SGLT2-Inhibition reverts urinary peptide changes associated with severe COVID-19: an in-silico proof-of-principle of proteomics-based drug repurposing

Severe COVID-19 is reflected by significant changes in multiple urine peptides. Based on this observation, a clinical test based on urinary peptides predicting COVID-19 severity, CoV50, was developed and registered as IVD in Germany. We have hypothesized that molecular changes displayed by CoV50, to a large degree likely reflective of endothelial damage, can be significantly reversed by specific drugs. To test this hypothesis, we have collected urinary peptide data from patients without COVID-19 prior and after drug treatment. The drugs chosen were selected based on availability of sufficient number of participants in the dataset (n>20) and potential value of drug therapies in the treatment of COVID-19 based on reports in the literature. In these participants without COVID-19, while spironolactone did not demonstrate a significant impact on CoV50 scoring, empagliflozin treatment resulted in a significant change in CoV50 scoring, indicative of a potential therapeutic benefit. The results serve as a proof-of-principle for a drug repurposing approach based on human urinary peptide signatures and support the initiation of a randomised control trial testing a potential positive effect of empagliflozin in the treatment of severe COVID-19, possibly via endothelial protective mechanisms.

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SGLT2‐Inhibition reverts urinary peptide changes associated with severe COVID‐19: An in‐silico proof‐of‐principle of proteomics‐based drug repurposing

PROTEOMICS ◽

10.1002/pmic.202100160 ◽

2021 ◽

pp. 2100160

Author(s):

Agnieszka Latosinska ◽

Justyna Siwy ◽

David Z. Cherney ◽

Bruce A. Perkins ◽

Harald Mischak ◽

...

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Sglt2 Inhibition ◽

Urinary Peptide ◽

Proof Of Principle

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Efficacy of ‘Foundations’, a Digital Mental Health App to Improve Mental Well-Being, during COVID-19: A Proof-of-Principle Randomised Controlled Trial (Preprint)

10.2196/preprints.30976 ◽

2021 ◽

Author(s):

Silvina Catuara-Solarz ◽

Bartlomiej Skorulski ◽

Inaki Estella ◽

Claudia Avella-Garcia ◽

Sarah Shepherd ◽

...

Keyword(s):

Mental Health ◽

Perceived Stress ◽

Intervention Group ◽

Well Being ◽

Self Report ◽

World Health ◽

Randomised Control Trial ◽

Control Group ◽

Mental Well Being ◽

Proof Of Principle

BACKGROUND Against a long-term trend of increasing demand, the COVID-19 pandemic has led to a global rise in common mental disorders. Now more than ever, there is an urgent need for scalable, evidence-based interventions to support mental well-being. OBJECTIVE The aim of this proof-of-principle study was to evaluate the efficacy of a mobile-based app in adults with self-reported symptoms of anxiety and stress in a randomised control trial that took place during the first wave of the COVID-19 pandemic in the UK. METHODS Adults with mild to severe anxiety and moderate to high levels of perceived stress were randomised to either the intervention or control arm. Participants in the intervention arm were given access to the app, Foundations, for the duration of the 4-week study. All participants were required to self-report a range of validated measures of mental well-being (10-item Connor-Davidson Resilience scale [CD-RISC-10]; 7-item Generalised Anxiety Disorder scale [GAD-7]; Office of National Statistics Four Subjective Well-being Questions [ONS-4]; World Health Organisation-5 Well-Being Index [WHO-5]) and sleep (Minimal Insomnia Scale [MISS]) at baseline and weeks 2 and 4; and, in addition, on perceived stress weekly (10-item Perceived Stress Score [PSS]). RESULTS 136 participants completed the study and were included in the final analysis. The intervention group (n=62) showed significant improvements compared to the control group (n=74) on measures of anxiety (GAD-7 score, delta from baseline to week 2 in the intervention group: -1.35 [SD 4.43]; control group: -0.23 [SD 3.24]; t134= 1.71 , P=.04), resilience (CD-RISC score, delta from baseline to week 2 in the intervention group: 1.79 [± SD 4.08]; control group: -0.31 [± SD 3.16]; t134 -3.37, P<.001), sleep (MISS score, delta from baseline to week 2 in the intervention group: -1.16 [± SD 2.67]; control group: -0.26 [± SD 2.29]; t134= 2.13, P=.01), and mental well-being (WHO-5 score, delta from baseline to week 2 in the intervention group: 1.53 [5.30]; control group: -0.23 [± SD 4.20]; t134= -2.16, P=.02) within 2 weeks of using Foundations, with further improvements emerging at week 4. Perceived stress was also reduced within the intervention group, although the results did not reach statistical significance relative to the control group (PSS score, delta from baseline to week 2 in the intervention group: -2.94 [± SD 6.84]; control group: -2.05 [± SD 5.34]; t134= 0.84, P=.20). CONCLUSIONS This study provides proof-of-principle that the digital mental health app, Foundations, can improve measures of mental well-being, anxiety, resilience, and sleep within 2 weeks of use, with greater effects after 4 weeks. It therefore offers potential as a scalable, cost-effective, and accessible solution to enhance mental well-being, even during times of crisis such as the COVID-19 pandemic.

