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Nucleic acid testing to confirm sustained virological response (SVR) after HCV therapy is technical, often expensive, and frequently unavailable where disease prevalence is highest. Alternative surrogate biomarkers merit evaluation. In a short-treatment trial in Vietnam (SEARCH-1; n = 52) we analysed how changes in alanine transaminase (ΔALT) and aspartate transaminase (ΔAST), from end of treatment (EOT) to EOT + 12 weeks, related to SVR, defined as HCV RNA < lower limit of quantification 12 weeks after EOT. In a separate UK trial (STOPHCV1; n = 202), we then tested the hypothesis that any elevation in ALT or AST between EOT and EOT12 is a sensitive screen for treatment failure. In SEARCH-1, among 48 individuals with data, 13 failed to achieve SVR. Median ΔALT and ΔAST were negative in cured patients but elevated when treatment failed [median ΔALT (IQR): -2 IU/L (-6, +2)] versus +17 IU/L (+7.5, +38) (p< 0.001). Amongst treatment failures, 12/13 had increase in ALT and 13/13 had increase in AST after EOT, compared with 12/35 in those cured. In STOPHCV1, 196/202 patients had evaluable data, of which 57 did not achieve SVR. A rise in ALT after EOT was 100% sensitive (95% C.I. [93.7 - 100%]) and 51% specific (42.4 - 59.7%) for detecting treatment failure. ΔAST >0 IU/L was 98.1% (89.9 - 99.9%) sensitive and 35.8% (27.3 - 45.1%) specific. A rise in ALT or AST after HCV therapy is a highly sensitive screen for treatment failure in mild liver disease. This finding could reduce costs and complexity of managing HCV.

Methods A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. Results Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was −0.19 (95 per cent c.i. −0.39 to −0.12) and − 0.01 (− 0.17 to −0.03) respectively. Conclusion Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, although these require external validation.

Background: Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. Methods: The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA) provides the most sensitive format. It has been exploited in a novel hybrid manner employing an S1 solid-phase preferentially presenting RBD once solid-phase bound, coupled with a labelled RBD conjugate, used in a two-step sequential assay. Findings: This assay showed a specificity of 100% on 825 pre COVID-19 samples and a potential sensitivity of 99.6% on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralisation and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine. The early response at presentation with illness, elevated responsiveness with disease severity, detection of asymptomatic seroconversion and persistence after the loss of antibody to the nucleoprotein (anti-NP) are all documented. Trial Registration: The ISARIC WHO CCP-UK study was registered at https://www.isrctn.com/ISRCTN66726260 and designated an Urgent Public Health Research Study by NIHR. Interpretation: The hybrid DABA displays the attributes necessary for an antibody test to be used in both clinical and reference serology. It allows the neutralising antibody response to be inferred early in infection and potentially in vaccine recipients. It is also of sufficient sensitivity to be used to provide serological confirmation of prior infection and provides a more secure measure for seroprevalence studies in the population generally than does anti-NP based on the Architect platform. Funding: This work is variously supported by grants from: the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059 and MC_PC_19078), MRC NIHR (grant CV220-111) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Wellcome Trust and Department for International Development (DID; 215091/Z/18/Z), the Bill and Melinda Gates Foundation (OPP1209135), Liverpool Experimental Cancer Medicine Centre (grant reference C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215-20013), EU Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE; FP7 project 602525), and NIHR Clinical Research Network for providing infrastructure support for this research. Declaration of Interests: RST, MOM and PC report patent pending (Patent Application No. 2011047.4 for “SARS-CoV-2 antibody detection assay). All other authors declare no competing interests. Ethics Approval Statement: The use of tissues was approved by the CDRTB Steering Committee in accordance with the responsibility delegated by the National Research Ethics Service (South Central Ethics Committee – C, NRES reference 15/SC/0089).

