Enabling Suzuki-Miyaura coupling of Lewis-basic arylboronic esters with a nonprecious metal catalyst.

The high cost and negative environmental impact of precious metal catalysts has led to increased demand for nonprecious alternatives for widely practiced reactions such as the Suzuki-Miyaura coupling (SMC). Ni-catalyzed versions of this reaction have failed to achieve high reactivity with Lewis-basic arylboron nucleophiles, especially pinacolboron esters. We describe the development of (PPh2Me)2NiCl2 as an inexpensive and air-stable precatalyst that addresses this challenge. Under activation by n-BuMgCl, this complex can catalyze the coupling of synthetically important heteroaryl pinacolborons with heteroaryl halides. Mildly basic conditions (aqueous K3PO4) allow the reaction to tolerate sensitive functional groups that were incompatible with other Ni-SMC methods. Experimental and computational studies suggest that catalyst inhibition by substitution of PPh2Me from Ni(ii) intermediates by Lewis basic reactants and products is disfavored relative to more commonly employed ligands in the Ni-SMC, which allows it to operate efficiently in the presence of Lewis bases such as unhindered pyridines.

Energy-dense, low-volume paediatric oral nutritional supplements improve total nutrient intake and increase growth in paediatric patients requiring nutritional support: results of a randomised controlled pilot trial.

Children with or at risk of faltering growth require nutritional support and are often prescribed oral nutritional supplements (ONS). This randomised controlled trial investigated the effects of energy-dense paediatric ONS (2.4 kcal/ml, 125 ml: cONS) versus 1.5 kcal/ml, 200 ml ONS (sONS) in community-based paediatric patients requiring oral nutritional support. Fifty-one patients (mean age 5.8 years (SD 3)) with faltering growth and/or requiring ONS to meet their nutritional requirements were randomised to cONS (n = 27) or sONS (n = 24) for 28 days. Nutrient intake, growth, ONS compliance and acceptability, appetite and gastro-intestinal tolerance were assessed. Use of the cONS resulted in significantly greater mean total daily energy (+ 531 kcal/day), protein (+ 10.1 g/day) and key micronutrient intakes compared with the sONS group at day 28 and over time, due to high ONS compliance (81% of patients ≥ 75%), maintained intake from diet alone and improved appetite in the cONS group, compared with the sONS group. Although growth increased in both intervention groups, results were significant in the cONS group (weight (p = 0.007), height (p < 0.001) and height z-score (p = 0.006)).Conclusions: This study shows that use of energy-dense (2.4 kcal/ml) low-volume paediatric-specific ONS leads to improved nutrient intakes, growth and appetite in paediatric patients requiring oral nutrition support compared with standard energy density ONS.Trial registration: The trial is registered at clinicaltrials.gov , identification number NCT02419599. What is Known: • Faltering growth is the failure of children to achieve adequate growth at a normal rate for their age and requires nutritional support, including the use of oral nutritional supplements (ONS). • Energy-dense, low-volume ONS have benefits over standard ONS in adults. What is New: • This is the first RCT to investigate the effects of energy-dense, low-volume ONS (2.4 kcal/ml, 125 ml) in children with faltering growth, showing significant improvements in total nutrient intake and increased growth. • Energy-dense, low-volume ONS can play a key role in the management of faltering growth.

Effects of Abdominal Aortic Aneurysm Size on Mid- and Long-term Mortality After Endovascular Aneurysm Repair.

PURPOSE: To investigate the effect of abdominal aortic aneurysm (AAA) size on mid- and long-term survival after endovascular aneurysm repair (EVAR). MATERIALS AND METHODS: Retrospective data were collected from 325 consecutive patients (mean age 69.7 ± 8.5 years; 323 men) who underwent EVAR for intact AAA at a single institution between January 2003 and December 2013. The primary endpoint was death at 3, 5, and 10 years after EVAR. Optimal cutoff points for AAA size and age were determined using receiver operating characteristics (ROC) curves. Time to event analyses (Kaplan-Meier curves and Cox proportional hazard models) were employed to determine any differences in all-cause mortality outcomes between AAA size groups. Cox models were adjusted for age and other comorbidities (hypertension, hyperlipidemia, coronary artery disease, smoking status, symptomatic status, and creatinine); the outcomes are reported as the hazard ratio (HR) with 95% confidence interval (CI). RESULTS: The cohort was dichotomized according to the ROC analysis, which defined an optimal cutoff point of 5.6 cm for AAA size and >70 years for age. The mean follow-up period post EVAR was 45.5±29.2 months. In total, 134 (41.2%) patients died during the 10-year follow-up. Thirty-day mortality was 1.1% (2/184) in the patients with AAA <5.6 cm and 2.1% (3/141) in patients with AAA ≥5.6 cm (p=0.45). All-cause mortality was not significantly affected by comorbidities. However, AAA size ≥5.6 cm was associated with increased 3-year mortality risk (HR 1.59, 95% CI 1.001 to 2.52, p<0.049) but not 5-year (HR 1.44, 95% CI 0.98 to 2.10, p=0.062) or 10-year mortality (HR 1.28, 95% CI 0.91 to 1.80, p=0.149). After adjusting for comorbidities, AAA size ≥5.6 cm was no longer significantly associated with morality at any time point. Using a larger size cutoff (AAA size ≥6.0 cm) resulted in improved statistical significance in the unadjusted model. In the adjusted Cox model, AAA size ≥6.0 cm was significantly associated with increased risk of mortality at 3 years (HR 1.67, 95% CI 1.01 to 2.77, p<0.047), but not at longer time points. CONCLUSION: Our study demonstrates that midterm survival after EVAR is significantly and independently associated with AAA size even after correcting for comorbidities. However, in the long term, preoperative AAA size is not an independent predictor of mortality.

