Specialty-Specific Entrustable Professional Activities: A Bridge to Internship.

Background Undergraduate medical education aims to prepare learners to become capable residents. New interns are expected to perform clinical tasks with distant supervision reliant on having acquired a medical degree. However, there is limited data to discuss what entrustment residency programs grant versus what the medical schools believe they have trained their graduates to perform. At our institution, we sought to foster an alliance between undergraduate medical education (UME) and graduate medical education (GME) toward specialty-specific entrustable professional activities (SSEPAs). These SSEPAs create a bridge to residency and help students structure the final year of medical school while striving for entrustability for day one of residency. This paper describes the SSEPA curriculum development process and student self-assessment of competence. Methodology We piloted an SSEPA program with the departments of Family Medicine, Internal Medicine, Neurology, and Obstetrics & Gynecology. Utilizing Kern's curriculum development framework, each specialty designed a longitudinal curriculum with a post-match capstone course. Students participated in pre-course and post-course self-assessments utilizing the Chen scale for each entrustable professional activity (EPA). Results A total of 42 students successfully completed the SSEPA curriculum in these four specialties. Students' self-assessed competence levels rose from 2.61 to 3.65 in Internal Medicine; 3.23 to 4.12 in Obstetrics and Gynecology; 3.62 to 4.13 in Neurology; and 3.65 to 3.79 in Family Medicine. Students across all specialties noted an increase in confidence from 3.45 to 4.38 in Internal Medicine; 3.3 to 4.6 in Obstetrics and Gynecology; 3.25 to 4.25 in Neurology; and 4.33 to 4.67 in Family Medicine. Conclusions A specialty-specific curriculum utilizing a competency-based framework for learners traversing the UME to GME journey in the final year of medical school improves learner confidence in their clinical abilities and may lead to an improved educational handoff between UME and GME.

The relationship between the elevation of haemoglobin A1c level, sleep quality and sleep duration in clinically diagnosed pre-diabetic patients in a nationally representative sample.

BACKGROUND/OBJECTIVES: Type 2 diabetes mellitus (T2DM) is one of the most common chronic illnesses in the United Kingdom accounting for approximately 15% of deaths per year. Growing evidence suggests that sleep duration and quality contributes towards this. This study aimed to determine whether there was a significant relationship between the elevation of haemoglobin A1c (HbA1c) level, sleep quality (SQ) and sleep duration (SD) in clinically diagnosed pre-diabetic patients. SUBJECTS/METHODS: Following referral from a relevant healthcare professional, participants (n = 40) were registered on the National Health Service England, funded Healthier You: National Diabetes Prevention Programme and completed a Pittsburgh Sleep Quality Index questionnaire to evaluate SQ and SD. RESULTS: A Spearman's correlation showed an association between HbA1c, SQ and SD measures. A simple linear regression showed a significant large positive association (rs = 0.913, p < 0.001) and significant regression (F (1) = 39, p < 0.001) with an R2 of 0.842 between HbA1c level and SQ. Additionally, a significant large negative association (rs = 0.757, p < 0.001) and significant regression was found (F (1) = 39, p < 0.001) with an R2 of 0.570 between HbA1c and SD. CONCLUSIONS: This study suggests a relationship between SQ, SD and the elevation of HbA1c which may contribute towards prevalence of T2DM and may help to increase adherence to diabetes prevention programmes.

Nonaneurysmal "Pseudo-Subarachnoid Hemorrhage" Computed Tomography Patterns: Challenges in an Acute Decision-Making Heuristics.

