bluuebunny/crossref_metadata_2025 huggingface dataset:
What level of neutralising antibody protects from COVID-19?
Authors: Khoury David S , Cromer Deborah , Reynaldi Arnold , Schlub Timothy E , Wheatley Adam K , Juno Jennifer A , Subbarao Kanta , Kent Stephen J , Triccas James A , Davenport Miles P
Published: March 2021

Both previous infection and vaccination have been shown to provide potent protection from COVID-19. However, there are concerns that waning immunity and viral variation may lead to a loss of protection over time. Predictive models of immune protection are urgently needed to identify immune correlates of protection to assist in the future deployment of vaccines. To address this, we modelled the relationship between in vitro neutralisation levels and observed protection from SARS-CoV-2 infection using data from seven current vaccines as well as convalescent cohorts. Here we show that neutralisation level is highly predictive of immune protection. The 50% protective neutralisation level was estimated to be approximately 20% of the average convalescent level (95% CI = 14-28%). The estimated neutralisation level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level (CI = 0.7-13%, p = 0.0004). Given the relationship between in vitro neutralization titer and protection, we then used this to investigate how waning immunity and antigenic variation might affect vaccine efficacy. We found that the decay of neutralising titre in vaccinated subjects over the first 3-4 months after vaccination was at least as rapid as the decay observed in convalescent subjects. Modelling the decay of neutralisation titre over the first 250 days after immunisation predicts a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralisation titres against some SARS-CoV-2 variants of concern are reduced compared to the vaccine strain and our model predicts the relationship between neutralisation and efficacy against viral variants. Our analyses provide an evidence-based prediction of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia
Authors: Palmer Duncan S , Howrigan Daniel P , Chapman Sinéad B , Adolfsson Rolf , Bass Nick , Blackwood Douglas , Boks Marco PM , Chen Chia-Yen , Churchhouse Claire , Corvin Aiden P , Craddock Nicholas , Curtis David , Di Florio Arianna , Dickerson Faith , Goes Fernando S , Jia Xiaoming , Jones Ian , Jones Lisa , Jonsson Lina , Kahn Rene S , Landén Mikael , Locke Adam , McIntosh Andrew , McQuillin Andrew , Morris Derek W , O’Donovan Michael C , Ophoff Roel A , Owen Michael J , Pedersen Nancy , Posthuma Danielle , Reif Andreas , Risch Neil , Schaefer Catherine , Scott Laura , Singh Tarjinder , Smoller Jordan W , Solomonson Matthew , St. Clair David , Stahl Eli A , Vreeker Annabel , Walters James , Wang Weiqing , Watts Nicholas A , Yolken Robert , Zandi Peter , Neale Benjamin M
Published: March 2021

Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA,AKAP11emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06,P= 2.83 × 10−9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.
A phase 2 study of the inhaled pan-JAK inhibitor TD-0903 in severe COVID-19: Part 1
Authors: Singh Dave , Bogus Maxim , Moskalenko Valentyn , Lord Robert , Moran Edmund J. , Crater Glenn D. , Bourdet David L. , Pfeifer Nathan D. , Woo Jacky , Kaufman Elad , Lombardi David A. , Weng Emily Y. , Nguyen Tuan , Woodcock Ashley , Haumann Brett , Saggar Rajeev
Published: March 2021

Background

Lung-targeted anti-inflammatory therapy could potentially improve outcomes in patients with COVID-19. The novel inhaled pan-Janus kinase (JAK) inhibitor TD-0903 was designed to optimise delivery to the lungs while limiting systemic exposure. Here, we report results from the completed Part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19.

Methods

Part 1 explored 3 doses of TD-0903 (1, 3, and 10 mg once-daily for 7 days) and placebo in a randomised, double-blind, ascending-dose study. Each dose cohort comprised 8 hospitalized patients (6:2 TD-0903:placebo) with PCR-confirmed COVID-19 requiring supplemental oxygen and receiving background standard-of-care therapy. Key objectives included safety and tolerability, pharmacokinetics, and oxygen saturation/fraction of inspired oxygen ratio; clinical outcomes were also explored. Data were summarised as descriptive statistics.

Results

Twenty-five patients were randomised to receive TD-0903 1 mg (n = 6), 3 mg (n = 7), 10 mg (n = 6), or placebo (n = 6). Almost all patients (92%) received background dexamethasone; 3 (12%) received remdesivir. TD-0903 was generally well tolerated with no drug-related serious adverse events. Low plasma concentrations of TD-0903 were observed at all doses. Clinically favourable numerical trends in patients receiving TD-0903 vs placebo included improved 8-point clinical status, shortened hospitalisation, improved oxygenation, and fewer deaths.

