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Mucosal-associated invariant T (MAIT) cells are innate-like, unconventional T cells that are present in peripheral blood and mucosal surfaces. A clear understanding of how MAIT cells in the mucosae function and their role in host immunity is still lacking. Therefore, our aim was to investigate MAIT cell distribution and their characteristics in the gastrointestinal (GI) mucosal tissue based on Vα7.2+CD161hi identification. We showed that Vα7.2+CD161hi T cells are present in both intraepithelial layer and lamina propriae of the GI mucosa, but have different abundance at each GI site. Vα7.2+CD161hi T cells were most abundant in the duodenum, but had the lowest reactivity to MR1-5-OP-RU tetramers when compared with Vα7.2+CD161hi T cells at other GI tissue sites. Striking discrepancies between MR1-5-OP-RU tetramer reactive cells and Vα7.2+CD161hi T cells were observed along each GI tissue sites. Vα7.2+CD161hi TCR repertoire was most diverse in the ileum. Similar dominant profiles of TRBV usage were observed among peripheral blood, duodenum, ileum, and colon. Some TRBV chains were detected at certain intestinal sites and not elsewhere. The frequency of peripheral blood Vα7.2+CD161hi T cells correlated with mucosal Vα7.2+CD161hi T cells in lamina propriae ileum and lamina propriae colon. The frequency of peripheral blood Vα7.2+CD161hi T cells in Helicobacter pylori-infected individuals was significantly lower than uninfected individuals, but this was not observed with gastric Vα7.2+CD161hi T cells. This study illustrates the biology of Vα7.2+CD161hi T cells in the GI mucosa and provides a basis for understanding MAIT cells in the mucosa and MAIT-related GI diseases.

Mucosal-associated invariant T (MAIT) cells are a major subset of innate-like T cells mediating protection against bacterial infection through recognition of microbial metabolites derived from riboflavin biosynthesis. Mouse MAIT cells egress from the thymus as two main subpopulations with distinct functions, namely, T-bet-expressing MAIT1 and RORγt-expressing MAIT17 cells. Previously, we reported that inducible T-cell costimulator and interleukin (IL)-23 provide essential signals for optimal MHC-related protein 1 (MR1)-dependent activation and expansion of MAIT17 cells in vivo. Here, in a model of tularemia, in which MAIT1 responses predominate, we demonstrate that IL-12 and IL-23 promote MAIT1 cell expansion during acute infection and that IL-12 is indispensable for MAIT1 phenotype and function. Furthermore, we showed that the bias toward MAIT1 or MAIT17 responses we observed during different bacterial infections was determined and modulated by the balance between IL-12 and IL-23 and that these responses could be recapitulated by cytokine coadministration with antigen. Our results indicate a potential for tailored immunotherapeutic interventions via MAIT cell manipulation.

The INPEX-led Ichthys Joint Venture has established strong partnerships with the Northern Territory Government (NTG), cultural organisations and Traditional Owner groups in the Northern Territory to deliver social and environmental offset programs. The key governance model for delivery of the offset programs is the Ichthys Project Voluntary Offset Agreement (IPVOA), which commits $91 M AUD over a 40-year period through a suite of offset programs. This paper focuses on the journey to partner with the NTG-run Aboriginal Ranger Grants Program (ARGP). Through the IPVOA, INPEX and its Ichthys Joint Venture participants will contribute $24 M AUD over 22 years, to the ARGP, for Aboriginal Ranger programs addressing specific species and their associated habitat throughout the Top End. This is the first time where industry has contributed to the ARGP to deliver positive outcomes in the NT. This has been achieved by fostering collaborative, engaging and trustworthy relationships with the Commonwealth and NT governments; engaging with the Aboriginal Land Management Advisory Group; and meeting with Aboriginal Ranger groups. The key has been finding a common ground between the perspectives and the priorities of all stakeholders for how best to deliver conservation management on country in the NT. This common ground is likely to evolve over the next 22 years as the INPEX-led Ichthys Joint Venture and NTG deliver environmental outcomes, promote a connection to country and empower Aboriginal Ranger groups to better manage their country for future generations.