Background Access to rapid diagnosis is key to the control and management of SARS-CoV-2. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) testing usually requires a centralised laboratory and significant infrastructure. We describe the development and diagnostic accuracy assessment of a novel, rapid point-of-care RT-PCR test, the DnaNudge® platform CovidNudge test, which requires no laboratory handling or sample pre-processing. Methods Nasopharyngeal swabs are inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as positive control. Between April and May 2020, swab samples were tested in parallel using the CovidNudge direct-to-cartridge platform and standard laboratory RT-PCR using swabs in viral transport medium. Samples were collected from three groups: self-referred healthcare workers with suspected COVID-19 (Group 1, n=280/386; 73%); patients attending the emergency department with suspected COVID-19 (Group 2, n=15/386; 4%) and hospital inpatient admissions with or without suspected COVID-19 (Group 3, n=91/386; 23%). Results Of 386 paired samples tested across all groups, 67 tested positive on the CovidNudge platform and 71 with standard laboratory RT-PCR. The sensitivity of the test varied by group (Group 1 93% [84-98%], Group 2 100% [48-100%] and Group 3 100% [29-100%], giving an average sensitivity of 94.4% (95% confidence interval 86-98%) and an overall specificity of 100% (95%CI 99-100%; Group 1 100% [98-100%]; Group 2 100% [69-100%] and Group 3 100% [96-100%]). Point of care testing performance was comparable during a period of high (25%) and low (3%) background prevalence. Amplification of the viral nucleocapsid (n1, n2, n3) targets were most sensitive for detection of SARS-CoV2, with the assay able to detect 1×104 viral particles in a single swab. Conclusions The CovidNudge platform offers a sensitive, specific and rapid point of care test for the presence of SARS-CoV-2 without laboratory handling or sample pre-processing. The implementation of such a device could be used to enable rapid decisions for clinical care and testing programs. Evidence before this study The WHO has highlighted the development of rapid, point-of-care diagnostics for detection of SARS-CoV-2 as a key priority to tackle COVID-19. The Foundation for Innovative Diagnostics (FIND) has identified over 90 point-of-care, near patient or mobile tests for viral detection of SARS-CoV-2. However, the most widely available rapid tests to date require some sample handling which limits their use at point-of-care. In addition, pressure on supply chains is restricting access to current diagnostics and alternatives are needed urgently. Added value of this study We describe the development and clinical validation of COVID nudge, a novel point-of-care RT-PCR diagnostic, evaluated during the first wave of the SARS-CoV-2 epidemic. The platform is able to achieve high analytic sensitivity and specificity from dry swabs within a self-contained cartridge. The lack of downstream sample handling makes it suitable for use in a range of clinical settings, without need for a laboratory or specialized operator. Multiplexed assays within the cartridge allow inclusion of a positive human control, which reduces the false negative testing rate due to insufficient sampling. Implication of the available evidence Point-of-care testing can relieve pressure on centralized laboratories and increase overall testing capacity, complementing existing approaches. These findings support a role for COVID Nudge as part of strategies to improve access to rapid diagnostics to SARS-CoV-2. Since May 2020, the system has been implemented in UK hospitals and is being rolled out nationwide. Competing Interest Statement CT, RS, MS, CI, MK, TH, SDM, FL, JB and AO are employees of DnaNudge. CT is named on the patent for method and apparatus for analyzing biological specimens on the DnaNudge platform (US Patent No: US 10,093,965 B216. LSPM has consulted for bioMerieux (2013 to 2020), DNAelectronics (2015), Dairy Crest (2017 to 2018), Pfizer (2018-2020), and Umovis Lab (2020), received speaker fees from Profile Pharma (2018), received research grants from the National Institute for Health Research (2013 to 2019), Leo Pharma (2016), and CW+ Charity (2018 to 2019), and received educational support from Eumedica (2016 to 2017). NM has received speaker fees from Beyer (2016) and Pfizer (2019) and received educational support from Eumedica (2016) and Baxter (2017). All other authors have no conflicts of interest to declare. Funding Statement The work was supported by the Biomedical Research Centre of Imperial College NHS Trust. M.M.G. is supported in part by the NIHR Imperial Biomedical Research Centre. GC is an NIHR Research Professor and Investigator within the NIHR London In-vitro Diagnostic Collaborative. Part of this work was supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University in partnership with Public Health England (PHE) [grant HPRU-2012-10041] and the NIHR Biomedical Research Centre, Oxford. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the Department of Health or Public Health England.

