Factors in Removing Job Restrictions for Cancer Survivors in the United Kingdom Royal Air Force.

Purpose To identify personal, occupational and clinical factors associated with the lifting of restrictions on duties among Royal Air Force (RAF) personnel who have returned to work after surviving primary cancer treatment. Methods A retrospective cohort of 205 RAF personnel aged 18-58 with cancer diagnosed between 2001 and 2011 was followed-up until May 2012. Personal, occupational, and clinical information was extracted from occupational health and primary care records. Predictors of the lifting of (a) employment restrictions on UK duties at 18 months after diagnosis and (b) the lifting of all deployment restrictions at the end of the study were analysed using logistic and Cox regression models. Results At 18 months, 62% of the cancer survivors had restrictions on their UK duties lifted. The positive independent predictors of unrestricted UK duties are testicular cancer (OR 5.34; 95% CI 1.21-23.6) and no treatment being required (16.8; 1.11-255.2). The lifting of all employment restrictions and return to full deployability was achieved by 41% of the participants (median time 2.1 years), with testicular cancer (HR 2.69; 95% CI 1.38-5.26) and age at diagnosis (1.05; 1.01-1.09) being the positive independent predictors of faster lifting of all restrictions. Conclusion Diagnostic group, prognosis and type of treatment are not the only predictor of employment outcome after cancer. Patient-centred factors such as smoking, age, fatigue, job status, job type and length of employment are also important predictors of return to pre-morbid job function in cancer survivors in the RAF.

Plate-based diversity subset screening generation 2: an improved paradigm for high-throughput screening of large compound files.

High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer.

Predictors of return to work in cancer survivors in the Royal Air Force.

PURPOSE: Return to work (RTW) is beneficial for cancer survivors, employers and society. However, little is known about predictors of RTW in the military environment. METHODS: A cohort of 194 Royal Air Force (RAF) personnel aged 18-58 who survived primary cancer treatment between 2001 and 2011 were followed up for 18 months. Information was obtained from occupational health and primary care records. Personal, occupational and clinical predictors of RTW were identified by Cox proportional hazards regression. RESULTS: The median sickness absence before RTW was 107 days. Six months after diagnosis 54 % of participants had RTW, and reached 80 % by 12 months. Time taken to RTW was predicted by age at diagnosis, rank, trade group, pre-diagnosis sickness absence, site of cancer, treatment modality, and prognosis. RTW at 18 months were predicted by higher rank (HR = 2.31; 95 % CI 1.46-3.65), and having melanoma (9.75; 4.97-19.13). Those receiving chemotherapy were significantly less likely to have RTW compared to other treatment modalities (0.18; 0.10-0.32). CONCLUSIONS: Rank, cancer diagnostic group, and treatment modality are the most important predictors of RTW in cancer survivors in the RAF. These predictors can be used to inform rehabilitation programmes and decisions on RTW.

United Kingdom military aeromedical evacuation in the post-9/11 era.

BACKGROUND: Recent UK military operations in support of the fight against terrorism have resulted in UK military casualties. Movement of these casualties through the military medical chain requires a highly sophisticated aeromedical evacuation capability with worldwide reach. Recognition of the determinants of evacuation allows development to ensure optimal future configurations of military aeromedical evacuation services. METHODS: The database recording aeromedical evacuations undertaken by the Royal Air Force was searched to provide demographic and clinical data for evacuations between 1 April 2003 and 31 March 2010. Diagnoses leading to evacuation were categorized according to International Classification of Diseases codes. RESULTS: There were 21,477 medical evacuations undertaken. Analysis demonstrated 85.9% were for men and 86.5% were for military personnel, of whom 72.0% were in the army. The most common reasons for evacuation in military patients were musculoskeletal/connective tissue disorders (N = 9192; 50.0%), trauma (N = 1303; 7.1%), and mental health disorders (N = 1151; 6.3%). The most common reasons for evacuation in nonmilitary patients were musculoskeletal/connective tissue disorders (N = 734; 23.8%), genitourinary disorders (N = 325; 10.5%), and circulatory disorders (N = 255; 8.3%). Nontraumatic diagnoses were the determinants of evacuation in 92.9% of military and 95.1% of nonmilitary patients; 17.8% of trauma patients and 0.5% of nontrauma patients utilized high-dependency care. DISCUSSION: The UK aeromedical evacuation system must have the capacity to evacuate large numbers of patients with nontraumatic diagnoses, but also the flexibility to accommodate smaller, more variable numbers of higher dependency trauma patients. The military medical chain must continually review the differing requirements of civilian patients transferred within their aeromedical system.

Plate-based diversity subset screening: an efficient paradigm for high throughput screening of a large screening file.

The screening files of many large companies, including Pfizer, have grown considerably due to internal chemistry efforts, company mergers and acquisitions, external contracted synthesis, or compound purchase schemes. In order to screen the targets of interest in a cost-effective fashion, we devised an easy-to-assemble, plate-based diversity subset (PBDS) that represents almost the entire computed chemical space of the screening file whilst comprising only a fraction of the plates in the collection. In order to create this file, we developed new design principles for the quality assessment of screening plates: the Rule of 40 (Ro40) and a plate selection process that insured excellent coverage of both library chemistry and legacy chemistry space. This paper describes the rationale, design, construction, and performance of the PBDS, that has evolved into the standard paradigm for singleton (one compound per well) high-throughput screening in Pfizer since its introduction in 2006.

