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2.
Journal of Hypertension ; 40:e172, 2022.
Article in English | EMBASE | ID: covidwho-1937717

ABSTRACT

Objective: Endothelial dysfunction is thought to underlie many of the complications of COVID-19 but to what degree this persists after recovery is unknown. Here we examine endothelial function in subjects previously hospitalized with COVID- 19, those with mild symptoms who were not hospitalized and negative controls (absence of SARS-CoV-2-antibodies). Endothelial function was measured as pulse wave response to the β2 adrenergic agonist salbutamol (PWRS) which is mediated through the nitric oxide - cyclic guanosine monophosphate pathway (NO-cGMP). Design and method: Echocardiography was used to exclude subjects with cardiac abnormalities. Tonometry of the radial artery (SphygmoCor, AtCor Medical, Sydney, Australia) was performed in duplicate by a single operator before and after inhalation of 200 mcg of salbutamol using a spacer device. The PWRS was taken as the change from baseline in augmentation index (Aix) as calculated by the SphygmoCor system. In a sub-sample, PWRS was assessed in the presence and absence of the phosphodiesterase type 5 inhibitor sildenafil which inhibits the breakdown of cGMP. Results: We recruited 88 subjects (49 men) aged 47.9 ± 14.3 (mean ± SD) years of whom 32 were previously hospitalized with COVID-19 (~6 months). Subjects previously hospitalized with COVID-19 were all previously assessed in a dedicated pulmonary clinic. Age, gender, BMI, smoking status, diabetes and estimated 10-year cardiovascular risk (Q-RISKâ3) were similar between the groups. Administration of salbutamol reduced AIx in controls and those with mild COVID-19 but produced an increase in AIx in previously hospitalized COVID-19 cases (mean [95% CI]): -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % respectively, P = 0.017 between the groups. In a sub-sample (11 hospitalized and 11 non-hospitalized) the PWRS was measured again 30 minutes after oral administration of sildenafil 25 mg. This produced a greater reduction in AIx: -5.28 [-9.00, -1.54] % in non-hospitalized and a reduction: -3.90 [-7.60, -0.21] % in hospitalized patients, and an overall improvement in the PWRS (P = 0.006). Conclusions: In subjects previously hospitalized with severe COVID-19, endothelial function is impaired for many months after hospital discharge and the impaired NO-cGMP mediated vasodilation may be reversed by sildenafil.

3.
ACS Omega ; 7(20): 17462-17471, 2022 May 24.
Article in English | MEDLINE | ID: covidwho-1860285

ABSTRACT

Mass spectrometry (MS) based diagnostic detection of 2019 novel coronavirus infectious disease (COVID-19) has been postulated to be a useful alternative to classical PCR based diagnostics. These MS based approaches have the potential to be both rapid and sensitive and can be done on-site without requiring a dedicated laboratory or depending on constrained supply chains (i.e., reagents and consumables). Matrix-assisted laser desorption ionization (MALDI)-time-of-flight (TOF) MS has a long and established history of microorganism detection and systemic disease assessment. Previously, we have shown that automated machine learning (ML) enhanced MALDI-TOF-MS screening of nasal swabs can be both sensitive and specific for COVID-19 detection. The underlying molecules responsible for this detection are generally unknown nor are they required for this automated ML platform to detect COVID-19. However, the identification of these molecules is important for understanding both the mechanism of detection and potentially the biology of the underlying infection. Here, we used nanoscale liquid chromatography tandem MS to identify endogenous peptides found in nasal swab saline transport media to identify peptides in the same the mass over charge (m/z) values observed by the MALDI-TOF-MS method. With our peptidomics workflow, we demonstrate that we can identify endogenous peptides and endogenous protease cut sites. Further, we show that SARS-CoV-2 viral peptides were not readily detected and are highly unlikely to be responsible for the accuracy of MALDI based SARS-CoV-2 diagnostics. Further analysis with more samples will be needed to validate our findings, but the methodology proves to be promising.

4.
Anaesthesia ; 77(4): 398-404, 2022 04.
Article in English | MEDLINE | ID: covidwho-1714114

ABSTRACT

Transferring critically ill patients between intensive care units (ICU) is often required in the UK, particularly during the COVID-19 pandemic. However, there is a paucity of data examining clinical outcomes following transfer of patients with COVID-19 and whether this strategy affects their acute physiology or outcome. We investigated all transfers of critically ill patients with COVID-19 between three different hospital ICUs, between March 2020 and March 2021. We focused on inter-hospital ICU transfers (those patients transferred between ICUs from different hospitals) and compared this cohort with intra-hospital ICU transfers (patients moved between different ICUs within the same hospital). A total of 507 transfers were assessed, of which 137 met the inclusion criteria. Forty-five patients underwent inter-hospital transfers compared with 92 intra-hospital transfers. There was no significant change in median compliance 6 h pre-transfer, immediately post-transfer and 24 h post-transfer in patients who underwent either intra-hospital or inter-hospital transfers. For inter-hospital transfers, there was an initial drop in median PaO2 /FI O2 ratio: from median (IQR [range]) 25.1 (17.8-33.7 [12.1-78.0]) kPa 6 h pre-transfer to 19.5 (14.6-28.9 [9.8-52.0]) kPa immediately post-transfer (p < 0.05). However, this had resolved at 24 h post-transfer: 25.4 (16.2-32.9 [9.4-51.9]) kPa. For intra-hospital transfers, there was no significant change in PaO2 /FI O2 ratio. We also found no meaningful difference in pH; PaCO2 ;, base excess; bicarbonate; or norepinephrine requirements. Our data demonstrate that patients with COVID-19 undergoing mechanical ventilation of the lungs may have short-term physiological deterioration when transferred between nearby hospitals but this resolves within 24 h. This finding is relevant to the UK critical care strategy in the face of unprecedented demand during the COVID-19 pandemic.


