule binding screens. The results also provide new insights, including non-additive effects of double-mutation or inhibition, into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.
Deep sequencing of DNA from urine of kidney allograft recipients to estimate the donor-specific DNA fraction
Authors: Belkadi Aziz , Thareja Gaurav , Dadhania Darshana , Lee John R. , Muthukumar Thangamani , Snopkowski Catherine , Li Carol , Halama Anna , Abdelkader Sara , Mahmoud Yasmin , Malek Joel , Suthanthiran Manikkam , Suhre Karsten
Published: December 2020

Renal transplantation is the method of choice for patients with end stage kidney failure. But transplanted allograft could be affected by viral and bacterial infections and immune rejections. The standard test for the diagnosis of acute pathologies in kidney transplants is the renal biopsy. However, noninvasive tests would be desirable. Various methods using different techniques have been developed by the transplantation community. But these methods expect improvements. We present here a cost-effective method based on estimating donor-specific DNA fraction in recipient urine based on sequencing of recipient urine DNA only. We hypothesized that in the no-pathology stage, the largest tissue types present in recipient urine are donor kidney cells and in case of rejection, a larger number of recipient immune cells would be observed. Extensive in-silico simulation was used to tune the sequencing parameters: number of variants and depth of coverage. Sequencing of DNA mixture from 2 healthy individuals showed the method high prediction accuracy (maximum error < 0.04). We then demonstrated the insignificant impact of familial relationship and ethnicity using an in-house and public database. Lastly, we performed recipient deep urine DNA sequencing in 32 samples representing two pathology groups: acute rejection (AR, 12 samples) and acute tubular injury (ATI, 11 samples) and 9 samples with no pathology. We found a significant association between the donor-specific DNA fraction in the two pathology groups compared to no pathology (P = 0.0064 for AR and P = 0.026 for ATI). We conclude that deep DNA sequencing of recipient urine offers a noninvasive means of diagnosing and prognosticating acute pathologies in the human kidney allograft.
Fetal estrogens are not involved in sex determination but critical for early ovarian differentiation
Authors: Jolivet Geneviève , Daniel-Carlier Nathalie , Harscoёt Erwana , Airaud Eloïse , Dewaele Aurélie , Pierson Cloé , Giton Frank , Boulanger Laurent , Daniel Nathalie , Mandon-Pépin Béatrice , Pannetier Maёlle , Pailhoux Eric
Published: December 2020

AROMATASE, encoded by theCYP19A1gene, is the cytochrome enzyme responsible for the synthesis of estrogens in vertebrates. In most mammals a peak of expression of theCYP19A1gene occurs in the fetal XX gonad when sexual differentiation starts up. To elucidate the role of this peak, we produced 3 lines of TALEN genetically editedCYP19A1KO rabbits, that were void of any production of estradiol. All KO XX rabbits developed as females, with aberrantly small sized ovaries at adulthood, an almost empty reserve of primordial follicles and very few large antrum follicles. Ovulation never occurred. Our histological, immunohistological and transcriptomic analyses showed that the surge of estradiol in the XX fetal rabbit gonad is dispensable for its determination as an ovary, or for meiosis. However, it is mandatory for the high proliferation and differentiation of both somatic and germ cells, and consequently for the establishment of the ovarian reserve.
Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products in vitro
Authors: He Chang-Long , Huang Lu-Yi , Wang Kai , Gu Chen-Jian , Hu Jie , Zhang Gui-Ji , Xu Wei , Xie You-Hua , Tang Ni , Huang Ai-Long
Published: December 2020

