Bridging the Gap: Comparison of Outpatient Clinic and Emergency Department Patients Undergoing Cholecystectomy.

INTRODUCTION: Literature shows failure of the outpatient clinic (OC) pathway after emergency department (ED) ultrasound diagnosis of symptomatic cholelithiasis (SC). We hypothesized SC to be more prevalent on final surgical pathology (FSP) in patients who successfully completed OC pathway. METHODS: This retrospective single-institution chart review compared OC and ED patients with right upper quadrant (RUQ) pain and cholelithiasis whom underwent cholecystectomy. Clinical evaluation was considered positive if RUQ pain >4 h, or + Murphy's sign. Ultrasound was positive if two of these three were present: sonographic Murphy's, wall thickness > 4 mm, or pericholecystic fluid. Results were compared with FSP. RESULTS: Six hundred-seven patients underwent cholecystectomy, 299 OC and 308 ED. OC was more likely to SC (23% versus 4.6%) (P < 0.0001) and ED acute cholecystitis (39.3% versus 4.7%). Chronic cholecystitis was the most common FSP in both OC (72%) and ED (56%) populations, of these, 73% of OC denied pain >4 h versus only 10% of ED (P < 0.001). Median time from evaluation to cholecystectomy was 14 d versus 14 h in the OC and ED respectively (P < 0.0001). CONCLUSIONS: While chronic cholecystitis was the most common FSP in both OC and ED, the majority of OC reported RUQ pain <4 h delineating these presentations. Duration of pain should be utilized as algorithm triage. We recommend patients with pain episode <4 h should complete OC algorithm with expedited cholecystectomy within 14 d.

PharmaMemory: an interactive, animated web application for learning autonomic physiology and pharmacology.

Medical students face challenging but important topics they must learn in short periods of time, such as autonomic pharmacology. Autonomic pharmacology is difficult in that it requires students to synthesize detailed anatomy, physiology, clinical reasoning, and pharmacology. The subject poses a challenge to learn as it is often introduced early in medical school curricula. To ease the difficulty of learning autonomic pharmacology, we created a free web application, PharmaMemory (www.pharmamemory.com), that interactively depicts the effects of high-yield autonomic drugs on the human body. PharmaMemory provides users with the opportunity to read and quiz themselves on the mechanisms, side effects, indications, and contraindications of these drugs while interacting with the application. We provided PharmaMemory to first-year medical students for three consecutive years of quality improvement and assessed the application's perceived effects on learning via user surveys. Survey feedback showed that users viewed PharmaMemory favorably and self-reported increased knowledge and confidence in the subject of autonomic pharmacology. Comments revealed that users liked the website's visuals, opportunity for challenged recall, and conciseness. PharmaMemory utilizes challenged recall, visual stimulation, and interactive learning to provide users with a multifaceted learning tool. Preliminary data suggest that students find this method of learning beneficial. Further studies are needed to assess PharmaMemory compared with more traditional learning methods such as PowerPoint or text-based learning. Additionally, further research is needed to quantitatively assess reduction in cognitive load.NEW & NOTEWORTHY PharmaMemory (www.pharmamemory.com) is a free web application that interactively depicts the effects of high-yield autonomic drugs on the human body.

Severe retinal degeneration in women with a c.2543del mutation in ORF15 of the RPGR gene.

PURPOSE: To describe the genotype-phenotype correlation and serial observations in a five-generation Czech family with X-linked retinitis pigmentosa (XLRP) associated with severe visual impairment in women. METHODS: Comprehensive ophthalmological examination including spectral domain optical coherence tomography (SD-OCT) was performed. Based on the pedigree structure and women being severely affected, autosomal dominant inheritance was suspected, and screening for known mutations by genotyping microarray was performed. Subsequently, direct sequencing of ORF15 RPGR was undertaken. RESULTS: Eighteen family members (nine women and nine men) were examined. A pathogenic variant, c.2543del in ORF15 of RPGR, was found to segregate with disease. The oldest woman and her two sisters had no perception of light in their sixth decade. Four women and five men had signs and symptoms of typical XLRP, including moderate to high myopia. Three other women also had moderate to high myopia and myopic astigmatism but without the presence of bone spicule-like formation. Severe disruption of macular architecture on SD-OCT was equally common in both sexes. Only one 32-year-old female carrier had clinically normal findings. Subfoveal choroidal thickness was decreased in all affected men and in all female carriers, except the only carrier with a normal fundus examination. CONCLUSIONS: The c.2543del mutation in ORF15 of RPGR is associated with a severe phenotype in the women in this family. The presence of a significant myopic refractive error, in the absence of male-to-male transmission, may be indicative of X-linked inheritance. Measurements of choroidal thickness may help in clinically identifying carrier status.

