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NK cells have potent antitumor capacity. They are enriched in the human liver, with a large subset specialized for tissue-residence. The potential for liver-resident versus liver-infiltrating NK cells to populate, and exert antitumor functions in, human liver tumors has not been studied. We examined liver-resident and liver-infiltrating NK cells directly from human hepatocellular carcinomas (HCCs) and liver colorectal (CRC) metastases, compared with matched uninvolved liver tissue. We found that NK cells were highly prevalent in both HCC and liver CRC metastases, although at lower frequencies than unaffected liver. Up to 79% of intratumoral NK cells had the CXCR6 CD69 liver-resident phenotype. Direct staining showed that liver-resident NK cells had increased NKG2D expression compared to their non-resident counterparts, but both subsets had NKG2D downregulation within liver tumors compared to uninvolved liver. Proliferation of intratumoral NK cells (identified by Ki67) was selectively impaired in those with the most marked NKG2D downregulation. Human liver tumor NK cells were functionally impaired, with reduced capacity for cytotoxicity and production of cytokines, even when compared to the hypo-functional tissue-resident NK cells in unaffected liver. Coculture of human liver NK cells with the human hepatoma cell line PLC/PRF/5, or with autologous HCC, recapitulated the defects observed in NK cells extracted from tumors, with downmodulation of NKG2D, cytokine production, and target cell cytotoxicity. Transwells and conditioned media confirmed a requirement for cell contact with PLC/PRF/5 to impose NK cell inhibition. IL-15 was able to recover antitumor functionality in NK cells inhibited by exposure to HCC cell lines or extracted directly from HCC. In summary, our data suggest that the impaired antitumor function of local NK cells reflects a combination of the tolerogenic features inherent to liver-resident NK cells together with additional contact-dependent inhibition imposed by HCC itself. The demonstration that IL-15 can recover hepatic NK cell function following tumor exposure supports its inclusion in immunotherapy strategies.

Background Assessment of possible infection with SARS‐CoV‐2, the novel coronavirus responsible for COVID‐19 illness, has been a major activity of infection services since the first reports of cases in December 2019. Objectives We report a series of 68 patients assessed at a Regional Infection Unit in the UK. Methods Between 29 January 2020 and 24 February 2020, demographic, clinical, epidemiological and laboratory data were collected. We compared clinical features between patients not requiring admission for clinical reasons or antimicrobials with those assessed as needing either admission or antimicrobial treatment. Results Patients assessed were aged from 0 to 76 years; 36/68 were female. Peaks of clinical assessments coincided with updates to the case definition for suspected COVID‐19. Microbiological diagnoses included SARS‐CoV‐2, mycoplasma pneumonia, influenza A, non‐SARS/MERS coronaviruses and rhinovirus/enterovirus. Nine of sixty‐eight received antimicrobials, 15/68 were admitted, 5 due to inability to self‐isolate. Patients requiring admission on clinical grounds or antimicrobials (14/68) were more likely to have fever or raised respiratory rate compared to those not requiring admission or antimicrobials. Conclusions The majority of patients had mild illness, which did not require clinical intervention. This finding supports a community testing approach, supported by clinicians able to review more unwell patients. Extensions of the epidemiological criteria for the case definition of suspected COVID‐19 lead to increased screening intensity; strategies must be in place to accommodate this in time for forthcoming changes as the epidemic develops.