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. To screen for antiviral drugs for COVID-19 treatment, we constructed a SARS-CoV-2 spike (S) pseudovirus system using an HIV-1-based lentiviral vector with a luciferase reporter gene to screen 188 small potential antiviral compounds. Using this system, we identified nine compounds, specifically, bis-benzylisoquinoline alkaloids, that potently inhibited SARS-CoV-2 pseudovirus entry, with EC50values of 0.1–10 μM. Mechanistic studies showed that these compounds, reported as calcium channel blockers (CCBs), inhibited Ca2+-mediated membrane fusion and consequently suppressed coronavirus entry. These candidate drugs showed broad-spectrum efficacy against the entry of several coronavirus pseudotypes (SARS-CoV, MERS-CoV, SARS-CoV-2 [S-D614, S-G614, N501Y.V1 and N501Y.V2]) in different cell lines (293T, Calu-3, and A549). Antiviral tests using native SARS-CoV-2 in Vero E6 cells confirmed that four of the drugs (SC9/cepharanthine, SC161/hernandezine, SC171, and SC185/neferine) reduced cytopathic effect and supernatant viral RNA load. Among them, cepharanthine showed the strongest anti-SARS-CoV-2 activity. Collectively, this study offers new lead compounds for coronavirus antiviral drug discovery.
Genome-wide association studies of LRRK2 modifiers of Parkinson's disease
Authors: Lai Dongbing , Alipanahi Babak , Fontanillas Pierre , Schwantes-An Tae-Hwi , Aasly Jan , Alcalay Roy N. , Beecham Gary W. , Berg Daniela , Bressman Susan , Brice Alexis , Brockman Kathrin , Clark Lorraine , Cookson Mark , Das Sayantan , Deerlin Vivianna Van , Farrer Matthew , Trinh Joanne , Gasser Thomas , Goldwurm Stefano , Gustavsson Emil , Klein Christine , Lang Anthony E. , Langston William J. , Latourelle Jeanne , Lynch Timothy , Marder Karen , Marras Connie , Martin Eden R. , McLean Cory Y. , Mejia-Santana Helen , Molho Eric , Myers Richard H. , Nuytemans Karen , Ozelius Laurie , Payami Haydeh , Raymond Deborah , Rogaeva Ekaterina , Rogers Michael P. , Ross Owen A. , Samii Ali , Saunders-Pullman Rachel , Schule Birgitt , Schulte Claudia , Scott William K. , Tanner Caroline , Tolosa Eduardo , Tomkins James E. , Vilas Dolores , Trojanowski John Q. , Uitti Ryan , Vance Jeffery M. , Visanji Naomi P. , Wszolek Zbigniew K. , Zabetian Cyrus P. , Mirelman Anat , Giladi Nir , Urtreger Avi Orr , Cannon Paul , Fiske Brian , Foroud Tatiana
Published: December 2020

Objective:
The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods:
We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results:
A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value=2.5E-08, beta=1.27, SE=0.23, risk allele: C) met genome-wide significance for the penetrance model. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value=1.1E-07; age-at-onset top variant: P-value=9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation:
This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.
Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials
Authors: Follmann Dean , Fintzi Jonathan , Fay Michael P. , Janes Holly E. , Baden Lindsey , Sahly Hana El , Fleming Thomas R. , Mehrotra Devan V. , Carpp Lindsay N. , Juraska Michal , Benkeser David , Donnell Deborah , Fong Youyi , Han Shu , Hirsch Ian , Huang Ying , Huang Yunda , Hyrien Ollivier , Luedtke Alex , Carone Marco , Nason Martha , Vandebosch An , Zhou Honghong , Cho Iksung , Gabriel Erin , Kublin James G. , Cohen Myron S. , Corey Lawrence , Gilbert Peter B. , Neuzil Kathleen M.
Published: December 2020

Background

Several candidate vaccines to prevent COVID-19 disease have entered large-scale phase 3 placebo-controlled randomized clinical trials and some have demonstrated substantial short-term efficacy. Efficacious vaccines should, at some point, be offered to placebo participants, which will occur before long-term efficacy and safety are known.

Methods

Following vaccination of the placebo group, we show that placebo-controlled vaccine efficacy can be derived by assuming the benefit of vaccination over time has the same profile for the original vaccine recipients and the placebo crossovers. This reconstruction allows estimation of both vaccine durability and potential vaccine-associated enhanced disease.

Results

Post-crossover estimates of vaccine efficacy can provide insights about durability, identify waning efficacy, and identify late enhancement of disease, but are less reliable estimates than those obtained by a standard trial where the placebo cohort is maintained. As vaccine efficacy estimates for post-crossover periods depend on prior vaccine efficacy estimates, longer pre-crossover periods with higher case counts provide better estimates of late vaccine efficacy. Further, open-label crossover may lead to riskier behavior in the immediate crossover period for the unblinded vaccine arm, confounding vaccine efficacy estimates for all post-crossover periods.

