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AimsPublic Health England has identified that in COVID-19, death rates among ethnic minorities far exceeds that of the white population. While the increase in ethnic minorities is likely to be multifactorial, to date, no studies have looked to see whether values for routine clinical biochemistry parameters differ between ethnic minority and white individuals.MethodsBaseline biochemical data for 22 common tests from 311 SARS-CoV-2 positive patients presenting to hospital in April 2020 in whom ethnicity data were available was retrospectively collected and evaluated. Data comparisons between ethnic minority and white groups were made for all patient data and for the subset of patients subsequently admitted to intensive care.ResultsWhen all patient data were considered, the ethnic minority population had statistically significant higher concentrations of C reactive protein (CRP), aspartate aminotransferase and gamma-glutamyl transferase, while troponin T was higher in the white group. A greater proportion of ethnic minority patients were subsequently admitted to intensive care, but when the presenting biochemistry of this subset of patients was compared, no significant differences were observed between ethnic minority and white groups.ConclusionOur data show for the first time that routine biochemistry at hospital presentation in COVID-19 differs between ethnic minority and white groups. Among the markers identified, CRP was significantly higher in the ethnic minority group pointing towards an increased tendency for severe inflammation in this group.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.

Competency-based medical education (CBME) curricula are becoming increasingly common in graduate medical education. Put simply, CBME is focused on educational outcomes, is independent of methods and time, and is composed of achievable competencies.1 In spite of widespread uptake, there remains much to learn about implementing CBME at the program level. Leveraging the collective experience of program leaders at Queen’s University, where CBME simultaneously launched across 29 specialty programs in 2017, this paper leverages change management theory to provide a short summary of how program leaders can navigate the successful preparation, launch, and initial implementation of CBME within their residency programs.

In caring for, welcoming, and advocating for families, faith communities have historically played a significant role in protecting children from maltreatment. Indeed, the concept of hospitality, a sacred duty to care for families who are less familiar to us just as we care for our own, is fundamental to most major faith traditions. This commitment to hospitality made faith communities ideal partners in Strong Communities for Children, a community-based child maltreatment prevention initiative first implemented in parts of three counties in South Carolina. This article provides an overview of the roles that faith communities played in the initiative and then describes the transformation undergone by one congregation as it deepened its engagement with Strong Communities and its efforts to prevent child maltreatment within its walls and in the broader community.

Purpose To have subject matter experts evaluate the Core Entrustable Professional Activities for Entering Residency (Core EPAs) with the EQual rubric to determine if revisions were required and, if applicable, how to focus revision efforts. Method Ten entrustable professional activity (EPA) experts were invited to evaluate the 13 Core EPAs. Experts had a 6-month window (December 2018-May 2019) to complete the evaluation, which contained the complete EQual rubric and 3 additional prompts, one of which-"Do you think this EPA requires revision?"-was limited to a "yes/no" response. Descriptive statistics for overall and domain-specific EQual rubric scores for each of the 13 Core EPAs were calculated. Free-text responses to why and/or how a Core EPA should be revised were summarized for any Core EPA that scored below a cutoff or for which the majority of experts recommended revision. Results Six experts completed the evaluation. Most Core EPAs' (9/13) overall score was above the cutoff, indicating that they align with the key domains of the EPA construct. The remaining 4 Core EPAs (2, 7, 9, and 13) scored below the overall cutoff, suggesting that they may require revision. A majority of experts felt that Core EPAs 6, 7, 9, and 13 required revision. With regard to domain-specific scores, Core EPAs 2, 3, 7, 9, and 13 were below the discrete units of work cutoff; Core EPAs 7, 9, and 13 were below the entrustable, essential, and important tasks of the profession of medicine cutoff; and Core EPA 9 was below the curricular role cutoff. Conclusions The Core EPAs represent a promising initial framework of EPAs for undergraduate medical education. Some Core EPAs might benefit from revision. The process of improving the Core EPAs must continue if they are to standardize outcomes for medical school graduates.