BACKGROUND: Acute aneurysmal subarachnoid hemorrhage (SAH) is a medical and neurosurgical emergency from ruptured brain aneurysm. Aneurysmal SAH is identified on brain computed tomography (CT) as increased density of basal cisterns and subarachnoid spaces from acute blood products. Aneurysmal SAH-like pattern on CT appears as an optical illusion effect of hypodense brain parenchyma and/or hyperdense surrounding cerebral cisterns and blood vessels termed as "pseudo-subarachnoid hemorrhage" (pseudo-SAH). METHODS: We reviewed clinical, laboratory, and radiographic data of all SAH diagnoses between January 2013 and January 2018, and found subsets of nonaneurysmal SAH, originally suspected to be aneurysmal in origin. We performed a National Library of Medicine search methodology using terms "subarachnoid hemorrhage," "pseudo," and "non-aneurysmal subarachnoid hemorrhage" singly and in combination to understand the sensitivity, specificity, and precision of pseudo-SAH. RESULTS: Over 5 years, 230 SAH cases were referred to our tertiary academic center and only 7 (3%) met the definition of pseudo-SAH. Searching the National Library of Medicine using subarachnoid hemorrhage yielded 27,402 results. When subarachnoid hemorrhage and pseudo were combined, this yielded 70 results and sensitivity was 50% (n = 35). Similarly, search precision was relatively low (26%) as only 18 results fit the clinical description similar to the 7 cases discussed in our series. CONCLUSIONS: Aneurysmal SAH pattern on CT is distinct from nonaneurysmal and pseudo-SAH patterns. The origin of pseudo-SAH terminology appears mostly tied to comatose cardiac arrest patients with diffuse dark brain Hounsfield units and cerebral edema, and is a potential imaging pitfall in acute medical decision-making.

The circadian regulator BMAL1 programmes responses to parasitic worm infection via a dendritic cell clock.

Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (TH2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong TH2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding-driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics. We deleted the circadian regulator BMAL1 in antigen-presenting dendritic cells (DCs) in vivo and found a loss of time-of-day dependency of helminth expulsion. RNAseq analyses revealed that IL-12 responses to worm antigen by circadian-synchronised DCs were dependent on BMAL1. Therefore, we find that circadian machinery in DCs contributes to the TH1/TH2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics.

Differential Spleen Remodeling Associated with Different Levels of Parasite Virulence Controls Disease Outcome in Malaria Parasite Infections.

Infections by malaria parasites can lead to very different clinical outcomes, ranging from mild symptoms to death. Differences in the ability of the spleen to deal with the infected red blood cells (iRBCs) are linked to differences in virulence. Using virulent and avirulent strains of the rodent malaria parasite Plasmodium yoelii, we investigated how parasite virulence modulates overall spleen function. Following parasite invasion, a difference in parasite virulence was observed in association with different levels of spleen morphology and iRBC rigidity, both of which contributed to enhanced parasite clearance. Moreover, iRBC rigidity as modulated by the spleen was demonstrated to correlate with disease outcome and thus can be used as a robust indicator of virulence. The data indicate that alterations in the biomechanical properties of iRBCs are the result of the complex interaction between host and parasite. Furthermore, we confirmed that early spleen responses are a key factor in directing the clinical outcome of an infection. IMPORTANCE The spleen and its response to parasite infection are important in eliminating parasites in malaria. By comparing P. yoelii parasite lines with different disease outcomes in mice that had either intact spleens or had had their spleens removed, we showed that upon parasite infection, the spleen exhibits dramatic changes that can affect parasite clearance. The spleen itself directly impacts RBC deformability independently of parasite genetics. The data indicated that the changes in the biomechanical properties of malaria parasite-infected RBCs are the result of the complex interaction between host and parasite, and RBC deformability itself can serve as a novel predictor of clinical outcome. The results also suggest that early responses in the spleen are a key factor directing the clinical outcome of an infection.

Therapeutic Implications of Peripheral Nerve Hyperexcitability in Muscle Cramping: A Retrospective Review.

PURPOSE: Muscle cramping due to peripheral nerve hyperexcitability (PNH) is poorly characterized. This retrospective study examines the prevalence of PNH and response to treatment. METHODS: The Duke EMG Database was queried to identify patients with muscle cramping tested for PNH from 2010 to 2015. Peripheral nerve hyperexcitability was defined by compound muscle action potential after-discharges on repetitive nerve stimulation. Response to treatment was determined by the treating physician's clinical impression 6 months after diagnosis or last documented visit. RESULTS: Seventy-two patients met inclusion criteria. Twenty-three (32%) patients had electrodiagnostic evidence of PNH. Of the patients with PNH, 74% had a good response to treatment whereas 37% of treated patients in the PNH-negative group (P = 0.0258). Carbamazepine and gabapentin were the most frequently used treatments with response rates of 70% and 77%, respectively. CONCLUSION: Muscle cramps associated with PNH respond well to symptomatic treatment, particularly with carbamazepine and gabapentin.