Conclusions

We advocate blinded crossover and continued follow-up of trial participants to best assess vaccine durability and potential delayed enhancement of disease. This approach allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain participants on placebo, yet still allows important insights about immunological and clinical effectiveness over time.
Predicting the need for escalation of care or death from repeated daily clinical observations and laboratory results in patients with SARS-CoV-2 during 2020: a retrospective population-based cohort study from the United Kingdom
Authors: Crooks Colin J , West Joe , Fogarty Andrew , Morling Joanne R , Grainge Matthew J , Gonem Sherif , Simmonds Mark , Race Andrea , Juurlink Irene , Briggs Stephen , Cruikshank Simon , Hammond-Pears Susan , Card Timothy R
Published: December 2020

Objectives: Currently used prognostic tools for patients with SARS-CoV-2 infection are based on clinical and laboratory parameters measured at a single point in time, usually on admission. We aimed to determine how dynamic changes in clinical and laboratory parameters relate to SARS-CoV-2 prognosis.

Design: retrospective, observational cohort study using routinely collected clinical data to model the dynamic change in prognosis of SARS-CoV-2.

Setting: a single, large hospital in England.

Participants: all patients with confirmed SARS-CoV-2 admitted to Nottingham University Hospitals (NUH) NHS Trust, UK from 1st February 2020 until 30th November 2020.

Main outcome measures: Intensive Care Unit (ICU) admission, death and discharge from hospital.

Statistical Methods: We split patients into 1st (admissions until 30th June) and 2nd (admissions thereafter) waves. We incorporated all clinical observations, blood tests and other covariates from electronic patient records and follow up until death or 30 days from the point of hospital discharge. We modelled daily risk of admission to ICU or death with a time varying Cox proportional hazards model.
Results: 2,964 patients with confirmed SARS-CoV-2 were included. Of 1,374 admitted during the 1st wave, 593 were eligible for ICU escalation, and 466 had near complete ascertainment of all covariates at admission. Our validation sample included 1,590 confirmed cases, of whom 958 were eligible for ICU admission. Our model had good discrimination of daily need for ICU admission or death (C statistic = 0.87 (IQR 0.85-0.90)) and predicted this daily prognosis better than previously published scores (NEWS2, ISCARIC 4C). In validation in the 2nd wave the score overestimated escalation (calibration slope 0.55), whilst retaining a linear relationship and good discrimination (C statistic = 0.88 (95% CI 0.81 -0.95)).

Conclusions: A bespoke SARS-CoV-2 escalation risk prediction score can predict need for clinical escalation better than a generic early warning score or a single estimation of risk at admission.
Socioeconomic inequalities associated with mortality for COVID-19 in Colombia: A cohort nation-wide study
Authors: Cifuentes Myriam Patricia , Rodriguez-Villamizar Laura Andrea , Rojas-Botero Maylen Liseth , Alvarez-Moreno Carlos Arturo , Fernandez-Nino Julian Alfredo
Published: December 2020

Background: After eight months of the COVID-19 pandemic, Latin American countries have some of the highest rates in COVID-19 mortality. Despite being one of the most unequal regions of the world, there is a scarce report of the effect of socioeconomic conditions on COVID-19 mortality in their countries. We aimed to identify the effect of some socioeconomic inequality-related factors on COVID-19 mortality in Colombia.

Methods: We conducted a survival analysis in a nation-wide retrospective cohort study of confirmed cases of COVID-19 in Colombia from March 2nd to October 26th, 2020. We calculated the time to death or recovery for each confirmed case in the cohort. We used an extended multivariable time-dependent Cox regression model to estimate the hazard risk ratio (HR) by age groups, sex, ethnicity, type of health insurance, area of residence, and socioeconomic strata.

Results: There were 1 033 218 confirmed cases and 30 565 deaths for COVID-19 in Colombia between March 2nd and October 26th. The risk of dying for COVID-19 among confirmed cases was higher in males (HR=1.68 95% CI: 1.64-1.72), in people older than 60 years (HR=296.58 95% CI: 199.22-441.51), in indigenous people (HR=1.20 95% CI: 1.08-1.33), in people with subsidized health insurance regime (HR=1.89 95% CI: 1.83-1.96), and in people living in the very low socioeconomic strata (HR=1.44 95% CI: 1.24-1.68).