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Thrombocytopenia in hospitalized patients: approach to the patient with thrombotic microangiopathy

Hematology ◽

10.1182/asheducation-2017.1.651 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 651-659 ◽

Cited By ~ 7

Author(s):

Marie Scully

Keyword(s):

Mutational Analysis ◽

Renal Involvement ◽

Specific Treatment ◽

Therapeutic Benefit ◽

Endothelial Damage ◽

Factor H ◽

Treatment Pathways ◽

Mortality And Morbidity ◽

Life Threatening ◽

Uremic Syndrome

Abstract Thrombotic microangiopathies (TMAs), specifically, thrombotic thrombocytopenic purpura (TTP) and complement-mediated hemolytic uremic syndrome (CM-HUS) are acute life-threatening disorders that require prompt consideration, diagnosis, and treatment to improve the high inherent mortality and morbidity. Presentation is with microangiopathic hemolytic anemia and thrombocytopenia (MAHAT) and variable organ symptoms resulting from microvascular thrombi. Neurological and cardiac involvement is most common in TTP and associated with poorer prognosis and primarily renal involvement in CM-HUS. TTP is confirmed by severe ADAMTS13 deficiency (which can be undertaken in real time) and CM-HUS by an abnormality in complement regulators, confirmed by mutational analysis (in 60% to 70% of cases) or the presence of Factor H antibodies (which may not be available for weeks or months). Plasma exchange (PEX) should be started as soon as possible following consideration of these TMAs. Differentiation of the diagnosis requires specific treatment pathways thereafter (immunosuppression primarily for TTP and complement inhibitor therapy for CM-HUS). As the diagnosis is based on MAHAT, there are a number of other medical situations that need to be excluded and these are discussed within the article. Other differentials presenting as TMAs may also be associated with micro- or macrovascular thrombosis, yet are more likely to be due to direct endothelial damage, many of which do not have a clear therapeutic benefit with PEX.

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Improving postal survey response using behavioural science: a nested randomised control trial

BMC Medical Research Methodology ◽

10.1186/s12874-021-01476-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Emily McBride ◽

Hiromi Mase ◽

Robert S. Kerrison ◽

Laura A. V. Marlow ◽

Jo Waller

Keyword(s):

Controlled Trial ◽

Postal Survey ◽

Survey Response ◽

Survey Study ◽

Randomised Control Trial ◽

Routine Practice ◽

Clinical Test ◽

Behavioural Science ◽

Cross Sectional ◽

Invitation Letter

Abstract Background Systematic reviews have identified effective strategies for increasing postal response rates to questionnaires; however, most studies have isolated single techniques, testing the effect of each one individually. Despite providing insight into explanatory mechanisms, this approach lacks ecological validity, given that multiple techniques are often combined in routine practice. Methods We used a two-armed parallel randomised controlled trial (n = 2702), nested within a cross-sectional health survey study, to evaluate whether using a pragmatic combination of behavioural science and evidenced-based techniques (e.g., personalisation, social norms messaging) in a study invitation letter increased response to the survey, when compared with a standard invitation letter. Participants and outcome assessors were blinded to group assignment. We tested this in a sample of women testing positive for human papillomavirus (HPV) at cervical cancer screening in England. Results Overall, 646 participants responded to the survey (response rate [RR] = 23.9%). Logistic regression revealed higher odds of response in the intervention arm (n = 357/1353, RR = 26.4%) compared with the control arm (n = 289/1349, RR = 21.4%), while adjusting for age, deprivation, clinical site, and clinical test result (aOR = 1.30, 95% CI: 1.09–1.55). Conclusion Applying easy-to-implement behavioural science and evidence-based methods to routine invitation letters improved postal response to a health-related survey, whilst adjusting for demographic characteristics. Our findings provide support for the pragmatic adoption of combined techniques in routine research to increase response to postal surveys. Trial registration ISRCTN, ISRCTN15113095. Registered 7 May 2019 – retrospectively registered.

