CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides.

The T cell antigen receptor (TCR) contains ten immunoreceptor tyrosine-based activation motif (ITAM) signaling sequences distributed within six CD3 subunits; however, the reason for such structural complexity and multiplicity is unclear. Here we evaluated the effect of inactivating the three CD3ζ chain ITAMs on TCR signaling and T cell effector responses using a conditional 'switch' mouse model. Unexpectedly, we found that T cells expressing TCRs containing inactivated (non-signaling) CD3ζ ITAMs (6F-CD3ζ) exhibited reduced ability to discriminate between low- and high-affinity ligands, resulting in enhanced signaling and cytokine responses to low-affinity ligands because of a previously undetected inhibitory function of CD3ζ ITAMs. Also, 6F-CD3ζ TCRs were refractory to antagonism, as predicted by a new in silico adaptive kinetic proofreading model that revises the role of ITAM multiplicity in TCR signaling. Finally, T cells expressing 6F-CD3ζ displayed enhanced cytolytic activity against solid tumors expressing low-affinity ligands, identifying a new counterintuitive approach to TCR-mediated cancer immunotherapy.

Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses.

The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens.

A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. RESULTS: A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. CONCLUSIONS: Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).

Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF.

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Coronary Artery Disease.

BACKGROUND: The Placebo-controlled Trial of Percutaneous Coronary Intervention for the Relief of Stable Angina (ORBITA-2) provided evidence for the role of percutaneous coronary intervention (PCI) for angina relief in stable coronary artery disease (CAD). Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are often used to guide PCI, however their ability to predict placebo-controlled angina improvement is unknown. METHODS: Participants with angina, ischemia, and stable CAD were enrolled and antianginal medications were stopped. Participants reported angina episodes daily for 2 weeks using the ORBITA-app. At the research angiogram, FFR and iFR were measured. After sedation and auditory isolation, participants were randomized to PCI or placebo, before entering a 12-week blinded follow-up phase with daily angina reporting. The ability of FFR and iFR, analyzed as continuous variables, to predict the placebo-controlled effect of PCI, was tested using Bayesian proportional odds modelling. RESULTS: Invasive physiology data were available in 279 patients (140 PCI and 139 placebo). The median (IQR) age was 65 years (59.0 to 70.5) and 223 (79.9%) were male. Median FFR was 0.60 (0.46 to 0.73) and median iFR was 0.76 (0.50 to 0.86). The lower the FFR or iFR, the greater the placebo-controlled improvement with PCI across all endpoints. There was strong evidence that a patient with an FFR at the lower quartile would have a greater placebo-controlled improvement in angina symptom score with PCI than a patient at the upper quartile (FFR 0.46 vs. 0.73: OR 2.01, 95% CrI 1.79 to 2.26, Pr(Interaction)>99.9%). Similarly, there was strong evidence that a patient with an iFR at the lower quartile would have a greater placebo controlled improvement in angina symptom score with PCI than a patient with an iFR at the upper quartile (iFR 0.50 vs. 0.86: OR 2.13, 95% CrI 1.87 to 2.45, Pr(Interaction) >99.9%). The relationship between benefit and physiology was seen in both Rose angina and Rose nonangina. CONCLUSIONS: Physiological stenosis severity, as measured by FFR and iFR, predicts placebo-controlled angina relief from PCI. Invasive coronary physiology can be used to target PCI to those patients who are most likely to experience benefit.

Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Primary bone diffuse large B-cell lymphoma (PB-DLBCL): a distinct extranodal lymphoma of germinal centre origin, with a common EZB-like mutational profile and good prognosis.