A 5-year review of atrial fibrillation in military aircrew.

INTRODUCTION: Atrial fibrillation (AF) is a common cause of disqualification from flying in both civilian and military aircrew. We reviewed 5 yr of atrial fibrillation management in the Royal Air Force (RAF) from both a clinical and occupational perspective. METHODS: Patients were identified from the RAF Medical Boards (RAFMB) electronic database using search terms "atrial," "fibrillation," and "arrhythmia." Management was compared to current RAF and national clinical guidelines and current civilian and military aviation medicine policy. RESULTS: Over the 5-yr period assessed, 23 aircrew were identified with AF. Paroxysmal AF (PAF) was the most common diagnosis. Five aircrew remained fit to fly with no limitations, 12 fit to fly with restrictions, and 6 were graded permanently unfit for flying, with one of these being medically discharged. DISCUSSION: The incidence and demographics of aircrew identified with AF in this paper is comparable to previous studies. All aircrew in our study were treated in accordance with current RAF/national guidelines. Emerging treatments such as radiofrequency ablation and the new anticoagulants remain to be assessed for suitability in a military context. CONCLUSION: Management of AF in RAF aircrew requires a holistic approach, with an awareness of the arrhythmogenic aviation environment in which RAF aircrew operate. Most RAF aircrew with AF will retain a restricted flying status, but this should be considered on a case-by-case basis.

Use of the DiscoveRx Hit hunter cAMPII assay for direct measurement of cAMP in Gs and Gi GPCRs.

G protein-coupled receptors (GPCRs) are druggable targets of great interest to the pharmaceutical industry. Generally, functional cell-based assays can be employed to detect agonists (inverse, partial, and full) in addition to allosteric and classical orthosteric antagonists. Several different homogenous assay systems can be used to monitor the signaling cascades of GPCRs. This chapter details the authors' collective experience of using the DiscoverX Hit Hunter cAMPII kit from GE Healthcare/DiscoverX Corporation for the direct quantification of cAMP levels in Gs and Gi GPCRs.

Using reporter gene technologies to detect changes in cAMP as a result of GPCR activation.

The measurement of cyclic adenosine monophosphate levels through reporter gene technology represents one of the most popular and cost-effective methods to assess changes in functional activity of G protein-coupled receptors (GPCRs). This chapter provides a generic protocol for the successful execution of a reporter gene assay for GPCRs, stably transfected within Chinese hamster ovary cell lines, signaling through the Gs pathway. It also highlights areas to investigate when developing reporter gene assays and additional factors to consider for assays that deviate from the protocol and cell line defined.

The impact of orthosteric radioligand depletion on the quantification of allosteric modulator interactions.

Radioligand binding assays remain a common method for quantifying the effects of allosteric modulators at G protein-coupled receptors. The allosteric ternary complex model (ATCM) is the simplest model applied to derive estimates of modulator affinity (K(B)) and cooperativity (alpha), which are necessary for understanding structure-activity relationships. However, the increasing drive toward assay miniaturization in modern drug discovery may lead to conditions where appreciable ligand depletion occurs in the assay. Theoretical simulations investigating the impact of orthosteric radioligand depletion on the estimation of ATCM parameters revealed the following. 1) For allosteric inhibitors, application of the standard ATCM to data obtained under depletion conditions leads to an underestimation of pK(B) and an overestimation of log alpha. 2) For allosteric enhancers, the opposite was noted, but not always; the nonlinear regression algorithm is more likely to struggle to converge to a satisfactory solution of (nondepletion) ATCM parameters in this situation. 3) Application of a novel ATCM that explicitly incorporates orthosteric ligand depletion will yield more reliable model estimates, provided the degree of depletion is not high (< approximately 50%). Subsequent experiments investigated the interaction between [3H]N-methylscopolamine and the allosteric enhancer, alcuronium, or inhibitor, gallamine, in the presence of increasing concentrations of M(2) muscarinic acetylcholine receptor and showed that application of an ATCM that explicitly incorporates radioligand depletion can indeed give more robust estimates of modulator affinity and cooperativity estimates than the standard model. These results have important implications for the quantification of allosteric modulator actions in binding-based discovery assays.

Postoperative nesiritide use following high-risk mitral valve replacement.

Nesiritide is primarily used in the treatment of acutely decompensated chronic heart failure. It may also be useful in the postoperative management of patients with an exacerbation of heart failure after cardiac surgery. The management of a patient with cardiogenic shock after acute papillary muscle rupture is described. The patient exhibited signs of postoperative heart failure, and nesiritide therapy was instituted to lower filling pressures and achieve diuresis. This drug may be useful when patients with heart failure undergo cardiac surgery and continue to show evidence of heart failure in the postoperative period.