bluuebunny/crossref_metadata_2025 huggingface dataset:
Preferences for Preoperative Education: A Qualitative Study of the Patient Perspective
Authors: Rockefeller Nicholas F. , Jeppson Peter , Komesu Yuko M. , Meriwether Kate V. , Ninivaggio Cara , Dunivan Gena
Published: January 2021

Objectives

The aim of this study is to identify and describe the information that is important to patients in preparation for surgery for pelvic floor disorders.

Methods

This qualitative study enrolled English- and Spanish-speaking patients who had undergone surgery for pelvic floor disorders in semistructured focus groups. We explored patients' attitudes and views regarding preoperative education, postoperative experiences, and quality of pain management. Focus groups were conducted until thematic saturation was reached. Deidentified focus group transcripts were analyzed with line-by-line coding and organized into themes using a team-based process.

Results

Four focus groups were conducted, 2 with English-speaking women (n = 14) and 2 with Spanish-speaking women (n = 10). Participants identified as non-Hispanic White 13/24 (54%) or Hispanic 11/24 (46%); 83% had at least a high school education and 50% had a bachelor's degree. Women reported 5 thematic domains of information that they deemed important for patients to know preoperatively: (1) preparation for surgery; (2) postoperative pain control expectations; (3) postoperative activity restrictions; (4) communication with care team; and (5) care experiences.

Conclusions

This study identifies information that is important to patients undergoing pelvic floor surgery. These patient-centered themes go beyond routine preoperative education and counseling. This information will aid future studies regarding the incorporation of patient-centered preoperative education and expectation setting with respect to improved pain control, patient satisfaction, and overall surgical experience.
Impact of obesity on outcomes after abdominal gunshot injury
Authors: Owattanapanich Natthida , Lewis Meghan , Schellenberg Morgan , Biswas Subarna , Matsushima Kazuhide , Lam Lydia , Demetriades Demetrios , Inaba Kenji
Published: January 2021

BACKGROUND

The impact of obesity, on outcomes after a gunshot wound, remains unclear. We hypothesized that patients with obesity have a higher burden of intraabdominal injuries after gunshot injury when compared with the nonobese population.

METHODS

The Trauma Quality Improvement Program database (2013–2017) was queried for all patients age ≥16 with abdominal gunshot injuries. Patients who died in the emergency department (ED), arrived without signs of life, had Abbreviated Injury Scale score ≥ 3 in any other region, or transferred from an outside hospital were excluded. The patient with obesity was defined by a body mass index ≥ 30. Demographics, injury data, and outcomes were abstracted and analyzed. Patients with obesity were compared to those with a body mass index < 30. Multivariate logistical regression was used to compare mortality between groups.

RESULTS

Of 34,138 patients with gunshot injuries, there were 2,616 (7.7%) with isolated abdominal injuries. Median age is 29 years (22–39 years), 86.7% men. Eight hundred twenty-seven (31.6%) were obese. The obese group was significantly older (32 [25–42] vs. 27 [22–37]; p < 0.001) with a higher incidence of hypertension (16.8% vs. 6.3%, p < 0.001) and diabetes mellitus (7.1% vs. 2.3%, p < 0.001). There was no difference in presenting vital signs, abdominal Abbreviated Injury Scale or Injury Severity Score between groups. The rate of superficial injuries and intraabdominal organ injuries were comparable between groups. Patients with obesity had significantly higher mortality (6.5% vs. 4.2%, p = 0.010), hospital length of stay (9 [7–16] vs. 9[6–14], p < 0.001), ventilator days (3 [2–5] vs. 3 [2–4], p = 0.015), and hospital-acquired pneumonia (3.5% vs. 1.7%, p = 0.005). On multivariate analysis, in addition to older age (odds ratio [OR], 1.050; p < 0.001), ED hypotension (OR, 3.192; p < 0.001), and ED tachycardia (OR, 3.714; p < 0.001), obesity was significantly associated with mortality (OR, 1.636; p = 0.021).

CONCLUSION

Patients with obesity are at a high risk of mortality after abdominal gunshot injury. Further prospective evaluation is warranted.

LEVEL OF EVIDENCE

Prognostic study, Level III.
Evaluation of the Berlin polytrauma definition: A Dutch nationwide observational study
Authors: Driessen Mitchell L.S. , Sturms Leontien M. , van Zwet Erik W. , Bloemers Frank W. , ten Duis Henk Jan , Edwards Michael J.R. , den Hartog Dennis , de Jongh Mariska A.C. , Leenhouts Peter A. , Poeze Martijn , Schipper Inger B. , Spanjersberg Richard , Wendt Klaus W. , de Wit Ralph J. , van Zutphen Stefan W.A.M. , Leenen Luke P.H.
Published: January 2021

BACKGROUND

The Berlin polytrauma definition (BPD) was established to identify multiple injury patients with a high risk of mortality. The definition includes injuries with an Abbreviated Injury Scale score of ≥3 in ≥2 body regions (2AIS ≥3) combined with the presence of ≥1 physiological risk factors (PRFs). The PRFs are based on age, Glasgow Coma Scale, hypotension, acidosis, and coagulopathy at specific cutoff values. This study evaluates and compares the BPD with two other multiple injury definitions used to identify patients with high resource utilization and mortality risk, using data from the Dutch National Trauma Register (DNTR).