Entrustable professional activities (EPAs), discrete profession-specific tasks requiring integration of multiple competencies, are increasingly used to help define and inform curricula of specialty training programmes. Although guidelines exist to help guide the developmental process, deciding what logic to use to draft a preliminary EPA framework poses a crucial but often difficult first step. The logic of an EPA framework can be defined as the perspective used by its developers to break down the practice of a profession into units of professional work. This study aimed to map dominant logics and their rationales across postgraduate medical education and fellowship programmes.A scoping review using systematic searches within five electronic databases (Medline, Embase, Google Scholar, Scopus and Web of Science) was performed. Dominant logics of included papers were identified using inductive coding and iterative analysis.In total, 42 studies were included. Most studies were conducted in the United States (n = 22; 52%), Canada (n = 6; 14%) and the Netherlands (n = 4; 10%). Across the reported range of specialties, family medicine (n = 4; 10%), internal medicine (n = 4; 10%), paediatrics (n = 3; 7%) and psychiatry (n = 3; 7%) were the most common. Three dominant logics could be identified, namely, 'service provision', 'procedures' and/or 'disease or patient categories'. The majority of papers (n = 37; 88%) used two or more logics when developing EPA frameworks (median = 3, range = 1-4). Disease or patient groups and service provision were the most common logics used (39% and 37%, respectively).Most programmes used a combination of logics when trying to capture the essential tasks of a profession in EPAs. For each of the three dominant logics, the authors arrived at a definition and identified benefits, limitations and examples. These findings may potentially inform best practice guidelines for EPA development.

In this paper, a form of adaptive weak-form market efficiency of the Romanian stock market is examined via a state-space approach. A general methodology for estimating evolving efficiency is proposed within the extended Kalman filter associated with the customized state-space models in this work. The suggested approach for measuring a time-varying degree of market efficiency is based on time-dependent autoregressive (AR) models where a conclusion regarding the evolving efficiency is deduced by tracking the changes in regression coefficients. Motivated by previous studies of the Bucharest stock exchange, we explore a structural time-series model that contains a stochastic trend and a white noise component. Monthly data covers the period from September 1997 to December 2020, which includes the period of the 2008–2009 global financial crisis and the recent COVID-19 recession. Our major findings reveal that the Romanian stock market is weak-form efficient at the end of our empirical study and has not been greatly affected by the first wave of the COVID-19 pandemic. However, it suffered severely during the 2008–2009 crisis, which is reflected in a lingering recovery process.

The adaptive market hypothesis (AMH) supplies a convincing motivation for why market efficiency should not be regarded as a stable property in time. This paper explores a Bayesian methodology for estimating weak-form market efficiency under the AMH using a test of evolving efficiency (TEE). More precisely, a generalized TEE (GTEE) approach is proposed in which the conditional first moment of a time series is assumed to be a nonlinear function of its conditional second moment, i.e., a nonlinear feedback term is present in the conditional mean equation. We then discuss a maximum likelihood estimation procedure for the resulting nonlinear model using the state-space approach and extended Kalman filtering. This methodology is used to estimate time-varying, weak-form market efficiency in four, specifically chosen, markets over a time-period that includes the global financial crisis of 2007/2008.

Entrustable professional activities (EPAs) have received much attention in the literature since they were first proposed in 2005. Useful guidelines, workshops, courses, and conferences have supported faculty in developing programs and designing assessment procedures using EPAs and entrustment decision-making. Yet, the need for clarification remains, particularly as more programs make the step from design to implementation.Well-written EPAs provide a natural construct to establish the outcome of training. To be useful, EPAs require more than a suitable title. This AMEE Guide elaborates eight sections of a full EPA description, and provides explanations and justifications for each. These sections are: title; specification and limitations; risks in case of failure; most relevant competency domains; knowledge, skills, attitudes and experiences; information sources to assess progress and support summative entrustment; entrustment/supervision level expected at which stage of training; and time period to expiration if not practiced.Constructing fully elaborated EPAs creates a shared mental model amongst learners and programs, informs competency-based curriculum design, directs ad-hoc and formal entrustment decision-making, and provides standards for certifying bodies and boundaries for scope of practice. The framework intends to support curricular leaders looking to adopt new EPAs, or revise and define established EPAs for competency-based education.