Subject(s)
COVID-19 , Critical Illness , Humans , Intensive Care Units , Pandemics , Patient Transfer , Retrospective Studies
5.
Autism & Developmental Language Impairments ; 6:20, 2021.
Article in English | Web of Science | ID: covidwho-1582458

ABSTRACT

Background and aims The COVID-19 pandemic has caused unprecedented disruption to people's lives, especially for families, whose children have been taken out of schools during lockdown restrictions and required to learn from home. Little is known, however, about the perceived impact of the lockdown restrictions on the educational experiences of autistic children and young people - a group whose conventional schooling experiences are already often challenging. In this study, we sought to (1) understand these experiences from the perspectives of autistic young people and their parents, and (2) identify the underlying sources of positive experiences at this challenging time, in order to inform the ways in which autistic children might flourish at school in more normal times. Methods Ninety-one Australian participants, including 16 autistic young people aged 12-18 years, 32 autistic parents and 43 non-autistic parents of autistic young people aged 3-18 years, took part in semi-structured interviews about their experiences of life during the initial phase of the COVID-19 pandemic. The interviews were subjected to reflexive, thematic analysis to identify themes and subthemes for each research question. Results Overall, our participants initially found the transition to learning from home extremely challenging, with parents reporting that the support received from schools was far from adequate. After that initial period of transition, however, many autistic children reported flourishing at home both educationally and personally. For these children and families, we identified three key ingredients essential to this flourishing, including: (i) the importance of connected, trusting relationships ('people');(ii) the sensory and social safety of home ('place');and (iii) the flexibility to pace and structure learning to suit the individual child ('time'). Conclusions While the initial COVID-19 lockdown presented many challenges to children learning at home, there were aspects of this otherwise-unsettling situation that enabled children to thrive and from which we can learn for the future.

6.
Cell Rep Med ; 2(5): 100288, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1213573

ABSTRACT

Individuals with coronavirus disease 2019 (COVID-19) frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single-cell RNA sequencing (scRNA-seq) and cytokine analyses of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific T cell activation and B cell responses. All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from an individual with COVID-19 and found that these monoclonal antibodies (mAbs) target antiviral and antineural antigens, including one mAb that reacted to spike protein and neural tissue. CSF immunoglobulin G (IgG) from 5 of 7 patients showed antineural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of individuals with COVID-19 and suggests a role of autoimmunity in neurologic sequelae of COVID-19.

7.
Oncologist ; 26(6): 483-491, 2021 06.
Article in English | MEDLINE | ID: covidwho-1081640

ABSTRACT

BACKGROUND: The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience. MATERIAL AND METHODS: Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data. RESULTS: Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events. CONCLUSION: EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care. IMPLICATIONS FOR PRACTICE: Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.


Subject(s)
COVID-19 , Electronic Nicotine Delivery Systems , Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/adverse effects , Cisplatin/adverse effects , Etoposide/adverse effects , Humans , Male , Neoplasms, Germ Cell and Embryonal/drug therapy , SARS-CoV-2 , Testicular Neoplasms/drug therapy
9.
Preprint in English | bioRxiv | ID: ppbiorxiv-293464

ABSTRACT

One third of COVID-19 patients develop significant neurological symptoms, yet SARS-CoV-2 is rarely detected in central nervous system (CNS) tissue, suggesting a potential role for parainfectious processes, including neuroimmune responses. We therefore examined immune parameters in cerebrospinal fluid (CSF) and blood samples from a cohort of patients with COVID-19 and significant neurological complications. We found divergent immunological responses in the CNS compartment, including increased levels of IL-12 and IL-12-associated innate and adaptive immune cell activation. Moreover, we found increased proportions of B cells in the CSF relative to the periphery and evidence of clonal expansion of CSF B cells, suggesting a divergent intrathecal humoral response to SARS-CoV-2. Indeed, all COVID-19 cases examined had anti-SARS-CoV-2 IgG antibodies in the CSF whose target epitopes diverged from serum antibodies. We directly examined whether CSF resident antibodies target self-antigens and found a significant burden of CNS autoimmunity, with the CSF from most patients recognizing neural self-antigens. Finally, we produced a panel of monoclonal antibodies from patients CSF and show that these target both anti-viral and anti-neural antigens--including one mAb specific for the spike protein that also recognizes neural tissue. This exploratory immune survey reveals evidence of a compartmentalized and self-reactive immune response in the CNS meriting a more systematic evaluation of neurologically impaired COVID-19 patients. One Sentence SummaryA subset of COVID-19 patients with neurologic impairment show cerebrospinal fluid-specific immune alterations that point to both neuroinvasion and anti-neural autoimmunity as potential causes of impairment.

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