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Improving Postal Survey Response Using Behavioural Science: A Nested Randomised Control Trial

10.21203/rs.3.rs-736289/v1 ◽

2021 ◽

Author(s):

Emily McBride ◽

Hiromi Mase ◽

Robert S. Kerrison ◽

Laura A.V. Marlow ◽

Jo Waller

Keyword(s):

Controlled Trial ◽

Postal Survey ◽

Survey Response ◽

Survey Study ◽

Randomised Control Trial ◽

Routine Practice ◽

Clinical Test ◽

Behavioural Science ◽

Cross Sectional ◽

Invitation Letter

Abstract Background Systematic reviews have identified effective strategies for increasing postal response rates to questionnaires; however, most studies have isolated single techniques, testing the effect of each one individually. Despite providing insight into explanatory mechanisms, this approach lacks ecological validity, given that multiple techniques are often combined in routine practice. Methods We used a two-armed randomised controlled trial (N = 2,702), nested within a cross-sectional health survey study, to evaluate whether using a pragmatic combination of behavioural science and evidenced-based techniques (e.g., personalisation, social norms messaging) in a study invitation letter increased response to the survey, when compared with a standard invitation letter. Results Overall, 646 participants responded to the survey (response rate [RR] = 23.9%). Logistic regression revealed higher odds of response in the intervention arm (N = 357/1,353, RR = 26.4%) compared with the control arm (N = 289/1,349, RR = 21.4%), while adjusting for age, deprivation, clinical site, and clinical test result (aOR = 1.30, 95% CI: 1.09–1.55). Conclusion Applying easy-to-implement behavioural science and evidence-based methods to routine invitation letters improved postal response to a health-related survey, whilst adjusting for demographic characteristics. Our findings provide support for the pragmatic and cost-effective adoption of combined techniques in routine research to increase response to postal surveys. Trial registration: ISRCTN, ISRCTN15113095. Registered 7 May 2019 – retrospectively registered: https://doi.org/10.1186/ISRCTN15113095

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Ultrastructure of pulmonary microvasculature in acute endotoxemia

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100083217 ◽

1978 ◽

Vol 36 (2) ◽

pp. 470-471

Author(s):

R. G. Gerrity ◽

M. Richardson

Keyword(s):

Polymorphonuclear Leukocytes ◽

Alveolar Epithelium ◽

Endothelial Damage ◽

Capillary Endothelium ◽

Type Ii Cells ◽

Type Ii ◽

Interstitial Edema ◽

Pulmonary Capillaries ◽

Lung Ultrastructure ◽

Fibrin Thrombi

Dogs were injected intravenously with E_. coli endotoxin (2 mg/kg), and lung samples were taken at 15 min., 1 hr. and 24 hrs. At 15 min., occlusion of pulmonary capillaries by degranulating platelets and polymorphonuclear leukocytes (PML) was evident (Fig. 1). Capillary endothelium was intact but endothelial damage in small arteries and arterioles, accompanied by intraalveolar hemorrhage, was frequent (Fig. 2). Sloughing of the surfactant layer from alveolar epithelium was evident (Fig. 1). At 1 hr., platelet-PML plugs were no longer seen in capillaries, the endothelium of which was often vacuolated (Fig. 3). Interstitial edema and destruction of alveolar epithelium were seen, and type II cells had discharged their granules into the alveoli (Fig. 4). At 24 hr. phagocytic PML's were frequent in peripheral alveoli, while centrally, alveoli and vessels were packed with fibrin thrombi and PML's (Fig. 5). In similar dogs rendered thrombocytopenic with anti-platelet serum, lung ultrastructure was similar to that of controls, although PML's were more frequently seen in capillaries in the former (Fig. 6).

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Characterization of homoepitaxial diamond films by Electron microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100088713 ◽

1991 ◽

Vol 49 ◽

pp. 880-881

Author(s):

D.P. Malta ◽

S.A. Willard ◽

R.A. Rudder ◽

G.C. Hudson ◽

J.B. Posthill ◽

...

Keyword(s):

Electron Microscopy ◽

Surface Defects ◽

Substrate Surface ◽

Diamond Films ◽

Chemical Vapor ◽

Polycrystalline Diamond ◽

Large Degree ◽

Rf Plasma ◽

Semiconducting Diamond

Semiconducting diamond films have the potential for use as a material in which to build active electronic devices capable of operating at high temperatures or in high radiation environments. A major goal of current device-related diamond research is to achieve a high quality epitaxial film on an inexpensive, readily available, non-native substrate. One step in the process of achieving this goal is understanding the nucleation and growth processes of diamond films on diamond substrates. Electron microscopy has already proven invaluable for assessing polycrystalline diamond films grown on nonnative surfaces.The quality of the grown diamond film depends on several factors, one of which is the quality of the diamond substrate. Substrates commercially available today have often been found to have scratched surfaces resulting from the polishing process (Fig. 1a). Electron beam-induced current (EBIC) imaging shows that electrically active sub-surface defects can be present to a large degree (Fig. 1c). Growth of homoepitaxial diamond films by rf plasma-enhanced chemical vapor deposition (PECVD) has been found to planarize the scratched substrate surface (Fig. 1b).

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