Background. Deficiency of 11β-hydroxylase is the second most common cause of congenital adrenal hyperplasia (CAH), presenting with hypertension, hypokalaemia, precocious puberty, and adrenal insufficiency. We report the case of a 6-year-old boy with cystic fibrosis (CF) found to have hypertension and cortisol insufficiency, which were initially suspected to be due to CAH, but were subsequently identified as being secondary to posaconazole therapy. Case Presentation. A 6-year-old boy with CF was noted to have developed hypertension after administration of two doses of Orkambi™ (ivacaftor/lumacaftor), which was subsequently discontinued, but the hypertension persisted. Further investigations, including echocardiogram, abdominal Doppler, thyroid function, and urinary catecholamine levels, were normal. A urine steroid profile analysis raised the possibility of CAH due to 11β-hydroxylase deficiency, and a standard short synacthen test (SST) revealed suboptimal cortisol response. Clinically, there were no features of androgen excess. Detailed evaluation of the medical history revealed exposure to posaconazole for more than 2 months, and the hypertension had been noted to develop two weeks after the initiation of posaconazole. Hence, posaconazole was discontinued, following which the blood pressure, cortisol response to the SST, and urine steroid profile were normalized. Conclusion. Posaconazole can induce a clinical and biochemical picture similar to CAH due to 11β-hydroxylase deficiency, which is reversible. It is prudent to monitor patients on posaconazole for cortisol insufficiency, hypertension, and electrolyte abnormalities.

Issue: Entrustable Professional Activities (EPAs) describe the core tasks health professionals must be competent performing prior to promotion and/or moving into unsupervised practice. When used fo...

BACKGROUND Adrenocortical carcinoma (ACC) is a rare malignancy, with an annual incidence of 1 or 2 cases per million. Biochemical diagnosis is challenging because up to two-thirds of the carcinomas are biochemically silent, resulting from de facto enzyme deficiencies in steroid hormone biosynthesis. Urine steroid profiling by GC-MS is an effective diagnostic test for ACC because of its capacity to detect and quantify the increased metabolites of steroid pathway synthetic intermediates. Corresponding serum assays for most steroid pathway intermediates are usually unavailable because of low demand or lack of immunoassay specificity. Serum steroid analysis by LC-MS/MS is increasingly replacing immunoassay, in particular for steroids most subject to cross-reaction. METHODS We developed an LC-MS/MS method for the measurement of serum androstenedione, corticosterone, cortisol, cortisone, 11-deoxycorticosterone, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate, pregnenolone, 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, and testosterone. Assay value in discriminating ACC from other adrenal lesions (phaeochromocytoma/paraganglioma, cortisol-producing adenoma, and lesions demonstrating no hormonal excess) was then investigated. RESULTS In ACC cases, between 4 and 7 steroids were increased (median = 6), and in the non-ACC groups, up to 2 steroids were increased. 11-Deoxycortisol was markedly increased in all cases of ACC. All steroids except testosterone in males and corticosterone and cortisone in both sexes were of use in discriminating ACC from non-ACC adrenal lesions. CONCLUSIONS Serum steroid paneling by LC-MS/MS is useful for diagnosing ACC by combining the measurement of steroid hormones and their precursors in a single analysis.

