Credible learning of hydroxychloroquine and dexamethasone effects on COVID-19 mortality outside of randomized trials

AbstractObjectivesTo investigate the effectiveness of hydroxychloroquine and dexamethasone on coronavirus disease (COVID-19) mortality using patient data outside of randomized trials.DesignPhenotypes derived from electronic health records were analyzed using the stability-controlled quasi-experiment (SCQE) to provide a range of possible causal effects of hydroxy-chloroquine and dexamethasone on COVID-19 mortality.Setting and participantsData from 2,007 COVID-19 positive patients hospitalized at a large university hospital system over the course of 200 days and not enrolled in randomized trials were analyzed using SCQE. For hyrdoxychloroquine, we examine a high-use cohort (n=766, days 1 to 43) and a later, low-use cohort (n=548, days 44 to 82). For dexamethasone, we examine a low-use cohort (n=614, days 44 to 101) and high-use cohort (n=622, days 102 to 200).Outcome measure14-day mortality, with a secondary outcome of 28-day mortality.ResultsHydroxycholoroquine could only have been significantly (p<0.05) beneficial if baseline mortality was at least 6.4 percentage points (55%) lower among patients in the later (low-use) than the earlier (high-use) cohort. Hydroxychloroquine instead proves significantly harmful if baseline mortality rose from one cohort to the next by just 0.3 percentage points. Dexamethasone significantly reduced mortality risk if baseline mortality in the later (high-use) cohort (days 102-200) was higher than, the same as, or up to 1.5 percentage points lower than that in the earlier (low-use) cohort (days 44-101). It could only prove significantly harmful if mortality improved from one cohort to the next by 6.8 percentage points due to other causes—an assumption implying an unlikely 84% reduction in mortality due to other causes, leaving an in-hospital mortality rate of just 1.3%.ConclusionsThe assumptions required for a beneficial effect of hydroxychloroquine on 14 day mortality are difficult to sustain, while the assumptions required for hydroxychloroquine to be harmful are difficult to reject with confidence. Dexamethasone, by contrast, was beneficial under a wide range of plausible assumptions, and was only harmful if a nearly impossible assumption is met. More broadly, the SCQE reveals what inferences can be credibly supported by evidence from non-randomized uses of experimental therapies, making it a useful tool when randomized trials have not yet produced clear evidence or to provide corroborative evidence from different populations.

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Performance of Electronic Structure Methods for the Description of Hückel-Möbius Interconversions in Extended π-Systems

10.26434/chemrxiv.10564115 ◽

2019 ◽

Author(s):

Tatiana Woller ◽

Ambar Banerjee ◽

Nitai Sylvetsky ◽

Xavier Deraet ◽

Frank De Proft ◽

...

Keyword(s):

Electronic Structure ◽

Basis Set ◽

Dft Methods ◽

Molecular Switching ◽

Wide Range ◽

Electronic Structure Methods ◽

Explicitly Correlated ◽

Relative Errors ◽

The Stability ◽

Basis Set Expansion

Expanded porphyrins provide a versatile route to molecular switching devices due to their ability to shift between several π-conjugation topologies encoding distinct properties. Taking into account its size and huge conformational flexibility, DFT remains the workhorse for modeling such extended macrocycles. Nevertheless, the stability of Hückel and Möbius conformers depends on a complex interplay of different factors, such as hydrogen bonding, p···p stacking, steric effects, ring strain and electron delocalization. As a consequence, the selection of an exchange-correlation functional for describing the energy profile of topological switches is very difficult. For these reasons, we have examined the performance of a variety of wavefunction methods and density functionals for describing the thermochemistry and kinetics of topology interconversions across a wide range of macrocycles. Especially for hexa- and heptaphyrins, the Möbius structures have a pronouncedly stronger degree of static correlation than the Hückel and figure-eight structures, and as a result the relative energies of singly-twisted structures are a challenging test for electronic structure methods. Comparison of limited orbital space full CI calculations with CCSD(T) calculations within the same active spaces shows that post-CCSD(T) correlation contributions to relative energies are very minor. At the same time, relative energies are weakly sensitive to further basis set expansion, as proven by the minor energy differences between MP2/cc-pVDZ and explicitly correlated MP2-F12/cc-pVDZ-F12 calculations. Hence, our CCSD(T) reference values are reasonably well-converged in both 1-particle and n-particle spaces. While conventional MP2 and MP3 yield very poor results, SCS-MP2 and particularly SOS-MP2 and SCS-MP3 agree to better than 1 kcal mol-1 with the CCSD(T) relative energies. Regarding DFT methods, only M06-2X provides relative errors close to chemical accuracy with a RMSD of 1.2 kcal mol-1. While the original DSD-PBEP86 double hybrid performs fairly poorly for these extended p-systems, the errors drop down to 2 kcal mol-1 for the revised revDSD-PBEP86-NL, again showing that same-spin MP2-like correlation has a detrimental impact on performance like the SOS-MP2 results.