BackgroundIn January 2021 Yorkshire Ambulance Service and Hull University Teaching Hospitals implemented a pilot COVID-19 lateral flow testing (LFT) and direct admissions pathway to assess the feasibility of using pre-hospital LFTs to bypass the Emergency Department. Due to lower than anticipated uptake of the pilot amongst paramedics, we undertook a service evaluation to assess reasons for low uptake and perceived potential benefits and risks associated with the pilot.MethodsWe undertook semi-structured telephone interviews with 12 paramedics and hospital staff. We aimed to interview paramedics who had taken part in the pilot, those who had received the project information but not taken part and ward staff receiving patients from the pilot. We transcribed interviews verbatim and analysed data using thematic analysis according to the principles of Braun & Clarke (Ref).ResultsParticipants who were involved in the pilot were overwhelmingly positive about the intervention, which they perceived as having limited risks and high potential benefits to the health service, patients and themselves and supported future roll-out. Participation in the pilot appeared to be positively influenced by high personal capacity for undertaking research (being ‘research-keen) and negatively influenced by ‘COVID-19 exhaustion’, electronic information overload and lack of time for training. Barriers to use of the pathway related to ‘poor timing’ of the pilot, restrictive patient eligibility and inclusion criteria. The rapid rollout meant that paramedics had limited knowledge or awareness of the pilot, and pilot participants reported poor understanding of the pilot criteria or the rationale for the criteria.ConclusionsAmbulance clinician involvement in rapid research pilots may be improved by using multiple recruitment methods (electronic and other), providing protected time for training and increased direct support for paramedics with lower personal capacity for research. Improved communication (including face-to-face approaches) may help understanding of eligibility criteria and increase appropriate recruitment.

AbstractObjectiveTo describe the incidence of, risk factors for, and impact of vaccines on primary SARS-CoV-2 infection during the second wave of the covid-19 pandemic in susceptible hospital healthcare workers in England.DesignMulticentre prospective cohort study.SettingNational Health Service secondary care health organisations (trusts) in England between 1 September 2020 and 30 April 2021.ParticipantsClinical, support, and administrative staff enrolled in the SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) study with no evidence of previous infection. Vaccination status was obtained from national covid-19 vaccination registries and self-reported.Main outcome measureSARS-CoV-2 infection confirmed by polymerase chain reaction. Mixed effects logistic regression was conducted to determine demographic and occupational risk factors for infection, and an individual based mathematical model was used to predict how large the burden could have been if vaccines had not been available from 8 December 2020 .ResultsDuring England’s second wave, 12.9% (2353/18 284) of susceptible SIREN participants became infected with SARS-CoV-2. Infections peaked in late December 2020 and decreased from January 2021, concurrent with the cohort’s rapid vaccination coverage and a national lockdown. In multivariable analysis, factors increasing the likelihood of infection in the second wave were being under 25 years old (20.3% (132/651); adjusted odds ratio 1.35, 95% confidence interval 1.07 to 1.69), living in a large household (15.8% (282/1781); 1.54, 1.23 to 1.94, for participants from households of five or more people), having frequent exposure to patients with covid-19 (19.2% (723/3762); 1.79, 1.56 to 2.06, for participants with exposure every shift), working in an emergency department or inpatient ward setting (20.8% (386/1855); 1.76, 1.45 to 2.14), and being a healthcare assistant (18.1% (267/1479); 1.43, 1.16 to 1.77). Time to first vaccination emerged as being strongly associated with infection (P<0.001), with each additional day multiplying a participant’s adjusted odds ratio by 1.02. Mathematical model simulations indicated that an additional 9.9% of all patient facing hospital healthcare workers would have been infected were it not for the rapid vaccination coverage.ConclusionsThe rapid covid-19 vaccine rollout from December 2020 averted infection in a large proportion of hospital healthcare workers in England: without vaccines, second wave infections could have been 69% higher. With booster vaccinations being needed for adequate protection from the omicron variant, and perhaps the need for further boosters for future variants, ensuring equitable delivery to healthcare workers is essential. The findings also highlight occupational risk factors that persisted in healthcare workers despite vaccine rollout; a greater understanding of the transmission dynamics responsible for these is needed to help to optimise the infection prevention and control policies that protect healthcare workers from infection and therefore to support staffing levels and maintain healthcare provision.Trial registrationISRCTN registry ISRCTN11041050.

