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Graphical abstract, Highlights • Native aortic root thrombus is a life-threatening complication in patients with HLHS. • Echo evaluation of the native aortic root is an important consideration. • Echo monitoring is a useful tool for assessment of thrombus response to therapy.

Improving the anti-tumour T cell response as a consequence of immunotherapy can result in eradication of tumour burden, however, the majority of patients fail with current treatment regimens and so novel immunotherapies with greater efficacy and improved tolerability are needed. The phosphoinositide-3-kinase (PI3K) family members that are directly involved in cell signalling comprise PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ, with the latter two isoforms expressed primarily by leukocytes. The survival and optimal function of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) is dependent on PI3Kδ, whereas tumour-associated macrophages (TAMs), use PI3Kγ. Blocking these signalling isoforms can boost development of effective anti-cancer immune responses and result in control of tumour burden. The dependence on different PI3K isoforms in immune cells makes targeting this pathway an attractive approach for tumour immunotherapy. Herein, we discuss how inhibiting specific PI3K isoforms in pro-tumoural Tregs, MDSCS and TAMs can unleash a powerful anti-tumour immune response, driven by CD8

Reducing the overuse of antimicrobials is imperative for the sake of minimizing antimicrobial-associated adverse effects, optimizing resource utilization, and curtailing the rise in multidrug-resistant organisms. Biomarkers reflect the host responses to infection and may assist with minimizing unnecessary antimicrobial usage.To review the literature pertaining to the performance of biomarkers specifically used to guide the duration of antimicrobial therapy (AMT).Randomized controlled trials, observational studies, and meta-analyses assessing biomarker-guided approaches to AMT decision-making and their impact on the duration of therapy were reviewed.Several randomized controlled trials and real-world observational studies have shown that a procalcitonin (PCT)-guided strategy can help clinicians individualize the duration of AMT, particularly among non-critically ill patients hospitalized with suspected respiratory tract infections when using a PCT cut-off value of0.25 μg/L and critically ill patients with respiratory tract infections or undifferentiated sepsis when using a PCT cut-off value of0.5 μg/L or ≥80% decline in the peak level. C-reactive protein is a non-specific marker of inflammation that may also assist with an early discontinuation of AMT; however, data are limited. Haematological biomarkers are prone to variance between individuals and are often influenced by medications and non-infectious conditions, making them less reliable for the purposes of AMT decision-making. Novel biomarkers such as multi-protein signatures and host gene expression tests have shown promise as tools to better differentiate between bacterial and non-bacterial infections; clinical studies are needed to determine whether they can be used to help optimize the duration of AMT.Studies have demonstrated that a PCT-guided strategy, when utilized appropriately, can help guide clinicians to individualize and often reduce the duration of AMT, especially in patients hospitalized with respiratory tract infections and those admitted to the intensive care unit with suspected respiratory tract infections or sepsis. The impact of utilizing other biomarkers is less clear and requires further study.

Limited data are available on the clinical presentation and outcomes of coronavirus disease (COVID-19) patients in the United States hospitalized under normal-caseload or nonsurge conditions. We retrospectively studied 72 consecutive adult patients hospitalized with COVID-19 in 2 hospitals in the San Francisco Bay area, California, USA, during March 13-April 11, 2020. The death rate for all hospitalized COVID-19 patients was 8.3%, and median length of hospitalization was 7.5 days. Of the 21 (29% of total) intensive care unit patients, 3 (14.3% died); median length of intensive care unit stay was 12 days. Of the 72 patients, 43 (59.7%) had underlying cardiovascular disease and 19 (26.4%) had underlying pulmonary disease. In this study, death rates were lower than those reported from regions of the United States experiencing a high volume of COVID-19 patients.