Conclusions

In Part 1 of this phase 2 trial, the novel inhaled JAK inhibitor TD-0903 showed potential for treatment of patients with severe COVID-19. TD-0903 3 mg is being evaluated in Part 2 of the randomised, double-blind, parallel-group trial in 198 hospitalized patients with COVID-19.
May we overcome the current serious limitations for distributing reconstituted mRNA vaccines?
Authors: Grau Santiago , Ferrández Olivia , Martín-García Elena , Maldonado Rafael
Published: March 2021

There is an urgent need to ameliorate the transport of the reconstituted vaccines to the vaccination sites to improve the COVID-19 vaccination campaigns. The maintenance of the integrity of the mRNA of the different COVID-19 reconstituted vaccines after continuous movement at room temperature during at least three hours ensures the safety of a ground transportation.
ROC plot and AUC with binary classifiers: pragmatic analysis of cognitive screening instruments
Authors: Mbizvo Gashirai K , Larner Andrew J
Published: March 2021

Receiver operating characteristic (ROC) plots are a performance graphing method showing the relative trade-off between test benefits (true positive rate) and costs (false positive rate) with the area under the curve (AUC) giving a scalar value of test performance. It has been suggested that ROC and AUC may be potentially misleading when examining binary predictors rather than continuous scales. The purpose of this study was to examine ROC plots and AUC values for two binary classifiers of cognitive status (applause sign, attended with sign), a cognitive screening instrument producing categorical data (Codex), and a continuous scale screening test (Mini-Addenbrooke’s Cognitive Examination), the latter two also analysed with single fixed threshold tests. For each of these plots, AUC was calculated using different methods. The findings indicate that if categorical or continuous measures are dichotomised then the calculated AUC may be an underestimate, thus affecting screening or diagnostic test accuracy which in the context of clinical practice may prove to be misleading.
Examining SARS-CoV-2 Interventions in Residential Colleges Using an Empirical Network
Authors: Hambridge Hali L. , Kahn Rebecca , Onnela Jukka-Pekka
Published: March 2021

Abstract

Universities have turned to SARS-CoV-2 models to examine campus reopening strategies1–9. While these studies have explored a variety of modeling techniques, all have relied on simulated data. Here, we use an empirical proximity network of college freshmen10, ascertained using smartphone Bluetooth, to simulate the spread of the virus. We investigate the role of testing, isolation, mask wearing, and social distancing in the presence of implementation challenges and imperfect compliance. Here we show that while frequent testing can drastically reduce spread if mask wearing and social distancing are not widely adopted, testing has limited impact if they are ubiquitous. Furthermore, even moderate levels of immunity can significantly reduce new infections, especially when combined with other interventions. Our findings suggest that while testing and isolation are powerful tools, they have limited benefit if other interventions are widely adopted. If universities can attain high levels of masking and social distancing, they may be able to relax testing frequency to once every two to four weeks.
Prognosis of Acute Ischaemic Stroke in Cancer Patients: A National Inpatient Sample Study
Authors: Pana Tiberiu A , Mohamed Mohamed O , Mamas Mamas A , Myint Phyo K
Published: March 2021

Background and Purpose

Whilst cancer is a risk factor for acute ischaemic stroke (AIS), its impact on AIS prognosis between metastatic and non-metastatic (MC and NMC) disease is poorly understood. Furthermore, the receipt of intravenous thrombolysis (IVT) and endovascular thrombectomy (ET) and their outcomes is poorly researched.

Methods

AIS admissions from the National Inpatient Sample (NIS) were included (October 2015-December 2017). Multivariable logistic regressions adjusting for a wide range of confounders analysed the relationship between NMC and MC and AIS in-hospital outcomes (mortality, prolonged hospitalisation >4 days and routine home discharge). Interaction terms with IVT and ET were also computed to explore their impact amongst cancer patients.

Results

221,249 records representative of 1,106,045 admissions were included. There were 38,855 (3.51%) patients with co-morbid cancers: NMC=53.78% and MC=46.22%. NMC was associated with 23% increased odds of in-hospital mortality (odds ratio (95% confidence interval) = 1.23 (1.07-1.42)), which was mainly driven by pancreatic and respiratory cancers. This association was entirely offset by both IVT and ET. MC was associated with 2-fold increased odds of in-hospital mortality (2.16 (1.90-2.45)), which was mainly driven by respiratory, pancreatic and colorectal cancers. This association was only offset by ET. Both NMC and MC were significantly associated with prolonged hospitalisation and decreased odds of routine discharge.

Conclusions

Cancer patients are at higher odds of acute adverse outcomes after AIS and warrant robust primary prevention. IVT and ET improve these outcomes and should thus be offered routinely unless otherwise contraindicated in this group of stroke patients.
Towards adaptive deep brain stimulation: clinical and technical notes on a novel commercial device for chronic brain sensing
Authors: Thenaisie Yohann , Palmisano Chiara , Canessa Andrea , Keulen Bart J. , Capetian Philipp , Jiménez Mayte Castro , Bally Julien F. , Manferlotti Elena , Beccaria Laura , Zutt Rodi , Courtine Grégoire , Bloch Jocelyne , van der Gaag Niels A. , Hoffmann Carel F. , Moraud Eduardo Martin , Isaias Ioannis U. , Contarinoe M. Fiorella
Published: March 2021

Background

Technical advances in deep brain stimulation (DBS) are crucial to improve therapeutic efficacy and battery life. A prerogative of new devices is the recording and processing of a given input signal to instruct the delivery of stimulation.

