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Calcineurin inhibitors (CNIs) are often used for solid organ transplantation recipients or patients with immune-mediated diseases. This systematic review and meta-analysis aims to understand how CNIs affect pregnancy and neonatal outcomes.Electronic databases were searched for observational studies assessing pregnancy and neonatal outcomes in CNI-treated patients. The pooled rate of each outcome was determined. Metaregression was conducted to identify contributing factors to the outcomes.We analysed 98 studies with a total of 5355 pregnancies in 4450 CNI-treated patients. The pooled rates of live birth and spontaneous abortion were 82.1% (95% confidence interval [CI] 76.7-86.4%) and 11.7% (95% CI 8.7-15.5%), respectively. The rates of preterm delivery (33.2%, 95% CI 29.2-37.5%), low birth weight (35.8%, 95% CI 27.7-44.8%) and preeclampsia (13.5%, 95% CI 9.4-19.2%) were 3-4 times higher than the rates of general population. Nearly half of the CNI-treated patients required caesarean delivery (43.5%, 95% CI 36.9-50.3%). The rates of stillbirth, neonatal and maternal death were 4.2% (95% CI 2.8-6.2%), 2.9% (95% CI 1.8-4.8%) and 2.3% (95% CI 1.3-4.1%), respectively. Metaregression showed that preeclampsia was significantly associated with the risks of preterm delivery and low birth weight. Older maternal age, prepregnancy hypertension and cyclosporine use increased the risk of preeclampsia.Given the higher mortalities in CNI-treated patients and their children than the general averages, their pregnancy is considered high risk. The risks of preterm delivery and low birth weight were primarily attributed to preeclampsia. Since prepregnancy hypertension increased its risk, an appropriate preconception blood pressure management may improve their outcomes.

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Static cold preservation remains the cornerstone for storing donor livers following procurement; however, the choice between University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK) remains controversial. Recent International Liver Transplantation Society (ILTS) guidelines have recommended avoiding HTK for donation after circulatory death (DCD) grafts based on older reports. We studied the latest US adult graft outcomes in three recent eras (2006-2010, 2011-2015, 2016-2020) comparing HTK and UW among 5956 DCD LTs: 3873 (65.0%) used UW and 1944 (32.7%) used HTK. In a total of 82,679 donation after brain death (DBD) liver transplantations (LTs), 63,511 (76.8%) used UW and 15,855 (19.2%) used HTK. The HTK group had higher 1-year and 5-year graft survival rates of 89.7% and 74.3%, respectively, compared with 85.9% and 70.8% in the UW group in the 2016-2020 era (p = 0.005). This difference remained when adjusted for important potential confounders (hazard ratio, 0.78; 95% confidence interval: 0.60, 0.99). There were no differences between groups among DCD LTs in the earlier eras or among DBD LTs in all eras (all p values0.05). The latest US data suggest that HTK is at least noninferior to UW for preserving DCD livers. These data support HTK use in DCD LT and contradict ILTS guidance.

BACKGROUND: The presence of esophageal varices is considered a relative contraindication to transesophageal echocardiography (TEE) by cardiology professional societies, so gastroenterologists are often consulted to perform upper endoscopy prior to TEE in patients with cirrhosis. AIM: Perform a systematic review to quantify the risk of bleeding complications in patients with cirrhosis following TEE METHODS: Two reviewers searched MEDLINE and EMBASE databases from January 1992 to May 2021 for studies reporting bleeding complications from TEE in patients with cirrhosis. We calculated the pooled incidence rate of bleeding events using the metaprop command with a random-effects model. RESULTS: We identified 21 studies comprising 4050 unique patients with cirrhosis; nine studies (n=3015) assessed risk of intraoperative TEE during liver transplant (LT) and twelve studies (n=1035) assessed bleeding risk in patients undergoing TEE for other indications. The pooled incidence of bleeding post-TEE was 0.37% (95%CI 0.04 – 0.94%) across all studies. Bleeding complications were low among patients undergoing TEE during LT as well as those undergoing TEE for other diagnostic reasons (0.97% vs 0.004%) and among studies with mean MELD >18 compared to those with mean MELD