AIMS: Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is not recognized as a separate entity by the current classification systems. Here we define and highlight its distinctive clinical presentation, morphology, phenotype, gene expression profile (GEP), and molecular genetics. METHODS: We collected 27 respective cases and investigated their phenotype, performed gDNA panel sequencing covering 172 genes, and carried out fluorescence in situ hybridization to evaluate MYC, BCL2, and BCL6 translocations. We attempted to genetically subclassify cases using the Two-step classifier and performed GEP for cell-of-origin subtyping and in silico comparison to uncover up- and downregulated genes as opposed to other DLBCL. RESULTS: Most cases (n = 22) were germinal centre B-cell-like (GCB) by immunohistochemistry and all by GEP. Additionally, PB-DLBCL had a mutational profile similar to follicular lymphoma and nodal GCB-DLBCL, with the exception of more frequent TP53 and B2M mutations. The GEP of PB-DLBCL was unique, and the frequency of BCL2 rearrangements was lower compared to nodal GCB-DLBCL. The Two-step classifier categorized eight of the cases as EZB, three as ST2, and one as MCD. CONCLUSION: This study comprehensively characterizes PB-DLBCL as a separate entity with distinct clinical and morpho-molecular features. These insights may aid in developing tailored therapeutic strategies and shed light on its pathogenesis.

Epidermal growth factor receptor/mitogen-activated kinase inhibitor treatment induces a distinct inflammatory hair follicle response that includes collapse of immune privilege.

BACKGROUND: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75-90% of patients, the pathobiology of which remains insufficiently understood. OBJECTIVES: To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. METHODS: Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization. RESULTS: The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, ß2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-ß1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs. CONCLUSIONS: The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

About 75­90% of people with cancer who are treated with drugs called EGFR inhibitors (EGFRi) and MEK inhibitors (MEKi) will get a skin condition called folliculitis. This is where the hair follicles become inflamed. Despite this, the reasons why some patients develop this are not well understood. In this study, we had three goals. We wanted to understand how these medications alter the skin's immune response and genetic processes. We also wished to determine the impact of the medications on the immune protection of hair follicles. Finally, we wanted to find early signs of inflammation in hair follicles caused by the medications. We studied scalp samples from people who got folliculitis after long-term EGFRi treatment and compared them to samples of healthy scalp skin. We also examined patients before and after they began EGFRi treatment. In the lab, we exposed healthy hair follicles to an EGFRi called 'erlotinib' or a MEKi called 'cobimetinib'. We then carried out detailed imaging and genetic analyses. We found that long-term treatment with EGFRi increased certain immune cells (called CD8+ T cells) in the hair follicle area. This led to a breakdown in the immune protection around hair follicles. A similar breakdown was found in lab-treated healthy follicles. Genetic changes linked to inflammation were also found. Our findings suggest that EGFRi and MEKi treatments could affect the natural immune defence of hair follicles in the scalp and cause folliculitis. Protecting the immune system and controlling inflammation might be the key to treating people with these drug-related skin conditions.

Impact of vessel volume on thermodilution measurements in patients with coronary microvascular dysfunction.

BACKGROUND: Two invasive methods are available to estimate microvascular resistance: bolus and continuous thermodilution. Comparative studies have revealed a lack of concordance between measurements of microvascular resistance obtained through these techniques. AIMS: This study aimed to examine the influence of vessel volume on bolus thermodilution measurements. METHODS: We prospectively included patients with angina with non-obstructive coronary arteries (ANOCA) undergoing bolus and continuous thermodilution assessments. All patients underwent coronary CT angiography to extract vessel volume. Coronary microvascular dysfunction was defined as coronary flow reserve (CFR) < 2.0. Measurements of absolute microvascular resistance (in Woods units) and index of microvascular resistance (IMR) were compared before and after volumetric adjustment. RESULTS: Overall, 94 patients with ANOCA were included in this study. The mean age was 64.7 ± 10.8 years, 48% were female, and 19% had diabetes. The prevalence of CMD was 16% based on bolus thermodilution, while continuous thermodilution yielded a prevalence of 27% (Cohen's Kappa 0.44, 95% CI 0.23-0.65). There was no correlation in microvascular resistance between techniques (r = 0.17, 95% CI -0.04 to 0.36, p = 0.104). The adjustment of IMR by vessel volume significantly increased the agreement with absolute microvascular resistance derived from continuous thermodilution (r = 0.48, 95% CI 0.31-0.63, p < 0.001). CONCLUSIONS: In patients with ANOCA, invasive methods based on coronary thermodilution yielded conflicting results for the assessment of CMD. Adjusting IMR with vessel volume improved the agreement with continuous thermodilution for the assessment of microvascular resistance. These findings strongly suggest the importance of considering vessel volume when interpreting bolus thermodilution assessment.

Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: a phase III randomised trial (contRAst 3).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors. METHODS: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12. RESULTS: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups. CONCLUSIONS: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population. TRIAL REGISTRATION NUMBER: NCT04134728.

Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis. METHODS: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. PRIMARY ENDPOINT: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12. RESULTS: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. PRIMARY ENDPOINT: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups. CONCLUSIONS: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib. TRIAL REGISTRATION NUMBERS: NCT03980483, NCT03970837.

Cardiopulmonary exercise testing and efficacy of percutaneous coronary intervention: a substudy of the ORBITA trial.

AIMS: Oxygen-pulse morphology and gas exchange analysis measured during cardiopulmonary exercise testing (CPET) has been associated with myocardial ischaemia. The aim of this analysis was to examine the relationship between CPET parameters, myocardial ischaemia and anginal symptoms in patients with chronic coronary syndrome and to determine the ability of these parameters to predict the placebo-controlled response to percutaneous coronary intervention (PCI). METHODS AND RESULTS: Patients with severe single-vessel coronary artery disease (CAD) were randomized 1:1 to PCI or placebo in the ORBITA trial. Subjects underwent pre-randomization treadmill CPET, dobutamine stress echocardiography (DSE) and symptom assessment. These assessments were repeated at the end of a 6-week blinded follow-up period.A total of 195 patients with CPET data were randomized (102 PCI, 93 placebo). Patients in whom an oxygen-pulse plateau was observed during CPET had higher (more ischaemic) DSE score [+0.82 segments; 95% confidence interval (CI): 0.40 to 1.25, P = 0.0068] and lower fractional flow reserve (-0.07; 95% CI: -0.12 to -0.02, P = 0.011) compared with those without. At lower (more abnormal) oxygen-pulse slopes, there was a larger improvement of the placebo-controlled effect of PCI on DSE score [oxygen-pulse plateau presence (Pinteraction = 0.026) and oxygen-pulse gradient (Pinteraction = 0.023)] and Seattle angina physical-limitation score [oxygen-pulse plateau presence (Pinteraction = 0.037)]. Impaired peak VO2, VE/VCO2 slope, peak oxygen-pulse, and oxygen uptake efficacy slope was significantly associated with higher symptom burden but did not relate to severity of ischaemia or predict response to PCI. CONCLUSION: Although selected CPET parameters relate to severity of angina symptoms and quality of life, only an oxygen-pulse plateau detects the severity of myocardial ischaemia and predicts the placebo-controlled efficacy of PCI in patients with single-vessel CAD.

Exploring cognitive impairment in the early stages of an out-of-hospital cardiac arrest - a consecutive case series study.

Cognitive deficits are common, although often mild, in out-of-hospital cardiac arrest patients. Prevalence and severity of cognitive deficits on discharge from acute hospital, however, are not systematically assessed in clinical practice, and not frequently reported in scientific literature, potentially hindering the development of appropriate follow-up care pathways for these patients. We hereby present data from a consecutive case series of 75 out-of-hospital cardiac arrest patients discharged from our hospital over a period of 16 months; for 46 of them we were able to obtain a cognitive profile around the time of discharge from hospital, with 37 of them experiencing cognitive deficits, ranging from mild to severe. Memory, verbal fluency and cognitive flexibility were the areas more frequently impaired. The patients we were able to assess did not differ for age, cerebral performance category score and time to return of spontaneous circulation from those we were unable to assess. Cognitive deficits were not associated with duration of "no/low blood flow" during cardiac arrest or with age. Our results suggest that cognitive deficits in the immediate aftermath of out-of-hospital cardiac arrest are common; however, these may be missed due to lack of systematic assessment and use of poorly sensitive cognitive tests.

Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial.

BACKGROUND: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. METHODS: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4-6 on modified Rankin scale). RESULTS: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84-1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80-1.26). CONCLUSIONS: Using a hospital's average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.

Prognostic indices in diffuse large B-cell lymphoma in the rituximab era: an analysis of the UK National Cancer Research Institute R-CHOP 14 versus 21 phase 3 trial.

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline ß2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.

Effects of stent postdilatation during primary PCI for STEMI: Insights from coronary physiology and optical coherence tomography.

OBJECTIVES: This study aimed to assess the impact of stent optimization by NC-balloon postdilatation (PD) during primary-PCI for STEMI with the use of coronary physiology and intracoronary imaging. METHODS: This was a prospective observational study (ClinicalTrials.gov:NCT02788396). Optical coherence tomography (OCT) and physiological measurements were performed immediately before and after PD with the operators blinded to all measurements. The index of microcirculatory resistance (IMR), coronary flow reserve (CFR) and fractional flow reserve (FFR) were measured. OCT analysis was performed for assessment of stent expansion, malapposition, in-stent plaque-thrombus prolapse (PTP) and stent-edge dissections (SED). The change in IMR before and after PD as a measure of microvascular injury was the primary objective of the study. RESULTS: Thirty-two STEMI patients undergoing primary-PCI had physiological measurements before and after PD. All patients received second-generation DES (diameter 3.1 ± 0.5 mm, length 29.9 ± 10.7 mm) and postdilatation with NC-balloons (diameter 3.6 ± 0.6 mm, inflation pressure 19.3 ± 2.0 atm). IMR (44.9 ± 25.6 vs. 48.8 ± 34.2, p = 0.26) and CFR (1.60 ± 0.89 vs. 1.58 ± 0.71, p = 0.87) did not change, while FFR increased after PD (0.91 ± 0.08 vs. 0.93 ± 0.06, p = 0.037). At an individual patient level, IMR increased in half of the cases. PD improved significantly absolute and relative stent expansion, reduced malapposition, and increased PTP. There was no difference in clinically relevant SED. CONCLUSION: In this exploratory, hypothesis-generating study, postdilatation during primary-PCI for STEMI improved stent expansion, apposition and post-PCI FFR, without a significant effect on coronary microcirculation overall. Nevertheless, IMR increased in a group of patients and larger studies are warranted to explore predictors of microcirculatory response to postdilatation.

The impact of endoscopic transsphenoidal pituitary adenoma surgery on endocrine function: a single-centre study.

INTRODUCTION: The outcome for pituitary endocrine function following endoscopic transsphenoidal surgery remains unclear. This study aims to evaluate endocrine outcomes following endoscopic surgery in order to provide a benchmark to assist in the counselling of patients perioperatively. METHODS: A prospectively held pituitary database was retrospectively analysed for all adult pituitary adenoma patients undergoing endoscopic surgery from May 2011 to May 2017. All operations were performed by a single neurosurgeon at a regional centre for pituitary surgery. Functioning and non-functioning adenomas were included. Hormonal status was assessed at most recent follow-up. RESULTS: One hundred forty-five patients (69 M, 76 F) were included in the study with a median age of 52 years. Median follow-up was 52 months. Eighty-eight patients (61%) were not taking any hormone replacement medications, whilst 57 patients (39%) required hormone replacement therapy (HRT) preoperatively. Preoperatively, 29 patients (20%) had hypothalamo-pituitary-adrenal (HPA) axis dysfunction, 39 patients (27%) had thyroid axis dysfunction, 11 males (16%) and 7 females (9%) had gonadal axis dysfunction, and one patient had preoperative diabetes insipidus. Postoperatively, 26 patients (18%) had a new deficiency in pituitary function, whilst 6 patients (11%) were able to cease HRT. Nineteen patients (13%) had new HPA axis deterioration, 12 (8%) had new thyroid axis dysfunction, 8 males (11%) and 4 females (5%) had gonadal axis deterioration, and 6 patients (4%) had new diabetes insipidus (DI). CONCLUSIONS: The ability to restore pituitary function following endoscopic surgery remains limited, whilst new deficits still occur. It is essential that patients are counselled accordingly as hormonal replacement therapy can have a significant impact on quality of life. Larger longer-term collaborative studies of endocrine outcome in endoscopic pituitary surgery are needed.