Objective

We studied the advances and pitfalls of one of the first commercially available devices capable of recording brain local field potentials (LFP) from the implanted DBS leads, chronically and during stimulation.

Methods

We collected clinical and neurophysiological data of the first 20 patients (14 with Parkinson’s disease [PD], five with various types of dystonia, one with chronic pain) that received the Percept™ PC in our centers. We also performed tests in a saline bath to validate the recordings quality.

Results

The Percept PC reliably recorded the LFP of the implanted site, wirelessly and in real time. We recorded the most promising clinically useful biomarkers for PD and dystonia (beta and theta oscillations) with and without stimulation. Critical aspects of the system are presently related to contact selection, artefact detection, data loss, and synchronization with other devices. Furthermore, we provide an open-source code to facilitate export and analysis of data.

Conclusion

New technologies will soon allow closed-loop neuromodulation therapies, capable of adapting the stimulation based on real-time symptom-specific and task-dependent input signals. However, technical aspects need to be considered to ensure clean synchronized recordings. The critical use by a growing number of DBS experts will alert new users about the currently observed shortcomings and inform on how to overcome them.
An“In-House”ELISA for SARS-CoV-2 RBD uncovers elevated immune response at higher altitudes
Authors: Rodrigo Tomas Grau , Diego Ploper , César Ávila , Esteban Vera Pingitore , Carolina Maldonado , Silvina Chaves , Benjamín Socias Sergio , Agustín Stagnetto , Silvia Navarro , Rossana Chahla , Mónica Aguilar , Conrado Llapur , Patricia Aznar , Malena Alcorta , Dardo Costas , Isolina Flores , Dar Heinze , Gabriela Apfelbaum , Raúl Mostoslavsky , Gustavo Mostoslavsky , Silvia Cazorla , Gabriela Perdigón , Rosana Chehín
Published: March 2021

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first reported in Wuhan has caused a global pandemic with dramatic health and socioeconomic consequences. The Coronavirus Disease 2019 (COVID-19) associated represents a challenge for health systems that had to quickly respond developing new diagnostic and therapeutic strategies. In the present work, we developed an “In House” ELISA with high sensitivity (92.2 %), specificity (100%) and precision (93.9%), with an area under the ROC curve (AUC) of 0.991, rendering the assay as an excellent serological test to correctly discriminate between SARS-COv-2 infected and non-infected individuals and study population seroprevalence. Among 758 patients evaluated for SARS-CoV-2 diagnosis in the province of Tucumán, Argentina, we found a Pearson correlation coefficient of 0.5048 between antibodies elicited against the RBD and the nucleocapsid (N) antigen. Additionally, 33.6% of individuals diagnosed with COVID-19 displayed mild levels of RBD-IgG antibodies, while 19% of the patients showed high antibody titers. Interestingly, patients with SARS-COV-2 infection over 60 years old elicited significantly higher levels of IgG antibodies against RBD compared to younger ones, while no difference was found between women and men. Surprisingly, individuals from a high altitude village displayed statistically significant higher and longer lasting anti-RBD antibodies compared to those from a city at a lower altitude, suggesting that a hypobaric hypoxia-adapted mechanism may act as a protective factor for COVID-19. To our knowledge, this is the first report correlating altitude with increased humoral immune response against SARS-Cov-2 infection.
Mapping the human genetic architecture of COVID-19 by worldwide meta-analysis
Authors:   The COVID-19 Host Genetics Initiative, Ganna Andrea
Published: March 2021

The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising up to 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases. They also represent potentially actionable mechanisms in response to infection. We further identified smoking and body mass index as causal risk factors for severe COVID-19. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was enabled by prioritization of shared resources and analytical frameworks. This working model of international collaboration provides a blue-print for future genetic discoveries in the event of pandemics or for any complex human disease.
Antimicrobial susceptibility patterns of respiratory Gram-negative bacterial isolates from COVID-19 patients in Switzerland
Authors: Gysin Marina , Acevedo Claudio Tirso , Haldimann Klara , Bodendoerfer Elias , Imkamp Frank , Bulut Karl , Buehler Philipp Karl , Brugger Silvio Daniel , Becker Katja , Hobbie Sven N.
Published: March 2021

Background

Bacterial superinfections associated with COVID-19 are common in ventilated ICU patients and impact morbidity and lethality. However, the contribution of antimicrobial resistance to the manifestation of bacterial infections in these patients has yet to be elucidated.

Methods

We collected 70 Gram-negative bacterial strains, isolated from the lower respiratory tract of ventilated COVID-19 patients in Zurich, Switzerland between March and May 2020. Species identification was performed using MALDI-TOF; antibiotic susceptibility profiles were determined by EUCAST disk diffusion and CLSI broth microdilution assays. SelectedPseudomonas aeruginosaisolates were analyzed by whole-genome sequencing.