It is well known that manufacturing operations can affect the environment, but hardly any research explores whether the natural environment shapes manufacturing operations. Specifically, we investigate whether water scarcity, which results from environmental conditions, influences manufacturing firms to lower their toxic releases to the environment. We created a data set that spans 2000–2016 and includes details on the toxic emissions of 3,092 manufacturing facilities in Texas. Additionally, our data set includes measures of the water scarcity experienced by these facilities. Our econometric analysis shows that manufacturing facilities reduce their toxic releases into the environment when they have experienced drought conditions in the previous year. We examine facilities that release toxics to water as well as facilities with no toxic releases to water. We find that the reduction in total releases (to all media) is driven mainly by those facilities that release toxic chemicals to water. Further investigation at a more granular level indicates that water scarcity compels manufacturing facilities to lower their toxic releases into media other than water (i.e., land or air). The impact of water scarcity on toxic releases to water is more nuanced. A full-sample analysis fails to link water scarcity to lower toxic releases to water, but a further breakdown shows that manufacturing facilities in counties with a higher incidence of drought do lower their toxic releases to water. We also find that facilities that release toxics to water undertake more technical and input modifications to their manufacturing processes when they face water scarcity. This paper was accepted by David Simchi-Levi, operations management.

BACKGROUND: Patients hospitalised with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. OBJECTIVES: To investigate efficacy of an acute coronary syndrome regimen in patients hospitalised with COVID-19 and coronary disease risk factors. PATIENTS/METHODS: A randomised controlled open-label trial across acute hospitals (UK and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28-days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, death). RESULTS: 320 patients from 9 centres were randomised. The trial terminated early due to low recruitment. At 30 days there was no significant difference in mortality (intervention: 11.5% vs control: 15%, unadjusted OR 0.73, 95%CI 0.38 to 1.41, p=0.355). Significant bleeds were infrequent and not significantly different between the arms (intervention: 1.9% vs control 1.9%, p>0.999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR 1.46, 95% CrI 0.88 to 2.37, Pr(Beta>0)=93%; adjusted OR 1.50, 95% CrI 0.91 to 2.45, Pr(Beta>0)=95%) and median time to discharge home was two days shorter (95% CrI -4 to 0, 2% probability that it was worse). CONCLUSIONS: Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I–related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in vivo in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in Mr1−/− mice, compared with wild-type mice. The antitumor activity observed in Mr1−/− mice required natural killer (NK) and/or CD8+ T cells and IFNγ. Adoptive transfer of MAIT cells into Mr1−/− mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1–dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy.Significance:Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics.This article is highlighted in the In This Issue feature, p. 1

Supplementary text and figures

This study is motivated by the challenges faced by clinics in sub-Saharan Africa in allocating scarce and unreliable supply of antiretroviral drugs (ARVs) among a large pool of eligible patients. Existing discussion of ARV allocation is focused on qualitative rules for prioritizing certain socioeconomic and demographic patient segments over others at the national level. However, such prioritization rules are of limited utility in providing quantitative guidance on scaling up of treatment programs at individual clinics. In this study, we take the perspective of a clinic administrator whose objective is to maximize the quality-adjusted survival of the entire patient population in its service area by allocating scarce and unreliable supply of drugs among two activities: initiating treatment for untreated patients and continuing treatment for previously treated patients. The key trade-off underlying this allocation decision is between the marginal health benefit obtained by initiating an untreated patient on treatment and that obtained by avoiding treatment interruption of a treated patient. This trade-off has not been explicitly studied in the clinical literature, which focuses either on the incremental value obtained from initiating treatment (over no treatment) or on the value of providing continuous treatment (over interrupted treatment) but not on the difference of the two. We cast the clinic's problem as a stochastic dynamic program and provide a partial characterization of the optimal policy, which consists of dynamic prioritization of patient segments and is characterized by state-dependent thresholds. We use this structure of the optimal policy to design a simpler Two-Period heuristic and show that it substantially outperforms the Safety-Stock heuristic, which is commonly used in practice. In our numerical experiments based on realistic parameter values, the performance of the Two-Period heuristic is within 4% of the optimal policy whereas that of the Safety-Stock heuristic can be as much as 20% lower than that of the optimal policy. Our model can serve as a basis for developing a decision support tool for clinics to design their ARV treatment program scale-up plans.