Background: Injectable interferon-based therapies have been used to treat hepatitis C virus (HCV) infection since 1991. International guidelines have now moved away from interferon-based therapy towards direct-acting antiviral (DAA) tablet regimens, because of their superior efficacy, excellent side-effect profiles, and ease of administration. Initially DAA drugs were prohibitively expensive for most healthcare systems. Access is now improving through the procurement of low-cost, generic DAAs acquired through voluntary licenses. However, HCV treatment costs vary widely, and many countries are struggling with DAA treatment scale-up. This is not helped by the limited cost data and economic evaluations from low- and middle-income countries to support HCV policy decisions. We conducted a detailed analysis of the costs of treating chronic HCV infection with interferon-based therapy in Vietnam. Understanding these costs is important for performing necessary economic evaluations of novel treatment strategies. Methods: We conducted an analysis of the direct medical costs of treating HCV infection with interferon alpha (IFN) and pegylated-interferon alpha (Peg-IFN), in combination with ribavirin, from the health sector perspective at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, in 2017. Results: The total cost of the IFN treatment regimen was estimated to range between US$1,120 and US$1,962. The total cost of the Peg-IFN treatment regimen was between US$2,156 and US$5,887. Drug expenses were the biggest contributor to the total treatment cost (54-89%) and were much higher for the Peg-IFN regimen. Conclusions: We found that treating HCV with IFN or Peg-IFN resulted in significant direct medical costs. Of concern, we found that all patients incurred substantial out-of-pocket costs, including those receiving the maximum level of support from the national health insurance programme. This cost data highlights the potential savings and importance of increased access to generic DAAs in low- and middle-income countries and will be useful within future economic evaluations.

Background The prevalence and persistence of antibodies following a peak SARS-CoV-2 infection provides insights into its spread in the community, the likelihood of reinfection and potential for some level of population immunity.Methods Prevalence of antibody positivity in England, UK (REACT2) with three cross-sectional surveys between late June and September 2020. 365104 adults used a self-administered lateral flow immunoassay (LFIA) test for IgG. A laboratory comparison of LFIA results to neutralization activity in panel of sera was performed.Results There were 17,576 positive tests over the three rounds. Antibody prevalence, adjusted for test characteristics and weighted to the adult population of England, declined from 6.0% [5.8, 6.1], to 4.8% [4.7, 5.0] and 4.4% [4.3, 4.5], a fall of 26.5% [-29.0, −23.8] over the three months of the study. There was a decline between rounds 1 and 3 in all age groups, with the highest prevalence of a positive result and smallest overall decline in positivity in the youngest age group (18-24 years: −14.9% [-21.6, −8.1]), and lowest prevalence and largest decline in the oldest group (75+ years: −39.0% [-50.8, −27.2]); there was no change in antibody positivity between rounds 1 and 3 in healthcare workers (+3.45% [-5.7, +12.7]).The decline from rounds 1 to 3 was largest in those who did not report a history of COVID-19, (−64.0% [-75.6, −52.3]), compared to −22.3% ([-27.0, −17.7]) in those with SARS-CoV-2 infection confirmed on PCR.Discussion These findings provide evidence of variable waning in antibody positivity over time such that, at the start of the second wave of infection in England, only 4.4% of adults had detectable IgG antibodies using an LFIA. Antibody positivity was greater in those who reported a positive PCR and lower in older people and those with asymptomatic infection. These data suggest the possibility of decreasing population immunity and increasing risk of reinfection as detectable antibodies decline in the population.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by the Department of Health and Social Care in England. We thank key collaborators on this work -- Ipsos MORI: Stephen Finlay, John Kennedy, Kevin Pickering, Duncan Peskett, Sam Clemens and Kelly Beaver; Institute of Global Health Innovation at Imperial College: Gianluca Fontana, Dr Hutan Ashrafian, Sutha Satkunarajah and Lenny Naar; Imperial College Healthcare NHS Trust: Robert Klaber; the Patient Experience Research Centre and the REACT Public Advisory Panel; NHS Digital for access to the NHS Register. HW is a NIHR Senior Investigator and acknowledges support from NIHR Biomedical Research Centre of Imperial College NHS Trust, NIHR School of Public Health Research, NIHR Applied Research Collaborative North West London, Wellcome Trust 205456/Z/16/Z. GC is supported by an NIHR Professorship. WSB is the Action Medical Research Professor, AD is an NIHR senior investigator and DA is an Emeritus NIHR Senior Investigator. SR acknowledges support from MRC Centre for Global Infectious Disease Analysis, National Institute for Health Research (NIHR) Health Protection Research Unit (HPRU), Wellcome Trust (200861/Z/16/Z, 200187/Z/15/Z), and Centres for Disease Control and Prevention (US, U01CK0005-01-02) PE is Director of the MRC Centre for Environment and Health (MR/L01341X/1, MR/S019669/1). PE acknowledges support from the NIHR Imperial Biomedical Research Centre and the NIHR HPRUs in Environmental Exposures and Health and Chemical and Radiation Threats and Hazards, the British Heart Foundation Centre for Research Excellence at Imperial College London (RE/18/4/34215) and the UK Dementia Research Institute at Imperial (MC_PC_17114). We thank the Huo Family Foundation for support of our work on COVID-19. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:We obtained research ethics approval from the South Central-Berkshire B Research Ethics Committee (IRAS ID: 283787) All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe original datasets generated or analysed, or both, during this study are not publicly available because of governance restrictions and the identifiable nature of the data.