Progression of chronic liver diseases is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections, impact gut microbiome composition and metabolite production. Using a multi-omics approach on 850 fecal samples from 263 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinalBifidobacteriaand reduced incidence of systemic infections and mortality.Bifidobacteriametabolize lactulose, produce high concentrations of acetate and acidify the gut lumen, which, in combination, can reduce the growth of antibiotic-resistant pathobionts such as Vancomycin-resistantEnterococcus faecium. Our studies suggest that lactulose andBifidobacteriaserve as a synbiotic to reduce rates of infection in patients with severe liver disease.

Monthly notices of the Royal Astronomical Society 515(1), 1365 - 1379 (2022). doi:10.1093/mnras/stac1601, We report on a search for persistent radio emission from the one-off fast radio burst (FRB) 20190714A, as well as from two repeating FRBs, 20190711A and 20171019A, using the MeerKAT radio telescope. For FRB 20171019A, we also conducted simultaneous observations with the High-Energy Stereoscopic System (H.E.S.S.) in very high-energy gamma rays and searched for signals in the ultraviolet, optical, and X-ray bands. For this FRB, we obtain a UV flux upper limit of |$1.39 \times 10^{-16}~{\rm erg\, cm^{-2}\, s^{-1}}$|Å^−1, X-ray limit of |$\sim 6.6 \times 10^{-14}~{\rm erg\, cm^{-2}\, s^{-1}}$| and a limit on the very high energy gamma-ray flux |$\Phi (E\gt 120\, {\rm GeV}) \lt 1.7\times 10^{-12}\, \mathrm{erg\, cm^{-2}\, s^{-1}}$|⁠. We obtain a radio upper limit of ∼15 |$\mu$|Jy beam^−1 for persistent emission at the locations of both FRBs 20190711A and 20171019A with MeerKAT. However, we detected an almost unresolved (ratio of integrated flux to peak flux is ∼1.7 beam) radio emission, where the synthesized beam size was ∼ 8 arcsec size with a peak brightness of |$\sim 53\, \mu$|Jy beam^−1 at MeerKAT and |$\sim 86\, \mu$|Jy beam^−1 at e-MERLIN, possibly associated with FRB 20190714A at z = 0.2365. This represents the first detection of persistent continuum radio emission potentially associated with a (as-yet) non-repeating FRB. If the association is confirmed, one of the strongest remaining distinction between repeaters and non-repeaters would no longer be applicable. A parallel search for repeat bursts from these FRBs revealed no new detections down to a fluence of 0.08 Jy ms for a 1 ms duration burst., Published by Oxford Univ. Press, Oxford

Background We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes. Methods We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure. Results Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64–2.15, p p Conclusions Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. Graphical abstract Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.

A deep survey of the Large Magellanic Cloud at ~0.1-100TeV photon energies with the Cherenkov Telescope Array is planned. We assess the detection prospects based on a model for the emission of the galaxy, comprising the four known TeV emitters, mock populations of sources, and interstellar emission on galactic scales. We also assess the detectability of 30 Doradus and SN 1987A, and the constraints that can be derived on the nature of dark matter. The survey will allow for fine spectral studies of N157B, N132D, LMC P3, and 30 Doradus C, and half a dozen other sources should be revealed, mainly pulsar-powered objects. The remnant from SN 1987A could be detected if it produces cosmic-ray nuclei with a flat power-law spectrum at high energies, or with a steeper index 2.3-2.4 pending a flux increase by a factor >3-4 over ~2015-2035. Large-scale interstellar emission remains mostly out of reach of the survey if its >10GeV spectrum has a soft photon index ~2.7, but degree-scale 0.1-10TeV pion-decay emission could be detected if the cosmic-ray spectrum hardens above >100GeV. The 30 Doradus star-forming region is detectable if acceleration efficiency is on the order of 1-10% of the mechanical luminosity and diffusion is suppressed by two orders of magnitude within, Accepted for publication in MNRAS. Corresponding authors: Pierrick Martin, Maria Isabel Bernardos Martin, Fabio Iocco