Rate of Secondary Intervention After Open Versus Endovascular Abdominal Aortic Aneurysm Repair.

BACKGROUND: Although long-term durability and improved perioperative outcome of endovascular abdominal aortic aneurysm (AAA) repair has been demonstrated, some studies have suggested an increased rate of secondary interventions compared with open AAA repair. More recent data suggest that rates between the two modalities may be similar. We investigated the rate of secondary intervention in patients undergoing endovascular aortic aneurysm repair (EVAR) or open AAA repair for intact AAA and the effect of secondary intervention on long-term mortality in these two groups of patients. METHODS: A retrospective, single-institution review was conducted between January 2003 and December 2012. Secondary intervention was defined as any intervention within 30 d of the procedure or an AAA repair-related procedure after 30 d, which included repair of endoleaks and incisional hernia repair. Group differences in demographic and baseline characteristics were examined using Cochran-Mantel-Haenszel and Wilcoxon rank sum tests for categorical and continuous variables, respectively. RESULTS: A total of 342 patients underwent operative repair of intact AAA. Two hundred seventy four patients underwent EVAR and 68 patients underwent open AAA repair. The mean age overall was 68.6 y and was not significantly different between the two repair groups. The overall rate of secondary intervention was significantly lower in the EVAR group compared with the open AAA repair group (11% versus 27%, P = 0.001). In the EVAR group, 30 patients underwent 37 secondary interventions. In the open repair group, 18 patients underwent 20 reinterventions. The most common secondary intervention was repair of type 2 endoleak (n = 13, 4.7% of patients) after EVAR and incisional hernia repair (n = 4, 5.9% of patients) after open AAA repair. Most secondary interventions (15/20) after open AAA repair occurred within 30 d, whereas most secondary intervention (33/37) after EVAR occurred after 30 d. Comparison of late (>30 d) reintervention between the two groups revealed a significantly lower rate of secondary intervention after open AAA repair (27.8% of all reinterventions after open versus 86.7% of all reinterventions after EVAR, P < 0.001). The overall 10-y mortality rate was 39.1%, and not statistically different between the two repair groups. Estimated survival analysis demonstrated no significant effect of secondary intervention on mortality after EVAR (logrank P = 0.45). Secondary intervention after open repair did not significantly affect long-term survival (logrank P = 0.05). CONCLUSIONS: This study highlights the dramatic change in practice pattern in AAA repair over time. In this study, patients treated with EVAR had a significantly lower overall rate of secondary intervention compared with patients treated with open AAA repair. This was likely secondary to increased perioperative morbidity and mortality and a bias toward more complex patients in the open repair group. In the long term, however, there were significantly fewer reinterventions after open AAA repair. Secondary interventions did not affect long-term survival after EVAR.

Suicide among Young People and Adults in Ireland: Method Characteristics, Toxicological Analysis and Substance Abuse Histories Compared.

OBJECTIVE: Information on factors associated with suicide among young individuals in Ireland is limited. The aim of this study was to identify socio-demographic characteristics and circumstances of death associated with age among individuals who died by suicide. METHODS: The study examined 121 consecutive suicides (2007-2012) occurring in the southern eastern part of Ireland (Cork city and county). Data were obtained from coroners, family informants, and health care professionals. A comparison was made between 15-24-year-old and 25-34-year-old individuals. Socio-demographic characteristics of the deceased, methods of suicide, history of alcohol and drug abuse, and findings from toxicological analysis of blood and urine samples taken at post mortem were included. Pearson's χ2 tests and binary logistic regression analysis were performed. RESULTS: Alcohol and/or drugs were detected through toxicological analysis for the majority of the total sample (79.5%), which did not differentiate between 15-24-year-old and 25-34-year-old individuals (74.1% and 86.2% respectively). Compared to 25-34-year-old individuals, 15-24-year-old individuals were more likely to engage in suicide by hanging (88.5%). Younger individuals were less likely to die by intentional drug overdose and carbon monoxide poisoning compared to older individuals. Younger individuals who died between Saturday and Monday were more likely to have had alcohol before dying. Substance abuse histories were similar in the two age groups. CONCLUSION: Based on this research it is recommended that strategies to reduce substance abuse be applied among 25-34-year-old individuals at risk of suicide. The wide use of hanging in young people should be taken into consideration for future means restriction strategies.

A microtitre plate assay for measuring glycosidase activity.

Glycosidases perform a wide range of functions in physiology and pathology, and are potential targets for the treatment of diseases such as influenza, cancer, AIDS and diabetes. This paper reports a convenient discontinuous colourimetric assay for the measurement of glycosidase activity. The assay utilises 4-nitrophenyl- substrates and quantities of product are determined by measuring absorbance at 405 nm. This assay is performed in a 96 well microtitre plate and has been used to characterise the properties of seven different glycosidases from bacteria, yeast and higher eukaryotes and their kinetic parameters determined. Assays in the presence of known inhibitors showed that inhibition modes can be determined, and IC(50) and K(i) values calculated. This assay appears to be of widely applicable and of general utility for the measurement of glycosidase activity and the evaluation of inhibitors.