Although metastatic disease is responsible for the majority of cancer deaths, tests of novel immunotherapies in mouse tumour models often focus on primary tumours without determining whether these therapies also target metastatic disease. This study examined the impact of depleting Foxp3+ regulatory T cells (Treg), on lung metastases, using a mouse model of breast cancer. After Treg-depletion, generation of an immune response to the primary tumour was a critical determinant for limiting development of metastasis. Indeed, resection of the primary tumour abrogated any effect of Treg-depletion on metastases. In addition, whilst the immune response, generated by the primary tumour, prevented metastases development, it had little impact on controlling established disease. Collectively, the data indicate that metastatic cells in the lung are not controlled by immune responses induced by the primary tumour. These findings indicate that targeting Tregs alone will not suffice for treating lung metastases. Electronic supplementary material The online version of this article (10.1007/s00262-020-02603-x) contains supplementary material, which is available to authorised users.

Inhibitory CD4+ T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity, but the mechanisms that underpin the development of such regulatory networks in vivo have remained obscure. To address this knowledge gap, we performed a comprehensive functional, phenotypic, and transcriptomic analysis of IL-10-producing CD4+ T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated TH1-like cells that developed at sites of viral persistence in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4+ T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4+ lineage suppressed the development of these inhibitory cells and also enabled better immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4+ T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the coexpression of Arg1.

Background Recent studies have demonstrated that blocking the PI3Kδ signalling enzyme (by administering a small molecule inhibitor, PI-3065) can potently improve the anti-tumour T-cell response through direct inhibition of Tregs. This treatment also has a negative impact on MDSC numbers but the primary mechanism driving this effect has remained unclear. Methods The 4T1 breast cancer mouse model was used in combination with PI-3065 to gain insights into the effect of PI3Kδ inhibition on MDSCs. Results PI-3065 treatment resulted in a concomitant reduction in MDSC expansion and tumour size. However, targeting Tregs independent of PI-3065 was also associated with reduced tumour volume and MDSC numbers. Surgical removal of tumours resulted in a rapid and significant decline in MDSC numbers, whilst ex vivo studies using cells from PI-3065-treated mice demonstrated no direct effect of the inhibitor on MDSC activity. Conclusions Our data suggest that MDSCs are not inhibited directly by PI-3065 treatment but that their reduced recruitment and immunosuppression within the tumour microenvironment is an indirect consequence of PI3Kδ-inhibition-driven tumour control. This indicates that PI3Kδ inhibition drives tumour immunity by breaking down multiple immunosuppressive pathways through both direct mechanisms (on Treg) and indirect mechanisms, secondary to tumour control (on MDSCs).

BackgroundDespite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors.MethodsMice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later.ResultsAs observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8+T cells, T cell factor 1 (TCF1)+T cells and CD69−T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3Kδ and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3Kδ inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3Kδ inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies.ConclusionsThese data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.

A young woman with mixed connective tissue disease complicated by erosive arthritis, secondary hypogammaglobulinemia due to rituximab, and a history of many infectious complications developed multiple nonhealing wounds, polyarticular joint pain, and leukocytosis. Radiographic studies demonstrated multiple scattered areas of osteomyelitis and complex abscesses. Purulent fluid drained from multiple sites did not yield a microbiologic diagnosis by standard culture technique, but Mycoplasma orale was ultimately identified using 16 S ribosomal RNA gene amplification and sequencing. We describe this unique case and review the literature.