Entrustable professional activities (EPAs) have become a cornerstone of assessment in competency-based medical education (CBME). Increasingly, EPAs are being adopted that do not conform to EPA standards. This study aimed to develop and validate a scoring rubric to evaluate EPAs for alignment with their purpose, and to identify substandard EPAs.The EQual rubric was developed and revised by a team of education scholars with expertise in EPAs. It was then applied by four residency program directors/CBME leads (PDs) and four nonclinician support staff to 31 stage-specific EPAs developed for internal medicine in the Royal College of Physicians and Surgeons of Canada's Competency by Design framework. Results were analyzed using a generalizability study to evaluate overall reliability, with the EPAs as the object of measurement. Item-level analysis was performed to determine reliability and discrimination value for each item. Scores from the PDs were also compared with decisions about revisions made independently by the education scholars group.The EQual rubric demonstrated high reliability in the G-study with a phi-coefficient of 0.84 when applied by the PDs, and moderate reliability when applied by the support staff at 0.67. Item-level analysis identified three items that performed poorly with low item discrimination and low interrater reliability indices. Scores from support staff only moderately correlated with PDs. Using the preestablished cut score, PDs identified 9 of 10 EPAs deemed to require major revision.EQual rubric scores reliably measured alignment of EPAs with literature-described standards. Further, its application accurately identified EPAs requiring major revisions.

The novel coronavirus, SARS-CoV-2, which causes COVID-19, has rapidly progressed to a global health emergency.1 COVID-19 predominantly presents with respiratory complications and associated mortality; however, emerging reports show that patients can present with cardiac involvement.1 Cardiovascular manifestations are not unique to COVID-19 as cardiac involvement have been reported with SARS-CoV and Middle East respiratory syndrome-CoV in the past.2 The pandemic in the UK has highlighted the higher risk to the Black, Asian and minority ethnic (BAME) population of adverse clinical outcomes compared with patients of white British ethnicity.3 Furthermore, BAME men aged over 50 years are noted to be at an even higher risk of severe COVID-19.4 We retrospectively reviewed the cardiac markers Troponin T, N-terminal pro B-type natriuretic peptide (NT-proBNP) and the inflammation marker C reactive protein (CRP) requested in patients with suspected COVID-19, admitted to a tertiary London hospital during the peak of the pandemic (April 2020) in the UK. Only patients who had a Troponin measurement (with or …

When religious institutions are discussed in the context of child maltreatment, the topic is typically sources of danger for children. Although some religious institutions are counted among the formal organizations in which child abuse has occurred and in which accusations have been covered up, to focus solely on religion and its institutions as sources of threat or to exclude them from discussions of addressing, preventing, and eradicating violence against children, would be a mistake. Throughout the world, there exist communities of faith that provide formal and informal resources, supports, and opportunities to children and families in their midst. This article provides a rationale for including religious institutions in conversations about and in efforts to protect children, examples of efforts by religious institutions to provide protection to children, a discussion of religion and its institutions as potential sources of risk for children, and suggestions for research on the role of religious institutions in child protection.

The past two decades have witnessed the application of new forms of conditionality to Australian social security policy. This paper argues that a distinctive feature has been the attempt to link receipt of government benefits to parental behaviour in order to address concerns about the welfare of children. With a view to providing a framework that can help to inform debates regarding the merits of these new forms of conditionality, this paper outlines the historical antecedents and philosophical framework of new conditionality. The paper also examines three pertinent Australian social security initiatives: the Maternity Immunisation Allowance, the Improving School Enrolment and Attendance through Welfare Reform Measure, and Compulsory Income Management. The paper concludes with some consideration of the potential pitfalls of new conditionality.

Adjuvants are essential components of cancer vaccine formulations to promote effective immune responses. We initially screened multiple immune-activating targets, including TLR and STING adjuvants using in-vitro assays to test their ability to activate bone marrow DC (BMDC) and showed STING had the most potent activation (i.e., MHC and co-stimulatory molecules) on DCs. Since STING and TLR signaling is non-redundant, TLR and STING adjuvants were combined to enhance DC activation. We utilized the multidimensional synergy of combinations (MuSyc), a novel synergy algorithm, to assess molecular synergy in combining STING and TLR adjuvants, and we noted that the combination of R848 (TLR7-8) plus STING agonists provided a synergistic efficacious and potent response on BMDCs. From this data-set, we generated a MuSYC synergy strategy where we will utilize max signal dose for STING adjuvant and ten times less of max signal dose for R848 (TLR7-8) to determine synergy for other assays. We tested this same MuSYC strategy for activation of human monocytic cell line THP-1 and determined that the synergy strategy induced similar or better activation effects compared to the max signal dose for both adjuvants. Finally, we tested the in-vivo anti-tumor immune response for the B16 melanoma and MOC2 head/neck tumor-bearing vaccination models that resulted in an improved anti-tumor response for the combinatorial STING-TLR adjuvanted vaccines compared to the single agents.

