Unravelling drug-drug interactions in pigs: Induction of hepatic cytochrome P450 1A (CYP1A) metabolism after the in-feed medication with the anthelmintic fenbendazole.

The anthelmintic fenbendazole (FBZ) undergoes hepatic S­oxygenation by monooxygenases belonging to the cytochrome P450 (CYP) and flavin-monooxygenase (FMO) families. The in-feed medication with FBZ induced CYP1A-dependent metabolism in pig liver. This fact may alter the metabolism of the anthelmintic itself, and of CYP1A substrates like aflatoxin B1 (AFB1). This work evaluated the effect of the in-feed administration of FBZ on CYP1A-dependent metabolism, on its own pattern of hepatic S­oxygenation, and on the metabolism of AFB1. Landrace piglets remained untreated (n = 5) or received a pre-mix of FBZ (n = 6) in feed for 9 days. Pigs were slaughtered for preparation of liver microsomes used for: CYP content determination; monitoring the CYP1A-dependent enzyme activities, 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD); measurement of FBZ (50 µM) S­oxygenation, and AFB1 (16 nM) disappearance from the incubation medium. In microsomes of FBZ-treated animals, EROD and MROD increased 19-fold (p = 0.002) and 14-fold (p = 0.003), respectively. An enhanced (3-fold, p = 0.004) participation of the CYP pathway in FBZ S­oxygenation was observed in the liver of piglets treated with the anthelmintic (210 ± 69 pmol/min.nmol CYP) compared to untreated animals (68 ± 34 pmol/min.nmol CYP). AFB1 metabolism was 93% higher (p = 0.009) in the liver of FBZ-treated compared to untreated pigs. Positive and significant (p < 0.05) correlations were observed between CYP1A-dependent enzyme activities and FBZ or AFB1 metabolism. The sustained administration of FBZ caused an auto-induction of the CYP1A-dependent S­oxygenation of this anthelmintic. The CYP1A induction triggered by the anthelmintic could amplify the production of AFB1 metabolites in pig liver, including the hepatotoxic AFB1-derived epoxide.+.

Effects of acaricides on the activities of monooxygenases in bovine liver microsomes.

Organophosphates (OPs), pyrethrins and fipronil, are acaricides commonly used in cattle, mainly as pour on formulations. Scant information is available on their potential interactions with hepatic xenobiotic metabolizing enzymes. This work aimed to evaluate in vitro the potential inhibitory effects of widely employed acaricides on catalytic activities mediated by hepatic cytochrome P450 (CYP) and flavin-monooxygenase (FMO) enzymes in cattle. Bovine (n = 4) liver microsomes were incubated in the absence (control assays) and in presence of different OPs (fenthion, chlorpyrifos, ethion, diazinon and dichlorvos), fipronil and cypermethrin at 0.1-100 µm. Five oxidative enzyme activities were assayed by spectrofluorimetric or HPLC methods: 7-ethoxyresorufin O-deethylase (for CYP1A1), methoxyresorufin O-demethylase (for CYP1A2), benzyloxyresorufin O-debenzylase (for CYP2B), testosterone 6-beta hydroxylase (for CYP3A) and benzydamine N-oxidase (for FMO). All acaricides, particularly phosphorothionate-containing OPs, inhibited to some extent more than one enzyme activity. The most frequent inhibitor was fenthion, which inhibited (p < .05) all enzyme activities tested (from 22% at 1 µm to 72% at 100 µm). However, low inhibitory potencies (IC50s higher than 7 µm) of all acaricides studied were observed against the catalytic activities assayed. Therefore, the risk of in vivo metabolic interactions due to inhibition of monooxygenases would be low under common husbandry conditions.

Colonoscopy performance monitoring: do we need to adjust for case mix?