Introduction The COVID-19 pandemic has brought the decision-making process regarding cardiopulmonary resuscitation into focus. This study aims to analyse Do-Not-Attempt CPR (DNACPR) documentation in older hospitalised patients before and during the COVID-19 pandemic. Methods This was a retrospective repeated cross-sectional study. Data including co-morbidities and resuscitation status was collected on 300 patients with COVID-19 hospitalised from March 1st to May 31 s t 2020. DNACPR documentation rates in patients aged ≥65 years with a diagnosis of COVID-19 were compared to those without COVID-19 admitted during the same period. Pre-COVID-19 pandemic DNACPR documentation rates were also examined. Factors associated with DNACPR order instatement during the first wave of the COVID-19 pandemic were identified. Results Of 300 COVID-19-positive patients, 28% had a DNACPR order documented during their admission. 50% of DNAR orders were recorded within 24 hours of a positive swab result for SARS-CoV-2. Of 131 patients aged 65 years or over within the cohort admitted with COVID-19, 60.3% had a DNACPR order compared to 25.4% of 130 patients ≥65 without COVID-19 (p Conclusion The COVID-19 pandemic has prompted more widespread and earlier decision-making regarding resuscitation status. Although case-fatality-rates were higher for older hospitalised patients with COVID-19, many older patients survived the illness. Advance care planning should be prioritised in all patients and should remain clinical practice despite the pandemic.

Hepatitis B virus reactivation (HBVr) can occur in patients treated with immunosuppressive medications. Risk stratification for HBVr based on hepatitis B virus (HBV) serology and viral load is an important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use. Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies. Tumor necrosis factor (TNF)-α inhibitors have been widely used for patients with inflammatory bowel disease, psoriasis, and rheumatic diseases. Further, the clinical benefits of interleukin (IL)-12/23, IL-17, or Janus kinases inhibitors have been demonstrated in these patients. It is well known that TNF-α inhibitor use can lead to HBVr, however, the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood. In this review, we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics, and immunological mechanisms of these medications causing HBVr.

AIM: To report an audit of the evaluation of suspected, unconfirmed cases of COVID-19 including chest computed tomography (CT), as compared to World Health Organization recommendations. METHODS: A clinical audit was undertaken examining the evaluation of patients with suspected COVID-19 with negative SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) results, with comparison to WHO recommendations. A retrospective chart review was undertaken for 90 patients examining investigations, in particular CT, used to clarify the diagnosis. RESULTS: Ninety patients underwent additional investigation. Seventy-five per cent adherence to WHO recommendations was observed. Fifty-two men (57.78%) and 38 (42.22%) women were investigated, with a median age of 69 years (range 20-96 years). Seventy-nine chest CT examinations demonstrated positive, indeterminate, and negative rates for COVID-19 of 3.79%, 24.1%, and 72.15% respectively. Three patients had discordant swab results with initially negative and subsequently positive results for SARS-CoV-2, resulting in false-negative rates of 5.1% for those retested. Combining discordant RT-PCR swab results, positive radiology, and patients treated as COVID-19-positive due to indeterminate radiology and highly consistent symptoms, resulted in a false-negative rate for initial SARS-CoV-2 RT-PCR swabs of 16.67%. CONCLUSION: Seventy-five per cent compliance with relevant WHO guidance and a false-negative rate for initial swabs of 16.67% was demonstrated. Further evidence is needed to fully determine the utility of chest CT in the diagnosis of COVID-19 in the context of initial false-negative RT-PCR results.