Conclusion: Our study provides evidence of socioeconomic inequalities in COVID-19 mortality in terms of age groups, sex, ethnicity, type of health insurance regime, and socioeconomic status.
Coordinating the morphogenesis-differentiation balance by tweaking the cytokinin-gibberellin equilibrium
Authors: Israeli Alon , Burko Yogev , Shleizer-Burko Sharona , Zelnik Iris Daphne , Sela Noa , Hajirezaei Mohammad R. , Fernie Alisdair R. , Tohge Takayuki , Ori Naomi , Bar Maya
Published: December 2020

Morphogenesis and differentiation are important stages in organ development and shape determination. However, how they are balanced and tuned during development is not fully understood. In the compound leaved tomato, an extended morphogenesis phase allows for the initiation of leaflets, resulting in the compound form. Maintaining a prolonged morphogenetic phase in early stages of compound-leaf development is dependent on delayed activity of several factors that promote differentiation, including CIN-TCP transcription factor (TF) LA, the MYB TF CLAU and the plant hormone Gibberellin (GA). Here, we investigated the genetic regulation of the morphogenesis-differentiation balance by studying the relationship between LA, CLAU and GA. Our genetic and molecular examination suggest thatLAis expressed more broadly thanCLAUand determines the spatio-temporal context of CLAU activity. We demonstrate that both LA and CLAU affect the Cytokinin/Gibberellin (CK/GA) balance. LA reduces the sensitivity of the leaf margin to CK, shown before to be also affected by CLAU. CLAU affects leaf active GA content and sensitivity, shown previously to be also influenced by LA. Therefore, LA and CLAU likely function in parallel pathways to promote leaf differentiation by converging on common downstream processes, including the CK/GA balance.
Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70
Authors: Kemp Steven A , Meng Bo , Ferriera Isabella ATM , Datir Rawlings , Harvey William T , Papa Guido , Lytras Spyros , Collier Dami A , Mohamed Ahmed , Gallo Giulia , Thakur Nazia ,   The COVID-19 Genomics UK (COG-UK) Consortium, Carabelli Alessandro M , Kenyon Julia C , Lever Andrew M , De Marco Anna , Saliba Christian , Culap Katja , Cameroni Elisabetta , Piccoli Luca , Corti Davide , James Leo C , Bailey Dalan , Robertson David L , Gupta Ravindra K.
Published: December 2020

SARS-CoV-2 amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide out of frame deletion in the S gene, which results in loss of two amino acids: H69 and V70. We report that in human infections ΔH69/V70 often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F, and in the latter two cases has followed the RBD mutation. One of the ΔH69/V70+ N501Y lineages, now known as B.1.1.7, has undergone rapid expansion and includes eight S gene mutations: RBD (N501Y and A570D), S1 (ΔH69/V70 and Δ144) and S2 (P681H, T716I, S982A and D1118H).In vitro, we show that ΔH69/V70 does not reduce serum neutralisation across multiple convalescent sera. However, ΔH69/V70 increases infectivity and is associated with increased incorporation of cleaved spike into virions. ΔH69/V70 is able to compensate for small infectivity defects induced by RBD mutations N501Y, N439K and Y453F. In addition, replacement of H69 and V70 residues in the B.1.1.7 spike reduces its infectivity and spike mediated cell-cell fusion. Based on our data ΔH69/V70 likely acts as a permissive mutation that allows acquisition of otherwise deleterious immune escape mutations. Enhanced surveillance for the ΔH69/V70 deletion with and without RBD mutations should be considered as a global priority not only as a marker for the B.1.1.7 variant, but potentially also for other emerging variants of concern. Vaccines designed to target the deleted spike protein could mitigate against its emergence as increased selective forces from immunity and vaccines increase globally.

Highlights

ΔH69/V70 is present in at least 28 SARS-CoV-2 lineages

ΔH69/V70 does not confer escape from convalescent sera

ΔH69/V70 increases spike infectivity and compensates for RBD mutations

ΔH69/V70 is associated with greater spike cleavage

B.1.1.7 requires ΔH69/V70 for optimal spike cleavage and infectivity
Intermittent ERK oscillations downstream of FGF in mouse embryonic stem cells
Authors: Raina Dhruv , Fabris Fiorella , Morelli Luis G. , Schröter Christian
Published: December 2020

