"There should be one spot that you can go:" BRCA mutation carriers' perspectives on cancer risk management and a hereditary cancer registry.

Individuals who carry BRCA1 or BRCA2 pathogenic variants are recommended to have extensive cancer prevention screening and risk-reducing surgeries. Uptake of these recommendations is variable, and there remains room for improvement in the risk management of BRCA carriers. This paper explores female BRCA carriers' experiences with the current model of care and their perspectives on (and interest in) an inherited cancer registry. Findings can inform the development of a dedicated high-risk screening and management program for these patients. Quantitative and qualitative data were gathered through a provincial descriptive survey and semi-structured qualitative interviews to assess BRCA carriers' opinions toward risk management services in the province of Newfoundland and Labrador (NL), Canada. Survey (n = 69) and interview data (n = 15) revealed continuity and coordination challenges with the current system of care of high-risk individuals. Respondents suggested an inherited cancer registry would help identify high-risk individuals and provide a centralized system of risk management for identified carriers. Respondents identified concerns about the privacy of their registry data, including who could access it. Findings suggest BRCA carriers see great value in an inherited cancer registry. Specifically, participants noted it could provide a centralized system to help improve the coordination of burdensome, life-long risk management. Important patient concerns about protecting their privacy and their health data confidentiality must be addressed in patient and public information and informed consent documents about a registry.

An approach to classifying occupational exposures to endocrine disrupting chemicals by sex hormone function using an expert judgment process.

Endocrine disrupting chemicals (EDCs) are exogenous substances that interfere with the endocrine system and cause adverse effects. We aimed to classify the effects of 24 known EDCs, prevalent in certain occupations, according to four modes of action (estrogenic, antiestrogenic, androgenic, and/or antiandrogenic). A literature search, stratified into four types of literature was conducted (namely: national and international agency reports; review articles; primary studies; ToxCastTM). The state of the evidence of each EDC on sex hormone function was summarized and reviewed by an expert panel. For each mode of action, the experts evaluated the likelihood of endocrine disruption in five categories: "No", "Unlikely", "Possibly", "Probably", and "Yes". Seven agents were categorized as "Yes," or having strong evidence for their effects on sex hormone function (antiandrogenic: lead, arsenic, butylbenzyl phthalate, dibutyl phthalate, dicyclohexyl phthalate; estrogenic: nonylphenol, bisphenol A). Nine agents were categorized as "Probable," or having probable evidence (antiandrogenic: bis(2-ethylhexyl)phthalate, nonylphenol, toluene, bisphenol A, diisononyl phthalate; androgenic: cadmium; estrogenic: copper, cadmium and; anti-estrogenic: lead). Two agents (arsenic, polychlorinated biphenyls) had opposing conclusions supporting both "probably" estrogenic and antiestrogenic effects. This synthesis will allow researchers to evaluate the health effects of selected EDCs with an added level of precision related to the mode of action.

Gallstones top to toe: what the radiologist needs to know.

Gallstone-related disease can have significant associated morbidity and mortality worldwide. The incidence of gallstone-related disease in the Western world is on the increase. There are multiple different pathological manifestations of gallstone disease: the presentation, diagnosis and associated complications of which vary significantly depending on anatomical location. The role of imaging in gallstone-related disease is broad with radiology playing an essential role in the diagnosis, management and follow-up of gallstone-related pathologies. This paper distills the broad range of gallstone-related pathologies into an anatomical map, discussing the disease processes involved at each point along the biliary tree and reviewing the strengths and weaknesses of different imaging modalities for each distinct disease process.

Use of Lean Six Sigma methodology shows reduction of inpatient waiting time for peripherally inserted central catheter placement.

AIM: The aim of this study was to assess the use of Lean Six Sigma methodology to improve the turnaround time (TAT) for inpatient peripherally inserted central catheter (PICC) placement. MATERIALS AND METHODS: Value stream mapping was used to analyse the workflow process for inpatient PICC placement and to divide it into its component parts. Unnecessary steps were eliminated and variation minimised in the remaining processes. The TAT for PICC line placement was recorded for the 6 months prior to implementation of changes, and subsequently, at the 6-month and 2-year follow-up points. RESULTS: Prior to implementing the changes, the mean TAT for PICC line placement was 3.74±3.28 days (95% confidence interval [CI]=3.3-4.17). Six months after implementation, the mean TAT was 1.89±1.82 days (95% CI=1.72-2.06, p<0.0001). The reduction was sustained such that at 2 years post-implementation the mean TAT was 1.88±1.87 days (95% CI=1.78-1.99, p<0.0001). This was achieved despite a 13.8% increase in overall interventional radiological activity. CONCLUSION: By applying Lean Six Sigma methodology to the complex multifactorial processes involved from ordering a PICC to its final insertion, it was possible to identify areas for improvement and to introduce simple, effective measures that resulted in a significant sustained decrease in the TAT without additional resources.