METHODS

The evaluation was performed based on 2015 to 2018 DNTR data. First, patient characteristics for 2AIS ≥3, Injury Severity Score (ISS) of ≥16, and BPD patients were compared. Second, the PRFs prevalence and odds ratios of mortality for 2AIS ≥3 patients were compared with those from the Deutsche Gesellschaft für Unfallchirurgie Trauma Register. Subsequently, the association between PRF and mortality was assessed for 2AIS ≥3–DNTR patients and compared with those with an ISS of ≥16.

RESULTS

The DNTR recorded 300,649 acute trauma admissions. A total of 15,711 patients sustained an ISS of ≥16, and 6,263 patients had suffered a 2AIS ≥3 injury. All individual PRFs were associated with a mortality of >30% in 2AIS ≥3–DNTR patients. The increase in PRFs was associated with a significant increase in mortality for both 2AIS ≥3 and ISS ≥16 patients. A total of 4,264 patients met the BPDs criteria. Overall mortality (27.2%), intensive care unit admission (71.2%), and length of stay were the highest for the BPD group.

CONCLUSION

This study confirms that the BPD identifies high-risk patients in a population-based registry. The addition of PRFs to the anatomical injury scores improves the identification of severely injured patients with a high risk of mortality. Compared with the ISS ≥16 and 2AIS ≥3 multiple injury definitions, the BPD showed to improve the accuracy of capturing patients with a high medical resource need and mortality rate.

LEVEL OF EVIDENCE

Epidemiological study, level III.
Quantifying lives lost due to variability in emergency general surgery outcomes: Why we need a national emergency general surgery quality improvement program
Authors: Hashmi Zain G. , Jarman Molly P. , Havens Joaquim M. , Scott John W. , Goralnick Eric , Cooper Zara , Salim Ali , Haider Adil H.
Published: January 2021

BACKGROUND

Nearly 4 million Americans present to hospitals with conditions requiring emergency general surgery (EGS) annually, facing significant morbidity and mortality. Unlike elective surgery and trauma, there is no dedicated national quality improvement program to improve EGS outcomes. Our objective was to estimate the number of excess deaths that could potentially be averted through EGS quality improvement in the United States.

METHODS

Adults with the American Association for the Surgery of Trauma–defined EGS diagnoses were identified in the Nationwide Emergency Department Sample 2006 to 2014. Hierarchical logistic regression was performed to benchmark treating hospitals into reliability adjusted mortality quintiles. Weighted generalized linear modeling was used to calculate the relative risk of mortality at each hospital quintile, relative to best-performing quintile. We then calculated the number of excess deaths at each hospital quintile versus the best-performing quintile using techniques previously used to quantify potentially preventable trauma deaths.

RESULTS

Twenty-six million EGS patients were admitted, and 6.5 million (25%) underwent an operation. In-hospital mortality varied from 0.3% to 4.1% across the treating hospitals. Relative to the best-performing hospital quintile, an estimated 158,177 (153,509–162,736) excess EGS deaths occurred at lower-performing hospital quintiles. Overall, 47% of excess deaths occurred at the worst-performing hospitals, while 27% of all excess deaths occurred among the operative cohort.

CONCLUSION

Nearly 200,000 excess EGS deaths occur across the United States each decade. A national initiative to enable structures and processes of care associated with optimal EGS outcomes is urgently needed to achieve “Zero Preventable Deaths after Emergency General Surgery.”

LEVEL OF EVIDENCE

Care management, level IV.
Enhancing trauma registries by integrating traffic records and geospatial analysis to improve bicyclist safety
Authors: Doucet Jay J. , Godat Laura N. , Kobayashi Leslie , Berndtson Allison E. , Liepert Amy E. , Raschke Eric , Denny John W. , Weaver Jessica , Smith Alan , Costantini Todd
Published: January 2021

BACKGROUND

Trauma registries are used to identify modifiable injury risk factors for trauma prevention efforts. However, these may miss factors useful for prevention of bicycle-automobile collisions, such as vehicle speeds, driver intoxication, street conditions, and neighborhood characteristics. We hypothesize that (GIS) analysis of trauma registry data matched with a traffic accident database could identify risk factors for bicycle-automobile injuries and better inform injury prevention efforts.

METHODS

The trauma registry of a US Level I trauma center was used retrospectively to identify bicycle-motor vehicle collision admissions from January 1, 2010, to December 31, 2018. Data collected included demographics, vitals, injury severity scores, toxicology, helmet use, and mortality.

Matching with the Statewide Integrated Traffic Records System was done to provide collision, victim and GIS information. The GIS mapping of collisions was done with census tract data including poverty level scoring. Incident hot spot analysis to identify statistically significant incident clusters was done using the Getis Ord Gi* statistic.