A paradigm shift in the delivery of services for diagnosis of inherited retinal disease.

OBJECTIVES: Current technologies for delivering gene testing are labour-intensive and expensive. Over the last 3 years, new high-throughput DNA sequencing techniques (next generation sequencing; NGS), with the capability to analyse multiple genes or entire genomes, have been rapidly adopted into research. This study examines the possibility of incorporating NGS into a clinical UK service context. METHODS: The study applied NGS of 105 genes to 50 patients known to be affected by inherited forms of blindness in the setting of a UK National Health Service-accredited diagnostic molecular genetics laboratory. The study assessed the ability of an NGS protocol to identify likely disease-causing genetic variants when compared with current methodologies available through UK diagnostic laboratories. RESULTS: Conventional testing is only applicable to the minority of patients with inherited retinal disease and identifies mutations in fewer than one in four of those patients tested. By contrast, the NGS assay is directed at all patients with such disorders and identifies disease-causing mutations in 50--55%, which is a dramatic increase. This includes patients with apparently 'sporadic' disease, and those for whom clinical management and prognosis are altered as a consequence of defining their disease at a molecular level. CONCLUSIONS: The new NGS approach delivers a step change in the diagnosis of inherited eye disease, provides precise diagnostic information and extends the possibility of targeted treatments including gene therapy. The approach represents an exemplar that illustrates the opportunity that NGS provides for broadening the availability of genetic testing. The technology will be applied to many conditions that are associated with high levels of genetic heterogeneity.

Experiences implementing a 6-month pilot of a 7-day community CNS service in an urban hospice in Scotland.

BACKGROUND: Patients and carers may face challenges in the out-of-hours period, with inadequate support and variations in service provision, including access to specialist palliative care. A pilot was undertaken to extend availability of the community clinical nurse specialist (CNS) team to include weekends and public holidays. AIM: To examine the need for a 7-day community CNS service. METHOD: Activity data was collected for 6 months and feedback was sought from service users and the CNS team. RESULTS: There were 132 out-of-hours telephone contacts in the 6-month period, generating 35 home visits. Almost two thirds of these calls were proactive, 'planned' contacts. Most unplanned calls (68%) were from a carer for advice about symptom management and support as the patient's condition changed. CONCLUSION: The pilot demonstrated the need for a CNS service 7 days a week, and the service is now embedded in practice. Seven-day working benefits patients and families while being valued by the professional team.

Assembling a safe and effective toolbox for integrated flea control and plague mitigation: Fipronil experiments with prairie dogs.

BACKGROUND: Plague, a widely distributed zoonotic disease of mammalian hosts and flea vectors, poses a significant risk to ecosystems throughout much of Earth. Conservation biologists use insecticides for flea control and plague mitigation. Here, we evaluate the use of an insecticide grain bait, laced with 0.005% fipronil (FIP) by weight, with black-tailed prairie dogs (BTPDs, Cynomys ludovicianus). We consider safety measures, flea control, BTPD body condition, BTPD survival, efficacy of plague mitigation, and the speed of FIP grain application vs. infusing BTPD burrows with insecticide dusts. We also explore conservation implications for endangered black-footed ferrets (Mustela nigripes), which are specialized predators of Cynomys. PRINCIPAL FINDINGS: During 5- and 10-day laboratory trials in Colorado, USA, 2016-2017, FIP grain had no detectable acute toxic effect on 20 BTPDs that readily consumed the grain. During field experiments in South Dakota, USA, 2016-2020, FIP grain suppressed fleas on BTPDs for at least 12 months and up to 24 months in many cases; short-term flea control on a few sites was poor for unknown reasons. In an area of South Dakota where plague circulation appeared low or absent, FIP grain had no detectable effect, positive or negative, on BTPD survival. Experimental results suggest FIP grain may have improved BTPD body condition (mass:foot) and reproduction (juveniles:adults). During a 2019 plague epizootic in Colorado, BTPDs on 238 ha habitat were protected by FIP grain, whereas BTPDs were nearly eliminated on non-treated habitat. Applications of FIP grain were 2-4 times faster than dusting BTPD burrows. SIGNIFICANCE: Deltamethrin dust is the most commonly used insecticide for plague mitigation on Cynomys colonies. Fleas on BTPD colonies exhibit the ability to evolve resistance to deltamethrin after repeated annual treatments. Thus, more tools are needed. Accumulating data show orally-delivered FIP is safe and usually effective for flea control with BTPDs, though potential acute toxic effects cannot be ruled out. With continued study and refinement, FIP might be used in rotation with, or even replace deltamethrin, and serve an important role in Cynomys and black-footed ferret conservation. More broadly, our stepwise approach to research on FIP may function as a template or guide for evaluations of insecticides in the context of wildlife conservation.

