Post-CCSD(T) corrections to bond distances and vibrational frequencies: the power of Λ\Lambda

The importance of post-CCSD(T) corrections as high as CCSDTQ56 for ground-state spectroscopic constants ($D_e$, $\omega_e$, $\omega_ex_e$, and $\alpha_e$) has been surveyed for a sample of two dozen mostly heavy-atom diatomics spanning a broad range of static correlation strength. While CCSD(T) is known to be an unusually felicitous `Pauling point' between accuracy and computational cost, performance leaves something to be desired for molecules with strong static correlation. We find CCSDT(Q)$_\Lambda$ to be the next `sweet spot' up, of comparable or superior quality to the much more expensive CCSDTQ. A similar comparison applies to CCSDTQ(5)$_\Lambda$ vs. CCSDTQ5, while CCSDTQ5(6)$_\Lambda$ is essentially indistinguishable from CCSDTQ56. A composite of CCSD(T)-X2C/ACV5Z-X2C with [CCSDT(Q)$_\Lambda$ -- CCSD(T)]/cc-pVTZ or even cc-pVDZ basis sets appears highly effective for computational vibrational spectroscopy. Unlike CCSDT(Q) which breaks down for the ozone vibrational frequencies, CCSDT(Q)$_\Lambda$ handles them gracefully.Comment: Mol. Phys., in press [Timothy J. Lee memorial issue

Management of coronary artery fistulae Patient selection and results of transcatheter closure

AbstractObjectivesWe report short-term findings in 33 patients after transcatheter closure (TCC) of coronary artery fistulae (CAF) and compare our results with those reported in the recent transcatheter and surgical literature.BackgroundTranscatheter closure of CAF has been advocated as a minimally invasive alternative to surgery.MethodsWe reviewed all patients presenting with significant CAF between January 1988 and August 2000. Those with additional complex cardiac disease requiring surgical management were excluded.ResultsOf 39 patients considered for TCC, occlusion devices were placed in 33 patients (85%) at 35 procedures and included coils in 28, umbrella devices in 6 and a Grifka vascular occlusion device in 1. Post-deployment angiograms demonstrated complete occlusion in 19, trace in 11, or small residual flow in 5. Follow-up echocardiograms (median, 2.8 years) in 27 patients showed no flow in 22 or small residual flow in 5. Of the 6 patients without follow-up imaging, immediate post-deployment angiograms showed complete occlusion in 5 or small residual flow in 1. Thus, complete occlusion was accomplished in 27 patients (82%). Early complications included transient ST-T wave changes in 5, transient arrhythmias in 4 and single instances of distal coronary artery spasm, fistula dissection and unretrieved coil embolization. There were no deaths or long-term morbidity. Device placement was not attempted in 6 patients (15%), because of multiple fistula drainage sites in 4, extreme vessel tortuosity in 1 and an intracardiac hemangioma in 1.ConclusionsA comparison of our results with those in the recent transcatheter and surgical literature shows similar early effectiveness, morbidity and mortality. From data available, TCC of CAF is an acceptable alternative to surgery in most patients

Wilms’ tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN)

Background: In the UK almost 7000 people are diagnosed with leukaemia each year, but despite continuing advances in diagnosis and treatment with new drugs, such as the tyrosine kinase inhibitors, the majority of these patients will eventually die from their disease. Until quite recently, the only treatment to offer the possibility of long-term disease-free survival was allogeneic stem cell transplantation. However, this carries a substantial risk of mortality and is available to only a minority of patients.Objectives: The aim of the study was to test the hypothesis that molecular and clinical responses, induced by T lymphocytes (T cells), can be predicted by increases in the number of CD8+ (cluster of differentiation 8-positive) T cells specific for the vaccine-encoded T-cell epitopes. This project also aimed to build on the established programme of deoxyribonucleic acid (DNA) fusion-gene vaccination delivered by intramuscular injection, exploiting a unique experience with electroporation, to induce durable immune responses with the aim of controlling disease by precision attack of the tumour by CD8+ T cells.Method: A non-randomised, open-label, single-dose-level Phase II clinical trial in two patient groups [chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML)] on stable doses of imatinib. Human leucocyte antigen A2-positive (HLA A2+) patients were vaccinated with two DNA vaccines: (1) p.DOM–WT1-37 (epitope sequence: VLDFAPPGA); and (2) p.DOM–WT1-126 (epitope sequence: RMFPNAPYL). The HLA A2-negative patients formed an unvaccinated control group. The sample size for the HLA A2+ group was originally determined following Simon’s optimal Phase II trial design (Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10). This was changed to A’Hern’s single-stage design during the course of the trial (A’Hern RP. Sample size tables for single-stage phase II designs. Stat Med 2001;20:859–66), which was endorsed by the trial’s independent oversight committees.Results: The study included 12 patients with CML who were vaccinated and nine patients with CML who were unvaccinated as the control group. Both the vaccines and the electroporation were safe, with no new or unexpected toxicities. The evaluation adverse events of special interest (heart, bone marrow, renal) did not reveal safety concerns. Two BCR–ABL (breakpoint cluster region–Abelson murine leukaemia viral oncogene homolog 1) responses were observed, both of which were defined as a major response, with one in each group. Two Wilms’ tumour antigen 1 (WT1) molecular responses were observed in the vaccinated group and one was observed in the control group. At an immunological level, the vaccine performed as expected.Conclusions: The study met its primary decision-making target with one major molecular response in BCR–ABL transcript levels. Overall, the data showed, in this clinical setting, the immunogenicity and safety of the vaccine.Limitations: The study did not complete recruitment and there were multiple hurdles that contributed to this failure. This is disappointing given the robust induction immune responses against WT1 T-cell responses in 7 out of 10 evaluable patients.Future work: Evaluation of the p.DOM–WT1 vaccines in AML remains attractive clinically, but it is unlikely to be feasible at this time. Combination of the DNA vaccine approach with strategies to expand T-cell responses with immunomodulatory antibodies is in development.Funding details: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership, and Bloodwise