Signal transduction networks process extracellular signals to guide cell fate decisions such as to divide, differentiate, or die. These networks can generate characteristic dynamic activities that are shaped by their cell-type specific architecture. The differentiation of pluripotent cells is controlled by FGF/ERK signaling. However, the dynamic activity of the FGF/ERK signaling network in this context remains unexplored. Here we use live cell sensors in wild type andFgf4mutant mouse embryonic stem cells to measure ERK dynamic activity in single cells, in response to defined ligand concentrations. We find that ERK activity oscillates in embryonic stem cells. Single cells can transit between oscillatory and non-oscillatory behavior, leading to heterogeneous dynamic activities in the population. Oscillations become more prevalent with increasing FGF4 dose, while maintaining a robust characteristic timescale. Our results suggest that FGF/ERK signaling operates in the vicinity of a transition point between oscillatory and non-oscillatory dynamics in embryonic stem cells.
Diagnostic accuracy of Loop mediated isothermal amplification coupled to Nanopore sequencing for the detection of SARS-CoV-2 infection at scale in symptomatic and asymptomatic populations
Authors: Ptasinska Anetta , Whalley Celina , Bosworth Andrew , Poxon Charlie , Bryer Clare , Grippon Seden , Wise Emma , Armson Bryony , Goring Alice , Cortes Nicholas J , Howson Emma , Snell Gemma , Forster Jade , Mattocks Chris , Frampton Sarah , Anderson Rebecca , Cleary David , Parker Joe , Boukas Konstantinos , Graham Nichola , Cellura Doriana , Garratt Emma , Skilton Rachel , Sheldon Hana , Collins Alla , Ahmad Nusreen , Friar Simon , Godfrey Keith , Williams Tim , Deans Sandi , Douglas Angela , Hill Sue L , Kidd Michael , Porter Deborah , Kidd Stephen P , Fowler Veronica , Williams Tony , Richter Alex G , Beggs Andrew D
Published: December 2020

Introduction:
Rapid, high throughput diagnostics are a valuable tool, allowing the detection of SARS-CoV-2 in populations, in order to identify and isolate people with asymptomatic and symptomatic infections. Reagent shortages and restricted access to high throughput testing solutions have limited the effectiveness of conventional assays such as reverse transcriptase quantitative PCR (RTqPCR), particularly throughout the first months of the pandemic. We investigated the use of LamPORE, where loop mediated isothermal amplification (LAMP) is coupled to nanopore sequencing technology, for the detection of SARS CoV 2 in symptomatic and asymptomatic populations.
Methods: In an asymptomatic prospective cohort; health care workers across four sites (Birmingham, Southampton, Basingstoke and Manchester) self swabbed with nasopharyngeal swabs weekly for three weeks and supplied a saliva specimen daily. These samples were tested for SARS CoV 2 RNA using the Oxford Nanopore LamPORE system and a reference RTqPCR assay on extracted sample RNA. A second retrospective cohort of 848 patients with influenza like illness from March 2020 to June 2020, were similarly tested from nasopharyngeal swabs.
Results: In the asymptomatic cohort a total of 1200 participants supplied 23,427 samples (3,966 swab, 19,461 saliva) over a three-week period. The incidence of SARS CoV 2 was 0.95% using LamPORE. Diagnostic sensitivity and specificity was > 99.5% in both swab and saliva asymptomatic samples as compared to the reference RTqPCR test. In the retrospective symptomatic cohort, the incidence was 13.4% and the sensitivity and specificity were 100%.
Conclusions: LamPORE is a highly accurate methodology for the detection of SARS CoV 2 in both the symptomatic and asymptomatic population settings and can be used as an alternative to RTqPCR.
The association of covid-19 infection with household food insecurity among Iranian population
Authors: Kalantari Naser , Ezzeddin Neda , Eini-Zinab Hassan
Published: December 2020

Objective: The aim of this study was to investigate the association of food insecurity score with the status of Covid-19 infection.
Design: An online cross-sectional study. Demographic and socio-economic information were collected by questionnaire. Household Food Insecurity Access Scale (HFIAS) was used in assessing household food security status. The analysis data was done by IBM SPSS 22.0, using Chi-square test, ANOVA test and Multinomial logistic regression model.
Setting: Iran
Participants: 2871 Iranian adults (over 18 years old)
Results: findings indicated that men [OR=0.60, CI= (0.41, 0.87), P<0.05], and healthcare personnel [OR=3.66, CI= (1.90, 7.05), P<0.001] were at higher risk for Covid-19. It was also shown that the food insecurity score is significantly higher among infected people compared to not-infected [OR=1.03, CI= (1.00, 1.05), P<0.05]. The comparison between suspected and not-infected individuals only indicated the significant differences in perceived COVID-19 prevention score, which was higher among not-infected people [OR=0.88, CI=(0.84,0.93), P<0.001].
Conclusion: Based on the results, in addition to long-term policies to improve food security, policymakers and planners need to plan and implement short-term policies (financial or food assistance) to reduce society vulnerability to the Covid-19.
Loss of filtration function in diabetic glomeruli is associated with ultrastructural changes in glomerular endothelial cell fenestrations
Authors: Finch Natalie , Fawaz Sarah , Neal Chris , Butler Matthew , Lee Vivian , Lay Abigai , Stevens Megan , Dayalan Lusyan , Band Hamid , Mellor Harry , Welsh Gavin , Foster Rebecca , Satchell Simon
Published: December 2020

