Infection in osteotomy around the knee: Incidence, management and outcomes in a high-volume case series.

PURPOSE: Current evidence around the management of osteotomy-related infection is insufficient to robustly underpin the expert statements formulated by a recent European consensus statement. We present a review of a large case series in a high-volume osteotomy practice to contribute to the understanding of the incidence, management and outcome of infection in this subspecialty area. METHODS: Analyses of two prospectively collected databases for all osteotomy around the knee and infections related to osteotomy were performed, along with a review of hospital readmission data to capture all osteotomy-related infections. Clinical notes were reviewed to assess patient demographics, incidence of infection, how infection was managed and clinical outcome. RESULTS: In a series of 822 osteotomies in 755 patients, there were 21 (2.8%) cases of suspected infection. Twelve (1.6%) were contemporaneously deemed 'superficial' and nine confirmed 'deep' infections (1.2%). Deep infections were all successfully managed with wound debridement, with or without plate removal, depending on union and time from initial surgery. One of these infections was noted during a revision procedure, but no revision was carried out as a direct result of infection, no external fixation was required and no infected nonunions were experienced. CONCLUSION: All of the cases in this series were managed successfully with debridement ± removal of the plate, without the need for revision or external fixation. Any potential signs of infection around an osteotomy, especially in the case of medial high tibial osteotomy, should raise awareness for deep infection and the need for further surgery due to the limited overlying soft tissue cover. This evidence supports the recent European Society of Sports Traumatology, Knee Surgery and Arthroscopy algorithm. LEVEL OF EVIDENCE: Level IV, case series.

Sources and determinants of free sugars intake by 5-year-old Australian children in the SMILE cohort.

Reducing free sugars intake is important for the prevention of dental caries and obesity in children. The study aimed to determine the amount and sources of free sugars known to contribute to dental caries, and identify sociodemographic determinants of intake by children aged 5 years in Australia. Cross-sectional analysis of dietary data from a cohort study, collected using a customized food frequency questionnaire were used to calculate free sugars intake as grams/day and percentage contribution to Estimated Energy Requirement (EER). The percent contribution of food sources to free sugars intake was derived. Sociodemographic determinants of achieving intakes within WHO thresholds (i.e., <5% and <10% Energy were explored with multinomial logistic regression. Complete data were available for 641 children (347 boys, 294 girls). Median (IQR) free sugars intake (g/day) was 31.6 (21.3-47.6) in boys and 28.1 (19.6-47.9) in girls. The median (IQR) percentage contribution to EER was 7.9 (5.4-12.7); 21% and 42% of children had intakes <5% EER and between 5% and <10%, respectively. The main sources of free sugars were: (1) Cakes, Biscuits and Cereal Bars; (2) Sweetened Milk Products (predominantly yoghurts) and (3) Desserts. Maternal university education, single-parent household, and maternal place of birth being Australia or New Zealand were associated with free sugars intake <5% EER. In conclusion, less than a quarter of 5-year-old children in the SMILE cohort achieved the WHO recommendations to limit free sugars to <5% EER. Strategies to lower free sugars intake could target priority populations such migrants, populations with lower levels of education or health literacy and identify areas for intervention in the wider food environments that children are exposed to.

Design and implementation of a web-based, respondent-driven sampling solution.

BACKGROUND: Respondent-driven sampling (RDS) refers both to a chain-referral sampling method and an analytical model for analysing sampled data. Web-based respondent-driven sampling (webRDS) uses internet-based recruitment coupled with an electronic survey to carry out RDS studies; there is currently no commercially available webRDS solution. We designed and developed a webRDS solution to support a research study aimed at estimating conflict-attributable mortality in Yemen. Our webRDS solution is composed of an existing survey platform (i.e. ODK) and a bespoke RDS system. The RDS system is designed to administer and manage an RDS survey cascade and includes: (1) an application programming interface, (2) a study participant client, and (3) an administrator interface. We report here on the design of the webRDS solution and its implementation. RESULTS: We consulted members of the Yemeni diaspora throughout the development of the solution. Technical obstacles were largely the result of: WhatsApp's policies on bulk messaging and automated messaging behaviour, the inherent constraints of SMS messaging, and SMS filtering behaviour. Language support was straight-forward yet time consuming. Survey uptake was lower than expected. Factors which may have impacted uptake include: our use of consumable survey links, low interest amongst the diaspora population, lack of material incentives, and the length and subject matter of the survey itself. The SMS/WhatsApp messaging integration was relatively complex and limited the information we could send potential participants. CONCLUSION: Despite lower-than expected survey uptake we believe our webRDS solution provides efficient and flexible means to survey a globally diverse population.

