Selective Fluorination Strategies

There is a great interest in the synthesis of fluorinated aromatic and heterocyclic compounds, which have a range of applications in the pharmaceutical industry. Many common routes to these compounds, however, are low yielding and or/expensive. This thesis is concerned with novel methods for the synthesis of fluoro-aromatics and fluoro-pyrazoles using conventional fluorinating agents, such as Selectfluor™, as well as using elemental fluorine and the flow reactor technology developed in Durham. Firstly, elemental fluorine was used to fluorinate a range of aromatics containing electron-donating substituents, using both batch and flow methods. These methods often afforded the desired compound but with little selectivity and low conversion from the starting materials. Following on from this, ipso fluoro-deboronation techniques using Selectfluor™, were employed to improve the selectivity and yields of the reaction and, in many cases, the desired mono-fluorinated arylfluoride could be accessed in good yield. A range of aryl boronic acid derivatives were explored as the substrate and the results showed that trifluoroborate salts were the most useful substrate. The ipso fluoro-deboronation of heterocyclic boronic acid derivatives was also investigated and showed some promising results. The synthesis of 4-fluoropyrazoles was investigated using three methods. Initially, a two-step process, where the 2-fluoro-1,3-diketone was synthesised and isolated and subsequently reacted with hydrazine, was employed. This allowed a range of 4-fluoropyrazoles to be obtained in high yield and purity. Secondly, a telescoped two-step continuous flow process was employed which did not require isolation of the intermediate 2-fluoro-1,3-diketone. This reaction gave good yields and required less solvent with significantly lower reaction times than the two-step process. Thirdly, C4 mono- and di-fluorination of 3,5-disubstituted pyrazoles was investigated using Selectfluor™ and elemental fluorine. This method gave low conversion from the starting material (50–60 %) but the desired 4-fluoropyrazoles and novel 4,4-difluoropyrazoles could be isolated

What's the Risk? Older Women Report Fewer Symptoms for Suspected Acute Coronary Syndrome than Younger Women.

The purpose of the study was to determine whether older (≥65 years) and younger (<65 years) women presenting to the emergency department (ED) with symptoms suggestive of acute coronary syndrome (ACS) varied on risk factors, comorbid conditions, functional status, and symptoms that have implications for emergent cardiac care. Women admitted to five EDs were enrolled. The ACS Symptom Checklist was used to measure symptoms. Comorbid conditions and functional status were measured with the Charlson Comorbidity Index and Duke Activity Status Index. Logistic regression models were used to evaluate symptom differences in older and younger women adjusting for ACS diagnosis, functional status, body mass index (BMI), and comorbid conditions. Analyses were stratified by age, and interaction of symptom by age was tested. Four hundred women were enrolled. Mean age was 61.3 years (range 21-98). Older women (n = 163) were more likely to have hypertension, hypercholesterolemia, never smoked, lower BMI, more comorbid conditions, and lower functional status. Younger women (n = 237) were more likely to be members of minority groups, be college-educated, and have a non-ACS discharge diagnosis. Younger women had higher odds of experiencing chest discomfort, chest pain, chest pressure, shortness of breath, nausea, sweating, and palpitations. Lack of chest symptoms and shortness of breath (key symptoms triggering a decision to seek emergency care) may cause older women to delay seeking treatment, placing them at risk for poorer outcomes. Younger African American women may require more comprehensive risk reduction strategies and symptom management

A Qualitative Study of Workplace Stress and Coping in Secondary Teachers in Ireland

Teacher stress has received scant attention in Ireland. This study examines teachers’ perceptions of their daily stresses and how they attempt to cope with such situations. Interviews were conducted with fifteen secondary teachers from a variety of school types in eastern Ireland. The teachers showed great concern for their students, with some being prepared to ignore school guidelines in order to deal with their pupils’ needs. Several particularly stressful factors were identified, including the maintenance of boundaries (especially when dealing with students with personal problems), dealing with disruptive student behaviour, and the heavy workload. These stresses closely mirrored those described in international literature. Levels of stress and methods of dealing with stress varied widely among the sample, with primary support coming from their colleagues. One strong finding was the lack of suitable training and preparation felt by the participants, particularly in methods of dealing with sensitive and stressful situations in pupils, and in appropriate means of reaction to student misbehaviour. It is recommended that teacher-training courses include explicit training in dealing with such situations

Las actitudes como factor clave en la inclusión universitaria

Las actitudes pueden facilitar o dificultar el proceso inclusivo en la educación superior. Los objetivos del presente estudio son determinar las actitudes del alumnado y docentes hacia la discapacidad y conocer las variables que influyen en dichas actitudes. Se ha realizado un estudio descriptivo de prevalencia realizado en la Universidade da Coruña (UDC) con docentes (n= 121) y alumnos/as (n= 345) utilizando un cuestionario validado, autoadministrado y anonimizado (CUNIDIS). Se realizó un análisis descriptivo y un ANOVA para determinar las variables asociadas a las diferentes actitudes. Los resultados obtenidos manifiestan que los participantes creen preciso adaptar los materiales utilizados en las aulas, pero no los criterios de evaluación y cualificación. Sin embargo, indican que estas adaptaciones no se llevan a cabo realmente. La mayoría de los docentes indicaron que no están suficientemente formados para dar respuesta a las necesidades de los estudiantes con discapacidad. Se considera, por lo tanto, que los estudiantes y docentes de la UDC presentan, de manera general, unas actitudes favorables hacia la inclusión de los estudiantes con discapacidad

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

BackgroundPatients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database.MethodsAn IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA.ResultsMedian survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0).ConclusionsBrain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com

Canine Prostate Cancer Cell Line (Probasco) Produces Osteoblastic Metastases In Vivo

In 2012, over 240,000 men were diagnosed with prostate cancer and over 28,000 died from the disease. Animal models of prostate cancer are vital to understanding its pathogenesis and developing therapeutics. Canine models in particular are useful due to their similarities to late-stage, castration-resistant human disease with osteoblastic bone metastases. This study established and characterized a novel canine prostate cancer cell line that will contribute to the understanding of prostate cancer pathogenesis