INTRODUCTION: Overall caecum intubation rate(oCIR) and overall polyp detection rate(oPDR) have been proposed as performance indicators, but varying complexity in case mix among endoscopists may potentially affect validity. The study aims to explore the effect of adjusting for case mix on individual endoscopist performance by calculating case mix-adjusted performance estimates (cmCIR and cmPDR) and comparing them to overall performance estimates (oCIR and oPDR). The study also provides an R program for case mix analysis. METHODS: Logistic regression associated endoscopist, colonoscopy indication, patient age and patient gender with the binary outcomes of cecum intubation and polyp detection. Case mix-adjusted performance indicators were calculated for each endoscopist based on logistic regression and bootstraps. Endoscopists were ranked from best to worst by overall and case mix-adjusted performance estimates, and differences were evaluated using percentage points(pp) and rank changes. RESULTS: The dataset consisted of 7376 colonoscopies performed by 47 endoscopists. The maximum rank change for an endoscopist comparing oCIR and cmCIR was eight positions, interquartile range (IQR 1-3). The maximum change in CIR was 1.95 percentage point (pp) (IQR 0.27-0.86). The maximum rank change in the oPDR versus cmPDR analysis was 17 positions (IQR 1.5-8.5). The maximum change in PDR was 11.21 pp (IQR 2.05-6.70). Three endoscopists improved their performance from significantly inferior to within the 95% confidence interval (CI) range of performance targets using case mix-adjusted estimates. CONCLUSIONS: The majority of endoscopists were unaffected by adjustment for case mix, but a few unfortunate endoscopists had an unfavourable case mix that could invite incorrect suspicion of inferior performance.

Medication with fenbendazole in feed: plasma concentrations and effects on hepatic xenobiotic metabolizing enzymes in swine.

Fenbendazole (FBZ), a benzymidazole (BZD) anthelmintic drug, is used for in-feed medication in pigs. BZD-containing drugs may induce cytochrome P450 isozymes (CYPs), particularly those members of the CYP1A subfamily. The current research evaluated the plasma and liver availability and metabolism of FBZ and its metabolites, oxfendazole (OFZ) and fenbendazole sulphone (FBZSO2), after the administration of the parent drug in feed, and characterized the effect of the sustained administration of the anthelmintic on the catalytic activities of xenobiotic metabolizing enzymes in pig liver. Five female Landrace piglets remained untreated (controls), and other six were treated with a pre-mix of FBZ, combined with feed, for 9 consecutive days as usually is recommended. Blood samples were collected from each treated animal up to day 9 and analyzed by HPLC; all animals were slaughtered for preparation of liver microsomes. Plasma concentration ratios OFZ/FBZ and FBZSO2/OFZ increased significantly (p < 0.05) from the beginning to the end of drug exposure, which may indicate an enhanced conversion of FBZ into its metabolites. FBZ represented 45.8 ± 3.4% of the total anthelmintic molecules in liver tissue. Increased CYP1A-dependent 7-ethoxy (24.5-fold, p = 0.0032) and 7-methoxyresorufin (17.2-fold, p = 0.0006) O-dealkylase activities was observed in liver microsomes from FBZ-treated animals. In addition, a 64% increase (p = 0.042) in the rate of FBZ S-oxidation was observed in pigs treated with the anthelmintic drug compared to that measured in untreated animals. Thus, the continuous FBZ administration may accelerate its own in vivo hepatic metabolism through the CYP1A pathway.

Clinical supervisors' perceptions and use of the fundamentals of care framework in supervision of nursing students.

AIM: To explore clinical supervisors' perceptions and use of the Fundamentals of Care framework in supervising nursing students in clinical placement in hospital settings. DESIGN: A qualitative study using focus group interviews. Reported in accordance with Consolidated Criteria for Reporting Qualitative Research. METHODS: Twelve clinical nurse supervisors working in medical, surgical or psychiatric wards in hospitals in Denmark participated in four focus groups conducted from September to November 2020. Data were analysed using thematic analysis. RESULTS: Clinical supervisor's perceptions and use of the framework are described in three themes: structuring students' clinical learning, supporting tool for learning what nursing care is and developing own supervision practice. CONCLUSION: Supervisors perceive the Fundamentals of Care framework positively and use it as a supporting tool to structure and facilitate students' reflection on what nursing is and requires. They perceive that having a shared framework across school and clinical setting contributes to a safe and positive learning environment. Furthermore, using the framework develops their own practice as clinical supervisors.

9p21.3 Microdeletion involving CDKN2A/2B in a young patient with multiple primary cancers and review of the literature.

Germline pathogenic variants in CDKN2A predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, whereas CDKN2B variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both CDKN2A and CDKN2B associated with a cancer predisposition syndrome (CPS) that constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a de novo germline 9p21 microdeletion involving the CDKN2A/CDKN2B genes, who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with CDKN2A/CDKN2B deletion.