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Insights into Potent Therapeutical Antileukemic Agent L-glutaminase Enzyme Under Solid-state Fermentation: A Review

Current Drug Metabolism ◽

10.2174/1389200221666200421122147 ◽

2020 ◽

Vol 21 (3) ◽

pp. 211-220 ◽

Cited By ~ 1

Author(s):

Chandrasai Potla Durthi ◽

Madhuri Pola ◽

Satish Babu Rajulapati ◽

Anand Kishore Kola

Keyword(s):

Solid State ◽

Solid State Fermentation ◽

Food Industry ◽

Energy Requirement ◽

Production Studies ◽

Wide Range ◽

Hybridoma Technology ◽

Bacteria And Fungi ◽

The Stability ◽

Glutaminase Activity

Aim & objective: To review the applications and production studies of reported antileukemic drug L-glutaminase under Solid-state Fermentation (SSF). Overview: An amidohydrolase that gained economic importance because of its wide range of applications in the pharmaceutical industry, as well as the food industry, is L-glutaminase. The medical applications utilized it as an anti-tumor agent as well as an antiretroviral agent. L-glutaminase is employed in the food industry as an acrylamide degradation agent, as a flavor enhancer and for the synthesis of theanine. Another application includes its use in hybridoma technology as a biosensing agent. Because of its diverse applications, scientists are now focusing on enhancing the production and optimization of L-glutaminase from various sources by both Solid-state Fermentation (SSF) and submerged fermentation studies. Of both types of fermentation processes, SSF has gained importance because of its minimal cost and energy requirement. L-glutaminase can be produced by SSF from both bacteria and fungi. Single-factor studies, as well as multi-level optimization studies, were employed to enhance L-glutaminase production. It was concluded that L-glutaminase activity achieved by SSF was 1690 U/g using wheat bran and Bengal gram husk by applying feed-forward artificial neural network and genetic algorithm. The highest L-glutaminase activity achieved under SSF was 3300 U/gds from Bacillus sp., by mixture design. Purification and kinetics studies were also reported to find the molecular weight as well as the stability of L-glutaminase. Conclusion: The current review is focused on the production of L-glutaminase by SSF from both bacteria and fungi. It was concluded from reported literature that optimization studies enhanced L-glutaminase production. Researchers have also confirmed antileukemic and anti-tumor properties of the purified L-glutaminase on various cell lines.

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Assessment of vitamin B12 deficiency and B12 screening trends for patients on metformin: a retrospective cohort case review

BMJ Nutrition, Prevention & Health ◽

10.1136/bmjnph-2020-000193 ◽

2021 ◽

pp. bmjnph-2020-000193

Author(s):

Darby Martin ◽

Jeet Thaker ◽

Maria Shreve ◽

Lois Lamerato ◽

Kartazyna Budzynska

Keyword(s):