AimsTo assess follow-up of sodium levels for in-patients prescribed antidepressants in practice compare to the standard of 3 monthly sodium levels for all patients who are prescribed antidepressants and at risk of hyponatraemiaMethodA list of the 20 most recently discharged patients from Meridian Ward, an older-adult functional inpatient ward, was prepared by the team administrator on 6th May 2020.We audited the entire duration of our patient's stay on Meridian Ward (we did not include periods of their admission when they were on other wards) using the electronic notes system, Carenotes.We also checked the electronic biochemistry results system, ICE, for sodium results, and the discharge summary for mentions of fluid restriction, medications and handover to GP of sodium-checking. We also checked scanned drug charts to see if they were on antidepressants and other implicated drugs.For people with episodes of hyponatraemia, in order to retrieve further info we looked at discharge summary and searched the activity notes for the following terms“Hyponat”“sodium”“fluid restrict”“Low na”We regarded the following conditions as risk factors for hyponatraemia:cardiacmalignancyrespiratoryhypothyroidrenalhepaticstrokeWe regarded following medications as risk factors:opioidsdiureticscarbamazepinetheophyllineantipsychoticsNSAIDsPPIsACE-IARBsamiodaronedomperidonesulphonylureasResult14 of the 20 patients were taking antidepressants. Of those: 13 were eligible for regular sodium monitoring due to risk factors 11 of these had 3-monthly sodium levels during admission For only 2 of these did we make a plan for the GP to continue to monitor the sodium level in community 3 had an episode of hyponatraemia implicated antidepressants: sertraline plus mirtazapine mirtazapine (very serious episode which caused seizure) sertraline for 2 of them an appropriate plan was made 1 without a plan - a mild hyponatraemia with nothing documented in the notesConclusionDuring their admission to Meridian Ward, 85% of patients taking antidepressants who had risk factors for hyponatraemia had three-monthly sodium levels in line with the trust guidance. However, only two patients (15%) had a plan for further sodium levels in the discharge summary sent to the GP. This highlights a need for improved awareness of risk factors for hyponatraemia and, in particular, improved communication with general practitioners who are going to take over prescribing of antidepressant medications.Recommendations3 monthly Na levels for all patients with risk factorsi.e. on any antidepressant prescribed PLUS any one of:>80 yearsHistory of low sodiumAKI during admissionRelevant comorbidities (see above)>1 antidepressantOther meds that can cause hyponatraemiaMore frequent monitoring for all those with with multiple risk factors AND who are starting/increasing antidepressant:baseline sodium plus repeat after 2 and 4 weeksCommunicate to GP the need for 3-monthly sodium monitoring for those with above risk factorsRe-audit in 6-12 months’ time

AimsTo quantify how many patients were prescribed high dose antipsychotic treatment (HDAT) and establish whether guidance for monitoring HDAT was being followed in an Assertive Outreach Team.BackgroundSevere mental health disorders are associated with significant premature mortality, predominantly due to physical health conditions. Antipsychotic medications are associated with side effects, including metabolic syndrome and QT prolongation, which increase the risk of serious physical illness. HDAT is defined as when the total dose of antipsychotics prescribed exceeds 100% of the maximum BNF dose, if each dose is expressed a percentage of its maximum dose. There is limited evidence of clinical benefit with HDAT but an increased risk of side effects. Patients prescribed HDAT should therefore be monitored for side effects and clinical benefit. Sussex Partnership NHS Foundation Trust developed a form specifically for this purpose, to be completed in addition to a physical health assessment.MethodAll patients on caseload were audited using the electronic notes. Current inpatients were excluded, as inpatient HDAT monitoring forms are attached to paper drug charts and therefore were not available for review.ResultA total of 61 patients were audited. Nine were excluded due to being inpatients. 16 were on community treatment orders and 26 were prescribed a long-acting antipsychotic injection. 10 were prescribed clozapine. The median number of medications prescribed was one. Four patients were prescribed HDAT ranging from 117-150% of the maximum BNF dose. Of these four, one had a HDAT form but this was out of date. 39 of 52 (75%) patients audited had had a physical health assessment in the past 12 months. Two of the 13 missing a physical health assessment were on HDAT.ConclusionPhysical health monitoring should be carried out for all patients on antipsychotics, but is particularly important for patients on HDAT. This audit identified a problem in both general physical health checks and HDAT monitoring. On discussion with the multi-disciplinary team a number of barriers to appropriate physical health monitoring were identified. There was a lack of awareness within the multi-disciplinary team that patients were receiving HDAT and regarding the implications for side effects. A reliable system to highlight the need for physical health checks was also missing and the team did not have sufficient equipment to perform the necessary checks. Identifying these barriers should enable improvements in physical health and HDAT monitoring which can be re-audited.