Metabolic stability of glyphosate and its environmental metabolite (aminomethylphosphonic acid) in the ruminal content of cattle.

Glyphosate (GLY) is one of the most commonly used herbicides worldwide. Both GLY and aminomethylphosphonic acid (AMPA), its main degradation product, may be present in feedstuffs offered to dairy cows. Although the major proportions of ingested GLY and AMPA are eliminated with faeces, a potential degradation of GLY to AMPA in the rumen of dairy cows has been suggested. Considering that the rumen plays a central role in the pre-systemic metabolism of xenobiotics, this research aimed to investigate whether or not GLY and AMPA are metabolised in the ruminal environment of cattle. The distribution of both compounds between the fluid and solid phases of the ruminal content (RC) was also evaluated. RC from 3 steers were collected in an abattoir. Aliquots were incubated (3-6 h) in anaerobiosis with GLY (15 µg/mL) and AMPA (1.5 µg/mL). Metabolic viability of RC was assessed by the measurement of the sulpho-reduction of the anthelmintic derivative albendazole sulphoxide (ABZSO) into albendazole (ABZ) in the absence (controls) or in presence of GLY and AMPA. Incubations of boiled (inactive) RC were used as controls. Samples were analysed by HLPC with fluorescence detection. Neither GLY nor AMPA were metabolised in metabolically active RC from cattle. Both compounds were predominantly found in the fluid phase compared to the solid (particulate) matter of RC. Neither GLY nor AMPA had a negative effect on the metabolic production of ABZ. A high metabolic stability of both compounds within the ruminal environment would be expected in vivo. Their presence in high proportion in the fluid phase of the ruminal content may give rise to a rapid flow of both GLY and AMPA to the posterior gastrointestinal tract. Negative effects on the ruminal biotransformation of therapeutically used drugs would not be expected when the herbicide and its degradation product are consumed with food.

Patients' experiences eating in a hospital - A qualitative study.

BACKGROUND AND AIMS: Even though there is a lot of focus on nutrition in hospitals, patients often continue to lose weight during their stay. A meal is a complex activity. Several factors have an influence on the intake of nutrition. The purpose of the study is to identify the experiences of patients about eating situations, wishes and needs in connection with meals during their stay in the hospital. METHODS: Twenty individual semi structured interviews were conducted at the North Denmark Regional Hospital and Aalborg University Hospital, Thisted. The inclusion criteria were age ≥18, cognitively and linguistically capable of participating and able to consume food ≥24 h. The participants were selected based on sex, age, and surgical and medical departments to ensure a broad representation. RESULTS: The patients experienced that the health professionals were friendly and caring and the food was really good. Despite general satisfaction, the patients reported many different experiences that are presented in the following themes: "The care relationship," "Meeting the system," "Influence from the surroundings," and "Social interaction with fellow patients and physical discomfort". The care relationship is considered to be essential. Some patients felt that they were met by helpful and accommodating health professionals while others felt rejected and corrected. The patients reacted to the health professionals being busy by adapting their expectations to the system and accepting the conditions. Hospital surroundings with catheter bags and IV drips influenced the patients and diminished their desire for food. The physical surroundings could make it difficult to sit comfortably when eating. Some patients wanted the company of other patients during their meal but would like to be able to choose with whom they shared their meals. Some patients tended to feel exposed and found it undignified and preferred to eat alone. CONCLUSIONS: The study indicates that it is important to ensure individual settings for the patients during meals and the focus should be on the relationship between patients and health professionals.

Improving colonoscopy quality through individualised training programmes.

INTRODUCTION: In Denmark, quality-improvement initiatives aimed at providing a better colonoscopy service are few. The primary objective of this study was to improve colonoscopy quality at Aalborg University Hospital, Denmark, using structured training programmes. The secondary aim was to introduce a system for individual colonoscopist performance monitoring. METHODS: We conducted a colonoscopy-quality pilot study covering two major quality performance indicators: caecum intubation rate (CIR) and polyp detection rate (PDR). The pilot study was followed by colonoscopy training programmes offering experienced colonoscopists colonoscopy skills upgrading, polypectomy and train-the-trainers courses taught by English experts. Junior doctors completed a 20-day module-based colonoscopy-training programme. A regional individual colonoscopy quality-reporting system was developed as a supplementary file within the electronic health records. RESULTS: The CIR increased from 87.1% to 92.1% (p less-than 0.001) and the PDR from 33.7% to 41.7% (p less-than 0.001) in the course of the structured training programme. Multivariable analysis adjusting for patient sex, patient age and colonoscopy indication showed a significant increase in CIR (p less-than 0.001), but not in PDR (p = 0.19). The colonoscopy quality reporting system was introduced and now provides biannual feedback to all colonoscopists. CONCLUSIONS: Quality-improvement initiatives may lead to an improved CIR and possibly PDR. Nationwide training programmes and performance monitoring should be implemented to further improve and monitor colonoscopy quality. FUNDING: none. TRIAL REGISTRATION: not relevant.