Viral infection triggers interferon-induced expulsion of live Cryptococcus neoformans by macrophages.

Cryptococcus neoformans is an opportunistic human pathogen, which causes serious disease in immunocompromised hosts. Infection with this pathogen is particularly relevant in HIV+ patients, where it leads to around 200,000 deaths per annum. A key feature of cryptococcal pathogenesis is the ability of the fungus to survive and replicate within the phagosome of macrophages, as well as its ability to be expelled from host cells via a novel non-lytic mechanism known as vomocytosis. Here we show that cryptococcal vomocytosis from macrophages is strongly enhanced by viral coinfection, without altering phagocytosis or intracellular proliferation of the fungus. This effect occurs with distinct, unrelated human viral pathogens and is recapitulated when macrophages are stimulated with the anti-viral cytokines interferon alpha or beta (IFNα or IFNß). Importantly, the effect is abrogated when type-I interferon signalling is blocked, thus underscoring the importance of type-I interferons in this phenomenon. Lastly, our data help resolve previous, contradictory animal studies on the impact of type I interferons on cryptococcal pathogenesis and suggest that secondary viral stimuli may alter patterns of cryptococcal dissemination in the host.

Clinical and Economic Impact of Implementing OVIVA Criteria on Patients With Bone and Joint Infections in Outpatient Parenteral Antimicrobial Therapy.

The OVIVA study demonstrated noninferiority for managing bone and joint infections (BJIs) with oral antibiotics. We report that 79.7% of OPAT patients being treated for BJIs at our center would be eligible for oral antibiotics, saving a median (IQR) 19.5 IV-antibiotic days (8.5-37) and GBP 1234 (569-2594) per patient.

In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis.

Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti-mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST molecular profiling categorised different mechanisms of immunological dysfunction in HIV-1 infection beyond the effects on CD4 T cells, each associated with increased risk of TB disease and amenable to host-directed therapies.

HIV-1 infection of macrophages dysregulates innate immune responses to Mycobacterium tuberculosis by inhibition of interleukin-10.

Human immunodeficiency virus (HIV)-1 and Mycobacterium tuberculosis (M. tuberculosis) both target macrophages, which are key cells in inflammatory responses and their resolution. Therefore, we tested the hypothesis that HIV-1 may modulate macrophage responses to coinfection with M. tuberculosis. HIV-1 caused exaggerated proinflammatory responses to M. tuberculosis that supported enhanced virus replication, and were associated with deficient stimulus-specific induction of anti-inflammatory interleukin (IL)-10 and attenuation of mitogen-activated kinase signaling downstream of Toll-like receptor 2 and dectin-1 stimulation. Our in vitro data were mirrored by lower IL-10 and higher proinflammatory IL-1ß in airway samples from HIV-1-infected patients with pulmonary tuberculosis compared with those with non-tuberculous respiratory tract infections. Single-round infection of macrophages with HIV-1 was sufficient to attenuate IL-10 responses, and antiretroviral treatment of replicative virus did not affect this phenotype. We propose that deficient homeostatic IL-10 responses may contribute to the immunopathogenesis of active tuberculosis and propagation of virus infection in HIV-1/M. tuberculosis coinfection.

Superior accuracy in knee double level osteotomy using a novel hybrid fixation technique compared to conventional double plating.