Background: The study of glomerular endothelial cell (GEnC) fenestrations including key regulatory factors is neglected despite their loss in diabetic nephropathy, a disease associated with decreased filtration function, being previously described.
Methods: We comprehensively characterised GEnC fenestral and renal filtration functional changes including measurement of glomerular ultrafiltration coefficient and glomerular filtration rate (GFR) in diabetic mice and humans. We further evaluated Eps homology domain protein-3 (Ehd3) as a potential regulator of GEnC fenestrations.
Results: This study identified loss of GEnC fenestration density which was associated with decreased renal filtration function in diabetic nephropathy. We also identified increased GEnC fenestration width, an ultrastructural change that may develop to maintain filtration surface area. GEnC fenestration width was negatively associated with renal filtration function considered a result of development of diaphragms in widening fenestrations providing resistance to filtration. The increased presence of diaphragmed fenestrations in diabetes was supported by increased PLVAP1 expression. We identified decreased glomerular Ehd3 expression in diabetes and demonstrated its association with GEnC fenestration measurements suggesting its role in regulating fenestrations. We further demonstrated reduced fenestration formation in vitro in an Ehd3 knockdown cell line. Ehd3 was positively associated with filtration function suggesting loss of glomerular Ehd3 expression in disease may contribute to declining glomerular filtration function through aberrant GEnC fenestration regulation.
Conclusions: This is the first study to demonstrate the critical role of GEnC fenestrations in renal filtration function and identify a key regulator, Ehd3, that may serve as a therapeutic target to retore filtration function in disease.
Utilization of the repeated squat-stand model for studying the directional sensitivity of the cerebral pressure-flow relationship
Authors: Labrecque Lawrence , Smirl Jonathan D , Brassard Patrice
Published: December 2020

Hysteresis in the cerebral pressure-flow relationship describes the superior ability of the cerebrovasculature to buffer cerebral blood flow changes when mean arterial pressure (MAP) acutely increases compared to when MAP acutely decreases. This phenomenon can be evaluated by comparing the change in middle cerebral artery mean blood velocity (MCAv) per change in MAP during either acute increases or decreases in MAP induced by repeated squat-stands (RSS). However, no real baseline can be employed for this particular protocol as there is no true stable reference point. Herein, we characterized a novel metric using the greatest MAP oscillations induced by RSS without using an independent baseline value and adjusted for time intervals (ΔMCAvT/ΔMAPT). We also examined whether this metric during each RSS transition were comparable between each other over a 5-min period. ΔMCAvT/ΔMAPTwas calculated using the minimum to maximum MCAv and MAP for each RSS performed at 0.05 Hz and 0.10 Hz. We compared averaged ΔMCAvT/ΔMAPTduring MAP increases and decreases in 74 healthy subjects [9 women; 32 ± 13 years]. ΔMCAvT/ΔMAPTwas lower for MAP increases than MAP decreases at 0.10 Hz RSS only (0.91 ± 0.34 vs. 1.01 ± 0.44 cm·s-1/mmHg; p = 0.0013). For both frequency and MAP direction, time during RSS had no effect on ΔMCAvT/ΔMAPT. This novel analytical method supports the use of the RSS model to evaluate the directional sensitivity of the pressure-flow relationship. These results contribute to the importance of considering the direction of MAP changes when evaluating dynamic cerebral autoregulation.