The choice of an optimal antiretroviral therapy (ART) in naive patients presenting late for initial therapy with advanced HIV infection, that is, with a CD4 cell count

Background and aims There are more adults than children living with congenital heart disease (CHD) in the United States, with a growing proportion requiring heart-liver transplantation (HLT). Our aim was to ascertain the frequency, outcomes, and prognostic factors in this patient population. Approach and results United Network for Organ Sharing data on adult patients who underwent heart transplantation (HT) from 2009 through March 2020 were analyzed. The primary study outcome was patient survival. Cox proportional-hazards modeling assessed for mortality associations. There were 1,084 HT recipients: 817 (75.4%) CHD HTs only, 74 (6.8%) CHD HLTs, 179 (16.5%) non-CHD HLTs, and 14 (1.3%) heart-liver-kidney transplants. The number of CHD HLTs increased from a prior rate of 4/year to 21/year in 2019. Among patients with CHD, the 5-year survival rates were 74.1% and 73.6% in HTs only and HLTs, respectively (P = 0.865). There was a higher rate of allograft failure attributable to rejection in CHD HTs only compared with CHD HLTs (3.2% versus 0.4%; P = 0.014). Only 25 out of 115 HT-performing hospitals undertook CHD HLTs. Higher-volume centers (averaging one CHD HLT per year) had a 5-year patient survival rate of 83.0% compared with 61.3% in lower-volume centers (P = 0.079). Among HLT recipients, total bilirubin (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.12) and diabetes (HR = 2.97, 95% CI = 1.21-7.31) were independently associated with increased mortality risk, whereas CHD and age were not. Conclusions The rate of HLT for adult CHD in the United States is rising dramatically. The survival outcomes between CHD HT only and CHD HLT groups are comparable; however, the HLT group had lower rates of acute rejection. Among HLT recipients, diabetes and elevated bilirubin are associated with increased posttransplant mortality risk. An average of one CHD HLT per year could be considered a minimum quality metric at transplant centers.

Background: Recent studies have identified the combination of vancomycin with piperacillin-tazobactam (VPT) to be associated with increased nephrotoxicity. Multiple, large cohort studies have found this widely used combination to have a higher risk of nephrotoxicity than other regimens in a variety of populations. Summary: This review summarizes the epidemiology and clinical features of VPT-associated acute kidney injury (AKI). Potential mechanisms involved in the pathogenesis of this phenomenon are also discussed. Key Message: VPT-associated nephrotoxicity is a recently recognized clinical entity. Clinical strategies to minimize the risk of toxicity in this setting include antimicrobial stewardship, monitoring of kidney function, and emerging data supporting the potential role for novel biomarkers in predicting and managing AKI.

BACKGROUND Direct-acting antiviral therapy made possible the novel practice of utilizing hepatitis C virus (HCV)-viremic (HCV RNA-positive) donors into HCV-negative recipients in the United States. Although initial reports of outcomes have been satisfactory, higher-quality longer-term outcomes remain to be elucidated. METHODS National data were examined from the Organ Procurement and Transplantation Network on adult patients in the United States who underwent a primary, single organ, deceased donor liver transplant from January 1, 2016 to March 31, 2020. Outcomes of HCV-negative recipients (R-) who received an allograft from donors who were HCV RNA-positive (D HCV+) donors were compared with HCV RNA-negative (D HCV-) donors. RESULTS There has been a 35-fold increase in D HCV+/R- liver transplants over the past 4 y in the United States, from 8 in 2016 to 280 in 2019. There was an almost 6-fold difference in this practice among UNOS geographic regions. Graft survival following D HCV+/R- liver transplantation was excellent, with 1-y rates being 91% and 90% and 2-y rates being 88.5% and 87% for D HCV+/R- and D HCV-/R-, respectively (P = 0.672). In multivariate analysis, adjusting for other donor and recipient attributes, D HCV+/R- was not associated with patient or graft survival. CONCLUSIONS The practice of D HCV+/R- continues to increase without discernible impact on medium-term outcomes. Notable geographic variation exists, suggesting inconsistent perceptions about the impact of D HCV+/R- transplantation on outcomes. These results strengthen the perceived safety in utilizing HCV-viremic donor organs as a donor pool expansion strategy, not only in the United States, but also worldwide.