Overnight Emergency CT Imaging: A 10-Year Experience at an Irish Tertiary Referral Hospital.

In recent years there has been increased utilisation of computed tomography (CT) imaging in developed countries, however there is a paucity of data regarding the utilisation of CT in the emergency overnight setting. We retrospectively analysed trends in 'overnight' (midnight to 8am) CT utilisation over a ten-year period at a single Irish tertiary referral hospital. Over the study period, we observed a significant increase in the proportion of CT imaging that was carried out overnight. There was no significant variation in the yield of pathological findings over the study period, which remained low (64% of CT studies were normal or had non-critical findings). The multiple factors which have contributed to the increased utilization of overnight emergency CT in recent years, the potential for reporting errors overnight and the implications therein for patient safety warrant consideration.

Imaging complex nutrient dynamics in mycelial networks.

Transport networks are vital components of multi-cellular organisms, distributing nutrients and removing waste products. Animal cardiovascular and respiratory systems, and plant vasculature, are branching trees whose architecture is thought to determine universal scaling laws in these organisms. In contrast, the transport systems of many multi-cellular fungi do not fit into this conceptual framework, as they have evolved to explore a patchy environment in search of new resources, rather than ramify through a three-dimensional organism. These fungi grow as a foraging mycelium, formed by the branching and fusion of threadlike hyphae, that gives rise to a complex network. To function efficiently, the mycelial network must both transport nutrients between spatially separated source and sink regions and also maintain its integrity in the face of continuous attack by mycophagous insects or random damage. Here we review the development of novel imaging approaches and software tools that we have used to characterise nutrient transport and network formation in foraging mycelia over a range of spatial scales. On a millimetre scale, we have used a combination of time-lapse confocal imaging and fluorescence recovery after photobleaching to quantify the rate of diffusive transport through the unique vacuole system in individual hyphae. These data then form the basis of a simulation model to predict the impact of such diffusion-based movement on a scale of several millimetres. On a centimetre scale, we have used novel photon-counting scintillation imaging techniques to visualize radiolabel movement in small microcosms. This approach has revealed novel N-transport phenomena, including rapid, preferential N-resource allocation to C-rich sinks, induction of simultaneous bi-directional transport, abrupt switching between different pre-existing transport routes, and a strong pulsatile component to transport in some species. Analysis of the pulsatile transport component using Fourier techniques shows that as the colony forms, it self-organizes into well demarcated domains that are identifiable by differences in the phase relationship of the pulses. On the centimetre to metre scale, we have begun to use techniques borrowed from graph theory to characterize the development and dynamics of the network, and used these abstracted network models to predict the transport characteristics, resilience, and cost of the network.

Design and synthesis of novel scaffolds for drug discovery: hybrids of beta-D-glucose with 1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one, the corresponding 1-oxazepine, and 2- and 4-pyridyldiazepines.

[structure: see text]. We describe the syntheses of novel tricyclic scaffolds that incorporate a fusion of a substituted pyranose ring with the seven-membered rings of 1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one and the corresponding oxazepine and pyridyldiazepine to generate the benzodiazepines, and the related heterocycles. In each instance, the pyranose rings contain three protected hydroxyls, suitable for selective derivatization.

Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis.

We show that carbohydrates constitute an attractive source of readily available, stereochemically defined scaffolds for the facile attachment of side chains contained in genetically encoded and other amino acids. beta-D- and beta-L-glucose, L-mannose, and the 6-deoxy-6-N-analogue of beta-D-glucose have been employed to synthesize peptidomimetics that bind the SRIF receptors on AtT-20 mouse pituitary cells, five cloned human receptor subtypes (hSSTRs), and the NK-1 receptor. The affinity profile of various sugar-based ligands at the hSSTRs is compared with that of SRIF. Compound 19 bound hSSTR4 with a Ki of 100 nM. Subtle structural changes affect affinities. Evidence is presented that suggests that one compound (8) binds both the AtT-20 cell receptors and the five hSSTRs via a unique mode. The SARs of the glycosides at SRIF receptors differ markedly from those at the NK-1 receptor. For example a 4-benzyl substituent is important for SRIF receptor binding, but the 4-desbenzyl analogue 27 was highly potent (IC50 of 27 nM) at the NK-1 receptor. A new, nonbasic method for the synthesis of base-sensitive ethers from primary and secondary alcohols is also described.