Muscle-Specific Receptor Tyrosine Kinase (MuSK) Myasthenia Gravis.

Autoimmune myasthenia gravis (MG) is the prototypic, antibody-mediated neuromuscular disease and is characterized by a decrease in the number of functional acetylcholine receptors (AChR) within the muscle end plate zone of the neuromuscular junction (NMJ). Although the pathophysiology of AChR-mediated myasthenia gravis has been extensively studied over the last 40 years since its original description by Patrick and Lindstrom (Science 180:871-872, 1973), less is known about the much more recently described muscle-specific kinase (MuSK) antibody-mediated MG. MuSK-MG has features clinically distinct from Ach-R MG, as well as a different pattern of response to treatment and a unique immunopathogenesis.

Adult absence semiology misinterpreted as mesial temporal lobe epilepsy.

Correct diagnosis of seizure type and epilepsy syndrome is the foundation for appropriate antiepileptic drug selection. Inappropriate medication choices occur in the treatment of generalized epilepsy and may aggravate some seizure types, including absence seizures, potentially leading to pseudo-drug resistance. Fortunately, a correct diagnosis of absence seizures is usually not difficult, though rarely demonstrates electroclinical overlap with focal seizures. EEG can be especially misleading when secondary bilateral synchronous discharges occur in patients with focal seizures. However, the semiology of focal seizures associated with mesial temporal lobe epilepsy has a characteristic and consistent semiology that is the mark of this common epilepsy syndrome in adulthood. We recently encountered a 53-year-old female with refractory seizures and a semiology strongly suggesting mesial temporal lobe epilepsy. Instead of focal seizures, prolonged absence seizures were validated by video-EEG monitoring and she became seizure-free after a change to broad-spectrum antiepileptic drugs. This case further expands our understanding of the complexity of semiology in electroclinical classification and the spectrum that may occur in adult absence seizures. It serves to underscore the need for ictal EEG recordings and the importance of concordance with the clinical course during the pre-surgical evaluation of patients with lesions and drug-resistant epilepsy. [Published with video sequences].

Dynamic changes in macrophage activation and proliferation during the development and resolution of intestinal inflammation.

Macrophages (Mφs) accumulate at sites of inflammation, and, because they can assume several functionally distinct states of activation, they can either drive or restrain inflammatory responses. Once believed to depend on the recruitment of blood monocytes, it is now clear that the accumulation of Mφs in some tissues can result from the proliferation of resident Mφs in situ. However, little is known about the proliferation and activation state of Mφ subsets in the gut during the development and resolution of intestinal inflammation. We show that inflammatory Mφs accumulate in the large intestine of mice during the local inflammatory response to infection with the gastrointestinal nematode parasite Trichuris muris. Classically activated Mφs predominate initially (as the inflammation develops) and then, following worm expulsion (as the inflammation resolves), both the resident and inflammatory populations of Mφs become alternatively activated. A small but significant increase in the proliferation of inflammatory Mφs is seen but only during the resolution phase of the inflammatory response following both worm expulsion and the peak in Mφ accumulation. In contrast to recent studies in the pleural and peritoneal cavities, the proliferation of resident and alternatively activated Mφs does not increase during the inflammatory response. Furthermore, in CCR2(-/-) mice, monocyte recruitment to the gut is impeded, and the accumulation of alternatively activated Mφs is greatly reduced. In conclusion, the recruitment of blood monocytes is the principle mechanism of Mφ accumulation in the large intestine. This study provides a novel insight into the phenotype and behavior of intestinal Mφ during infection-driven inflammation.

An antagonist of the retinoid X receptor reduces the viability of Trichuris muris in vitro.

BACKGROUND: Trichuriasis is a parasitic disease caused by the human whipworm, Trichuris trichiura. It affects millions worldwide, particularly in the tropics. This nematode parasite burrows into the colonic epithelium resulting in inflammation and morbidity, especially in children. Current treatment relies mainly on general anthelmintics such as mebendazole but resistance to these drugs is increasingly problematic. Therefore, new treatments are urgently required. METHODS: The prospect of using the retinoid X receptor (RXR) antagonist HX531 as a novel anthelmintic was investigated by carrying out multiple viability assays with the mouse whipworm Trichuris muris. RESULTS: HX531 reduced both the motility and viability of T. muris at its L3, L4 and adult stages. Further, bioinformatic analyses show that the T. muris genome possesses an RXR-like receptor, a possible target for HX531. CONCLUSIONS: The study suggested that Trichuris-specific RXR antagonists may be a source of much-needed novel anthelmintic candidates for the treatment of trichuriasis. The identification of an RXR-like sequence in the T. muris genome also paves the way for further research based on this new anthelmintic lead compound.