NAFLD is the most prevalent liver disease globally, affecting 20% of the world population. Healthcare resource utilization (HRU) attributable to NAFLD has been difficult to define. We performed a case control study on NAFLD patients from 2005 to 2015 in a large integrated healthcare system with an affiliated insurance company that prospectively captures HRU information. Outcomes encompassed costs, liver transplantation and mortality rates. There were 17,085 patients, of which 4512 were NAFLD cases and 12,573 were non-NAFLD controls. The cohorts were similar in age and gender distribution (p > 0.05). The NAFLD cohort had a younger mean age of death (60.9 vs. 63.3, p = 0.004) and had over twice the number of annual healthcare visits (14.6 vs. 7.1). The increased overall annual overall cost attributable to NAFLD (in 2015 $) was $449/year. Overall, NAFLD was independently associated with 17% higher annual attributable healthcare costs. More advanced NAFLD (FS 3–4) was associated with a 40% increase in median annual healthcare costs (vs. FS 0-2). The strongest predictors of HRU among patients with NAFLD were advanced fibrosis and medical co-morbidities. The rate of liver transplantation was 18 times greater (0.054%/year) in the NAFLD compared with the non-NAFLD cohort, while mortality rate was 1.7 times greater. Within a large, integrated healthcare system a diagnosis of NAFLD is independently associated with a 17% overall excess in HRU and a several-fold increase liver transplantation and mortality. Although the dollar amounts will change over time and between healthcare systems, the proportional need for HRU will have broad applicability and implications.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by potentially life-threatening recurrent vascular thrombosis, miscarriage, and the presence of antiphospholipid antibodies, including anti-cardiolipin, anti-beta 2 glycoprotein, and lupus anticoagulant. It is additionally associated with false-positive rapid plasma reagin titer. APS can either be primary, presenting in the absence of another autoimmune disorder, or secondary, presenting with another autoimmune disorder. Data on the epidemiology of APS are limited, but 1 study found the annual incidence and prevalence to be 2.1 and 50 per 100,000, respectively.1 The epidemiology of APS is further limited in pediatric patients, as it is likely underdiagnosed due to a lack of pediatric-specific clinical criteria.2 Interestingly, children may have a higher rate of progression from primary to secondary APS.3,4 Cutaneous manifestations are common in APS, arising in 18% of cases, including livedo reticularis (LR), Raynaud phenomenon, atrophie blanche, anetoderma, urticaria, malignant atrophic papulosis, purpura fulminans, ulcerative skin lesions, pseudovasculitic lesions,5,6 and reactive angioendotheliomatosis.7 Although APS has been associated with various skin conditions, it has no established association with eccrine angiomatous hamartomas (EAHs). EAHs are rare, benign, acquired, or congenital neoplasms of eccrine and angiomatous structures, often within the middle or deep dermis, that usually present on the distal extremities with varied clinical features, including pain and hyperhidrosis.8,9 Herein we report a case of APS presenting as pain within a foot lesion, with changes consistent with EAH on pathology.