Cell death mechanisms in T lymphocytes vary according to their developmental stage, cell subset and activation status. The cell death control mechanisms of mucosal-associated invariant T (MAIT) cells, a specialized T cell population, are largely unknown. Here we report that MAIT cells express key necroptotic machinery; receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein, in abundance. Despite this, we discovered that the loss of RIPK3, but not necroptotic effector MLKL or apoptotic caspase-8, specifically increased MAIT cell abundance at steady-state in the thymus, spleen, liver and lungs, in a cell-intrinsic manner. In contrast, over the course of infection with Francisella tularensis, RIPK3 deficiency did not impact the magnitude of the expansion nor contraction of MAIT cell pools. These findings suggest that, distinct from conventional T cells, the accumulation of MAIT cells is restrained by RIPK3 signalling, likely prior to thymic egress, in a manner independent of canonical apoptotic and necroptotic cell death pathways.

Background To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. Methods We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. Results ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors ( Conclusions We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.

T-cell receptor

T-cell immunity is important for recovery from COVID-19 and provides heightened immunity for re-infection. However, little is known about the SARS-CoV-2-specific T-cell immunity in virus-exposed individuals. Here we report virus-specific CD4+ and CD8+ T-cell memory in recovered COVID-19 patients and close contacts. We also demonstrate the size and quality of the memory T-cell pool of COVID-19 patients are larger and better than those of close contacts. However, the proliferation capacity, size and quality of T-cell responses in close contacts are readily distinguishable from healthy donors, suggesting close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection. Additionally, asymptomatic and symptomatic COVID-19 patients contain similar levels of SARS-CoV-2-specific T-cell memory. Overall, this study demonstrates the versatility and potential of memory T cells from COVID-19 patients and close contacts, which may be important for host protection., T cells compose a critical component of the immune response to coronavirus infection with SARS-CoV-2. Here the authors characterise the T cell response to SARS CoV-2 in patients and their close contacts, and show the presence of SARS-CoV-2 specific T cells in the absence of detectable virus infection.

BackgroundTo achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.MethodsWe performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n=40/579) of these tumors and completed additional validation by ultrabright telomeric fociin situon a subset of these tumors. We used CCA to validateTelomereHunterfor computational prediction of ALT status and focus subsequent analyses on pediatric high-grade glioma (pHGG) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.ResultsALT is common in pHGG (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (ATRXmutations occur in 50% of ALT+ pHGG and in 30% of ALT-pHGG. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. Conclusions: We demonstrate thatATRXis mutated in only a subset of ALT+ pHGG, suggesting other mechanisms ofATRXloss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with development of ALT in patients with pHGG.Key PointsATRX alterations are frequent, but not required, for an ALT phenotype in pHGGspHGG patients with germline mismatch repair variants have higher rate of ALT + tumorsTelomereHunteris validated to predict ALT in pHGGsImportance of the StudyWe performed orthogonal molecular and computational analyses to detect the presence of alternative lengthening of telomeres in a highly characterized cohort of pediatric brain tumors. We demonstrate that many pHGG utilize ALT without a mutation in ATRX, suggesting either loss of function of ATRX via an alternative mechanism or an alternate means of development of ALT. We show that germline variants in MMR genes are significantly associated with ALT in pHGG. Our work adds to the biological understanding of the development of ALT and provides an approach to stratify patients who may benefit from future ALT-directed therapies in this patient population.

Presented on Wednesday 18 May: Session 11 The INPEX-led Ichthys Joint Venture has established strong partnerships with the Northern Territory Government (NTG), cultural organisations and Traditional Owner groups in the Northern Territory to deliver social and environmental offset programs. The key governance model for delivery of the offset programs is the Ichthys Project Voluntary Offset Agreement (IPVOA), which commits $91 M AUD over a 40-year period through a suite of offset programs. This paper focuses on the journey to partner with the NTG-run Aboriginal Ranger Grants Program (ARGP). Through the IPVOA, INPEX and its Ichthys Joint Venture participants will contribute $24 M AUD over 22 years, to the ARGP, for Aboriginal Ranger programs addressing specific species and their associated habitat throughout the Top End. This is the first time where industry has contributed to the ARGP to deliver positive outcomes in the NT. This has been achieved by fostering collaborative, engaging and trustworthy relationships with the Commonwealth and NT governments; engaging with the Aboriginal Land Management Advisory Group; and meeting with Aboriginal Ranger groups. The key has been finding a common ground between the perspectives and the priorities of all stakeholders for how best to deliver conservation management on country in the NT. This common ground is likely to evolve over the next 22 years as the INPEX-led Ichthys Joint Venture and NTG deliver environmental outcomes, promote a connection to country and empower Aboriginal Ranger groups to better manage their country for future generations. To access the presentation click the link on the right. To read the full paper click here