Evaluation of a novel endotracheal tube suctioning system incorporating an inflatable sweeper.

INTRODUCTION: Accumulation of secretions in an endotracheal tube can increase the resistance to flow resulting in an increased patient work of breathing when the patient is interacting with the ventilator. Retained secretions can also serve as an infection risk. Standard suction catheters are limited in their ability to keep the lumen of the endotracheal tube clear. A novel closed-suction catheter has been introduced that incorporates a balloon at its distal end that, when inflated, physically scrapes secretions out of the endotracheal tube (CleanSweep catheter (CSC), Teleflex, Morrisville NC). We hypothesized that the CSC would be more efficient at removing secretions from inside the endotracheal tube than a standard suction catheter (SSC). METHODS: We performed a bench study examining resistive pressures across different sizes of endotracheal tubes when cleaned by the CSC as compared with an SSC. This study was followed by a prospective crossover study again comparing the CSC with an SSC in intubated intensive care unit patients receiving mechanical ventilation and requiring frequent suctioning. RESULTS: For the bench study the CSC was significantly better in reducing airway resistive pressures (P < 0.001). In the prospective crossover study the CSC over 2 h also removed significantly more secretions than the SSC (P < 0.05). CONCLUSION: Both our bench and crossover clinical study demonstrated improved clearance of secretions with the CSC vs an SSC. Further research is needed to ascertain the clinical outcome benefits of enhanced secretion removal.

Dobutamine Stress Echocardiography Ischemia as a Predictor of the Placebo-Controlled Efficacy of Percutaneous Coronary Intervention in Stable Coronary Artery Disease: The Stress Echocardiography-Stratified Analysis of ORBITA.

BACKGROUND: Dobutamine stress echocardiography is widely used to test for ischemia in patients with stable coronary artery disease. In this analysis, we studied the ability of the prerandomization stress echocardiography score to predict the placebo-controlled efficacy of percutaneous coronary intervention (PCI) within the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina). METHODS: One hundred eighty-three patients underwent dobutamine stress echocardiography before randomization. The stress echocardiography score is broadly the number of segments abnormal at peak stress, with akinetic segments counting double and dyskinetic segments counting triple. The ability of prerandomization stress echocardiography to predict the placebo-controlled effect of PCI on response variables was tested by using regression modeling. RESULTS: At prerandomization, the stress echocardiography score was 1.56±1.77 in the PCI arm (n=98) and 1.61±1.73 in the placebo arm (n=85). There was a detectable interaction between prerandomization stress echocardiography score and the effect of PCI on angina frequency score with a larger placebo-controlled effect in patients with the highest stress echocardiography score (Pinteraction=0.031). With our sample size, we were unable to detect an interaction between stress echocardiography score and any other patient-reported response variables: freedom from angina (Pinteraction=0.116), physical limitation (Pinteraction=0.461), quality of life (Pinteraction=0.689), EuroQOL 5 quality-of-life score (Pinteraction=0.789), or between stress echocardiography score and physician-assessed Canadian Cardiovascular Society angina class (Pinteraction=0.693), and treadmill exercise time (Pinteraction=0.426). CONCLUSIONS: The degree of ischemia assessed by dobutamine stress echocardiography predicts the placebo-controlled efficacy of PCI on patient-reported angina frequency. The greater the downstream stress echocardiography abnormality caused by a stenosis, the greater the reduction in symptoms from PCI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.