RESULTS

Of 25,535 registry admissions, 531 (2.1%) were bicyclists struck by automobiles, 425 (80.0%) were matched to Statewide Integrated Traffic Records System. Younger age (odds ratio [OR], 1.026; 95% confidence interval [CI], 1.013–1.040, p < 0.001), higher census tract poverty level percentage (OR, 0.976; 95% CI, 0.959–0.993, p = 0.007), and high school or less education (OR, 0.60; 95 CI, 0.381–0.968; p = 0.036) were predictive of not wearing a helmet. Higher census tract poverty level percentage (OR, 1.019; 95% CI, 1.004–1.034; p = 0.012) but not educational level was predictive of toxicology positive—bicyclists in automobile collisions. Geographic information systems analysis identified hot spots in the catchment area for toxicology-positive bicyclists and lack of helmet use.

CONCLUSION

Combining trauma registry data and matched traffic accident records data with GIS analysis identifies additional risk factors for bicyclist injury. Trauma centers should champion efforts to prospectively link public traffic accident data to their trauma registries.

LEVEL OF EVIDENCE

Prognostic and Epidemiological, level III.
Physical Performance and Cognition in a Diverse Cohort
Authors: George Kristen M. , Gilsanz Paola , Peterson Rachel L. , Glymour Medellena Maria , Mayeda Elizabeth Rose , Mungas Dan M. , Miles Sunita Q. , Whitmer Rachel A.
Published: January 2021

Background:

The authors assessed the cross-sectional association of physical function measures with cognition in the Kaiser Healthy Aging and Diverse Life Experiences Cohort.

Methods:

Analyses included 1369 participants (24% Asian, 26% Black, 18% Latino, 32% White). Grip strength was measured using a hand-held dynamometer (kilograms) and gait speed was measured over a 4-m walk (seconds/meter). The Spanish and English Neuropsychological Assessment Scales was used to evaluate cognitive domains of executive function, semantic memory, and verbal episodic memory. Physical function measures (per SD) were associated with cognitive test z-scores in linear regression models adjusted for demographic, behavioral, and clinical factors. Racial/ethnic differences were tested using interaction terms and stratification.

Results:

Stronger grip was associated with better executive function [β=0.10 (95% confidence interval, 0.05-0.15)], semantic memory [β=0.13 (0.09-0.18)] and verbal episodic memory [β=0.07 (0.02-0.13)] with no racial/ethnic differences. Faster gait was associated with better executive function [β=0.29 (0.22-0.36)], semantic memory [β=0.23 (0.16-0.30)], and verbal episodic memory [β=0.20 (0.13-0.27)]; however, the association between gait speed and executive function varied by race/ethnicity with the strongest associations in Asians and Whites.

Conclusion:

Across race/ethnicity, grip strength and gait speed were associated with cognition with racial/ethnic differences in the association of gait speed and executive function.
Severe Relapses of Neuromyelitis Optica Spectrum Disorder During Treatment With Dimethyl Fumarate
Authors: Javadian Nina , Magrouni Hana , Ghaffarpour Majid , Ranji-Burachaloo Sakineh
Published: January 2021

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system, characterized by a specific antibody that selectively binds aquaporin-4 channel.

This is a report of an NMOSD case, with severe attacks of optic neuritis and myelitis after initiate of dimethyl fumarate (DMF).

We suggested that DMF could deteriorate the neuromyelitis optica (NMO) disease course, which results in serious morbidity and mortality in patients. Thus, initiation of DMF should be avoided before ruling out NMOSD in patients experiencing demyelinating attacks, especially in the case of recurrent optic neuritis or myelopathy and concurrency of other rheumatologic diseases.
High heritability of telomere length, but low evolvability, and no significant heritability of telomere shortening in wild jackdaws
Authors: Bauch Christina , Boonekamp Jelle J. , Korsten Peter , Mulder Ellis , Verhulst Simon
Published: January 2021

Telomere length (TL) and shortening rate predict survival in many organisms. Evolutionary dynamics of TL in response to survival selection depend on the presence of genetic variation that selection can act upon. However, the amount of standing genetic variation is poorly known for both TL and TL shortening rate, and has not been studied for both traits in combination in a wild vertebrate. We used experimental (cross-fostering) and statistical (animal models) means to disentangle and estimate genetic and environmental contributions to TL variation in pedigreed free-living jackdaws (Corvus monedula). TL was measured twice early in life (age- and interval-standardized), when shortening is highest, using the high-precision TRF technique, adapted to exclude interstitial telomeric sequences. TL shortened significantly during the nestling phase (10.4 bp/day), was highly repeatable within individuals (R=0.97) and genetically correlated between the two ages (rG>0.99). Additive genetic effects explained the major part of TL variation between individuals, with heritability on average estimated ath2=0.74. Parent- offspring regressions yielded similar estimates for the sexes when accounting for changes in paternal TL over life. Cohort effects explained a small but significant part of TL variation. Heritable variation for telomere shortening was negligible. Despite the high heritability of TL, its evolvability, which scales the additive genetic variance by mean TL, was close to zero. Hence evolutionary change of TL is likely to be slow despite significant selection.
Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial
Authors: Holubovska Olha , Bojkova Denisa , Elli Stefano , Bechtel Marco , Boltz David , Muzzio Miguel , Peng Xinjian , Sala Frederico , Cosentino Cesare , Mironenko Alla , Milde Jens , Lebed Yuriy , Stammer Holger , Goy Andrew , Guerrini Marco , Mueller Lutz , Cinatl Jindrich , Margitich Victor , te Velthuis Aartjan J. W.
Published: January 2021