News & Noteworthy

Repeated squat-stand maneuvers are able to examine the directional sensitivity of the cerebral pressure-flow relationship. These maneuvers induce stable physiological cyclic changes where brain blood flow changes with blood pressure increases are buffered more than decreases. These results highlight the importance of considering directional blood pressure changes within cerebral autoregulation.
The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression
Authors: Gentile Alessandra , Bensimon-Brito Anabela , Priya Rashmi , Maischein Hans-Martin , Piesker Janett , Günther Stefan , Gunawan Felix , Stainier Didier Y.R.
Published: December 2020

The zinc finger transcription factor Snai1 is a well-known regulator of epithelial-to-mesenchymal transition (EMT)1, 2; it is required for mesoderm ingression in flies3and neural crest delamination in vertebrates4. During cardiac development, Snai1-regulated EMT is necessary for myocardial precursor migration and valve formation5, 6. However, a role for Snai1 in maturing cardiomyocytes (CMs) has not been reported. Here, using genetic, transcriptomic and chimeric analyses in zebrafish, we find that Snai1b is required for myocardial wall integrity. Global loss ofsnai1bleads to the extrusion of CMs away from the cardiac lumen, a process we show is dependent on cardiac contractility. Examining CM junctions insnai1bmutants, we observed that N-cadherin localization was compromised, thereby likely weakening cell-cell adhesion. In addition, extruding CMs exhibit increased actomyosin contractility basally, as revealed by the specific enrichment of canonical markers of actomyosin tension - phosphorylated myosin light chain (active myosin) and the α-catenin epitope α-18. By comparing the transcriptome of wild-type andsnai1bmutant hearts at early stages of CM extrusion, we found the dysregulation of intermediate filament genes in mutants including the upregulation ofdesmin b. We tested the role ofdesmin bin myocardial wall integrity and found that CM-specificdesmin boverexpression led to CM extrusion, recapitulating thesnai1bmutant phenotype. Altogether, these results indicate that Snai1 is a critical regulator of intermediate filament gene expression in CMs, and that it maintains the integrity of the myocardial epithelium during embryogenesis, at least in part by repressingdesmin bexpression.
Corporal Punishment in Schools in the Jaffna District of Sri Lanka – A students’ view
Authors: Sathiadas M G , Antonyraja Annieston , Viswalingam Arunath , Arunthavavinajagamoorthy Shubanki
Published: December 2020

Purpose:

Corporal-punishment has been prevailing in Sri- Lanka despite the strict law against it. Objectives of this study was to find the prevalence of corporal punishment in schools and the knowledge, perceptions and actions in the children.

Methods:

A community based cross sectional descriptive study done among school students from Jaffna district using a pretested questionnaire containing 40 questions. Multistage stratified proportionate cluster sampling was used to recruit the students. Scoring systems were used to determine the knowledge and perception of Corporal-punishment. Data was analyzed using SPSS version 20.

Results:

A total of 1130 students were recruited with mean age of 17.58±0.5y. A total of 687(60.7%) said they received some form of corporal punishment at least once during the school term. Physical punishment (64.5%) was common followed by psychological (27.1%). Teachers (54.8%) were the main group involved in corporal-punishment. Mean score for the knowledge was 11.11 and a good knowledge score was seen in 37.3% of the students. Participants with good knowledge favored law against it (p value<0.05), take legal action (P value<0.05) and supported complete prohibition of it (P value<0.05). Nearly 2% (n=22) had good perception and 40.8% (n=461) had a more positive perception. Majority (86.3%) preferred an alternative way of discipline and felt it was detrimental to the future (89.5%).

Conclusion:

Corporal-punishment was experienced by majority of the students in school and the students were aware that it was illegal and those with good knowledge were willing to take legal action.
Robot-Assisted SpiderMass forin vivoReal-Time Topography Mass Spectrometry Imaging
Authors: Ogrinc Nina , Kruszewski Alexandre , Chaillou Paul , Saudemont Philippe , Lagadec Chann , Salzet Michel , Duriez Christian , Fournier Isabelle
Published: December 2020

Mass Spectrometry Imaging (MSI) has shown to bring invaluable information for biological and clinical applications. However, conventional MSI is generally performedex vivofrom tissue sections. Here, we develop a novel MS-based method forin vivomass spectrometry imaging. By coupling the SpiderMass technology - that providesin vivominimally invasive analysis – to a robotic arm of high accuracy, we demonstrate that images can be acquired from any surface by moving the laser probe above the surface. By equipping the robotic arm with a sensor, we are also able to both get the topography image of the sample surface and the molecular distribution, and then and plot back the molecular data, directly to the 3D topographical image without the need for image fusion. This is shown for the first time with the 3D topographic MS-Based whole-body imaging of a mouse. Enabling fast in vivo MSI bridged to topography pave the way for surgical applications to excision margins.