Very-high Energy (VHE) gamma-ray astroparticle physics is a relatively young field, and observations over the past decade have surprisingly revealed almost two hundred VHE emitters which appear to act as cosmic particle accelerators. These sources are an important component of the Universe, influencing the evolution of stars and galaxies. At the same time, they also act as a probe of physics in the most extreme environments known - such as in supernova explosions, and around or after the merging of black holes and neutron stars. However, the existing experiments have provided exciting glimpses, but often falling short of supplying the full answer. A deeper understanding of the TeV sky requires a significant improvement in sensitivity at TeV energies, a wider energy coverage from tens of GeV to hundreds of TeV and a much better angular and energy resolution with respect to the currently running facilities. The next generation gamma-ray observatory, the Cherenkov Telescope Array Observatory (CTAO), is the answer to this need. In this talk I will present this upcoming observatory from its design to the construction, and its potential science exploitation. CTAO will allow the entire astronomical community to explore a new discovery space that will likely lead to paradigm-changing breakthroughs. In particular, CTA has an unprecedented sensitivity to short (sub-minute) timescale phenomena, placing it as a key instrument in the future of multi-messenger and multi-wavelength time domain astronomy. I will conclude the talk presenting the first scientific results obtained by the LST-1, the prototype of one CTAO telescope type - the Large-Sized Telescope, that is currently under commission., PoS: Proceedings of Science, 395, ISSN:1824-8039, Proceedings of 37th International Cosmic Ray Conference (ICRC2021)

Background: Liver stiffness measurements can be used to assess liver fibrosis and can be acquired by transient elastography using FibroScan® and with Acoustic Radiation Force Impulse imaging. The study aimed to establish liver stiffness measurement scores using FibroScan® and Acoustic Radiation Force Impulse in a chronic hepatitis C cohort and to explore the correlation and agreement between the scores and the factors influencing agreement. Methods: Patients had liver stiffness measurements acquired with FibroScan® (right lobe of liver) and Acoustic Radiation Force Impulse (right and left lobe of liver). We used Spearman’s correlation to explore the relationship between FibroScan® and Acoustic Radiation Force Impulse scores. A Bland–Altman plot was used to evaluate bias between the mean percentage differences of FibroScan® and Acoustic Radiation Force Impulse scores. Univariable and multivariable analyses were used to assess how factors such as body mass index, age and gender influenced the agreement between liver stiffness measurements. Results: Bland-Altman showed the average (95% CI) percentage difference between FibroScan® and Acoustic Radiation Force Impulse scores was 27.5% (17.8, 37.2), p ® and Acoustic Radiation Force Impulse scores ( r (95% CI) = −0.41 (−0.57, −0.21), p ® and Acoustic Radiation Force Impulse scores. Body mass index was the biggest influencing factor on differences between FibroScan® and Acoustic Radiation Force Impulse ( r = 0.12 (0.01, 0.23), p = 0.05). Acoustic Radiation Force Impulse scores at segment 5/8 and the left lobe showed good correlation ( r (95% CI) = 0.83 (0.75, 0.89), p Conclusion: FibroScan® and Acoustic Radiation Force Impulse had similar predictive values for the assessment of liver stiffness in patients with chronic hepatitis C infection; however, the level of agreement varied across lower and higher scores.

Few studies to date have explored the health-related quality of life (HRQoL) in patients with long COVID.The Anticipate Study is a prospective single-centre observational cohort study. Hospitalised and nonhospitalised patients were seen at a dedicated post-COVID clinic at a 2-4 month (Timepoint 1) and 7-14 month follow-up (Timepoint 2). The main objectives of this study are to assess the longitudinal impact of COVID-19 in patients using the 12-item Short Form Survey (SF-12) score, a health-related quality of life tool, and to identify predictors of developing post-COVID-19 syndrome (PoCS). In addition, we aimed to describe symptomatology and identify predictors of PoCS at 1-year.A total of 155 patients were enrolled, 105 (68%) were female aged 43.3 (31-52) years. In total 149 (96%) and 94 (61%) patients completed follow-up at median 96 (76-118) days and 364 (303-398) days. The overall cohort had significantly reduced physical composite score (PCS) of the SF-12 (45.39 [10.58] vs 50 [10], p = 0.02). Participants with PoCS had significantly lower scores than those without symptoms at 1-year follow-up (37.2 [10.4] v 46.1 [10.9] p0.001), and scores for these patients did not improve over the 2 Timepoints (PCS 34.95 [10.5] - 37.2 [10.4], p = 0.22). Fatigue was the most common symptom. Those with 5 or more symptoms at initial diagnosis had lower PCS and mental composite score (MCS) at 1-year. Predictors of PoCS at 1-year were lower PCS and higher baseline heart rate (HR) at clinic review median 3 months after COVID-19.Patients with PoCS have lower PCS scores during follow-up, which did not significantly improve up to a 1-year follow-up. Lower PCS scores and higher HR at rest can be used in the weeks after COVID-19 can help predict those at risk of PoCS at 1 year.