RPGR mutation analysis and disease: an update.

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene are the most common single cause of retinitis pigmentosa, accounting for up to 15 to 20% of cases in Caucasians. A total of 240 different RPGR mutations have been reported, including 24 novel ones in this work, which are associated with X-linked retinitis pigmentosa (XLRP) (95%), cone, cone-rod dystrophy, or atrophic macular atrophy (3%), and syndromal retinal dystrophies with ciliary dyskinesia and hearing loss (2%). All disease-causing mutations occur in one or more RPGR isoforms containing the carboxyl-terminal exon open reading frame 15 (ORF15), which are widely expressed but show their highest expression in the connecting cilia of rod and cone photoreceptors. Of reported RPGR mutations, 55% occur in a glutamic acid-rich domain within exon ORF15, which accounts for only 31% of the protein. RPGR forms complexes with a variety of other proteins and appears to have a role in microtubular organization and transport between photoreceptor inner and outer segments.

Hospice at home 1: the development of a crisis intervention service.

This article is the first in a series of two which report on the development and evaluation of a rapid response crisis intervention service for patients in the advanced stages of cancer. A number of recent studies have identified the need for rapid response teams who are able to provide palliative and specialist palliative care in the home setting (King et al, 2000; Mantz, 2000; Thomas, 2001). By providing an overview of the relevant literature and describing the experience of developing this scheme the authors' aim is to share good practice with interested professionals who may be contemplating setting up similar schemes. This article outlines the development of a 'hospice at home' scheme until its launch and identifies the strategies used to ensure the early success of the project.

Hospice at home 2: evaluating a crisis intervention service.

This article presents an evaluation of a rapid-response crisis-intervention service, hospice at home (H@H), for patients with advanced cancer. The project took place in Glasgow, UK, between July 1999 and May 2001. An integral part of the (H@H) project was the concurrent evaluation, which attempted to explore a range of service and user outcomes. The service was able to prevent admission to, or facilitate discharge from, institutional care on 62 occasions. The evaluation found significant improvements in some areas of pain and symptom management. High levels of satisfaction were recorded by all service users. A partial cost analysis revealed that the medical and nursing support costs for the (H@H) would have been substantially reduced if throughput had been higher. The (H@H) project team agreed that a valuable lesson learned from the project was the importance of involving all key players from the outset when determining the requirements of a new service initiative.

A clinical molecular genetic service for United Kingdom families with choroideraemia.

A diagnosis of choroideraemia (CHM) can be made clinically, based on the fundus examination and a family history consistent with X-linked inheritance. Molecular genetic testing offers a means of confirming the clinical diagnosis, establishing carrier status and allows presymptomatic diagnosis for families who wish to pursue these options. The aim of this study was to examine the uptake and assess the results from a diagnostic molecular genetics service for CHM. We have carried out a comprehensive audit of all molecular genetic results of UK NHS patients and families referred to the North West Regional Molecular Genetics Laboratory in Manchester, UK over a 55 month period. 110 people were referred to this service for testing including diagnostic, carrier and predictive requests. Putative pathogenic mutations were identified in 65/83 (78%) of male index cases. The identification of a familial pathogenic change enabled carrier testing in 16 asymptomatic females and predictive testing in 3 males. Case examples illustrate the range of cases referred for testing and also reflect the need for genetic counselling that results from offering a molecular diagnostic service such as this. Clinical molecular testing for CHM is available clinically and can be used to support the clinical diagnosis and management of patients with choroideraemia as well as their families. Case studies demonstrate the need to provide genetic testing to families and the potential clinical utility of testing.