Results

P. aeruginosa(46%) andEnterobacterales(36%) comprised the two largest etiologic groups. Drug resistance inP. aeruginosaisolates was high for piperacillin/tazobactam (65.6%), cefepime (56.3%), ceftazidime (46.9%) and meropenem (50.0%).Enterobacteralesisolates showed slightly lower levels of resistance to piperacillin/tazobactam (32%), ceftriaxone (32%), and ceftazidime (36%). AllP. aeruginosaisolates and 92% ofEnterobacteralesisolates were susceptible to aminoglycosides, with apramycin found to provide best-in-class coverage. Genotypic analysis of consecutiveP. aeruginosaisolates in one patient revealed a frameshift mutation in the transcriptional regulatornalCthat coincided with a phenotypic shift in susceptibility to β-lactams and quinolones.

Conclusions

Considerable levels of antimicrobial resistance may have contributed to the manifestation of bacterial superinfections in ventilated COVID-19 patients, and may in some cases mandate consecutive adaptation of antibiotic therapy. High susceptibility to amikacin and apramycin suggests that aminoglycosides may remain an effective second-line treatment of ventilator-associated bacterial pneumonia, provided efficacious drug exposure in lungs can be achieved.
Methylome-wide association study of early life stressors and adult mental health reveals a relationship between birth date and cell type composition in blood
Authors: Howard David M. , Pain Oliver , Arathimos Ryan , Barbu Miruna C. , Amador Carmen , Walker Rosie M. , Jermy Bradley , Adams Mark J. , Deary Ian J. , Porteous David , Campbell Archie , Sullivan Patrick F. , Evans Kathryn L. , Arseneault Louise , Wray Naomi R. , Meaney Michael , McIntosh Andrew M. , Lewis Cathryn M.
Published: March 2021

The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes in adulthood are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data was assayed at 713,522 CpG sites from 9,537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive data on genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes were conducted using DNA methylation data collected from adult whole blood samples. Two genes involved with different developmental pathways (PRICKLE2 and ABI1) were annotated to CpG sites associated with preterm birth (P < 1.27 × 10 −9). A further two genes important to the development of sensory pathways (SOBP and RPGRIP1) were annotated to sites associated with low birth weight (P < 4.35 × 10−8). Genes and gene-sets annotated from associated CpGs sites and methylation profile scores were then used to quantify any overlap between the early life environment and mental health traits. However, there was no evidence of any overlap after applying a correction for multiple testing. Time of year of birth was found to be associated with a significant difference in estimated lymphocyte and neutrophil counts. Early life environments influence the risk of developing mental health disorders later in life; however, this study provides no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.
The impact of the UK’s first COVID-19 lockdown on rates of violence and aggression on psychiatric inpatient wards
Authors: Payne-Gill James , Whitfield Corin , Beck Alison
Published: March 2021

Aims

Inpatient life in UK mental health hospitals was profoundly altered during the first wave of the COVID-19 pandemic. We analysed whether these changes impacted the rate of violent and aggressive incidents across acute adult wards and psychiatric intensive care units in a South London NHS Mental Health Trust during the first UK lockdown.

Methods

We used an interrupted time series analysis to assess whether the rate of violent and aggressive incidents changed during the lockdown period from 23rd March 2020 to 15th June 2020. We used a quasi-poisson general additive model to model the weekly rate of violent incidents as a function of a seasonal trend, time trend, and impact of lockdown, using data from 1st January 2017 to 27th September 2020.

Results

There was a 35% increase in the rate of incidents of violence and aggression [IR = 1.35, 95% CI: 1.15 – 1.58, p < 0.001] between March 23rd 2020 and June 15th 2020. In addition, there was strong evidence of temporal (p < 0.001) and seasonal trends (p < 0.001).

Conclusions

Our results suggest that restrictions to life increased the rate of violent incidents on the mental health wards studied here.
Multicenter, Randomized, Open-Label, Comparative Study of Therapeutic Efficacy, Safety and Tolerability of BNO 1030 application in the technology of delayed prescription of antibiotics in patients with severe acute tonsillitis
Authors: Popovych V. I. , Koshel I. V. , Malofiichuk O. N. , Pyletska L. I. , Semeniuk O. A. , Martynnyk O. V. , Orlovska R. N. , Leta O. I.
Published: March 2021

Acute bacterial tonsillitis occurs in 20 –30 % of immunocompetent children; however, the frequency of antibacterial drug prescriptions reaches up to 90 %. Delayed antibiotic prescription is recommended by current guidelines. The study objective was to determine the efficacy of phytoneering extract BNO 1030 in the technology of delayed antibiotic prescription in patients with severe acute tonsillitis.