Retrospective Cohort ◽

Protective Factor ◽

Vitamin B12 Deficiency ◽

Older Age ◽

Secondary Outcome ◽

Vitamin B ◽

Case Review ◽

Large Hospital ◽

Hospital System ◽

B12 Deficiency

ObjectivesOur study investigated the use of vitamin B12 testing in a large cohort of patients on metformin and assesses appropriateness and benefits of screening recommendations for vitamin B12 deficiency.DesignThis retrospective cohort study included insured adult patients who had more than 1 year of metformin use between 1 January 2010 and 1 October 2016 and who filled at least two consecutive prescriptions of metformin to establish compliance. The comparison group was not exposed to metformin. Primary outcome was incidence of B12 deficiency diagnosed in patients on metformin. Secondary outcome was occurrence of B12 testing in the patient population on metformin. Records dated through 31 December 2018 were analysed.SettingLarge hospital system consisting of inpatient and outpatient data base.ParticipantsA diverse, adult, insured population of patients who had more than 1 year of metformin use between 1 January 2010 and 1 October 2016 and who filled at least two consecutive prescriptions of metformin.ResultsOf 13 489 patients on metformin, 6051 (44.9%) were tested for vitamin B12 deficiency, of which 202 (3.3%) tested positive (vs 2.2% of comparisons). Average time to test was 990 days. Average time to test positive for deficiency was 1926 days. Factors associated with testing were linked to sex (female, 47.8%), older age (62.79% in patients over 80 years old), race (48.98% white) and causes of malabsorption (7.11%). Multivariable logistic regression showed older age as the only factor associated with vitamin B12 deficiency, whereas African-American ethnicity approached significance as a protective factor.ConclusionsBased on our study’s findings of vitamin B12 deficiency in patients on metformin who are greater than 65 years old and have been using it for over 5 years, we recommend that physicians consider screening in these populations.

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Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients

Critical Care ◽

10.1186/s13054-021-03499-4 ◽

2021 ◽

Vol 25 (1) ◽

Cited By ~ 3

Author(s):

Savino Spadaro ◽

Alberto Fogagnolo ◽

Gianluca Campo ◽

Ottavio Zucchetti ◽

Marco Verri ◽

...

Keyword(s):

Plasma Levels ◽

Endothelial Injury ◽

University Hospital ◽

Intercellular Adhesion Molecule ◽

Secondary Outcome ◽

Intercellular Adhesion Molecule 1 ◽

Mechanically Ventilated ◽

Adhesion Protein ◽

Alveolar Epithelial ◽

Angiopoietin 2

Abstract Background Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. Methods This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. Results In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). Conclusions COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053, Date of registration: April 13, 2020

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Contagion Management at the Méditerranée Infection University Hospital Institute

Journal of Clinical Medicine ◽

10.3390/jcm10122627 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2627

Author(s):

Pierre-Edouard Fournier ◽

Sophie Edouard ◽

Nathalie Wurtz ◽

Justine Raclot ◽

Marion Bechet ◽

...

Keyword(s):

Infectious Disease ◽

Early Diagnosis ◽

Personal Protective Equipment ◽

Early Stage ◽

Point Of Care ◽

University Hospital ◽

Protective Equipment ◽

Monitoring Point ◽

Epidemiological Monitoring ◽

Wide Range

The Méditerranée Infection University Hospital Institute (IHU) is located in a recent building, which includes experts on a wide range of infectious disease. The IHU strategy is to develop innovative tools, including epidemiological monitoring, point-of-care laboratories, and the ability to mass screen the population. In this study, we review the strategy and guidelines proposed by the IHU and its application to the COVID-19 pandemic and summarise the various challenges it raises. Early diagnosis enables contagious patients to be isolated and treatment to be initiated at an early stage to reduce the microbial load and contagiousness. In the context of the COVID-19 pandemic, we had to deal with a shortage of personal protective equipment and reagents and a massive influx of patients. Between 27 January 2020 and 5 January 2021, 434,925 nasopharyngeal samples were tested for the presence of SARS-CoV-2. Of them, 12,055 patients with COVID-19 were followed up in our out-patient clinic, and 1888 patients were hospitalised in the Institute. By constantly adapting our strategy to the ongoing situation, the IHU has succeeded in expanding and upgrading its equipment and improving circuits and flows to better manage infected patients.

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Risk factors for severity on admission and the disease progression during hospitalisation in a large cohort of patients with COVID-19 in Japan

BMJ Open ◽

10.1136/bmjopen-2020-047007 ◽

2021 ◽

Vol 11 (6) ◽

pp. e047007

Author(s):

Mari Terada ◽

Hiroshi Ohtsu ◽

Sho Saito ◽

Kayoko Hayakawa ◽

Shinya Tsuzuki ◽

...