Purpose: This study aimed to compare two different double-level knee osteotomy (DLO) fixation techniques. The primary outcome reported the radiological coronal plane correction and its accuracy. The secondary outcomes reported the correction outliers, the clinical outcomes, the 5-year postoperative satisfaction and the complications. Methods: A retrospective review of a single surgeon osteotomy database identified 52 cases of DLO between 2011 and 2019, of which 24 cases met the inclusion criteria. Patients were categorised into two groups: the nail-plate (NP) group fixed with a magnetic extendable intramedullary tibial nail and femoral conventional plate, and the double-plate (DP) group fixed with conventional plates (tibia and femur). Radiographic parameters were recorded, including the mechanical femorotibial angle (mFTA), medial proximal tibial angle (MPTA), mechanical lateral distal femoral angle (mLDFA), joint line convergence angle (JLCA) and weight-bearing line ratio (Mikulicz %). Surgical accuracy was calculated as the difference between the achieved and the planned correction. Outliers were defined as those with a greater than 10% difference from the planned correction. Simple knee value scores and visual analogue scale for pain were recorded preoperatively and postoperatively at 2 and 5 years. Five-year patient satisfaction was recorded. Results: A total of 24 patients were included: the NP group (n = 12) and the DP group (n = 12). Significant coronal plane corrections were achieved in the NP group for the mean mFTA (preoperative 167.9° ± 3.4° to postoperative 182.1° ± 1.4°), the mean MPTA (preoperative 83.5° ± 2.9° to postoperative 91.3° ± 2.8°) and the mean mLDFA (preoperative 89.8° ± 3.4° to postoperative 85.9° ± 4.4°). Similarly, significant coronal plane corrections were achieved in the DP group for the mean mFTA (preoperative 168.6° ± 4.4° to postoperative 182.2° ± 2°), the mean MPTA (preoperative 84.2° ± 2° to postoperative 88.3° ± 4.1°) and the mean mLDFA (preoperative 90.7° ± 2.9° to postoperative 83.9° ± 1.7°) (all p < 0.05). The mean correction accuracy was higher for the NP versus DP group at 3.4 ± 3.4% versus 7.1 ± 3.9% (intergroup p < 0.05). There were no outliers in the NP group versus two outliers (overcorrected) (16.7%) in the DP group. Significant clinical improvement was reported in both groups at 2 and 5 years postoperatively (all p < 0.05). Conclusion: Superior correction accuracy and no outliers were achieved in hybrid fixation double-level knee osteotomy compared to the conventional double-plating technique. The magnetic extendable nail offers the advantage of fine-tuning the correction postoperatively and could be a potential research template for future designs of postoperative correction implants. Level of Evidence: Level III, retrospective cohort study.

Evaluation of reduced ('Lite') compression versus brief bandaging to manage post-operative pain after total knee arthroplasty surgery; a single-centre randomised controlled trial.

PURPOSE: Investigate efficacy of reduced compression bandage for the control of pain after total knee arthroplasty. PATIENTS & METHODS: Prospective, single-centre, randomised controlled trial involving data for 56 out of 94 consented patients; 29 standard care versus 27 Andoflex TLC Calamine Lite. Comparison of standard care (non-compression bandage applied for up to one day) versus Andoflex TLC Calamine Lite (25-30 mmHg) two-layer compression bandage worn for five days. Outcomes measured with validated pain (McGill, 10-cm visual scale) and functionality (KOOS) tools. RESULTS: At day 5 post-surgery, the median pain level was 3.0 cm vs 4.0 cm (p-value 0.47, Mann-Whitney U test) respectively. Generic pain levels, pain types, and knee functionality did not differ between the interventions at days 3/5/12 and week 6 post-surgery. An exception was the degree of 'tender' pain at day 12, which was significantly lower in the Andoflex TLC Calamine Lite arm (p-value 0.041, Mann-Whitney U test). Binary logistic regression analysis showed that application of Andoflex TLC Calamine Lite, administration of oxycodone, and male sex were all significantly associated with less 'tender' pain. CONCLUSION: Reduced compression bandaging does not affect overall pain levels post knee arthroplasty surgery, but may alleviate pain experienced as 'tender', highlighting the different types of pain that may be experienced. Patients' need for, and the use of, opioid medication (oxycodone) is a significant confounding variable when assessing adjuvant therapy to control pain. The applicability of reduced compression bandaging may therefore be limited and is less efficient than medical pain control.