Methods

In the multicenter, randomized, open-label, comparative study, 182 out of 200 randomized children with acute tonsillitis aged 6 –12 years completed the study. Evaluation criteria: a reduced severity of sore throat when swallowing and at rest, throat irritation at rest, hyperemia of the tonsils assessed by a physician according to a 4-point scale at each visit compared to Visit 1, dynamics of self-assessment of general well-being, intensity of sore throat and difficulty swallowing according to a 10-point visual analogue scale, frequency of antibiotic prescriptions, therapeutic benefit from BNO 1030 in days.

Results

The use of phytotherapeutic medicinal product BNO 1030 in addition to the standard symptomatic treatment of severe acute tonsillitis provides a clinically significant, adequate reduction in the symptom severity assessed by a physician at V2 (p < 0.005). There are significant differences in the patient’s self-assessment of the symptoms from treatment Day 2 (p < 0.005). This allows to significantly reduce the duration of systemic antipyretic administration (p < 0.005). In the first days of treatment, when a decision on delay of antibiotic prescription is made, a therapeutic benefit in two days in patients of the treatment group was observed compared to the control group. The use of BNO 1030 in patients with severe acute tonsillitis significantly reduces, by 43.7 % or 2.3 times, the need for prescribing antibiotic therapy as part of the technology of delayed antibiotic prescription (p < 0.005). During treatment, no side effects and complications of the disease were recorded.

Conclusion

BNO 1030 is a safe and effective medicinal product for the treatment of severe acute tonsillitis in children aged 6 –12 years. It provides a significant therapeutic benefit when administered in addition to standard symptomatic therapy and reduces the irrational antibiotic prescription.

Trial registration

ClinicalTrials.gov Identifier: NCT04537819https://clinicaltrials.gov/ct2/show/NCT04537819?term=ATi-2&draw=2&rank=1
Environmental impact and life cycle financial cost of hybrid (reusable/ single-use) instruments versus single-use equivalents in laparoscopic cholecystectomy
Authors: Rizan Chantelle , Bhutta Mahmood F
Published: March 2021

Background

Hybrid surgical instruments contain both single-use and reusable components, potentially bringing together advantages from both approaches. The environmental and financial costs of such instruments have not previously been evaluated.

Methods

We used Life Cycle Assessment to evaluate the environmental impact of hybrid laparoscopic clip appliers, scissors and ports used for a laparoscopic cholecystectomy, comparing these with single-use equivalents. We modelled this using SimaPro and ReCiPe midpoint and endpoint methods to determine 18 midpoint environmental impacts including the carbon footprint, and three aggregated endpoint impacts. We also conducted life cycle cost analysis of products, taking into account unit cost, decontamination, and disposal costs.

Results

The environmental impact of using hybrid instruments for a laparoscopic cholecystectomy was lower than single-use equivalents across 17 midpoint environmental impacts, with mean average reductions of 60%. The carbon footprint of using hybrid versions of all three instruments was around one-quarter of single-use equivalents (1,756 g versus 7,194 g CO2e per operation), and saved an estimated 1.13 e-5 DALYs (disability associated life years, 74% reduction), 2.37 e-8 species.year (loss of local species per year, 76% reduction), and US $ 0.6 in impact on resource depletion (78% reduction). Scenario modelling indicated that environmental performance of hybrid instruments was better even if there was low number of reuses of instruments, decontamination with separate packaging of certain instruments, decontamination using fossil-fuel rich energy sources, or changing carbon intensity of instrument transportation. Total financial cost of using a combination of hybrid laparoscopic instruments was less than half that of single-use equivalents (GBP £131 versus £282).

Conclusion

Adoption of hybrid laparoscopic instruments could play an important role in meeting carbon reduction targets for surgery, and also save money.
Kinetics and seroprevalence of SARS-CoV-2 antibodies – a comparison of 3 different assays
Authors: Kahre Elisabeth , Galow Lukas , Unrath Manja , Haag Luise , Blankenburg Judith , Dalpke Alexander H. , Lück Christian , Berner Reinhard , Armann Jakob P.
Published: March 2021

Purpose

Comparing seroprevalence and antibody kinetics in three different commercially available assays for SARS-CoV-2.

Methods

Serostatus of COVID-19 patients was analyzed 5 months and 10 months after their infection, using three different assays: Diasorin LIAISON®, Euroimmun®, Abbott Diagnostics® ARCHITECT.

Results

Seropositivity at baseline differed significantly depending on the assay (Diasorin 81%, Euroimmun 83%, Abbott 59%). At follow-up antibody levels detected in the Diasorin assay were stable, while there was a significant loss in seropositivity in the Euroimmun and Abbott assays.

Conclusion

There are significant differences in SARS-CoV-2 antibody kinetics based on the specific assay used.