Objectives Tocilizumab is a humanized monoclonal antibody which targets and inhibits interleukin-6 (IL-6) and has demonstrated efficacy in treating diseases associated with hyper-inflammation. Data are suggestive of tocilizumab as a potential treatment for patients with COVID-19 infection. The aim of this study is to determine the safety and efficacy of standard dose versus low dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation on time to intubation, non-invasive ventilation and/or all-cause mortality. Trial design This trial is a phase 2, open label, two-stage, multicentre, randomised trial. Participants Adult subjects with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation requiring admission to hospital at St. Vincent’s University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Inclusion criteria Aged 18 years or older. Confirmed SARS-CoV2 infection (as defined by positive PCR). Evidence of hyper inflammatory state as evidenced by at least three of the following: Documented temperature >38°C in the past 48 hours, IL6 >40 pg/ml, or in its absence D-dimer >1.5 μgFEU /ml, Elevated CRP (>100mg/L) and/or a three-fold increase since presentation, Elevated ferritin X5 ULN, Elevated LDH (above the ULN), Elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging. Moderate to severe respiratory failure as defined by PaO2/FiO2≤300mmHg. Intervention and comparator Intervention for participants in this trial is SOC plus Tocilizumab compared to SOC alone (comparator). For Stage 1, following randomisation, subjects will receive either (Arm 1) SOC alone or (Arm 2) SOC plus Tocilizumab (standard single dose – 8mg/kg, infused over 60 minutes. Once stage 1 has fully recruited, subsequent participants will be enrolled directly into Stage 2 and receive either (Arm 1) SOC plus Tocilizumab (standard single dose – 8mg/kg, infused over 60 minutes or (Arm 2) SOC plus Tocilizumab (standard single dose – 4mg/kg, infused over 60 minutes). Main outcomes The primary endpoint for this study is the time to a composite primary endpoint of progression to intubation and ventilation, non-invasive ventilation or death within 28 days post randomisation. Randomisation Eligible patients will be randomised (1:1) using a central register. Randomisation will be performed through an interactive, web-based electronic data capturing database. In stage 1, eligible participants will be randomised (1:1) to (Arm 1) SOC alone or to (Arm 2) SOC with single dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. In stage 2, eligible participants will be randomised (1:1) to receive either (Arm 1) single, standard dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes or (Arm 2) reduced dose (4mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. Blinding This study is open label. The study will not be blinded to investigators, subjects, or medical or nursing staff. The trial statistician will be blinded for data analysis and will be kept unaware of treatment group assignments. To facilitate this, the randomisation schedule will be drawn up by an independent statistician and objective criteria were defined for the primary outcome to minimize potential bias. Numbers to be randomised In stage 1, 90 subjects will be randomised 1:1, 45 to SOC and 45 subjects to SOC plus Tocilizumab (8mg/kg, infused over 60 minutes). In stage 2, sample size calculation for the dose evaluation stage will use data generated from stage 1 using the same primary endpoint as in stage 1. Trial Status The COVIRL002 trial (Protocol version 1.4, 13th May 2020) commenced in May 2020 at St. Vincent’s University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Recruitment is proceeding with the aim to achieve the target sample size on or before April 2021. Trial registration COVIRL002 was registered 25 June 2020 under EudraCT number: 2020-001767-86 and Protocol identification: UCDCRC/20/02. Full protocol The full protocol for COVIRL002 is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).