Keyword(s):

Risk Factors ◽

Mechanical Ventilation ◽

Chronic Respiratory Disease ◽

Major Effect ◽

Secondary Outcome ◽

Healthcare Facilities ◽

Wide Range ◽

Registration Number ◽

Using Data ◽

Obesity Hypertension

ObjectivesTo investigate the risk factors contributing to severity on admission. Additionally, risk factors of worst severity and fatality were studied. Moreover, factors were compared based on three points: early severity, worst severity and fatality.DesignAn observational cohort study using data entered in a Japan nationwide COVID-19 inpatient registry, COVIREGI-JP.SettingAs of 28 September 2020, 10480 cases from 802 facilities have been registered. Participating facilities cover a wide range of hospitals where patients with COVID-19 are admitted in Japan.ParticipantsParticipants who had a positive test result on any applicable SARS-CoV-2 diagnostic tests were admitted to participating healthcare facilities. A total of 3829 cases were identified from 16 January to 31 May 2020, of which 3376 cases were included in this study.Primary and secondary outcome measuresPrimary outcome was severe or nonsevere on admission, determined by the requirement of mechanical ventilation or oxygen therapy, SpO2 or respiratory rate. Secondary outcome was the worst severity during hospitalisation, judged by the requirement of oxygen and/orinvasive mechanical ventilation/extracorporeal membrane oxygenation.ResultsRisk factors for severity on admission were older age, men, cardiovascular disease, chronic respiratory disease, diabetes, obesity and hypertension. Cerebrovascular disease, liver disease, renal disease or dialysis, solid tumour and hyperlipidaemia did not influence severity on admission; however, it influenced worst severity. Fatality rates for obesity, hypertension and hyperlipidaemia were relatively lower.ConclusionsThis study segregated the comorbidities influencing severity and death. It is possible that risk factors for severity on admission, worst severity and fatality are not consistent and may be propelled by different factors. Specifically, while hypertension, hyperlipidaemia and obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation.Trial registration numberUMIN000039873. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045453

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Polymer-Drug Conjugates as Nanotheranostic Agents

Journal of Nanotheranostics ◽

10.3390/jnt2010005 ◽

2021 ◽

Vol 2 (1) ◽

pp. 63-81

Author(s):

Sajana Manandhar ◽

Erica Sjöholm ◽

Johan Bobacka ◽

Jessica M. Rosenholm ◽

Kuldeep K. Bansal

Keyword(s):

Drug Delivery ◽

Drug Release ◽

Treatment Options ◽

The Body ◽

Drug Conjugates ◽

Imaging Characteristics ◽

Wide Range ◽

Systemic Side Effects ◽

Theranostic Agents ◽

The Stability

Since the last decade, the polymer-drug conjugate (PDC) approach has emerged as one of the most promising drug-delivery technologies owing to several benefits like circumventing premature drug release, offering controlled and targeted drug delivery, improving the stability, safety, and kinetics of conjugated drugs, and so forth. In recent years, PDC technology has advanced with the objective to further enhance the treatment outcomes by integrating nanotechnology and multifunctional characteristics into these systems. One such development is the ability of PDCs to act as theranostic agents, permitting simultaneous diagnosis and treatment options. Theranostic nanocarriers offer the opportunity to track the distribution of PDCs within the body and help to localize the diseased site. This characteristic is of particular interest, especially among those therapeutic approaches where external stimuli are supposed to be applied for abrupt drug release at the target site for localized delivery to avoid systemic side effects (e.g., Visudyne®). Thus, with the help of this review article, we are presenting the most recent updates in the domain of PDCs as nanotheranostic agents. Different methodologies utilized to design PDCs along with imaging characteristics and their applicability in a wide range of diseases, have been summarized in this article.

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Long-term improvements following a residential combined physical and psychological programme for chronic low back pain

BMJ Open Quality ◽

10.1136/bmjoq-2020-001068 ◽

2021 ◽

Vol 10 (2) ◽

pp. e001068

Author(s):

Shaun Wellburn ◽

Cormac G Ryan ◽

Andrew Coxon ◽

Alastair J Dickson ◽

D John Dickson ◽

...