Abstract There have been numerous reports of patients initially misdiagnosed in the 2009 H1N1 influenza and coronavirus disease 2019 (COVID-19) pandemics within the literature. A systematic review was undertaken to collate misdiagnoses during the H1N1 and COVID-19 pandemics and identify which cognitive biases may contribute to this. MEDLINE, Embase, Cochrane and MedRxiv databases were searched for misdiagnoses or cognitive biases resulting in misdiagnosis, occurring during the H1N1 or COVID-19 virus pandemics. Eligible studies were assessed for quality using JBI criteria; primary outcome was the final diagnosis. Sixty-nine studies involving 2551 participants were included. We identified 686 cases of misdiagnosis, categorized as viral respiratory infection, other respiratory infection, non-respiratory infection, and non-infective. Misdiagnoses are listed and relevant investigations are offered. No article described prospective assessment of decision making in the pandemic setting or debiasing diagnostic thinking. Further research is required to understand why misdiagnoses occur and harm arises and how clinicians can be assisted in their decision making in a pandemic context. Various misdiagnoses have occurred during the H1N1 and COVID-19 pandemics, with the most common being lower respiratory tract infection. There was some evidence of resulting harm. Despite insufficient information to recommend measures against misdiagnosis, we offer investigations to consider.

A young female patient presented with features of ascites and cholecystitis. She was subsequently diagnosed with an acute Epstein-Barr virus infection. This is a rare presentation of a common infection. The patient was managed conservatively and the illness resolved within 6 weeks.

COVID-19 medicines delivery units (CMDU) were established in late December 2021 to deliver early antiviral therapy to patients classified as at risk with the aim of preventing hospitalization. We performed a service evaluation at 4 CMDUs in England. We assessed demographics and triage outcomes of CMDU referral, uptake of antiviral therapy, and the rate of subsequent hospitalizations within 2 weeks of CMDU referral. Over a 3-week period, 4788 patients were referred and 3989 were ultimately assessed by a CMDU. Overall, 832 of the patients referred (17%) were judged eligible for treatment and 628 (13%) were ultimately prescribed an antiviral agent. The overall rate of admission within 14 days was 1%. Patients who were admitted were significantly older than those who did not require hospitalization. Of patients prescribed molnupiravir and sotrovimab, 1.8% and 3.2%, respectively, were admitted. There was a high volume of referrals to CMDU service during the initial surge of the Omicron wave in the United Kingdom. A minority of patients were judged to be eligible for therapy. In a highly vaccinated population, the overall hospitalization rate was low.

Natural killer (NK) cells are implicated in tumour surveillance and control in a number of settings. The liver contains large numbers of NK cells and hepatocellular carcinoma (HCC) has been shown to express various ligands that permit interactions with NK cells, some of which have been shown to have prognostic significance. Similar prognostic associations have been shown for colorectal cancer, a tumour which commonly metastasizes to the liver. However the mechanistic underpinning of these effects is unclear. This thesis describes a survey of soluble NKG2D ligand expression in patients with HCC caused by chronic hepatitis B (CHB), patients with CHB without cancer, and healthy controls. ULBP1 was found to be raised in HCC patients; where it was associated with poor survival, and in active CHB; where it was associated with hepatitis B viral load. ULBP1 was not seen in secondary liver tumours, suggesting that this protein may be useful as a biomarker of severe disease or to monitor treatment response. The other NKG2D ligands MICA, MICB, ULBP2 and ULBP3 were not found to be elevated in patient serum. Soluble NKG2D ligands did not affect NKG2D expression by circulating NK cells. Tumour infiltrating NK cells have the potential to be important effector cells, but are functionally defective. This work builds on recent advances in the understanding of liver-resident NK cells to characterise the functional defect in primary and secondary liver cancers, using human ex vivo intrahepatic and tumour-infiltrating NK cells. Using an in vitro model of HCC we have investigated the mechanisms for this defect and examine the potential for IL- 15 to restore NK cell cytotoxicity and cytokine production. Ex-vivo tumourinfiltrating NK cells had reduced NKG2D expression, IFNγ production and degranulation potential compared with paired intrahepatic NK cells, but maintained expression of NKp46. We were able to recapitulate this phenotype by co-culture with an HCC cell line, but were not able to protect NK cells from NKG2D downregulation and functional inhibition by NKG2D blockade. However, IL-15 was able to restore function after HCC exposure. This model may serve as an in-vitro assay for future therapeutics targeting tumour-infiltrating NK cells.