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously. Enisamium (laboratory code FAV00A, trade name Amizon®) is an orally active inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. Here we show that enisamium can inhibit SARS-CoV-2 infections in NHBE and Caco-2 cells. In vitro, the previously identified enisamium metabolite VR17-04 directly inhibits the activity of the SARS-CoV-2 RNA polymerase. Docking and molecular dynamics simulations suggest that VR17-04 prevents GTP and UTP incorporation. To confirm enisamium’s antiviral properties, we conducted a double-blind, randomized, placebo-controlled trial in adult, hospitalized COVID-19 patients, which needed medical care either with or without supplementary oxygen. Patients received either enisamium (500 mg per dose) or placebo for 7 days. A pre-planned interim analysis showed in the subgroup of patients needing supplementary oxygen (n = 77) in the enisamium group a mean recovery time of 11.1 days, compared to 13.9 days for the placebo group (log-rank test; p=0.0259). No significant difference was found for all patients (n = 373) or those only needing medical care (n = 296). These results thus suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis and that enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen.

Significance statement

SARS-CoV-2 is the causative agent of COVID-19. Although vaccines are now becoming available to prevent SARS-CoV-2 spread, the development of antivirals remains necessary for treating current COVID-19 patients and combating future coronavirus outbreaks. Here, we report that enisamium, which can be administered orally, can prevent SARS-CoV-2 replication and that its metabolite VR17-04 can inhibit the SARS-CoV-2 RNA polymerase in vitro. Moreover, we find that COVID-19 patients requiring supplementary oxygen, recover more quickly than patients treated with a placebo. Enisamium may therefore be an accessible treatment for COVID-19 patients.
Geographical and temporal variation in reduction of malaria infection among children under five years of age throughout Nigeria
Authors: Oyibo Wellington , Ntadom Godwin , Uhomoibhi Perpetua , Oresanya Olusola , Ogbulafor Nnenna , Ajumobi Olufemi , Okoh Festus , Maxwell Kolawole , Ezeiru Sonachi , Nwokolo Ernest , Amajoh Chioma , Ezeigwe Nnenna , Audu Mohammed , Conway David J.
Published: January 2021

Background

Global progress in reducing malaria has stalled since 2015. Analysis of the situation is particularly needed in Nigeria, the country with by far the largest share of the burden, where approximately a quarter of all cases in the world are estimated to occur.

Methods

We analysed data from three nationwide surveys (Malaria Indicator Surveys in 2010 and 2015, and a National Demographic and Health Survey in 2018), with malaria parasite prevalence in children under five years of age determined by sampling from all 36 states of Nigeria, and blood slide microscopy performed in the same accredited laboratory for all samples. Changes over time were evaluated by calculating prevalence ratio (PR) values with 95% confidence intervals (CI) for each state, together with Mantel-Haenszel adjusted prevalence ratios (PRadj) for each of the six major geopolitical zones of the country.

Results

Between 2010 and 2018 there were significant reductions in parasite prevalence in 25 states, but not in the remaining 11 states. Prevalence decreased most in southern zones of the country (South West PRadj= 0.53; South East PRadj= 0.59; South South PRadj= 0.51) and the North Central zone (PRadj= 0.36). Changes in the north were less marked, but were significant and indicated overall reductions by more than 20% (North West PRadj= 0.74; North East PRadj= 0.76). Changes in the south occurred mostly between 2010 and 2015, whereas those in the north were more gradual and most continued after 2015. Recent changes were not correlated with survey-reported variation in use of preventive measures.

Conclusion

Reductions in malaria infection in children under five have occurred in most individual states in Nigeria since 2010, but substantial geographical variation in the timing and extent indicate challenges to be overcome to enable global malaria reduction.
Pragmatic, open-label, single-center, randomized, phase II clinical trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus in patients with severe pneumonia secondary to COVID-19: the TACROVID trial protocol
Authors: Solanich X , Antolí A , Padullés N , Fanlo-Maresma M , Iriarte A , Mitjavila F , Capdevila O , Molina M , Sabater J , Bas J , Mensa-Vilaró A , Niubó J , Calvo N , Bolivar S , Rigo-Bonnin R , Arregui L , Tebé C , Hereu P , Videla S , Corbella X
Published: January 2021

Introduction

Some COVID-19 patients evolve to severe lung injury and systemic hyperinflammatory syndrome triggered by both the coronavirus infection and the subsequent host-immune response. Accordingly, the use of immunomodulatory agents has been suggested but still remains controversial. Our working hypothesis is that methylprednisolone pulses and tacrolimus may be an effective and safety drug combination for treating severe COVID-19 patients.

Methods and analysis

TACROVID is a randomized, open-label, single-center, phase II trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) versus SoC alone, in patients at advanced stage of COVID-19 disease with lung injury and systemic hyperinflammatory response. Patients are randomly assigned (1:1) to one of two arms (42 patients in each group). The primary aim is to assess the time to clinical stability after initiating randomization. Clinical stability is defined as body temperature ≤ 37.5°C, and PaO2/FiO2 > 400 and/or SatO2/FiO2 > 300, and respiratory rate ≤24 rpm; for 48 consecutive hours.