GVAX, a genetically modified whole cell vaccine, is thought to work by recruiting and activating APCs which then traffic to the draining lymph node and elicit tumor-specific T cells. GVAX has little therapeutic benefit as a monotherapy, but when combined with a Toll-like receptor (TLR) 4 adjuvant, TLR Enhanced GVAX (TEGVAX) significantly reduces tumor burden in mouse models. Paradoxically, the increased therapeutic benefit of TEGVAX corresponds with a decrease in delivery of tumor antigen to the dLN suggesting a different mechanism of tumor suppression than GVAX. To determine if TEGVAX alters the priming of CD8 T cells, we performed longitudinal studies of OT-1 CD8 T cell proliferation in vivo. GVAX induced rapid proliferation of OT-1 cells, whereas TEGVAX failed to induce any. We then determined if TEGVAX required myeloid or NK cells to function. TEGVAX reduced B16-mOVA tumor burden in NK depleted, but not myeloid cell depleted mice. To determine if T cell circulation from the dLN to the tumor was necessary, we administered FTY720, which sequesters circulating T cells in lymph nodes, prior to vaccination. TEGVAX significantly reduced B16-mOVA tumor growth even in the presence of FTY720 treatment, suggesting T cell priming was not required. Immune phenotyping of TEGVAX treated B16 tumors and showed the presence of activated tumor infiltrating tissue-resident memory (Trm) T cells. Our results demonstrate that combining a TLR4 agonist with GVAX completely alters the immune response to GVAX vaccination. TEGVAX primes naïve T cells poorly and does not require T cell circulation to reduce tumor growth. These findings suggest that TEGVAX functions by eliciting a tumor-specific Trm T cell response independent of lymph node priming.

Introduction: Multi-modal therapy for adrenocortical carcinoma (ACC) includes surgery, therapy with the adrenolytic agent mitotane and systemic chemotherapy. Achievement of therapeutic mitotane concentrations (≥14 mg/l) has been related to improved outcomes. Aim: To evaluate the effectiveness of a defined* high dose protocol mitotane therapy in patients with advanced ACC (stages III and IV). Methods: Review of patients presenting to KCH with stage III or IV ACC and the mitotane concentration achieved through the Lysosafe monitoring service. Results: N=57 patients were referred and first diagnosed with ACC (2008-17) of whom 44 patients had stage III or IV disease at diagnosis and were managed actively with surgery and/or mitotane therapy. 40/44 patients underwent surgical resection of the primary tumour;11/22 patients with stage IV disease subsequently received systemic chemotherapy [10 patients received a combination of etoposide, doxorubicin and cisplatin (EDP) and 1 patient received a combination of carboplatin and etoposide]. 38/44 patients were initiated on mitotane therapy. The median overall survival of patients with stage IV disease was 25.3 months. The median survival for stage III has not been reached. An additional 9 patients had prior management, including surgery, elsewhere and were referred for mitotane initiation. A total of 47 patients were therefore included in the mitotane pharmacokinetic analysis. Six patients were excluded: 3 patients died shortly after mitotane initiation, 1 patient withdrew due to a severe reaction and 2 patients had not completed 12 weeks therapy at the time of submission. Of the remaining 41 patients, 33 commenced the ‘high dose’ protocol and the remainder the ‘low dose’ protocol. For patients on the high dose protocol, 25/33 (76%) reached a mitotane concentration ≥14 mg/l within 12 weeks of initiation of therapy, compared to 3 patients from the low dose protocol group (P=0.084). In the high dose protocol group, 21 patients (84%) maintained therapeutic drug concentrations in ≥50% of the subsequent follow-up samples and 12 patients (48%) maintained therapeutic drug concentrations in ≥75% of subsequent samples. Conclusion: The use of high dose protocol mitotane therapy is a successful strategy to achieve and maintain therapeutic drug concentrations when treating patients with advanced ACC (stages III and IV). In combination with an assertive surgical approach and optimal chemotherapy, this has resulted in outcomes that compare favourably (median OS 25.5 months in stage IV disease) with previously published series which describe a median OS

Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood- and urine-derived cells through forced expression of Steroidogenic Factor-1 and activation of PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes and secreted steroid hormones in response to stimuli. hiSCs successfully engrafted into the mouse kidney capsule and underwent intra-adrenal differentiation. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications to study adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies.

Summary Background Although postgraduate trainees play a well-accepted role in medical education, little consideration has traditionally been given to senior undergraduate trainees as teachers. Recently, research has shown senior medical students (SMS) can play an effective teaching role for junior medical students (JMS) in non-clinical medical settings. Purpose The purpose of our study was to understand the perceptions of SMSs as teachers in a clinical environment for JMS. Method All students who participated in our peer-led bedside teaching programme from September 2010 to May 2012 were invited to complete a questionnaire following their teaching session. Fifty-six of 70 JMS (80%) and 15 of 15 SMS (100%) participated. Survey questions addressed learning, bedside experiences, teacher effectiveness and the overall usefulness of these sessions. The data collected were analysed for significance of the perceptions reported. Results We found students reported positive and statistically significant results in all domains examined. JMS reported that sessions were highly valuable learning, improved confidence and comfort at the bedside, had excellent teaching and were a valuable addition to their clinical skills training. SMS reported getting highly valuable learning through preparation and developing improved comfort in a teaching role. Little consideration has traditionally been given to senior undergraduate trainees as teachers Conclusions Our findings demonstrate that peer-directed learning in undergraduate medical education can be effectively implemented in the clinical arena.

Concerns about the potential for significant environmental impact from residues of human pharmaceuticals emerged at the beginning of the 21st century. Since then there has been an exponential rise in the number of publications and conferences on this "problem". However, this intense focus on human pharmaceuticals is misplaced. Pharmaceuticals do not consist of a coherent group of substances with similar chemical, structural, biological or toxicological properties. Pharmaceuticals are only identifiable from their use: in other words substances can be divided into two classes, those that are used as pharmaceuticals and those for which a possible pharmaceutical use has not yet been discovered. For example, nitro-glycerine, Warfarin and dimethyl fumarate, initially sold respectively as an explosive, a rodenticide and a mould inhibitor have subsequently all been used as pharmaceuticals. As analytical science advances, an increasing range of environmental contaminants, including pharmaceuticals, is being identified at sub μgL(-1) concentrations. Although, human and environmental exposure to these contaminants will be low, all of them need to be subjected to risk assessment on a case by case basis. Many of these substances, including human pharmaceuticals, may have little, if any, impact on human health or the environment, however for some substances there may be a significant risk and in these cases appropriate action should be taken. However considering all human pharmaceuticals as a special case, isolated from the wider range of emerging contaminants, is scientifically unjustifiable and diverts resources away from the consideration of other substances that may be of considerably more significance.

