Causes and outcomes of emergency presentation of rectal cancer

Emergency presentation of rectal cancer carries a relatively poor prognosis, but the roles and interactions of causative factors remain unclear. We describe an innovative statistical approach which distinguishes between direct and indirect effects of a number of contextual, patient and tumour factors on emergency presentation and outcome of rectal cancer. All patients diagnosed with rectal cancer in Ireland 2004–2008 were included. Registry information, linked to hospital discharge data, provided data on patient demographics, comorbidity and health insurance; population density and deprivation of area of residence; tumour type, site, grade and stage; treatment type and optimality; and emergency presentation and hospital caseload. Data were modelled using a structural equation model with a discrete‐time survival outcome, allowing us to estimate direct and mediated effects of the above factors on hazard, and their inter‐relationships. Two thousand seven hundred and fifty patients were included in the analysis. Around 12% had emergency presentations, which increased hazard by 80%. Affluence, private patient status and being married reduced hazard indirectly by reducing emergency presentation. Older patients had more emergency presentations, while married patients, private patients or those living in less deprived areas had fewer than expected. Patients presenting as an emergency were less likely to receive optimal treatment or to have this in a high caseload hospital. Apart from stage, emergency admission was the strongest determinant of poor survival. The factors contributing to emergency admission in this study are similar to those associated with diagnostic delay. The socio‐economic gradient found suggests that patient education and earlier access to endoscopic investigation for public patients could reduce emergency presentation.     

Microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma: A systematic review and meta-analysis

Purpose: Radiofrequency ablation (RFA) and microwave ablation (MWA) are the two main percutaneous techniques for the treatment of unresectable hepatocellular carcinoma (HCC). However, to date, studies comparing the two therapies have provided discordant results. The aim of this meta-analysis is to evaluate the efficacy and safety of the two treatments for HCC patients. Materials and methods: A computerised bibliographic search was performed on PubMed/MEDLINE, Embase, Google Scholar and Cochrane library databases. The rates of complete response (CR), local recurrence (LRR), 3-year survival (SR) and major complications were compared between the two treatment groups by using the Mantel-Haenszel test in cases of low heterogeneity or the DerSimonian and Laird test in cases of high heterogeneity. Sources of heterogeneity were investigated using subgroup analyses. In order to confirm our finding, sensitivity analysis was performed restricting the analysis to high-quality studies. Results: One randomised controlled trial (RCT) and six retrospective studies with 774 patients were included in the meta-analysis. A non-significant trend of higher CR rates in the patients treated with MWA was found (odds ratio (OR)?=?1.12, 95% confidence interval (CI) 0.67–1.88, p?=?0.67]. Overall LRR was similar between the two treatment groups (OR 1.01, 95% CI 0.53–1.87, p?=?0.98) but MWA outperformed RFA in cases of larger nodules (OR 0.46, 95% CI 0.24–0.89, p?=?0.02). 3-year SR was higher after RFA without statistically significant difference (OR 0.95, 95% CI 0.58–1.57, p?=?0.85). Major complications were more frequent, although not significantly, in MWA patients (OR 1.63, 95% CI 0.88–3.03, p?=?0.12). Conclusions: Our results indicate a similar efficacy between the two percutaneous techniques with an apparent superiority of MWA in larger neoplasms.     

Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists

In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for human immunodeficiency virus (HIV). A large number of small-molecule CCR5 antagonists have been reported that show potent activities in blocking chemokine function and HIV entry. To facilitate the design and development of next generation CCR5 antagonists, docking models for major classes of CCR5 antagonists were created by using site-directed mutagenesis and CCR5 homology modeling. Five clinical candidates: maraviroc, vicriviroc, aplaviroc, TAK-779, and TAK-220 were used to establish the nature of the binding pocket in CCR5. Although the five antagonists are very different in structure, shape, and electrostatic potential, they were able to fit in the same binding pocket formed by the transmembrane (TM) domains of CCR5. It is noteworthy that each antagonist displayed a unique interaction profile with amino acids lining the pocket. Except for TAK-779, all antagonists showed strong interaction with Glu283 in TM 7 via their central basic nitrogen. The fully mapped binding pocket of CCR5 is being used for structure-based design and lead optimization of novel anti-HIV CCR5 inhibitors with improved potency and better resistance profile.     

Design, synthesis, and structure-activity relationship studies of 4-quinolinyl- and 9-acrydinylhydrazones as potent antimalarial agents

Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed.     

Characterization of soluble glycoprotein D-mediated herpes simplex virus type 1 infection

Herpes simplex virus type 1 (HSV-1) entry into permissive cells involves attachment to cell-surface glycosaminoglycans (GAGs) and fusion of the virus envelope with the cell membrane triggered by the binding of glycoprotein D (gD) to cognate receptors. In this study, we characterized the observation that soluble forms of the gD ectodomain (sgD) can mediate entry of gD-deficient HSV-1. We examined the efficiency and receptor specificity of this activity and used sequential incubation protocols to determine the order and stability of the initial interactions required for entry. Surprisingly, virus binding to GAGs did not increase the efficiency of sgD-mediated entry and gD-deficient virus was capable of attaching to GAG-deficient cells in the absence of sgD. These observations suggested a novel binding interaction that may play a role in normal HSV infection.     

Superior Postimplant Dosimetry Achieved Using Dynamic Intraoperative Dosimetry for Permanent Prostate Brachytherapy

PurposeLow-dose-rate brachytherapy is a highly effective treatment modality for prostate carcinoma, but postimplant dosimetry quality is essential and correlated with likelihood of treatment success. Registered ultrasound and fluoroscopy (iRUF) can facilitate real-time intraoperative monitoring and plan adaptation, with the aim of attaining superior dosimetric outcomes. The purpose of this research was to compare clinical postimplant dosimetric results of iRUF-guided brachytherapy against brachytherapy using standard ultrasound-guided intraoperative dosimetry methods.Methods and MaterialsWe analyzed postimplant dosimetry in 292 patients treated with Pd-103 between January 2007 and December 2018. All patients had postimplant dosimetry measured on day 0 to 1 using fused magnetic resonance/computed tomography assessment. Fifty-two patients were treated in 2 prospective clinical trials using iRUF intraoperative dosimetry, including 6 patients in a pilot study and 46 treated in a phase 2 study. Postimplant dosimetry in iRUF-treated patients was compared with dosimetry from 240 patients treated using standard (real-time ultrasound) intraoperative seed tracking.ResultsFor every parameter measuring dose coverage to the prostate, iRUF patients had significantly higher values, irrespective of adjustment for year of treatment. In adjusted analyses, parameters of dose to urethra and rectum were not significantly higher among iRUF-treated patients.ConclusionsUse of iRUF intraoperative dosimetry was associated with improved postimplant dose coverage in prostate, without associated increases in doses to urethra or rectum.     

Is Poor Sleep Quality Associated With Greater Disability in Patients With Multiple Sclerosis?

Poor sleep is a serious burden for patients with multiple sclerosis (MS). The aim of this study is to assess whether the association between sleep quality and disability in MS patients is direct or mediated by depression, pain, and fatigue. We collected data from 152 patients with MS who filled out the Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Inventory and one item of the Short Form-36 regarding pain. The relationship between poor sleep and disability was found to be indirect, mediated by depression (p < 0.05), pain (p < 0.001) and physical fatigue (p < 0.01). Treatment of sleep disturbances may have beneficial effects beyond improving sleep. It may reduce depression, pain, and physical fatigue, which in turn may lessen disability.