Discussion

Methylprednisolone and tacrolimus might be beneficial to treat those COVID-19 patients progressing into severe pulmonary failure and systemic hyperinflammatory syndrome. The rationale for its use is the fast effect of methylprednisolone pulses and the ability of tacrolimus to inhibit both the CoV-2 replication and the secondary cytokine storm. Interestingly, both drugs are low-cost and can be manufactured on a large scale; thus, if effective and safe, a large number of patients could be treated in developed and developing countries.

Trial registration number

NCT04341038 / EudraCT: 2020-001445-39
Wastewater Virus Detection Complements Clinical COVID-19 Testing to Limit Spread of Infection at Kenyon College
Authors: Barich Daniel , Slonczewski Joan L.
Published: January 2021

In-person college instruction during the 2020 pandemic required effective and economical monitoring of COVID-19 prevalence. Kenyon College and the Village of Gambier conducted measurement of SARS-CoV-2 RNA from the village wastewater plant and from an on-campus sewer line. Wastewater RNA detection revealed virus prevalence leading to individual testing and case identification. Wastewater surveillance also showed when case rates had subsided, thus limiting the need for individual clinical testing. Overall, wastewater virus surveillance allows more targeted use of individual testing and increases community confidence in student population management.
Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate
Authors: Prieto-Fernández Endika , Egia-Mendikute Leire , Vila-Vecilla Laura , Bosch Alexandre , Barreira-Manrique Adrián , Lee So Young , García-del Río Ana , Antoñana-Vildosola Asier , Jiménez-Lasheras Borja , Moreno-Cugnon Leire , Jiménez-Barbero Jesús , Berra Edurne , Ereño-Orbea June , Palazon Asis
Published: January 2021

A main clinical parameter of COVID-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein of SARS-CoV-2 to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2 and neuropilin-1 (NRP1), which might in part explain the observed reduction of the infection rate. In addition, hypoxia inhibits the binding of the spike to NCI-H460 human lung epithelial cells by decreasing the cell surface levels of heparan sulfate (HS), a known attachment receptor of SARS-CoV-2. This interaction is also reduced by lactoferrin, a glycoprotein that blocks HS moieties on the cell surface. The expression of syndecan-1, an HS-containing proteoglycan expressed in lung, is inhibited by hypoxia on a HIF-1α-dependent manner. Hypoxia or deletion of syndecan-1 results in reduced binding of the RBD to host cells. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of COVID-19.
Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces shedding of SARS-CoV-2 D614G in rhesus macaques
Authors: van Doremalen Neeltje , Purushotham Jyothi N. , Schulz Jonathan E. , Holbrook Myndi G. , Bushmaker Trenton , Carmody Aaron , Port Julia R. , Yinda Claude K. , Okumura Atsushi , Saturday Greg , Amanat Fatima , Krammer Florian , Hanley Patrick W. , Smith Brian J. , Lovaglio Jamie , Anzick Sarah L. , Barbian Kent , Martens Craig , Gilbert Sarah , Lambe Teresa , Munster Vincent J.
Published: January 2021

Intramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 protected rhesus macaques against pneumonia but did not reduce shedding of SARS-CoV-2. Here we investigate whether intranasally administered ChAdOx1 nCoV-19 reduces shedding, using a SARS-CoV-2 virus with the D614G mutation in the spike protein. Viral load in swabs obtained from intranasally vaccinated hamsters was significantly decreased compared to controls and no viral RNA or infectious virus was found in lung tissue, both in a direct challenge and a transmission model. Intranasal vaccination of rhesus macaques resulted in reduced shedding and a reduction in viral load in bronchoalveolar lavage and lower respiratory tract tissue. In conclusion, intranasal vaccination reduced shedding in two different SARS-CoV-2 animal models, justifying further investigation as a potential vaccination route for COVID-19 vaccines.
Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation
Authors: Garcia Maria A. , Barreras Paula V. , Lewis Allie , Pinilla Gabriel , Sokoll Lori J. , Kickler Thomas , Mostafa Heba , Caturegli Mario , Moghekar Abhay , Fitzgerald Kathryn C. ,   Hopkins Neuro-COVID-19 Group, Pardo Carlos A.
Published: January 2021

BACKGROUND

Neurological complications occur in COVID-19. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 subjects with neurological complications and determine presence of neuroinflammatory changes implicated in pathogenesis.

METHODS

Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity (critical, severe, moderate, mild). COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n=82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA.

RESULTS

CSF from COVID-19 subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis or specific increases in pro-inflammatory markers or cytokines (IL-6, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 in CSF of COVID-19 and non-COVID-19 stroke subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke and critical COVID-19. CSF-hsCRP was present almost exclusively in COVID-19 cases.

CONCLUSION

The paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. Elevated CSF-NF-L indicates neuroaxonal injury in COVID-19 cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.