Adult mortality patterns in Yemen before and during armed conflict: evidence from a web survey of the global diaspora.

BACKGROUND: The ongoing war in Yemen has created a severe and protracted crisis that has left nearly three-quarters of the population in need of urgent humanitarian assistance. Despite eight years of conflict there exist few robust estimates of how the conflict (and the conflict combined with the COVID-19 pandemic) have affected mortality in Yemen. As the security situation has limited access to affected populations we have designed a novel alternative to local mortality surveys. METHODS: We used a web-based, respondent-driven sampling method to disseminate a mortality survey amongst the global Yemeni diaspora. We used Cox proportional hazards survival models to estimate the association between the exposure (i.e. between the pre-conflict, conflict, and conflict/pandemic periods) and mortality risk, adjusted for gender and birth cohort. RESULTS: Eighty-nine eligible respondents completed the survey. Respondents provided data on the status of 1704 individuals of whom 85 (5%) had died; of these 65 (3.8%) were reported to have died in Yemen. An analysis of survivorship of respondents' parents after their 50th birthday (adjusted for gender and birth cohort) provided weak evidence that the war and pandemic periods were associated with higher mortality when compared to the pre-war period. Analysis of the subset of individuals who died in Yemen also suggested an increased, but non-significant hazard of dying during the war/pandemic period: this association tended towards significance when allowing for varying degrees of out-migration from Yemen across the cohort. The number of deaths amongst respondents' siblings and children under five in Yemen were too low to allow meaningful analysis. CONCLUSIONS: Our data suggest increased mortality during the war/pandemic period, compared to the pre-war period, among older Yemeni adults. However, our findings require careful interpretation as our study design cannot establish causation, and as our small and non-representative sample appeared skewed towards higher-income, urban communities. Surveys of diaspora populations offer a promising means of describing mortality patterns in crisis-affected populations; though, large numbers of respondents are likely required to achieve accurate mortality estimates and to adjust for selection bias.

Epistasis and immunity: the role of genetic interactions in autoimmune diseases.

Autoimmune disorders are a complex and varied group of diseases that are caused by breakdown of self-tolerance. The aetiology of autoimmunity is multi-factorial, with both environmental triggers and genetically determined risk factors. In recent years, it has been increasingly recognized that genetic risk factors do not act in isolation, but rather the combination of individual additive effects, gene-gene interactions and gene-environment interactions determine overall risk of autoimmunity. The importance of gene-gene interactions, or epistasis, has been recently brought into focus, with research demonstrating that many autoimmune diseases, including rheumatic arthritis, autoimmune glomerulonephritis, systemic lupus erythematosus and multiple sclerosis, are influenced by epistatic interactions. This review sets out to examine the basic mechanisms of epistasis, how epistasis influences the immune system and the role of epistasis in two major autoimmune conditions, systemic lupus erythematosus and multiple sclerosis.

Application of compression bandaging post-osteotomy results in altered pain profile; results of a single-centre randomised controlled trial.

PURPOSE: To assess if application of dual-layer compression bandage to osteotomy patients post-surgery can positively influence levels of post-operative pain and swelling. PATIENTS & METHODS: Prospective, single-centre, randomised controlled trial comparing standard care, non-compression bandaging, versus Coban™ 2 (3M). Seven day application of the latter to index leg of osteotomy patients. RESULTS: Primary outcome data was available for 36 out of 49 study subjects (18 standard care versus 18 Coban™ 2 subjects). Median 10-cm scale pain levels showed a statistically non-significant difference at day 5 and day 12 post-surgery between standard care and Coban™ 2 respectively: 5.5 cm vs 2.5 cm (p-value 0.068) and 4.0 cm vs 2.3 cm (p-value 0.39). However, on day 12 (p-value 0.029) and week 6 (p-value 0.027), 'throbbing pain' was significantly higher for Coban™ 2 patients. Changes in limb swelling measures, comparing before and after the surgical procedure, did not differ between treatment arms. Compression led to more patients reporting bandage-related discomfort (6% standard care versus 63% Coban™ 2 patients). CONCLUSION: Compression bandaging changes the post-surgery pain profile in osteotomy patients, but does not reduce leg swelling. Any subsequent leg compression trials must take into account patient comfort and titrate intervention length and compression rates.