ObjectiveTo establish the feasibility of a multicentre randomised controlled trial to assess the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy in children with uncomplicated acute appendicitis.DesignFeasibility randomised controlled trial with embedded qualitative study to inform recruiter training to optimise recruitment and the design of a future definitive trial.SettingThree specialist paediatric surgery centres in the UK.PatientsChildren (aged 4–15 years) with a clinical diagnosis of uncomplicated acute appendicitis.InterventionsAppendicectomy or a non-operative treatment pathway (comprising broad-spectrum antibiotics and active observation).Main outcome measuresPrimary outcome measure was the proportion of eligible patients recruited. Secondary outcomes evaluated adherence to interventions, data collection during follow-up, safety of treatment pathways and clinical course.ResultsFifty per cent of eligible participants (95% CI 40 to 59) approached about the trial agreed to participate and were randomised. Repeated bespoke recruiter training was associated with an increase in recruitment rate over the course of the trial from 38% to 72%. There was high acceptance of randomisation, good patient and surgeon adherence to trial procedures and satisfactory completion of follow-up. Although more participants had perforated appendicitis than had been anticipated, treatment pathways were found to be safe and adverse event profiles acceptable.ConclusionRecruitment to a randomised controlled trial examining the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy for the treatment of uncomplicated acute appendicitis in children is feasible.Trial registration numberNCT15830435.

X-ray free-electron lasers (XFELs) open a new era of X-ray based research by generating extremely intense X-ray flashes. To further improve the spectrum brightness, a self-seeding FEL scheme has been developed and demonstrated experimentally. As the next step, new-generation FELs with high repetition rates are being designed, built and commissioned around the world. A high repetition rate would significantly speed up the scientific research; however, alongside this improvement comes new challenges surrounding thermal management of the self-seeding monochromator. In this paper, a new configuration for self-seeding FELs is proposed, operated under a high repetition rate which can strongly suppress the thermal effects on the monochromator and provides a narrow-bandwidth FEL pulse. Three-dimension time-dependent simulations have been performed to demonstrate this idea. With this proposed configuration, high-repetition-rate XFEL facilities are able to generate narrow-bandwidth X-ray pulses without obvious thermal concern on the monochromators.

We compare how several forms of multicriteria decision analysis (MCDA) can enhance the practice of alternatives assessment (AA). We report on a workshop in which 12 practitioners from US corporations, government agencies, NGOs, and consulting organizations applied different MCDA techniques to 3 AA case studies to understand how they improved the decision process. Participants were asked to select a preferred alternative in each case using a different decision analysis approach: their unaided decision-making method, individual or lightly facilitated group multiattribute value theory (MAVT), and more extensively facilitated group structured decision making (SDM). Surveys conducted after each exercise revealed that participants were positive toward the use of formal decision-making methods for AA, reporting meaningful increases in their understanding of the trade-offs involved and their own values. Participants also reported challenges with each approach. While the MCDA techniques were reported to enhance transparency and communication, they did not consistently lead to higher satisfaction with a decision and/or outcome, and they were not more likely to be adopted within their organizations than unaided approaches. More formal decision-making methods have promise in the context of AA, but practitioners will need more guidance to use such tools successfully. Practitioners will also need to define what "success" constitutes; different approaches may be called for depending on whether the objective is increased understanding, satisfaction with the outcome, satisfaction with the process, or something else. Integr Environ Assess Manag 2021;17:27-41. © 2020 SETAC.

Community-acquired pneumonia (CAP) contributes substantially to morbidity and mortality in children under the age of 5 years. In examining bronchoalveolar lavages (BALs) of children with CAP, we found that interleukin-17 (IL-17) production was significantly increased in severe CAP. Immune profiling showed that mucosal-associated invariant T (MAIT) cells from the BALs, but not blood, of CAP patients actively produced IL-17 (MAIT17). Single-cell RNA-sequencing revealed that MAIT17 resided in a BAL-resident PLZFhiCD103+ MAIT subset with high expression of hypoxia-inducible factor 1α (HIF-1α), reflecting the hypoxic state of the inflamed tissue. CAP BALs also contained a T-bet+ MAIT1 subset and a novel DDIT3+ (DNA damage-inducible transcript 3-positive) MAIT subset with low expression of HIF1A. Furthermore, MAIT17 differed from T-helper type 17 (Th17) cells in the expression of genes related to tissue location, innateness, and cytotoxicity. Finally, we showed that BAL monocytes were hyper-inflammatory and elicited differentiation of MAIT17. Thus, tissue-resident MAIT17 cells are induced at the infected respiratory mucosa, likely influenced by inflammatory monocytes, and contribute to IL-17-mediated inflammation during CAP.