Trial registration number, date of registration

DRKS00022549, 29.07.2020 “retrospectively registered”
Impact of close interpersonal contact on COVID-19 incidence: evidence from one year of mobile device data
Authors: Crawford Forrest W. , Jones Sydney A. , Cartter Matthew , Dean Samantha G. , Warren Joshua L. , Li Zehang Richard , Barbieri Jacqueline , Campbell Jared , Kenney Patrick , Valleau Thomas , Morozova Olga
Published: March 2021

Close contact between people is the primary route for transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). We sought to quantify interpersonal contact at the population-level by using anonymized mobile device geolocation data. We computed the frequency of contact (within six feet) between people in Connecticut during February 2020 – January 2021. Then we aggregated counts of contact events by area of residence to obtain an estimate of the total intensity of interpersonal contact experienced by residents of each town for each day. When incorporated into a susceptible-exposed-infective-removed (SEIR) model of COVID-19 transmission, the contact rate accurately predicted COVID-19 cases in Connecticut towns during the timespan. The pattern of contact rate in Connecticut explains the large initial wave of infections during March–April, the subsequent drop in cases during June–August, local outbreaks during August–September, broad statewide resurgence during September–December, and decline in January 2021. Contact rate data can help guide public health messaging campaigns to encourage social distancing and in the allocation of testing resources to detect or prevent emerging local outbreaks more quickly than traditional case investigation.

One sentence summary

Close interpersonal contact measured using mobile device location data explains dynamics of COVID-19 transmission in Connecticut during the first year of the pandemic.
Type I, II, and III interferon signatures correspond to COVID-19 disease severity
Authors: Kim Myung-Ho , Salloum Shadi , Wang Jeffrey Y , Wong Lai Ping , Regan James , Lefteri Kristina , Manickas-Hill Zachary ,   MGH COVID-19 Collection & Processing Team, Li Jonathan Z , Sadreyev Ruslan I , Yu Xu G , Chung Raymond T
Published: March 2021

We analyzed the plasma levels of interferons and cytokines, and the expression of interferon-stimulated genes in peripheral blood mononuclear cells in COVID-19 patients with different disease severity. Mild patients exhibited transient type I interferon responses, while ICU patients had prolonged type I interferon responses with hyper-inflammation mediated by interferon regulatory factor 1. Type II interferon responses were compromised in ICU patients. Type III interferon responses were induced in the early phase of SARS-CoV-2 infection, even in convalescent patients. These results highlight the importance of type I and III interferon responses during the early phase of infection in controlling COVID-19 progression.
Dynamic versus Continuous Interventions: Optimizing Lockdown Policies for COVID-19
Authors: Akinci Kaan , Fdez Javier , Peña-Tapia Elena , Witkowski Olaf
Published: March 2021

In the context of the ongoing COVID-19 pandemic, while millions of people await the administration of a vaccine, social distancing remains the leading approach towards the effect commonly known as “flattening the curve” of infections. Over the last year, governmental administrations throughout the globe have implemented various lockdown policies in hopes of slowing down the transmission of the disease. However, the current lack of consensus on when and how these policies should be implemented reflects the need for further studies regarding these questions. In this paper, we tackle the issue of lockdown policy management, in particular in terms of lockdown placement (how often, when, and how long these periods should be), in order to minimize the peak of infections in a specific population. We introduce a novel combination of classic mathematical disease modelling using the equation-based SEIR model, and Evolutionary Strategies (ES) for optimizing the peak of infections. The method is evaluated using data collected in different countries, and a particular focus is placed on the study of the effect of specific model parameters on lockdown optimization, such as the transmission rate (β), of which 4 alternative modelling functions have been proposed and analyzed. Our results indicate that this transmission rate parameter significantly influences the resulting optimal strategies. In particular, the presence of a gradual decay of the rate of transmission during lockdown leads to longer, more sparsely placed confinement periods while an abrupt, instantaneous drop in the amount of contacts per person favors shorter but more frequent lockdowns. Although these results are limited by the scope of action provided by the simplicity of the SEIR model, they suggest that the influence of the evolution of the rate of transmission along the disease should be assessed in further studies with alternative optimization strategies (agent-based) and models (SEIRSHUD).
Lung function changes of divers after single deep heliox diving
Authors: Bao Xiao-Chen , Fang Yi-Qun , Yang Tao , Sun Yong-jun , Ma Jun , Xu Ji , Wang Nan , Wang Fang-Fang
Published: March 2021