FUNDING

This work was supported by NIH R01-NS110122 and The Bart McLean Fund for Neuroimmunology Research.
High school science fair: Experiences of two groups of undergraduate bioscience students
Authors: Grinnell Frederick , Dalley Simon , Reisch Joan
Published: January 2021

Science fairs offer potential opportunities for students to learn first-hand about the practices of science. Over the past six years we have been carrying out voluntary and anonymous surveys with regional and national groups of high school and post high school students to learn about their high school science fair experiences regarding help received, obstacles encountered, and opinions about the value and impact of science fair. Understanding what students think about science fairs will help educators make science fairs more effective learning opportunities. In this paper, we focus on the findings with two national groups of post high school students – undergraduate research fellows (SURF students) who did research at UT Southwestern Medical Center during 2014-2019 and undergraduates biology students attending the 2019 Howard Hughes Medical Institute Science Education Alliance (SEA) summer symposium. About 25% of the students who completed surveys indicated that they had participated in high school science fair, but more than half attended high schools where science fairs were unavailable. Effectively, 6 out of every 10 students participated in science fair if available. Students who could have participated in high school science fair but chose not to do so identifiednot enough timeandcoming up with their project ideaas major reasons why not. About half the SURF students favored requiring non-competitive science fair regardless whether they themselves had participated in science fair. On the other hand, less than 1 in 5 thought that competitive science fair should be required.Introduction to the scientific processandgeneral learningwere mentioned most frequently as the reasons to require non-competitive science fair; these reasons were mentioned rarely in connection with competitive science fair. Unlike the national cohort of high school students we surveyed previously, who mostly did science fair in 9thand 10thgrades, SURF students participated in science fair throughout high school and were twice as likely as high school students to have carried out science fair more than once. In conclusion, our findings suggest that participation of the undergraduate bioscience majors in high school science fairs occurs far more frequently than recognized previously. The findings emphasize further the importance of incentivizing rather than requiring science fair participation, especially in 9thand 10thgrades, and the potential value of developing non-competitive science fairs.
Potent SARS-CoV-2 Neutralizing Antibodies Directed Against Spike N-Terminal Domain Target a Single Supersite
Authors: Cerutti Gabriele , Guo Yicheng , Zhou Tongqing , Gorman Jason , Lee Myungjin , Rapp Micah , Reddem Eswar R. , Yu Jian , Bahna Fabiana , Bimela Jude , Huang Yaoxing , Katsamba Phinikoula S. , Liu Lihong , Nair Manoj S. , Rawi Reda , Olia Adam S. , Wang Pengfei , Chuang Gwo-Yu , Ho David D. , Sheng Zizhang , Kwong Peter D. , Shapiro Lawrence
Published: January 2021

Numerous antibodies that neutralize SARS-CoV-2 have been identified, and these generally target either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the viral spike. While RBD-directed antibodies have been extensively studied, far less is known about NTD-directed antibodies. Here we report cryo-EM and crystal structures for seven potent NTD-directed neutralizing antibodies in complex with spike or isolated NTD. These structures defined several antibody classes, with at least one observed in multiple convalescent donors. The structures revealed all seven antibodies to target a common surface, bordered by glycansN17,N74,N122, andN149. This site – formed primarily by a mobile β-hairpin and several flexible loops – was highly electropositive, located at the periphery of the spike, and the largest glycan-free surface of NTD facing away from the viral membrane. Thus, in contrast to neutralizing RBD-directed antibodies that recognize multiple non-overlapping epitopes, potent NTD-directed neutralizing antibodies target a single supersite.
Mechanisms shaping the synergism of zeaxanthin and PsbS in photoprotective energy dissipation in the photosynthetic apparatus of plants
Authors: Welc Renata , Luchowski Rafal , Kluczyk Dariusz , Zubik Monika , Grudzinski Wojciech , Maksim Magdalena , Reszczynska Emilia , Sowinski Karol , Mazur Radosław , Nosalewicz Artur , Gruszecki Wieslaw I.
Published: January 2021

Safe operation of photosynthesis is vital to plants and is ensured by the activity of numerous processes protecting chloroplasts against photo-damage. The harmless dissipation of excess excitation energy is believed to be the main photoprotective mechanism and is most effective with the simultaneous presence of PsbS protein and zeaxanthin, a xanthophyll accumulated in strong light as a result of the xanthophyll cycle activity. Here we address the problem of specific molecular mechanisms underlying the synergistic effect of zeaxanthin and PsbS. The experiments were conducted withArabidopsis thaliana, the wild-type and the mutants lacking PsbS (npq4) and affected in the xanthophyll cycle (npq1), with the application of multiple molecular spectroscopy and imaging techniques. Research results lead to the conclusion that PsbS interferes with the formation of tightly packed aggregates of thylakoid membrane proteins, thus enabling the incorporation of xanthophyll cycle pigments into such structures. It was found that xanthophylls trapped within supramolecular structures, most likely in the interfacial protein region, determine their photophysical properties. The structures formed in the presence of violaxanthin are characterized by minimized dissipation of excitation energy. In contrast, the structures formed in the presence of zeaxanthin show enhanced excitation quenching, thus protecting the system against photo-damage.
Impact of South African 501.V2 Variant on SARS-CoV-2 Spike Infectivity and Neutralization: A Structure-based Computational Assessment
Authors: Cheng Mary Hongying , Krieger James M , Kaynak Burak , Arditi Moshe , Bahar Ivet
Published: January 2021

Motivation

The SARS-CoV-2 variants emerging from South Africa (501.V2) and the UK (B.1.1.7) necessitate rapid assessment of the effects of the corresponding amino acid substitutions in the spike (S) receptor-binding domain (RBD) of the variants on the interactions with the human ACE2 receptor and monoclonal antibodies (mAbs) reported earlier to neutralize the spike.