Colonoscopy adverse events: are we getting the full picture?

INTRODUCTION: Colonoscopy adverse events (AEs) are commonly underreported and standardised reporting is rarely used. We aimed to investigate AEs associated with colonoscopy in a real world setting, using the American Society of Gastrointestinal Endoscopy (ASGE) lexicon. METHODS: This retrospective cohort study of AEs related to outpatient colonoscopies performed in the North Denmark Region from 2015 to 2018 identified AEs from readmission within eight days or death within 30 days of colonoscopy. AEs were investigated in electronic health records and categorised, attributed and graded according to the ASGE lexicon. RESULTS: Of 49,445 colonoscopies performed, 1141 were potentially associated with AEs (23.07‰). Electronic health record review left 489 AEs attributed to colonoscopy (9.9‰); categorised as cardiovascular (0.65‰), pulmonary (0.36‰), thromboembolic (0.10‰), instrumental incl. perforations (0.99‰), bleeding (3.07‰), infection (0.87‰), drug reactions (0.04‰), pain (2.00‰), integument (damage to skin/bones) (0.34‰) and other (1.62‰) AEs. Ten (0.20‰) AEs were fatal, but only one was procedure related (perforation). All shearing force perforations occurred in the sigmoid colon. Most polypectomy perforations occurred in the caecum (60%). CONCLUSIONS: Colonoscopy carries important procedure and non-procedure related risks. Non-procedure related AEs are likely underreported. Better attention to patients with pre-existing diseases and further colonoscopist training may lower AE rates. A standardised colonoscopy AE reporting system is warranted.

Superior vena caval thrombosis after a neonatal arterial switch procedure.

Superior vena cava (SVC) and inferior vena cava obstructions were once well-documented complications from the Mustard repair for D-transposition of the great arteries (TGA), occurring in 10%-40% patients; however, they are rarely documented with the current, more common arterial switch operation (ASO). Similarly, SVC thrombosis is an uncommon, severe complication following neonatal cardiac surgery. We report a case of persistent SVC thrombosis, SVC syndrome, and chylothorax arising after ASO, refractory to thrombolysis and stent placement. A 6-day-old neonate with prenatally known TGA underwent an arterial switch procedure. Despite an initially unremarkable postoperative course, he developed respiratory difficulty after starting enteral feeding. Soft-tissue swelling was noted in the neck, chest, and upper face. An SVC thrombus was identified with cardiac catheterization. Multiple thrombolytic modalities were attempted. His postoperative course was further complicated by recurrent chylothoraces, respiratory failure, sepsis, anasarca, and renal failure. He was eventually transferred to a larger center for a special lymphatics evaluation, where two lymphovenous anastomoses were unsuccessful. He was sent to his home hospital, where he died from extended-spectrum beta-lactamase Klebsiella sepsis. Early diagnosis of SVC syndrome and prompt thrombolysis may prevent the complications encountered in this patient. More research is needed in neonatal thrombolysis and anticoagulation.

Exploring nursing students' use of the Fundamentals of Care framework in case-based work.