Preparation and validation of the first WHO international genetic reference panel for Fragile X syndrome.

Fragile X syndrome is the most common inherited form of mental retardation. It is caused by expansion of a trinucleotide (CGG)n repeat sequence in the 5' untranslated region of the FMR1 gene, resulting in promoter hypermethylation and suppression of FMR1 transcription. Additionally, pre-mutation alleles in carrier males and females may result in Fragile X tremor ataxia syndrome and primary ovarian insufficiency, respectively. Fragile X is one of the most commonly requested molecular genetic tests worldwide. Quality assessment schemes have identified a wide disparity in allele sizing between laboratories. It is therefore important that clinical laboratories have access to characterized reference materials (RMs) to aid accurate allele sizing and diagnosis. With this in mind, a panel of genotyping RMs for Fragile X syndrome has been developed, which should be stable over many years and available to all diagnostic laboratories. Immortalized cell lines were produced by Epstein-Barr virus transformation of lymphocytes from consenting patients. Genomic DNA was extracted in bulk and RM aliquots were freeze-dried in glass ampoules. Twenty-one laboratories from seventeen countries participated in a collaborative study to assess their suitability. Participants evaluated the samples (blinded, in triplicate) in their routine methods alongside in-house and commercial controls. The panel of five genomic DNA samples was endorsed by the European Society of Human Genetics and approved as an International Standard by the Expert Committee on Biological Standardization at the World Health Organization.

Establishment of the first WHO international genetic reference panel for Prader Willi and Angelman syndromes.

Prader Willi and Angelman syndromes are clinically distinct genetic disorders both mapping to chromosome region 15q11-q13, which are caused by a loss of function of paternally or maternally inherited genes in the region, respectively. With clinical diagnosis often being difficult, particularly in infancy, confirmatory genetic diagnosis is essential to enable clinical intervention. However, the latter is challenged by the complex genetics behind both disorders and the unmet need for characterised reference materials to aid accurate molecular diagnosis. With this in mind, a panel of six genotyping reference materials for Prader Willi and Angelman syndromes was developed, which should be stable for many years and available to all diagnostic laboratories. The panel comprises three Prader Willi syndrome materials (two with different paternal deletions, and one with maternal uniparental disomy (UPD)) and three Angelman syndrome materials (one with a maternal deletion, one with paternal UPD or an epigenetic imprinting centre defect, and one with a UBE3A point mutation). Genomic DNA was bulk-extracted from Epstein-Barr virus-transformed lymphoblastoid cell lines established from consenting patients, and freeze-dried as aliquots in glass ampoules. In total, 37 laboratories from 26 countries participated in a collaborative study to assess the suitability of the panel. Participants evaluated the blinded, triplicate materials using their routine diagnostic methods against in-house controls or externally sourced uncertified reference materials. The panel was established by the Expert Committee on Biological Standardization of the World Health Organization as the first International Genetic Reference Panel for Prader Willi and Angelman syndromes.

Mutations within the protein Z-dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia.

Protein Z-dependent protease inhibitor (ZPI) is a serpin that inhibits the activated coagulation factors X and XI. The precise physiological significance of ZPI in the control of haemostasis is unknown although a deficiency of ZPI may be predicted to alter this balance. The coding region of the ZPI gene was screened for mutations using denaturing high-performance liquid chromatography. 16 mutations/polymorphisms within the coding region of ZPI were identified including two mutations, which generated stop codons at residues R67 and W303. We observed nonsense mutations within the ZPI gene in 4.4% of thrombosis patients (n = 250) compared with 0.8% of controls (n = 250). The difference in distribution of stop codon mutations between thrombosis patients and controls was significant (P = 0.02) with an odds ratio of 5.7 (95% confidence interval, 1.25-26.0). Our results suggest an association between ZPI deficiency and venous thrombosis and we propose that ZPI deficiency is potentially a new form of thrombophilia.