This work surveys stakeholders of America’s Marine Highway to identify their perceived influence on each other’s resource allocation decision making. The value/criticality of the resource held by the stakeholder group can be indirectly measured by the influence exerted by the group on its peers and its external stakeholders. The stakeholder map visualizes how the various stakeholder groups influence each other. Survey of the US Marine Highway stakeholders reveals peers as the most dominant influence among shippers, environmental advocates, and regulators. Results suggest that only suppliers and transportation providers exhibit distinct dominance of customer-supplier influence over that of their peers. This snapshot of stakeholder relationships is a powerful tool for both businesses as well as regulators in their pursuit of shared objectives in a network-centric environment. Stakeholder relationship influence results, and their graphical illustration, contribute to understanding the underlying dynamics of a changing value advantage in the current and coming decades of shipping.

Global shipping pattern is widely used to assess vessel-borne pollution risk and inform environmental policymaking. Due to ice retreat under climate change, new trans-Arctic navigation routes may b...

Background In human blood, mucosal-associated invariant T (MAIT) cells are abundant T cells that recognize antigens presented on non-polymorphic major histocompatibility complex-related 1 (MR1) molecules. The MAIT cells are activated by mycobacteria, and prior human studies indicate that blood frequencies of MAIT cells, defined by cell surface markers, decline during tuberculosis (TB) disease, consistent with redistribution to the lungs. Methods We tested whether frequencies of blood MAIT cells were altered in patients with TB disease relative to healthy Mycobacterium tuberculosis-exposed controls from Peru and South Africa. We quantified their frequencies using MR1 tetramers loaded with 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil. Results Unlike findings from prior studies, frequencies of blood MAIT cells were similar among patients with TB disease and latent and uninfected controls. In both cohorts, frequencies of MAIT cells defined by MR1-tetramer staining and coexpression of CD161 and the T-cell receptor alpha variable gene TRAV1-2 were strongly correlated. Disease severity captured by body mass index or TB disease transcriptional signatures did not correlate with MAIT cell frequencies in patients with TB. Conclusions Major histocompatibility complex (MHC)-related 1-restrictied MAIT cells are detected at similar levels with tetramers or surface markers. Unlike MHC-restricted T cells, blood frequencies of MAIT cells are poor correlates of TB disease but may play a role in pathophysiology.

Background Lichen sclerosus (LS), (balanitis xerotica obliterans), causes pathological phimosis. Many boys present with obstructive symptoms, the cause is usually obvious on examination so ultrasound scans (USS) of the urinary tract are not routinely indicated. We review a series of abnormal USS in boys with LS. Methods Retrospective note review for boys undergoing surgical treatment for LS between 2000 and 2017. Seventy-eight boys had a USS prior to surgery, those with abnormal USS form the study population. Boys with neuropathic bladder or congenital urinary tract abnormalities were excluded. Results Nineteen of 78 boys (24%), mean age 9 years, were included. Seventeen had obstructive symptoms, 13 had culture proven UTIs, 12 had new onset incontinence. On USS 3 (17%) had acute retention, 8 (78%) had an isolated post-void residual volume (PVR) > 10% of estimated bladder capacity (EBC); 3 had bladder wall thickening +/− PVR > 10%, 5 had upper tract changes. Symptoms resolved with successful treatment of LS. Six boys had post treatment USS, abnormalities resolved in 5. Conclusions Clinicians should consider LS in boys presenting with UTIs, new onset incontinence and obstructive urinary tract symptoms. Routine USS are not indicated though should be considered in those with an atypical history or examination. Type of Study Case Series. Level of Evidence Level 4.