AIMS AND OBJECTIVES: To explore how nursing students perceive and use the conceptual Fundamentals of Care framework in case-based work in nursing education and furthermore to describe influencing factors on perceptions and use of the framework. BACKGROUND: The Fundamentals of Care framework has been integrated in core courses in two Schools of Nursing in Region North Denmark in response to studies reporting that nursing students and newly graduated nurses lack the knowledge, skills and competencies to meet the challenges of delivering fundamental care in clinical practice. An integration of the framework in case-based work in nursing education has not previously been studied. DESIGN AND METHODS: The study design was focused ethnography. Data were collected using participant observations, focus group interviews and individual interviews. Four groups of four to five nursing students participating in case-based work sessions and three faculty members from two Schools of Nursing were included. The study adhered to COREQ. RESULTS: The results show an uncertainty among the students about how to understand and use the conceptual framework in case-based work. The uncertainties derive from diversities in faculty members' perceptions and curricular planning among others. However, the framework appears to support the students' learning about what nursing is and requires. CONCLUSIONS: The study indicates that integrating Fundamentals of Care framework in case-based work may be one way of teaching nursing students the complexities of integrated fundamental nursing care. However, there is a need to consider how to support students in articulating Fundamentals of Care, and to draw attention to the influence of role models and curricular planning. RELEVANCE TO EDUCATIONAL PRACTICE: The study provides knowledge relevant when customising future educational interventions regarding the integration of Fundamentals of Care in nursing education and may provide valuable knowledge of evaluation strategies.

The Influence of Perioperative Fluid Therapy on N-terminal-pro-brain Natriuretic Peptide and the Association With Heart and Lung Complications in Patients Undergoing Colorectal Surgery: Secondary Results of a Clinical Randomized Assessor-blinded Multicenter Trial.

OBJECTIVE: To investigate the influence of intravenous (iv) fluid volumes on the secretion of N-terminal-pro-brain natriuretic peptide (NT-Pro-BNP) in colorectal surgical patients and its association with cardiopulmonary complications (CPC). In addition, to examine if preoperative NT-Pro-BNP can predict the risk for postoperative CPC. METHODS: Blood samples from patients enrolled in a previously published clinical randomized assessor-blinded multicenter trial were analyzed. Included were adult patients undergoing elective colorectal surgery with the American-Society-of-Anesthesiologists-scores of 1-3. Samples from 135 patients were available for analysis. Patients were allocated to either a restrictive (R-group) or a standard (S-group) iv-fluid regimen, commencing preoperatively and continuing until discharge. Blood was sampled every morning until the fourth postoperative day. The primary outcome for this study was NT-Pro-BNP changes and its association with fluid therapy and CPC. RESULTS: The S-group received more iv-fluid than the R-group on the day-of-surgery [milliliter, median (range) 6485 (4401-10750) vs 3730 (2250-8510); P < 0.001] and on the first postoperative day. NT-Pro-BNP was elevated in the S-group compared with the R-group on all postoperative days [area under the curve: median (interquartile range) pg/mL: 3285 (1697-6179) vs 1290 (758-3719); P < 0.001 and in patients developing CPC vs no-CPC (area under the curve), median (interquartile range): 5196 (1823-9061) vs 1934 (831-5301); P = 0.005]. NT-pro-BNP increased with increasing fluid volumes all days (P < 0.003). Preoperative NT-Pro-BNP predicted CPC [odds ratio (confidence interval): 1.573 (0.973-2.541), P = 0.032; positive predictive value = 0.257, negative predictive value = 0.929]. CONCLUSIONS: NT-pro-BNP increases with iv-fluid volumes given to colorectal surgical patients, and the level of NT-Pro-BNP is associated with CPC. Preoperative NT-Pro-BNP is predictive for CPC, but the diagnostic value is low.Clinicaltrials.gov NCT03537989.

In vitro and in vivo effects of chlorpyrifos and cypermethrin on blood cholinesterases in sheep.

The combination of the organophosphate (OP) chlorpyrifos (CPF) and the pyrethroid cypermethrin (CPM) is commonly marketed as pour-on formulations for the control of sheep lice, ked, and blowflies. CPF irreversibly inhibits acetylcholinesterases (AChE), while pyrethroids are not AChE inhibitors. However, combinations of pyrethroids with OPs showed a highly synergistic effect on AChE inhibition. Thus, the aim of the current work was to evaluate in vitro and in vivo the inhibitory potency of both pesticides, alone and in combination with AChE and butyrylcholinesterase (BChE) activities in sheep blood. In vitro, IC50 values were similar after CPF or CPF plus CPM incubations. The pour-on coadministration of recommended doses of CPF and CPM did not cause a significant inhibition of AChE and BChE in sheep blood. Only slight percentages of inhibition of their catalytic activities were observed when both drugs were given at 4-fold higher dose rates. The lower systemic availability of topical administration of OPs in sheep may help to explain the lower degree of inhibition of blood AChE and BChE in vivo. The results emerged from this research are a further contribution to the knowledge of the risks of implementing higher dosage regimens of OPs-containing antiparasitic formulations.