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections affect millions of persons around the globe and cause profound morbidity and mortality. A major intersection exists between these two epidemics, with HCV infection being more common in persons with HIV than in the general population, largely due to shared routes of transmission. HCV co-infection increases risk for liver- and non-liver-related morbidity and mortality, making HCV treatment a priority in HIV co-infected persons, but the treatment of HCV in co-infected patients has been daunting for multiple reasons. Until recently, HCV treatment has frequently been deferred due to the low rates of cure, significant adverse effects, burdensome duration of therapy and drug–drug interactions with HIV antiretroviral medications. Untreated HCV has resulted in significant health consequences for the millions of those infected and has led to multiple downstream impacts on our healthcare systems around the world. The development of a remarkable number of new HCV direct-acting agents (DAAs) that are significantly more efficacious and tolerable than the previous interferon-based regimens has transformed this important field of medicine, with the potential to dramatically reduce the burden of infection and improve health outcomes in this population. This review will summarize the epidemiology and clinical impact of HIV/HCV co-infection and current approaches to the treatment of HCV in HIV/HCV co-infected patients.

Improved survival with combination antiretroviral therapy has led to a dramatic increase in the number of human immunodeficiency virus (HIV)-infected individuals 50years of age or older such that by 2020 more than 50% of HIV-infected persons in the United States will be above this age. Recent studies confirm that antiretroviral therapy should be offered to all HIV-infected patients regardless of age, symptoms, CD4+ cell count, or HIV viral load. However, when compared with HIV-uninfected populations, even with suppression of measurable HIV replication, older individuals are at greater risk for cardiovascular disease, malignancies, liver disease, and other comorbidities.

Introduction : HIV patients are at risk of renal dysfunction directly from HIV, indirectly from chronic inflammation as well as from antiretroviral drug toxicity. In particular, tenofovir (TDF) has been associated with proximal renal tubular dysfunction. A joint HIV–renal clinic was set up in 2009 to facilitate a timely review and minimize additional follow-up appointments. Brighton has a cohort of 2,150 HIV patients, 90% are on ARVs with 910/1,935 (47.0%) on regimens including TDF. This study aims to investigate the utility of this clinic and describe renal disease in this cohort. Materials and Methods : Notes of patients scheduled for assessment at the clinic between 2012 and 2014 were reviewed. Demographics, HIV history, number of visits, reason for referral and outcome information were collected. Results : Sixty-five patients, median age 51 years (28–88) and median duration of HIV 163 months (20–335), were reviewed. Forty-two were taking TDF for a mean of 55.8 months (9–122). Forty-two patients were reviewed once with a median number of visits of 1 (1–4). Of those on TDF with proteinuria, 5 (13.2%) had TDF toxicity diagnosed and were discontinued at once, 27 continued with close monitoring with a further 7 subsequently discontinuing; total discontinued were 12 (32%). Overall, blood pressure control was the commonest intervention, 23/65 (35.4%), with 8/12 (66.7%) in the non-TDF proteinuria group. Four (6%) patients underwent renal biopsy (2 focal segmental glomerulosclerosis, 1 IgA nephropathy and 1 glomerulonephritis and granuloma). In 4 (6%) creatinine rise was attributed to NSAIDs, creatine or protein supplements usage. Conclusions : TDF toxicity was the commonest reason for referral but only a minority (13.2%) needed to discontinue immediately. Optimizing BP control was the most frequent outcome suggesting this is an underappreciated cause for renal dysfunction amongst HIV physicians, as were other causes such as creatine and protein supplement usage. Running a “one-stop-shop” clinic supports continuation of tenofovir in patients with proteinuria, and supports the diagnosis and management of poorly controlled hypertension and streamlines the management of these patients. (Published: 2 November 2014) Citation : Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Scott J and Williams D. Journal of the International AIDS Society 2014, 17(Suppl 3) :19566 http://www.jiasociety.org/index.php/jias/article/view/19566 | http://dx.doi.org/10.7448/IAS.17.4.19566