Results

Molecular modeling and simulations reveal that N501Y, shared by both variants, increases ACE2 binding affinity, and may impact the collective dynamics of the ACE2-RBD complex, occupying a central hinge site that modulates the overall dynamics of the complex. In contrast, the substitutions K417N and E484K in the South African variant 501.V2 would reduce the ACE2-binding affinity by abolishing two interfacial salt bridges that facilitate RBD binding to ACE2, K417(S)-D30(ACE2) and E484 (S)-K31(ACE2). These two mutations may thus be more than compensating the attractive effect induced by N501Y, overall resulting in an ACE2-binding affinity comparable to that of the wildtype RBD. Further analysis of the impact of these mutations on the interactions with mAbs targeting the spike indicate that the substitutions K417N and E484K may also abolish the salt bridges between the spike and selected mAbs, such as REGN10933, BD23, H11_H4, and C105, thus reducing the binding affinity and effectiveness of these mAbs.

Contact

bahar@pitt.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
Explainable AI enables clinical trial patient selection to retrospectively improve treatment effects in schizophrenia
Authors: Mellem Monika S. , Kollada Matt , Tiller Jane , Lauritzen Thomas
Published: January 2021

Background

Heterogeneity among patients’ responses to treatment is prevalent in psychiatric disorders. Personalized medicine approaches – which involve parsing patients into subgroups better indicated for a particular treatment – could therefore improve patient outcomes and serve as a powerful tool in patient selection within clinical trials. Machine learning approaches can identify patient subgroups but are often not “explainable” due to the use of complex algorithms that do not mirror clinicians’ natural decision-making processes.

Methods

Here we combine two analytical approaches – Personalized Advantage Index and Bayesian Rule Lists – to identify paliperidone-indicated schizophrenia patients in a way that emphasizes model explainability. We apply these approaches retrospectively to randomized, placebo-controlled clinical trial data to identify a paliperidone-indicated subgroup of schizophrenia patients who demonstrate a larger treatment effect (outcome on treatment superior than on placebo) than that of the full randomized sample as assessed with Cohen’s d. For this study, the outcome corresponded to a reduction in the Positive and Negative Syndrome Scale (PANSS) total score which measures positive (e.g., hallucinations, delusions), negative (e.g., blunted affect, emotional withdrawal), and general psychopathological (e.g., disturbance of volition, uncooperativeness) symptoms in schizophrenia.

Results

Using our combined explainable AI approach to identify a subgroup more responsive to paliperidone than placebo, the treatment effect increased significantly over that of the full sample (p<0.0001 for a one-sample t-test comparing the full sample Cohen’s d=0.82 and a generated distribution of subgroup Cohen’s d’s with mean d=1.22, std d=0.09). In addition, our modeling approach produces simple logical statements (if-then-else), termed a “rule list”, to ease interpretability for clinicians. A majority of the rule lists generated from cross-validation found two general psychopathology symptoms, disturbance of volition and uncooperativeness, to predict membership in the paliperidone-indicated subgroup.

Conclusions

These results help to technically validate our explainable AI approach to patient selection for a clinical trial by identifying a subgroup with an improved treatment effect. With these data, the explainable rule lists also suggest that paliperidone may provide an improved therapeutic benefit for the treatment of schizophrenia patients with either of the symptoms of high disturbance of volition or high uncooperativeness.

Trial Registration

clincialtrials.gov identifier: NCT 00083668; registered May 28, 2004
T-cell Receptor Diversity Estimates for Repertoires (TCRDivER) uses sequence similarity to find signatures of immune response
Authors: Vujović Milena , Marcatili Paolo , Chain Benny , Kaplinsky Joseph , Andresen Thomas Lars
Published: January 2021

We propose TCRDivER, a global approach to T-cell repertoire comparison using diversity profiles sensitive to both clone size and sequence similarity. As immunotherapies improve, the long standing biological interest in connecting outcome with T cell receptor (TCR) repertoire status has become more urgent. Here we show that new insights can be extracted from high throughput repertoire sequencing data. Most current efforts focus on identification of immunisation-specific sequence motifs or on monitoring changes in frequency of individual clones. Applying TCRDivER to murine spleen samples shows it characterises an additional dimension of repertoire variation, beyond conventional diversity estimates, allowing distinction between immunised and non-immunised samples. We further apply TCRDivER to repertoires from human blood. In both cases we show characteristic relationships between repertoire features. These reveal biologically interpretable relationships between sequence similarity and clonal expansions. We thereby demonstrate a new tool for investigation in clinical and research applications.
Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery
Authors: Quante Markus , Iske Jasper , Heinbokel Timm , Desai Bhavna N. , Biefer Hector Rodriguez Cetina , Nian Yeqi , Krenzien Felix , Uehara Hirofumi , Maenosono Ryoichi , Azuma Haruhito , Pratschke Johann , Falk Christine , Lo Tammy , Sheu Eric , Tavakkoli Ali , Perkins David , Alegre Maria-Luisa , Banks Alexander S. , Elkhal Abdallah , Tullius Stefan G.
Published: January 2021

Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities.