Risk of post-colonoscopy colorectal cancer in Denmark: time trends and comparison with Sweden and the English National Health Service.

BACKGROUND: The post-colonoscopy colorectal cancer (PCCRC) rate is a key quality indicator for colonoscopy. Previously published PCCRC rates have been difficult to compare owing to differences in methodology. The primary aim of this study was to compare Danish PCCRC rates internationally and to calculate Danish PCCRC rates using the World Endoscopy Organization (WEO) consensus method for future comparison. The secondary aim was to identify factors associated with PCCRC. METHODS: National registries were used to examine the risk of PCCRC. The Danish 3-year rate of PCCRC (PCCRC-3yr) was calculated using previously published methods from England, Sweden, and the WEO. Poisson regression analysis was performed to identify factors associated with PCCRC. RESULTS: The Danish PCCRC-3yr was significantly higher than the rate in the English NHS (relative risk [RR] 1.12, 95 % confidence interval [CI] 1.05 - 1.19) and Sweden (RR 1.15, 95 %CI 1.06 - 1.24). The Danish PCCRC-3yr based on the WEO consensus method fell from 22.5 % in 2001 to 7.9 % in 2012. The multivariable Poisson regression model found PCCRC to be significantly associated with diverticulitis (RR 3.25, 95 %CI 2.88 - 3.66), ulcerative colitis (RR 3.44, 95 %CI 2.79 - 4.23), hereditary cancer (age < 60 years: RR 7.39, 95 %CI 5.77 - 9.47; age ≥ 60 years: RR 3.81, 95 %CI 2.74 - 5.31), and location in the transverse (RR 1.57, 95 %CI 1.28 - 1.94) and ascending colon (RR 1.85, 95 %CI 1.64 - 2.08). CONCLUSIONS: The PCCRC-3yr was higher in Denmark than in comparable countries. Differences in colonoscopist training, background, and certification are possible contributing factors. A review of colonoscopist training and certification in Denmark, and continuous audit and feedback of colonoscopist performance may reduce PCCRC-3yr.

The pathology and aetiology of subcortical clefts in infants.

In infants, traumatic surface contusions of the brain are rare but subcortical clefts or cysts, variously labelled "contusional tears", "contusional clefts", "cortical tears" or "parenchymal lacerations" have been ascribed to trauma, and are even said to be characteristic of shaking and abuse. We describe the pathology of subcortical clefts or haemorrhages in seven infants. In none were the axonal swellings characteristic of traumatic axonal injury seen in relation to the clefts. Subpial bleeding was associated with clefts in all the cases of recent onset. We hypothesize that subcortical clefts are not due to direct mechanical forces of trauma but are part of a secondary cascade caused by impaired venous drainage which may or may not follow trauma. The finding of subcortical and subpial haemorrhages should prompt a search for CVT. We consider the term "contusion" is not accurate and is misleading.

A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course.

An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible assembly of the α-/ß-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with features of primary neurodegeneration, and a homogenous clinical course. These patients were homozygous for a TBCD missense variant c.[3099C>G]; p.(Asn1033Lys), which we show has a high carrier frequency in the Faroese population (2.6%). The patients had similar age of onset as the previously reported patients (n = 24), but much shorter survival, which could be caused by either differences in supportive treatment, or alternatively, that shorter survival is intrinsic to the Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.

Consensus on procedures to include in a simulation-based curriculum in ophthalmology: a national Delphi study.