Cryoglobulinemic vasculitis in a patient with CREST syndrome.

Cryoglobulinemic vasculitis is a rare entity. Although it has been reported in diffuse systemic sclerosis, it has not been reported in calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia (CREST) syndrome. We report a patient with cryoglobulinemic vasculitis with CREST syndrome who did not have typical clinical features of vasculitis. This 58-year-old woman presented with mild generalized weakness and a diagnosis of CREST syndrome, which included Raynaud's syndrome, dysphagia and telangiectasias. She was positive for serum cryoglobulins, which led to a sural nerve biopsy. The biopsy results were consistent with cryoglobulinemic vasculitis. Cryoglobulinemic vasculitis has not been previously reported in CREST syndrome to our knowledge. Additionally, the patient also had limited clinical symptoms. Our patient displays the importance of checking for cryoglobulins and obtaining a nerve biopsy when the serum is positive. Both of these diagnostic tests were integral for directing appropriate treatment for this patient.

Improved prognostic diagnosis of systemic lupus erythematosus in an early stage of disease by a combination of different predictive biomarkers identified by proteome analysis.

BACKGROUND: Since the original characterizations of the pathological features defining glomerulonephritis in systemic lupus erythematosus (SLE) were reported, numerous studies have linked the development of pathology to the abnormal expression of protein in urine. The determination of proteinuria is important and necessary; however, this alone is not predictive enough to confirm a suspected diagnosis, especially in an early state of disease when symptoms are not yet observed. Furthermore, several studies have already highlighted the pitfalls of proteinuria both as a clinical prognostic marker and as a factor predicting the progressive loss of renal function. Therefore, the identification of more accurate and predictive biomarkers is urgently needed. To address this, comparative urinary and kidney profiling was performed in the MRL-lpr/lpr mouse as a model of lupus tubulointerstitial nephritis and lupus glomerulonephritis corresponding to SLE in humans. RESULTS: Tamm-Horsfall glycoprotein (THG; uromodulin) and beta2-microglubulin (ß2M) were identified as immune process-related molecules in the urine and kidney of the MRL-lpr/lpr mouse model. Furthermore, we show that the combinatory expression profile of THG and ß2M as biomarkers, normalized by the proteinuria level, is more predictive than proteinuria determination alone. Data were confirmed by comparative urinary profiling of SLE in mice by Western blot and quantitative polymerase chain reaction (qPCR) analysis. CONCLUSION: Based on our results, we are able to diagnose SLE in the MRL-lpr/lpr mouse in a very early state of disease, when the proteinuria level alone is not able to confirm a suspected diagnosis. The pre-validation of our urinary biomarkers is associated with clinical outcomes of glomerulonephritis in humans and merits additional investigation. Further conformations of our predictive biomarkers in the urine of SLE patients in the course of a clinical study are still ongoing.

The retinoic acid receptor agonist Am80 increases mucosal inflammation in an IL-6 dependent manner during Trichuris muris infection.

PURPOSE: Vitamin A metabolites, such as all-trans-retinoic acid (RA) that act through the nuclear receptor; retinoic acid receptor (RAR), have been shown to polarise T cells towards Th2, and to be important in resistance to helminth infections. Co-incidentally, people harbouring intestinal parasites are often supplemented with vitamin A, as both vitamin A deficiency and parasite infections often occur in the same regions of the globe. However, the impact of vitamin A supplementation on gut inflammation caused by intestinal parasites is not yet completely understood. METHODS: Here, we use Trichuris muris, a helminth parasite that buries into the large intestine of mice causing mucosal inflammation, as a model of both human trichuriasis and IBD, treat with an RARα/ß agonist (Am80) and quantify the ensuing pathological changes in the gut. RESULTS: Critically, we show, for the first time, that rather than playing an anti-inflammatory role, Am80 actually exacerbates helminth-driven inflammation, demonstrated by an increased colonic crypt length and a significant CD4(+) T cell infiltrate. Further, we established that the Am80-driven crypt hyperplasia and CD4(+) T cell infiltrate were dependent on IL-6, as both were absent in Am80-treated IL-6 knock-out mice. CONCLUSIONS: This study presents novel data showing a pro-inflammatory role of RAR ligands in T. muris infection, and implies an undesirable effect for the administration of vitamin A during chronic helminth infection.