Mucosal-associated invariant T (MAIT) cells are activated by microbial riboflavin-based metabolite antigens when presented by MR1. How modifications to the potent antigen 5-OP-RU affect presentation by MR1 and MAIT cell activation remains unclear. Here we design 20 derivatives, termed altered metabolite ligands (AMLs), to dissect the impact of different antigen components on the human MAIT-MR1 axis. Analysis of 11 crystal structures of MAIT T cell antigen receptor (TCR)-MR1-AML ternary complexes, along with biochemical and functional assays, shows that MR1 cell-surface upregulation is influenced by ribityl and non-ribityl components of the ligand and the hydrophobicity of the MR1-AML interface. The polar ribityl chain of the AML strongly influences MAIT cell activation potency through dynamic compensatory interactions within a MAIT TCR-MR1-AML interaction triad. We define the basis by which the MAIT TCR can differentially recognize AMLs, thereby providing insight into MAIT cell antigen specificity and potency.

Mucosal-associated invariant T (MAIT) cells are innate-like, unconventional T cells that are present in peripheral blood and mucosal surfaces. A clear understanding of how MAIT cells in the mucosae function and their role in host immunity is still lacking. Therefore, our aim was to investigate MAIT cell distribution and their characteristics in the gastrointestinal (GI) mucosal tissue based on Vα7.2

Objectives To identify when obstetricians would deliver a fetus with antenatal hydronephrosis and normal liquor. Designed as snap-shot survey. Setting: Survey Monkey link. Population/sample were obstetrics and fetal medicine consultants who received the survey link via closed professional forums on the North West Coast Maternity Clinical Network, Facebook, and publicly on Twitter. Methods Survey link publicised as above, obstetric consultants were asked at what gestation would they deliver a fetus with antenatal hydronephrosis and normal liquor; and what criteria would they use to make that decision. Main outcome measures were number of years in practice, gestation at delivery, anteroposterior diameter (APD) of renal pelvis. Results A total of 44/102 respondents (43%) would deliver prior to 40 weeks (median no. of years as consultant 10 years [IQR 5–17]) vs. those who would not (median years as consultant 5.5 [IQR 3–12]). Re APD threshold of delivery: 17 indicated delivery if the APD were 20 mm, 10 if it were 21–30 mm and 16 if it were >30 mm. Re gestation at which they would deliver: 13 indicated 37–38 weeks, 13 indicated 38–39 weeks and 17 indicated 39–40 weeks. Reasons selected for delivery before term were obstetric anxiety n=2, maternal request n=2, maternal anxiety n=2 and concern about fatal renal damage/renal damage n=34. Conclusions A surprising number of respondents would consider early delivery of a fetus with hydronephrosis and normal liquor despite the lack of evidence of benefit. The evidence supporting term delivery means that early term delivery is only indicated for obstetric reasons in this scenario.

People with Cystic Fibrosis (CF) develop pulmonary inflammation, chronic infection and structural lung damage early in life, with these manifestations being prevalent among preschool children and infants. While early immune events are believed to play critical roles in shaping the progression, severity and disease burden later in life, T cells and their subsets are poorly studied in the CF lung, particularly during the formative early stages of disease.Using flow cytometry, we analyzed Mucosal Associated Invariant T (MAIT) cells, γδ T cells, and Natural Killer T (NKT)-like cells in bronchoalveolar lavage (BAL) samples from seventeen children with CF, aged two to six years old. The effect of age, sex and lung infections on the frequencies of these cells in BAL samples was analysed (grouped data were tested for normality and compared byNo difference was noted in the proportions of unconventional T cells related to the sex or age of the children. The frequency of γδ T cells and MAIT cells appeared unchanged by infection status. However, viral infections were associated with a significant increase in the proportion of NKT-like cells.By evaluating T cells in the lungs of children during the early formative stages of CF, this study identified potentially important interactions between these cells and viral pathogens.

The dynamic interaction between the CMV virus and host immune response remains obscure, thus hindering the diagnosis and therapeutic management of patients with HSCT. The current diagnosis of CMV viremia depends on viral load estimation. Medical intervention based on viral load, can be unnecessary or poorly timed for many patients. Here we examined the clinical features and blood samples of patients with HSCT and assessed the CMV reactivation kinetics and corresponding CMV antigen-specific T-cell response in individual patients based on a peptide pool stimulation T-cell assay, which showed that CMV-specific CD8