PURPOSE: The number of available simulation-based models for technical skills training in ophthalmology is rapidly increasing, and development of training programmes around these procedures should follow a structured approach. The aim of this study was to identify all technical procedures that should be integrated in a simulation-based curriculum in ophthalmology. METHODS: Key opinion leaders involved in the education of ophthalmologists in Denmark including heads of departments, heads of clinical education, professors and board members of the society were invited to participate in a three-round Delphi process. Round 1 aimed at identifying technical procedures that physicians should be able to perform competently when completing specialty training; round 2 involved characterization of each procedure including frequency, number of operators, risk and/or discomfort for patients associated with an inexperienced physician, and feasibility of simulation-based training; round 3 included a priority ranking of procedures. RESULTS: The response rate for each round was 71%, 64% and 64%, respectively. Sixty-five procedures were reduced to 25 prioritized procedures during the three rounds. Two-thirds of the procedures that were identified and highly prioritized were therapeutic procedures such as intravitreal injection therapy, yttrium-aluminium-garnet laser iridotomy/capsulotomy, minor ocular surface procedures and retinal argon laser therapy. The diagnostic procedures that were prioritized were ocular ultrasound, superficial keratectomy and optical coherence tomography (OCT). CONCLUSION: The Delphi process identified and prioritized 25 procedures that should be practised in a simulation-based environment to achieve competency before working with patients. The list may be used to guide the development of future training programmes for ophthalmologists.

Association between perceived stress, multimorbidity and primary care health services: a Danish population-based cohort study.

OBJECTIVES: Mental stress is common in the general population. Mounting evidence suggests that mental stress is associated with multimorbidity, suboptimal care and increased mortality. Delivering healthcare in a biopsychosocial context is key for general practitioners (GPs), but it remains unclear how persons with high levels of perceived stress are managed in primary care. We aimed to describe the association between perceived stress and primary care services by focusing on mental health-related activities and markers of elective/acute care while accounting for mental-physical multimorbidity. DESIGN: Population-based cohort study. SETTING: Primary healthcare in Denmark. PARTICIPANTS: 118 410 participants from the Danish National Health Survey 2010 followed for 1 year. Information on perceived stress and lifestyle was obtained from a survey questionnaire. Information on multimorbidity was obtained from health registers. OUTCOME MEASURES: General daytime consultations, out-of-hours services, mental health-related services and chronic care services in primary care obtained from health registers. RESULTS: Perceived stress levels were associated with primary care activity in a dose-response relation when adjusted for underlying conditions, lifestyle and socioeconomic factors. In the highest stress quintile, 6.8% attended GP talk therapy (highest vs lowest quintile, adjusted incidence rate ratios (IRR): 4.96, 95% CI 4.20 to 5.86), 3.3% consulted a psychologist (IRR: 6.49, 95% CI 4.90 to 8.58), 21.5% redeemed an antidepressant prescription (IRR: 4.62, 95% CI 4.03 to 5.31), 23.8% attended annual chronic care consultations (IRR: 1.22, 95% CI 1.16 to 1.29) and 26.1% used out-of-hours services (IRR: 1.47, 95% CI 1.51 to 1.68). For those with multimorbidity, stress was associated with more out-of-hours services, but not with more chronic care services. CONCLUSION: Persons with high stress levels generally had higher use of primary healthcare, 4-6 times higher use of mental health-related services (most often in the form of psychotropic drug prescriptions), but less timely use of chronic care services.

Determining procedures for simulation-based training in radiology: a nationwide needs assessment.

OBJECTIVES: New training modalities such as simulation are widely accepted in radiology; however, development of effective simulation-based training programs is challenging. They are often unstructured and based on convenience or coincidence. The study objective was to perform a nationwide needs assessment to identify and prioritize technical procedures that should be included in a simulation-based curriculum. METHODS: A needs assessment using the Delphi method was completed among 91 key leaders in radiology. Round 1 identified technical procedures that radiologists should learn. Round 2 explored frequency of procedure, number of radiologists performing the procedure, risk and/or discomfort for patients, and feasibility for simulation. Round 3 was elimination and prioritization of procedures. RESULTS: Response rates were 67 %, 70 % and 66 %, respectively. In Round 1, 22 technical procedures were included. Round 2 resulted in pre-prioritization of procedures. In round 3, 13 procedures were included in the final prioritized list. The three highly prioritized procedures were ultrasound-guided (US) histological biopsy and fine-needle aspiration, US-guided needle puncture and catheter drainage, and basic abdominal ultrasound. CONCLUSION: A needs assessment identified and prioritized 13 technical procedures to include in a simulation-based curriculum. The list may be used as guide for development of training programs. KEY POINTS: • Simulation-based training can supplement training on patients in radiology. • Development of simulation-based training should follow a structured approach. • The CAMES Needs Assessment Formula explores needs for simulation training. • A national Delphi study identified and prioritized procedures suitable for simulation training. • The prioritized list serves as guide for development of courses in radiology.