Objectives

This study detects the changes in pulmonary function of divers after 80m, 100 m, and 120 m helium-oxygen (heliox) dive. Methods: A total of 26 divers participated in the experiment, of which 15 divers performed the 80m dive, 5 divers performed the 100m dive, and 6 divers performed the 120m dive. The exposure phases included breathing heliox or air in water and O2 in the hyperbaric chamber. Pulmonary function (forced flow-volume) was measured twice before diving, within 30 minutes after diving, and 24 hours after diving. The parameters examined were forced vital capacity (FVC), forced expired volume in 1 second (FEV1), forced expired flow from 25% to 75% volume expired (FEF25-75%), 25-75 percent maximum expiratory flow as compared with vital capacity (MEF 25-75%) and peak expiratory flow (PEF). Results: FEV1/FVC and MEF25% markedly decreased (p = 0.0395, p = 0.0496) within 30min after the 80m dive, but returned to base values at 24h after the dive. Other indicators showed a downward trend within 30min after 80m heliox diving (no statistical difference). Interestingly, FEV1, FEV1/FVC, PEF, MEF decreased after 100m heliox dives, but there was no statistical difference. However, in the 120m heliox dive, FEV1/FVC and MEF75% significantly decreased again after diving (p = 0.0098, p = 0.0073). The relatively small number and more proficient diving skills of divers in 100m and 120m diving may be responsible for the inconsistent results. But when the diving depth reached 120m, results again showed a significant statistical change. Conclusion: Single deep heliox diving can cause temporary expiratory and small airway dysfunction, which can be recovered at 24h after diving.
MRI versus mammography plus ultrasound in women at intermediate breast cancer risk: study design and protocol of the MRIB multicentre randomized controlled trial
Authors: Bonelli Luigina Ada , Calabrese Massimo , Belli Paolo , Corcione Stefano , Losio Claudio , Montemezzi Stefania , Pediconi Federica , Petrillo Antonella , Zuiani Chiara , Camera Lucia , Carbonaro Luca Alessandro , Cozzi Andrea , De Falco Alfano Daniele , Gristina Licia , Panzeri Marta , Poirè Ilaria , Schiaffino Simone , Tosto Simona , Trecate Giovanna , Trimboli Rubina Manuela , Valdora Francesca , Viganò Sara , Sardanelli Francesco
Published: March 2021

Background

In women at high/intermediate lifetime risk of breast cancer (BC-LTR), contrast-enhanced magnetic resonance imaging (MRI) added to mammography ±ultrasound (Mx±US) increases sensitivity but decreases specificity. An alternative strategy, MRI alone, potentially more cost-effective, has never been explored. This study aims to assess the characteristics of women who participated in a randomized trial offering MRI alone.

Methods

In this feasibility multicentre randomized controlled trial we compared MRI alone versus Mx+US in women at intermediate BC-risk (allocation ratio 1:1). Eligible women were aged 40 –59, with a 15–30% LTR and/or extremely dense breasts. Two screening rounds per woman were planned in ten centres experienced in MRI screening. Primary endpoint: rate of cancers detected in the two arms after 5 years of follow-up. Secondary endpoints: distribution of the risk profiles among the women enrolled in the trial; distribution of pathological stages and histology of cancers detected; interval cancer rate in the two arms.

Results

From 07/2013 to 11/2015, 1,254 women (mean age 47 years) were enrolled: 624 were assigned to Mx+US, 630 to MRI. Most of them were aged below 50 (72%) and premenopausal (45%), 52% used oral contraceptives. Among postmenopausal women, 15% had used hormone replacement therapy. Breast and/or ovarian cancer in mother and/or sisters were reported by 37% of enrolled women, extreme breast density was recorded for 79%, 41% had a 15–30% BC-LTR.

Conclusions

The distribution of BC-risk profile major determinants (breast density and family of breast and ovarian cancer) of enrolled women varied across centres.

Trial registration

NCT02210546

Key points

Mammography plus ultrasound are commonly used to screen women with dense breasts

Supplemental ultrasound increases BC detection rate but also false-positives and potential overdiagnosis

Whether increased BC detection by US translates into reduced mortality is unknown

MRI alone could be more risk- and cost-effective than mammography plus ultrasound
Insulin-stimulated adiponectin secretion in pregnancy is mediated by inhibition of adiponectin ubiquitination and degradation and is impaired in obesity
Authors: Aye Irving L. M. H. , Rosario Fredrick J. , Kramer Anita , Kristiansen Oddrun , Michelsen Trond M. , Powell Theresa L. , Jansson Thomas
Published: March 2021

In pregnancy, adiponectin serves as an endocrine link between maternal adipose tissue, placental function and fetal growth, with low adiponectin promoting placental function and fetal growth. Circulating adiponectin levels are decreased in obese pregnant women and in gestational diabetes, which is believed to contribute to the insulin resistance and increased risk of fetal overgrowth associated with these conditions. However, the molecular mechanisms governing adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood. Using visceral adipose tissue from lean and obese pregnant mice, we show that obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination and decreased total abundance of adiponectin. Moreover, adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes. We have identified key molecular pathways regulating adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.
Telencephalic outputs from the medial entorhinal cortex are copied directly to the hippocampus
Authors: Tsoi Sau Yee , Öncül Merve , Svahn Ella , Robertson Mark , Bogdanowicz Zuzanna , McClure Christina , Sürmeli Gülşen
Published: March 2021