Geochemical profiles from the North Atlantic Ocean suggest that the vertical δ13C structure of the water column at intermediate depths did not change significantly between glacial and interglacial time over much of the Pleistocene, despite large changes in ice volume and iceberg delivery from nearby landmasses. The most anomalous δ13C profiles are from the extreme interglaciations of the late Pleistocene. This compilation of data suggests that, unlike today (an extreme interglaciation), the two primary sources of northern deep water, Norwegian-Greenland Sea and Labrador Sea/subpolar North Atlantic, had different characteristic δ13C values over most of the Pleistocene. We speculate that the current open sea ice conditions in the Norwegian-Greenland Sea are a relatively rare occurrence and that the high-δ13C deep water that forms in this region today is geologically unusual. If northern source deep waters can have highly variable δ13C, then this likelihood must be considered when inferring past circulation changes from benthic δ13C records.

Benthic foraminiferal carbon isotope records from a suite of drill sites in the North Atlantic are used to trace variations in the relative strengths of Lower North Atlantic Deep Water (LNADW), Upper North Atlantic Deep Water (UNADW), and Southern Ocean Water (SOW) over the past 1 Myr. During glacial intervals, significant increases in intermediate-to-deep δ13C gradients (commonly reaching >1.2‰) are consistent with changes in deep water circulation and associated chemical stratification. Bathymetric δ13C gradients covary with benthic foraminiferal δ18O and covary inversely with Vostok CO2, in agreement with chemical stratification as a driver of atmospheric CO2 changes. Three deep circulation indices based on δ13C show a phasing similar to North Atlantic sea surface temperatures, consistent with a Northern Hemisphere control of NADW/SOW variations. However, lags in the precession band indicate that factors other than deep water circulation control ice volume variations at least in this band.

We have determined this item to be in the public domain according to US copyright law through information in the bibliographic record and/or US copyright renewal records. The digital version is available for all educational uses worldwide. Please contact HathiTrust staff at hathitrust-help@umich.edu with any questions about this item., Eddy, Mary Baker, 1821-1910., (OCoLC)29350376., Sdr-nrlfGLAD247548-B., Http://hdl.handle.net/2027/uc1.b297757.

We have determined this item to be in the public domain according to US copyright law through information in the bibliographic record and/or US copyright renewal records. The digital version is available for all educational uses worldwide. Please contact HathiTrust staff at hathitrust-help@umich.edu with any questions about this item., Great Britain--Politics and government--1837-1901., (LCCN)03031997., (OCoLC)ocm00490847., Sdr-ia-srlf1210254., JN216 .F2., JN 216 .F56 1903., Http://hdl.handle.net/2027/uc2.ark:/13960/t6sx6gz10.