Use of non-technical skills can predict medical student performance in acute care simulated scenarios

Background Though the importance of physician non-technical (NT) skills for safe patient care is recognized, NT skills of medical students, our future physicians, has received little attention. This study aims to investigate the relationship of medical student NT skills and clinical performance during acute care team simulation (ACTS). Methods Forty-one medical students participated in ACTS. A nurse confederate facilitated and evaluated clinical performance. Two raters assessed participants’ NT skills using an adapted NT assessment tool and overall NT skills score was calculated. Regressions predicting clinical performance using NT constructs were conducted. Results Overall NT skills score significantly predicted students’ clinical performance (r2 = 0.178, p = 0.006). Four of the five individual NT constructs also significantly predicted performance: communication (r2 = 0.120, p = 0.027), situation awareness (r2 = 0.323, p < 0.001), leadership (r2 = 0.133, p = 0.019), and decision making (r2 = 0.163, p = 0.009). Conclusions Medical student NT skills can predict clinical performance during ACTS. NT skills assessments can be used for targeted education for better feedback to students

Assessing Anti-HCMV Cell Mediated Immune Responses in Transplant Recipients and Healthy Controls Using a Novel Functional Assay

HCMV infection, reinfection or reactivation occurs in 60% of untreated solid organ transplant (SOT) recipients. Current clinical approaches to HCMV management include pre-emptive and prophylactic antiviral treatment strategies. The introduction of immune monitoring to better stratify patients at risk of viraemia and HCMV mediated disease could improve clinical management. Current approaches quantify T cell IFNγ responses specific for predominantly IE and pp65 proteins ex vivo, as a proxy for functional control of HCMV in vivo. However, these approaches have only a limited predictive ability. We measured the IFNγ T cell responses to an expanded panel of overlapping peptide pools specific for immunodominant HCMV proteins IE1/2, pp65, pp71, gB, UL144, and US3 in a cohort of D+R– kidney transplant recipients in a longitudinal analysis. Even with this increased antigen diversity, the results show that while all patients had detectable T cell responses, this did not correlate with control of HCMV replication in some. We wished to develop an assay that could directly measure anti-HCMV cell-mediated immunity. We evaluated three approaches, stimulation of PBMC with (i) whole HCMV lysate or (ii) a defined panel of immunodominant HCMV peptides, or (iii) fully autologous infected cells co-cultured with PBMC or isolated CD8+ T cells or NK cells. Stimulation with HCMV lysate often generated non-specific antiviral responses while stimulation with immunodominant HCMV peptide pools produced responses which were not necessarily antiviral despite strong IFNγ production. We demonstrated that IFNγ was only a minor component of secreted antiviral activity. Finally, we used an antiviral assay system to measure the effect of whole PBMC, and isolated CD8+ T cells and NK cells to control HCMV in infected autologous dermal fibroblasts. The results show that both PBMC and especially CD8+ T cells from HCMV seropositive donors have highly specific antiviral activity against HCMV. In addition, we were able to show that NK cells were also antiviral, but the level of this control was highly variable between donors and not dependant on HCMV seropositivity. Using this approach, we show that non-viraemic D+R+ SOT recipients had significant and specific antiviral activity against HCMV

Prednisolone or pentoxifylline for alcoholic hepatitis

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists.METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline.RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002).CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).</p

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REST Regulates Distinct Transcriptional Networks in Embryonic and Neural Stem Cells

The maintenance of pluripotency and specification of cellular lineages during embryonic development are controlled by transcriptional regulatory networks, which coordinate specific sets of genes through both activation and repression. The transcriptional repressor RE1-silencing transcription factor (REST) plays important but distinct regulatory roles in embryonic (ESC) and neural (NSC) stem cells. We investigated how these distinct biological roles are effected at a genomic level. We present integrated, comparative genome- and transcriptome-wide analyses of transcriptional networks governed by REST in mouse ESC and NSC. The REST recruitment profile has dual components: a developmentally independent core that is common to ESC, NSC, and differentiated cells; and a large, ESC-specific set of target genes. In ESC, the REST regulatory network is highly integrated into that of pluripotency factors Oct4-Sox2-Nanog. We propose that an extensive, pluripotency-specific recruitment profile lends REST a key role in the maintenance of the ESC phenotype