Longer Term Outcomes Following High Tibial Osteotomy for Osteoarthritis: A Prospective, Multi-Centre Observational Study Comparing Tomofix and OPTY-LINE Devices.

PURPOSE: Assessing surgical accuracy and patient-recorded outcome measures for patients fitted with either the OPTY-LINE intramedullary realignment system or the Tomofix plate for medial opening wedge high tibial osteotomy (HTO). PATIENTS AND METHODS: Two matched case series of patients with symptomatic medial compartment osteoarthritis without other significant knee pathology. One group comprised of 19 patients receiving the Tomofix plate, whereas another comprised of 12 patients receiving the OPTY-LINE intramedullary nail. Patella-centred long leg alignment radiographs were assessed to calculate surgical accuracy in all cases. Patients completed knee injury osteoarthritis outcome scores (KOOS) and osteotomy surgery patient satisfaction questionnaires pre-operatively and at 24 months post-surgery. RESULTS: Absolute surgical accuracy at 2 years post-surgery was a mean 4.2 [standard deviation 3.7] for OPTY-LINE versus 9.2 [SD 7.8] for Tomofix (p = 0.11, Mann-Whitney U test). On average, patients in either the OPTY-LINE or Tomofix cohort reported at least a minimal perceptible clinical improvement-minimum average improvement of 15-for all five KOOS themes. No significant difference in change of KOOS scores over time or patient satisfaction levels were observed between the two cohorts. CONCLUSION: The OPTY-LINE device for HTO performs to a similar level as the Tomofix device. Surgical accuracy data are promising for OPTY-LINE, but does not seem to readily translate into difference in patient-reported outcomes compared to Tomofix. Even longer follow-up periods, to measure survival rates, and true randomised trials on larger samples can elucidate if there is a benefit for using one device over the other.

Transcriptional response modules characterize IL-1ß and IL-6 activity in COVID-19.

Dysregulated IL-1ß and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines in vivo are urgently needed to complement clinical trials of therapeutic targeting of IL-1ß and IL-6 in COVID-19. We show that the expression of IL-1ß or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in immunopathology modelled by juvenile idiopathic arthritis (JIA) and rheumatoid arthritis. In COVID-19, elevated expression of IL-1ß and IL-6 response modules, but not the cytokine transcripts themselves, is a feature of infection in the nasopharynx and blood but is not associated with severity of COVID-19 disease, length of stay, or mortality. We propose that IL-1ß and IL-6 transcriptional response modules provide a dynamic readout of functional cytokine activity in vivo, aiding quantification of the biological effects of immunomodulatory therapies in COVID-19.

Implementation and evaluation of a COVID-19 rapid follow-up service for patients discharged from the emergency department.

The COVID-19 pandemic has necessitated rapid adaptation of healthcare providers to new clinical and logistical challenges. Following identification of high levels of emergency department (ED) reattendance among patients with suspected COVID-19 at our centre, we piloted a rapid remote follow-up service for this patient group. We present our service framework and evaluation of our pilot cohort of 192 patients. We followed up patients by telephone within 36 hours of their ED attendance. Pulse oximetry was used for remote monitoring of a subset of patients. Patients required between one and six consecutive telephone assessments, dependent on illness severity, and 23 patients were recalled for in-person assessment. Approximately half of patients with confirmed or probable COVID-19 required onward referral for respiratory follow-up. This framework reduced unplanned ED reattendances in comparison with a retrospective comparator cohort (4.7% from 22.6%). We reproduced these findings in a validation cohort with a high prevalence of acute COVID-19, managed through the clinic in September-October 2020, where we identified an unplanned ED reattendance rate of 5.2%. We propose that rapid remote follow-up is a mechanism by which ambulatory patients can be clinically supported during the acute phase of illness, with benefits both to patient care and to health service resilience.

Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study.

BACKGROUND: We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing. METHODS: We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew's Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for "viral infection", "transcriptome", "biomarker", and "blood". We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity. FINDINGS: We identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27-47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91-0·99), sensitivity 0·84 (0·70-0·93), and specificity 0·95 (0·85-0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91-0·95). INTERPRETATION: Our findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge. FUNDING: Barts Charity, Wellcome Trust, and National Institute of Health Research.

Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease.

Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1ß and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1ß and IL-6 promote TH17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.

Transcriptional response modules characterise IL-1ß and IL-6 activity in COVID-19.

Dysregulated IL-1ß and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines in vivo are urgently needed to complement clinical trials of therapeutic targeting of IL-1ß and IL-6 in COVID-19. We show that the expression of IL-1ß or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in immunopathology modelled by juvenile idiopathic arthritis (JIA) and rheumatoid arthritis. In COVID-19, elevated expression of IL-1ß and IL-6 response modules, but not the cytokine transcripts themselves, is a feature of infection in the nasopharynx and blood, but is not associated with severity of COVID-19 disease, length of stay or mortality. We propose that IL-1ß and IL-6 transcriptional response modules provide a dynamic readout of functional cytokine activity in vivo, aiding quantification of the biological effects of immunomodulatory therapies in COVID-19.

Delayed healthcare seeking and prolonged illness in healthcare workers during the COVID-19 pandemic: a single-centre observational study.

OBJECTIVES: To describe a cohort of self-isolating healthcare workers (HCWs) with presumed COVID-19. DESIGN: A cross-sectional, single-centre study. SETTING: A large, teaching hospital based in Central London with tertiary infection services. PARTICIPANTS: 236 HCWs completed a survey distributed by internal staff email bulletin. 167 were women and 65 men. MEASURES: Information on symptomatology, exposures and health-seeking behaviour were collected from participants by self-report. RESULTS: The 236 respondents reported illness compatible with COVID-19 and there was an increase in illness reporting during March 2020 Diagnostic swabs were not routinely performed. Cough (n=179, 75.8%), fever (n=138, 58.5%), breathlessness (n=84, 35.6%) were reported. Anosmia was reported in 42.2%. Fever generally settled within 1 week (n=110/138, 88%). Several respondents remained at home and did not seek formal medical attention despite reporting severe breathlessness and measuring hypoxia (n=5/9, 55.6%). 2 patients required hospital admission but recovered following oxygen therapy. 84 respondents (41.2%) required greater than the obligated 7 days off work and 9 required greater than 3 weeks off. CONCLUSION: There was a significant increase in staff reporting illness compatible with possible COVID-19 during March 2020. Subsequent serology studies at the same hospital study site have confirmed sero-positivity for COVID-19 up to 45% by the end of April 2020 in frontline HCWs. The study revealed a concerning lack of healthcare seeking in respondents with significant red flag symptoms (severe breathlessness, hypoxia). This study also highlighted anosmia as a key symptom of COVID-19 early in the pandemic, prior to this symptom being more widely recognised as a feature of COVID-19.

Brief tools to measure obesity-related behaviours in children under 5 years of age: A systematic review.

INTRODUCTION: Valid and reliable tools for measuring obesity-related behaviours in young children that are brief and can be administered quickly and cost-effectively in large-scale population studies are needed. The objectives of this systematic review were to describe brief tools that measure dietary intake, physical activity, sedentary behaviour, and sleep in young children. METHODS: A systematic review of studies published in English in six databases (CINAHL, Medline, Embase, PsycINFO, HaPI, and Cochrane) prior to April 2018 was undertaken using the PROSPERO protocol and PRISMA guidelines. Included studies were those reporting the psychometric properties of brief (≤15 items) tools that measure dietary, activity, or sleep-related behaviours, alone or in combination, in children birth to 4.9 years of age. RESULTS: The search identified 11 379 papers, 200 full-text articles were screened for eligibility, and 12 met the inclusion criteria. Three studies measured two behavioural domains, while most assessed a single behaviour (three diet, five physical activity, one sleep, and none sedentary behaviour). Only two (one diet, one sleep) focused on the under 2 age group. Few studies assessed reliability, and validity and findings were mixed. CONCLUSIONS: There is a need to develop brief tools to measure early life obesity-related behaviours, particularly those assessing sedentary behaviour and sleep and tools that cover multiple domains.