The emergence of patient specific instrumentation has seen an expansion from simple radiographs to plan total knee arthroplasty (TKA) with modern systems using computed tomography (CT) or magnetic resonance imaging scans. Concerns have emerged regarding accuracy of these non-weight bearing modalities to assess true mechanical axis. The aim of our study was to compare coronal alignment on full length standing AP imaging generated by the EOS acquisition system with the CT coronal scout image.Eligible patients underwent unilateral or bilateral primary TKA for osteoarthritis under the care of investigating surgeon between 2017 and 2022, with both EOS X-Ray Imaging Acquisition System and CT scans performed preoperatively. Coronal mechanical alignment was measured on the supine coronal scout CT scan and the standing HKA EOS.Pre-operative lower limb coronal alignment was assessed on 96 knees prior to TKA on the supine coronal scout CT scan and the standing HKA EOS. There were 56 males (56%), and 44 right knees (44%). The mean age was 68 years (range 53-90). The mean coronal alignment was 4.7 degrees (SD 5.3) on CT scan and 4.6 degrees (SD 6.2) on EOS (p=0.70). There was a strong positive correlation of coronal alignment on CT scan and EOS (pearson0.927, p=0.001). The mean difference between EOS and CT scan was 0.9 degrees (SD 2.4). Less than 3 degrees variation between measures was observed in 87% of knees. On linear regression for every 1° varus increase in CT HKA alignment, the EOS HKA alignment increased by 0.93° in varus orientation. The model explained 86% of the variability.CT demonstrates excellent reliability for assessing coronal lower limb alignment compared to EOS in osteoarthritic knees. This supports the routine use of CT to plan TKA without further weight bearing imaging in routine cases.

Background Genetics studies in the porcine immune system have enhanced selection practices for disease resistance phenotypes and increased the efficacy of porcine models in biomedical research; however limited functional annotation of the porcine immunome has hindered progress on both fronts. Among epigenetic mechanisms that regulate gene expression, DNA methylation is the most ubiquitous modification made to the DNA molecule and influences transcription factor binding as well as gene and phenotype expression. Human and mouse DNA methylation studies have improved mapping of regulatory elements in these species, but comparable studies in the pig have been limited in scope. Results We performed whole-genome bisulfite sequencing to assess DNA methylation patterns in nine pig immune cell populations: CD21+ and CD21− B cells, four T cell fractions (CD4+, CD8+, CD8+CD4+, and SWC6γδ+), natural killer and myeloid cells, and neutrophils. We identified 54,391 cell differentially methylated regions (cDMRs), and clustering by cDMR methylation rate grouped samples by cell lineage. 32,737 cDMRs were classified as cell lowly methylated regions (cLMRs) in at least one cell type, and cLMRs were broadly enriched in genes and regions of intermediate CpG density. We observed strong correlations between differential methylation and expression across immune cell populations, with cell-specific low methylation disproportionately impacting genes exhibiting enriched gene expression in the same cell type. Motif analysis of cLMRs revealed cell type-specific enrichment of transcription factor binding motifs, indicating that cell-specific methylation patterns may influence accessibility by trans-acting factors. Lastly, cDMRs were enriched for immune capacity GWAS SNPs, and many such overlaps occurred within genes known to influence immune cell development and function (CD8B, NDRG1). Conclusion Our DNA methylation data improve functional annotation of the porcine genome through characterization of epigenomic regulatory patterns that contribute to immune cell identity and function, and increase the potential for identifying mechanistic links between genotype and phenotype.

IntroductionSuction rectal biopsy (SRB) is a key diagnostic tool in Hirschsprung’s disease. The original Noblett device has been superseded by modern alternatives including the Rbi2 rectal biopsy gun. We describe a comparison of biopsy results from the Noblett device and the Rbi2 gun and an investigation into significant post-biopsy bleeding episodes with the latter.MethodsA retrospective review of SRB episodes between 2006 and 2014 was undertaken to audit biopsy success rates. Significant post-procedure bleeding after SRB with the Rbi2 gun prompted further investigations.ResultsBiopsies taken with the Noblett gun were more likely to be inadequate (Noblett 82/197 (40%) vs Rbi2 77/438 (18%)). After biopsy with the Rbi2 gun, 2 infants suffered from significant bleeding requiring resuscitation, blood product support and multiple theater episodes. As there were no reported cases of bleeding with the Rbi2 gun, a report was made to the Medicines & Healthcare products Regulatory Agency who identified incorrect biopsy technique as a potential contributing factor. A questionnaire of trainees and consultants found unexpected individual variation in SRB technique, with some users applying excessive suction.ConclusionsSignificant bleeding occurred after SRB with the Rbi2 gun, excessive suction was thought to be the cause.