We performed sleeve-gastrectomies (SGx) in a pre-clinical mouse model of diet-induced obesity (DIO), delineating the effects on long-term remission from obesity. SGx resulted in sustained weight loss and improved glucose tolerance. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of taurodeoxycholic acid (TDCA) and L-valine in DIO mice. Notably, TDCA and L-Valine levels were restored after SGx in both human and mice to levels comparable with lean controls.

Strikingly, combined systemic treatment with TDCA and valine induced a profound weight loss in DIO mice analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone.

In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.
A modified fluctuation assay reveals a natural mutator phenotype that drives mutation spectrum variation withinSaccharomyces cerevisiae
Authors: Jiang Pengyao , Ollodart Anja R. , Sudhesh Vidha , Herr Alan J. , Dunham Maitreya J. , Harris Kelley
Published: January 2021

Although studies ofSaccharomyces cerevisiaehave provided many insights into mutagenesis and DNA repair, most of this work has focused on a few laboratory strains. Much less is known about the phenotypic effects of natural variation withinS. cerevisiae’s DNA repair pathways. Here, we use natural polymorphisms to detect historical mutation spectrum differences among several wild and domesticatedS. cerevisiaestrains. To determine whether these differences are likely caused by genetic mutation rate modifiers, we use a modified fluctuation assay with aCAN1reporter to measurede novomutation rates and spectra in 16 of the analyzed strains. We measure a 10-fold range of mutation rates and identify two strains with distinctive mutation spectra. These strains, known as AEQ and AAR, come from the panel’s “Mosaic beer” clade and share an enrichment for C>A mutations that is also observed in rare variation segregating throughout the genomes of several Mosaic beer and Mixed origin strains. Both AEQ and AAR are haploid derivatives of the diploid natural isolate CBS 1782, whose rare polymorphisms are enriched for C>A as well, suggesting that the underlying mutator allele is likely active in nature. We use a plasmid complementation test to show that AAR and AEQ share a mutator allele in the DNA repair geneOGG1, which excises 8-oxoguanine lesions that can cause C>A mutations if left unrepaired.
Immunological and cardio-vascular pathologies associated with SARS-CoV-2 infection in golden syrian hamster
Authors: Rizvi Zaigham Abbas , Dalal Rajdeep , Sadhu Srikant , Kumar Yashwant , Shrivastava Tripti , Gupta Sonu Kumar , Agarwal Suruchi , Tripathy Manas Ranjan , Yadav Amit Kumar , Medigeshi Guruprasad R. , Pandey Amit Kumar , Samal Sweety , Asthana Shailendra , Awasthi Amit
Published: January 2021

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in golden Syrian hamster (GSH) causes lung pathology and resembles human coronavirus disease (Covid-19). However, extra-pulmonary pathologies of SARS-CoV-2 infection that result in long Covid remains undefined in GSH. Here, usingin silicomodelling we show that hamster angiotensin-converting enzyme-2 (ACE-2) and neuropilin-1 (NRP-1) interaction with SARS-CoV-2 is similar to human. Intranasal SARS-CoV-2 infection in GSH resulted in early onset of lung pathologies marked by aggressive inflammatory response. Remarkably, late phase of SARS-CoV2 infection in GSH showed cardiovascular complications (CVC) characterized by ventricular hypertrophy, ventricular wall thickening, interstitial coronary fibrosis and altered lipidomics with elevated cholesterol, low-density lipoprotein and long chain fatty acid triglycerides. Moreover, serum metabolomics profile of infected GSH correlated with Covid19 patients. Together, we propose GSH as a suitable animal model to study immediate and long Covid19 pathologies that could be extended to therapeutics against Covid19 related CVC.
Symptomatic fever management in children: A systematic review of national and international guidelines
Authors: Green Cari , Kraft Hanno , Guyatt Gordon , Martin David
Published: January 2021

Introduction

A comprehensive assessment of the recommendations made by clinical practice guidelines (CPGs) on symptomatic fever management in children has not been carried out.

Methods

Searches were conducted on Pubmed, google scholar, pediatric society websites and guideline databases to locate CPGs from each country. Rather than assessing overall guideline quality, the level of evidence for each recommendation was evaluated according to criteria of the Oxford Centre for Evidence-Based Medicine (OCEBM). A GRADE assessment was undertaken to assess the body of evidence related to a single question: the threshold for initiating antipyresis.

Results

74 guidelines were retrieved. Recommendations for antipyretic threshold, type and dose; ambient temperature; dress/covering; activity; fluids; nutrition; proctoclysis; external applications; complementary/herbal recommendations; media; and age-related treatment differences all varied widely. OCEBM evidence levels for most recommendations were low (Level 3-4) or indeterminable. The GRADE assessment revealed a very low level of evidence for a threshold for antipyresis.

Conclusion

There is no recommendation on which all guidelines agree, and many are inconsistent with the evidence – this is true even for recent guidelines. The threshold question is of fundamental importance and has not yet been answered. Guidelines for the most frequent intervention (antipyresis) remain problematic.