Keyword(s):

Low Back Pain ◽

Back Pain ◽

Outcome Measures ◽

Chronic Low Back Pain ◽

Rating Scale ◽

Secondary Outcome ◽

Low Back ◽

Residential Setting ◽

Wide Range

ObjectivesEvaluate the outcomes and explore experiences of patients undergoing a residential combined physical and psychological programme (CPPP) for chronic low back pain.DesignA longitudinal observational cohort design, with a parallel qualitative design using semistructured interviews.SettingResidential, multimodal rehabilitation.Participants136 adults (62 male/74 female) referred to the CPPP, 100 (44 male/56 female) of whom completed the programme, during the term of the study. Ten (2 male/8 female) participated in the qualitative evaluation.InterventionA 3-week residential CPPP.Outcome measuresPrimary outcome measures were the STarT Back screening tool score; pain intensity—11-point Numerical Rating Scale; function—Oswestry Disability Index (ODI); health status/quality of life—EQ-5D-5L EuroQol five-Dimension-five level; anxiety—Generalised Anxiety Disorder-7; depression—Patient Health Questionnaire-9. Secondary outcome measures were the Global Subjective Outcome Scale; National Health Service Friends and Family Test;.ResultsAt discharge, 6 and 12 months follow ups, there were improvements from baseline that were greater than minimum clinically important differences in each of the outcomes (with the sole exception of ODI at discharge). At 12 months, the majority of people considered themselves a lot better (57%) and were extremely likely (86%) to recommend the programme to a friend. The qualitative data showed praise for the residential nature of the intervention and the opportunities for interaction with peers and peer support. There were testimonies of improvements in understanding of pain and how to manage it better. Some participants said they had reduced, or stopped, medication they had been taking to manage their pain.ConclusionsParticipants improved, and maintained long term, beyond minimum clinically important differences on a wide range of outcomes. Participants reported an enhanced ability to self-manage their back pain and support for the residential setting.

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No-z Model for Magnetic Fields of Different Astrophysical Objects and Stability of the Solutions

Data ◽

10.3390/data6010004 ◽

2021 ◽

Vol 6 (1) ◽

pp. 4

Author(s):

Evgeny Mikhailov ◽

Daniela Boneva ◽

Maria Pashentseva

Keyword(s):

Magnetic Field ◽

Magnetic Fields ◽

Large Scale ◽

Point Of View ◽

Accretion Discs ◽

Wide Range ◽

Astrophysical Objects ◽

Alpha Effect ◽

The Stability ◽

The Magnetic Field

A wide range of astrophysical objects, such as the Sun, galaxies, stars, planets, accretion discs etc., have large-scale magnetic fields. Their generation is often based on the dynamo mechanism, which is connected with joint action of the alpha-effect and differential rotation. They compete with the turbulent diffusion. If the dynamo is intensive enough, the magnetic field grows, else it decays. The magnetic field evolution is described by Steenbeck—Krause—Raedler equations, which are quite difficult to be solved. So, for different objects, specific two-dimensional models are used. As for thin discs (this shape corresponds to galaxies and accretion discs), usually, no-z approximation is used. Some of the partial derivatives are changed by the algebraic expressions, and the solenoidality condition is taken into account as well. The field generation is restricted by the equipartition value and saturates if the field becomes comparable with it. From the point of view of mathematical physics, they can be characterized as stable points of the equations. The field can come to these values monotonously or have oscillations. It depends on the type of the stability of these points, whether it is a node or focus. Here, we study the stability of such points and give examples for astrophysical applications.

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Comparative study of finite element analysis of steel silos with rectangular and I stiffeners

Sustainability Agri Food and Environmental Research ◽

10.7770/safer-v10n1-art2457 ◽

2021 ◽

Vol 10 (1) ◽

pp. 9

Author(s):

Prasad Lakshmi ◽

Neethu Elsa Anil

Keyword(s):

Reinforced Concrete ◽

Element Analysis ◽

Plate Structures ◽

Steel Reinforced Concrete ◽

Wide Range ◽

Earthquake Load ◽

The Stability ◽

Dynamic Loading Conditions ◽

Steel Silos ◽

Static And Dynamic Loading

Silos are used by a wide range of industries to store bulk solids in quantities ranging from a few tones to hundreds or thousands of tones. They can be constructed of steel or reinforced concrete. Steel bins range from heavily stiffened flat plate structures to efficient unstiffened shell structures. They can be closed or open. They are subjected to many different static and dynamic loading conditions, mainly due to the unique characteristics of stored materials. Wind and earthquake load often undermine the stability of the silos. A steel silo with and without stiffeners is adopted and static structural analysis and dynamic analysis is done. The analysis is done by idealizing geometry, material and boundary conditions. Keywords: steel, reinforced concrete, silos.

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