Trichuris muris research revisited: a journey through time.

The mouse whipworm Trichuris muris has long been used as a tractable model of human Trichuriasis. Here we look back at the history of T. muris research; from the definition of the species and determination of its life cycle, through to the complex immune responses that we study today. We highlight the key research papers that have developed our understanding of immune responses to this parasite, and reflect on how original concepts have been transformed, as our knowledge of immunology has grown. Although we have a good understanding of host­parasite interactions in the context of the underlying cellular immunology, there are still many aspects of the biology of the Trichuris parasite that remain undefined. We predict that advances in parasite biology will be key in the future development of new and improved treatments for Trichuriasis.

The goblet cell is the cellular source of the anti-microbial angiogenin 4 in the large intestine post Trichuris muris infection.

BACKGROUND: Mouse angiogenin 4 (Ang4) has previously been described as a Paneth cell-derived antimicrobial peptide important in epithelial host defence in the small intestine. However, a source for Ang4 in the large intestine, which is devoid of Paneth cells, has not been defined. METHODOLOGY/PRINCIPAL FINDINGS: Analysis was performed on Ang4 expression in colonic tissue by qPCR and immunohistochemistry following infection with the large intestine dwelling helminth parasite Trichuris muris. This demonstrated an increase in expression of the peptide following infection of resistant BALB/c mice. Further, histological analysis of colonic tissue revealed the cellular source of this Ang4 to be goblet cells. To elucidate the mechanism of Ang4 expression immunohistochemistry and qPCR for Ang4 was performed on colonic tissue from T. muris infected mouse mutants. Experiments comparing C3H/HeN and C3H/HeJ mice, which have a natural inactivating mutation of TLR4, revealed that Ang4 expression is TLR4 independent. Subsequent experiments with IL-13 and IL-4 receptor alpha deficient mice demonstrated that goblet cell expression of Ang4 is controlled either directly or indirectly by IL-13. CONCLUSIONS: The cellular source of mouse Ang4 in the colon following T. muris infection is the goblet cell and expression is under the control of IL-13.

Preoperative dental anxiety and mood changes during nitrous oxide inhalation.

BACKGROUND: An estimated 35 million Americans experience significant apprehension about dental procedures, while an additional 10 to 12 million are considered to be "dental phobic" and avoid needed dental care altogether. Nitrous oxide is a general anesthetic used at subanesthetic concentrations to reduce anxiety during dental procedures. The purpose of this study was to characterize mood changes during nitrous oxide inhalation in patients with different levels of preoperative dental anxiety. METHODS: Forty-six patients who were to receive nitrous oxide during a dental procedure completed two anxiety scales. These patients were categorized into three groups: low anxiety, or LA, moderate anxiety, or MA, and high anxiety, or HA. They completed a visual analog scale of subjective effects before, during and after the dental procedure. RESULTS: A number of visual analog ratings, the majority of which could be considered pleasant, increased during nitrous oxide administration. It is significant that this increase in pleasant mood occurred in the HA and MA groups to the same degree as it did in the LA group. Patients in the HA and MA groups had elevated preoperative visual analog ratings of "anxious" that were reduced during nitrous oxide administration to a level equivalent to that reported by patients who had low preoperative anxiety. Patients in the HA group also had elevated preoperative visual analog ratings of "having unpleasant thoughts" and "feel bad" compared with the LA group. These ratings were reduced in the HA group to a level equivalent to that reported by patients in the LA group. CONCLUSIONS AND CLINICAL IMPLICATIONS: Regardless of their preoperative anxiety level, patients experienced a number of mood-altering effects during nitrous oxide inhalation, the majority of which could be considered pleasant. Ratings of an unpleasant nature decreased markedly in patients with high anxiety. These findings suggest that nitrous oxide may be an effective therapy in reducing patient anxiety during dental procedures.