Retention of patients with a diagnosis of diabetes in selected managed care plans.

This study was designed to determine the extent of retention of patients in staff-model HMOs. Study groups with Type II diabetes were compared with a control group without diabetes. Each study group (three groups of approximately 400 patients, drawn from three MCOs) was enrolled in a staff-model HMO in 1990. Patients were then followed for five consecutive years through 1995. The age- and gender-matched control groups (approximately 400 patients randomly selected from each of the three MCOs) were identified from managed care plan enrollees without a diagnosis of diabetes. It was found that the retention rates of patients with diabetes are higher than those without diabetes in two plans. For the third plan, the retention rates among patients with diabetes were the same as the control group's. The first year of enrollment was found to be the most important predictor of patient retention. The findings of this study strongly suggest plans seek methods to optimize treatments and delay the natural history, morbidity, and exacerbations associated with diabetes, since there is a higher probability that these patients will be members in the future.

Synthesis of potent cyclic hexapeptide NK-1 antagonists. Use of a minilibrary in transforming a peptidal somatostatin receptor ligand into an NK-1 receptor ligand via a polyvalent peptidomimetic.

The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substance P. Conversely the NK-1 receptor binds substance P but not the above ligands. In contrast, the beta-D-glucosides 1 and 2, designed to mimic the beta-turn of 6a, bind both receptors. This observation led us to attempt the conversion of 6a into the first potent, selective cyclic hexapeptide ligand for the NK-1 receptor. To this end, we combined design with a minilibrary approach. The goal was accomplished with surprising ease, leading to the NK-1 receptor antagonist 9 (IC50 2.0 +/- 0.4 nM). This demonstrates that peptidomimetics, incorporating in this case the promiscuous beta-D-glucose scaffold, can provide valuable clues about receptor similarities not revealed by their endogenous ligands. In addition, this work suggests that the use of libraries and rational design need not be mutually exclusive approaches to lead discovery.

Case report: pleural encasement secondary to acinar adenocarcinoma of the submandibular gland.

We present a case of a 42-year-old male with metastatic pleural encasement of the lung with extension into the mediastinum, resulting from an acinar adenocarcinoma of the submandibular gland diagnosed 30 years previously. The radiographic and CT appearances are presented, with a literature review.

Endocytosis of GPI-linked membrane folate receptor-alpha.

GPI-linked membrane folate receptors (MFRs) have been implicated in the receptor-mediated uptake of reduced folate cofactors and folate-based chemotherapeutic drugs. We have studied the biosynthetic transport to and internalization of MFR isoform alpha in KB-cells. MFR-alpha was synthesized as a 32-kD protein and converted in a maturely glycosylated 36-38-kD protein 1 h after synthesis. 32-kD MFR-alpha was completely soluble in Triton X-100 at 0 degree C. In contrast, only 33% of the 36-38-kD species could be solubilized at these conditions whereas complete solubilization was obtained in Triton X-100 at 37 degrees C or in the presence of saponin at 0 degree C. Similar solubilization characteristics were found when MFR-alpha at the plasma membrane was labeled with a crosslinkable 125I-labeled photoaffinity-analog of folic acid as a ligand. Triton X-100-insoluble membrane domains containing MFR-alpha could be separated from soluble MFR-alpha on sucrose flotation gradients. Only Triton X-100 soluble MFR-alpha was internalized from the plasma membrane. The reduced-folate-carrier, an integral membrane protein capable of translocating (anti-)folates across membranes, was completely excluded from the Triton X-100-resistant membrane domains. Internalized MFR-alpha recycled slowly to the cell surface during which it remained soluble in Triton X-100 at 0 degree C. Using immunoelectron microscopy, we found MFR-alpha along the entire endocytic pathway: in clathrin-coated buds and vesicles, and in small and large endosomal vacuoles. In conclusion, our data indicate that a large fraction, if not all, of internalizing MFR-alpha bypasses caveolae.