Complementary actions of the neocortex and the hippocampus enable encoding and long-term storage of experience dependent memories. Standard models for memory storage assume that sensory signals reach the hippocampus from superficial layers of the entorhinal cortex (EC). Deep layers of the EC on the other hand relay hippocampal outputs to the telencephalic structures including many parts of the neocortex. Here we show that cells in Layer 5a of the medial EC send a copy of their telencephalic outputs back to the CA1 region of the hippocampus. Combining cell-type specific anatomical tracing, high-throughput RNA-sequencing based projection mapping and optogenetics aided circuit mapping, we show that these projections have a unique topography and target hippocampal pyramidal cells and interneurons. Our results suggest that rather than serving as a relay, deep EC may coordinate hippocampal-neocortical interactions in spatial cognition and memory.
Alpha satellite insertion close to an ancestral centromeric region
Authors: Giannuzzi Giuliana , Logsdon Glennis A. , Chatron Nicolas , Miller Danny E. , Reversat Julie , Munson Katherine M. , Hoekzema Kendra , Bonnet-Dupeyron Marie-Noëlle , Rollat-Farnier Pierre-Antoine , Baker Carl A. , Sanlaville Damien , Eichler Evan E. , Schluth-Bolard Caroline , Reymond Alexandre
Published: March 2021

Human centromeres are mainly composed of alpha satellite DNA hierarchically organized as higher-order repeats (HORs). Alpha satellite dynamics is shown by sequence homogenization in centromeric arrays and by its transfer to other centromeric locations, for example during the maturation of new centromeres. We identified during prenatal aneuploidy diagnosis by FISH ade novoinsertion of alpha satellite DNA from the centromere of chromosome 18 (D18Z1) into cytoband 15q26. Although bound by CENP-B, this locus did not acquire centromeric functionality as demonstrated by lack of constriction and absence of CENP-A binding. The insertion was associated with a 2.8 kbp deletion and likely occurred in the paternal germline. The site was enriched in long terminal repeats (LTRs) and located ~10 Mbp from the location where a centromere was ancestrally seeded and became inactive in the common ancestor of humans and apes 20-25 million years ago. Long read mapping to the T2T-CHM13 human genome assembly revealed that the insertion derives from a specific region of chromosome 18 centromeric 12-mer HOR array in which the monomer size follows a regular pattern. The rearrangement did not directly disrupt any gene or predicted regulatory element and did not alter the methylation status of the surrounding region, consistent with the absence of phenotypic consequences in the carrier. This case demonstrates a likely rare but new class of structural variation that we name ‘alpha satellite insertion’. It also expands our knowledge on alphoid DNA dynamics and conveys the possibility that alphoid arrays can relocate near vestigial centromeric sites.
Bidirectional modulation of pain-related behaviors in the zona incerta
Authors: Singh Sudhuman , Valdivia Spring , Soler-Cedeño Omar , Adke Anisha P. , Benowitz Barbara , Velasquez Daniela , Wilson Torri D. , Carrasquillo Yarimar
Published: March 2021

Central amygdala neurons expressing protein kinase C-delta (CeA-PKCδ) are sensitized following nerve injury and promote pain-related responses in mice. The neural circuits underlying modulation of pain-related behaviors by CeA-PKCδ neurons, however, remain unknown. In this study, we identified a functional monosynaptic inhibitory neural circuit that originates in CeA-PKCδ neurons and terminates in the ventral region of the zona incerta (ZI), a subthalamic structure previously linked to pain processing. Behavioral experiments further show that chemogenetic inhibition of GABAergic ZI neurons is sufficient to induce bilateral hypersensitivity in uninjured mice as well as contralateral hypersensitivity after nerve injury. In contrast, chemogenetic activation of GABAergic ZI neurons reverses nerve injury-induced hypersensitivity, demonstrating that silencing of the ZI is required for injury-induced behavioral hypersensitivity. Our results identify a previously unrecognized inhibitory efferent pathway from CeA-PKCδ neurons to the ZI and demonstrate that ZI-GABAergic neurons can bidirectionally modulate pain-related behaviors in mice.
Characterization and Heterotic Grouping of Traditional Assam rice (Oryza sativaL.)
Authors: Kumar Praveen , Sarma Debojit , Hazarika Mainu
Published: March 2021

Parents of heterotic hybrids are derived from different heterotic groups with high genetic divergence. Classification of traditional Assam rice germplasm in divergent pools will be advantageous to maximize the heterosis and thereby to ensure food security. In the present investigation, a group of 60 upland rice genotypes were characterized using 53 polymorphic simple sequence repeats (SSR) markers out of 83 molecular markers. The genetic divergence study using unweighted Neighbour-joining (UNJ) method clustered the 60 genotypes into 3 major clusters. The eleven most divergent genotypes identified were crossed in half diallel fashion to determine the mid-parent and better-parent heterosis values for the objective of heterotic grouping. No correlation between heterosis and genetic distance can be attributable to the use of a subset of markers not linked to yield or concerned. In genetic distance based heterotic grouping, the intra-group hybrids were recorded a higher frequency of crosses, grain yield per plant, specific combining ability effect, mid parent heterosis, better parent heterosis and standard parent heterosis value than those of inter-group hybrids. Overall, sn extensive choice of parents with attractive traits constellation leading to increased yield of the hybrids for much better complementation must be stressed along with a substantial hereditary distance for augmentation of yield heterosis.