Background Refeeding syndrome (RS) is a potentially fatal condition that can occur following the re-introduction of nutrition after a period of starvation. Hypophosphataemia following the reintroduction of nutrition is often the only reliable biochemical marker of RS. Refeeding index (RI) generated from baseline insulin-like growth factor-1 (IGF-1) and leptin has been proposed as a useful biochemical marker for the identification of patients at risk of developing refeeding hypophosphataemia (RH). Methods A prospective study included 52 patients referred for parenteral nutrition (PN). The sensitivity and specificity of IGF-1 measured using a sensitive assay was compared to the RI in predicting the development of RH (a ≥30% drop in PO4 during the first 36-h of PN administration). Leptin and IGF-1 were analysed on baseline samples using a quantitative enzyme-linked immunoassay. Daily blood samples were collected from all patients for routine biochemistry for the full duration of PN administration. Results High sensitivity IGF-1 measurement alone was comparable with the RI, using receiver–operating characteristic (ROC) curve analysis, with areas under the curve being 0.79 and 0.80, respectively, and superior to leptin alone (0.72) for predicting ≥30% drop in PO4. The cut-off value for IGF-1 that gave best sensitivity (91% [95% CI 75–98%]) and specificity (65% [95% CI 41–85%]) was 63.7 µg/L, with a likelihood ratio of 2.59. Conclusion Baseline IGF-1 is an objective, sensitive and specific biochemical marker in identifying patients who are at high risk of developing RH prior to PN administration and therefore may have a role in clinical practice.

Exogenous bile acid (BA) administration is associated with beneficial metabolic effects very similar to those seen after Roux-en-Y gastric bypass (RYGB) surgery. Re-routing of bile into a biliopancreatic limb with simultaneous exclusion of food occurs after RYGB, with subsequent increased fasting plasma BAs. The study assessed fasting and post-prandial plasma BA response before and 15 months after RYGB.The prospective study recruited 63 obese individuals (43 females), aged 43 (36-56) [median (IQR)] years. Blood samples were collected before and every 30 min for 120 min after a standard 400 kcal meal. Fasting and post-prandial plasma BAs, glucagons like peptide-1 (GLP-1), -tyrosine (PYY), fasting C-reactive protein (CRP), glucose and insulin were measured and homeostasis model assessment-insulin resistance (HOMA-IR) was calculated.Following RYGB, body mass index, CRP, fasting glucose and HOMA-IR decreased; 43.7 (39.3-49.2) kg/m(2) to 29.2 (25.1-35.0) kg/m(2), 7.9 (4.1-11.9) mg/L to 0.4 (0.2-1.0) mg/L, 5.5 (5.0-6.0) mmol/L to 4.6 (4.3-4.9) mmol/L and 5.9 (3.5-9.2) to 1.7 (1.1-2.2), respectively, all P0.001. Fasting total BAs, GLP-1 and PYY increased after RYGB; 1.69 (0.70-2.56) µmol/L to 2.43 (1.23-3.82) µmol/L (P = 0.02), 6.8 (1.5-15.3) pmol/L to 17.1 (12.6-23.9) pmol/L (P0.001) and 4.0 (1.0-7.1) pmol/L to 15.2 (10.0-28.3) pmol/L (P0.001), respectively. The area under the curve for post-prandial total BAs, total glycine-conjugated BAs, GLP-1 and PYY were greater after RYGB; 486 (312-732) µmol/L/min versus 1012 (684-1921) µmol/L/min, 315 (221-466) µmol/L/min versus 686 (424-877) µmol/L/min, 3679 (3162-4537) pmol/L/min versus 5347 (4727-5781) pmol/L/min and 1887 (1423-2092) pmol/L/min versus 3296 (2534-3834) pmol/L/min, respectively, all P0.0001.Weight loss following RYGB is associated with an increase in post-prandial plasma BA response due to larger amounts of glycine-conjugated BAs. This suggests up regulation of BA production and conjugation after RYGB.

Background Bile acids (BAs) play an important role in releasing incretin hormones via the enteroendocrine L-cell surface TGR5 receptors. The aim of this study was to investigate the difference in BA concentration at baseline and in response to a meal stimulus between type 2 diabetes mellitus (T2DM) and a matched normoglycaemic group. Materials and methods A cross-sectional study of 12 patients with known T2DM and 12 matched normoglycaemic controls compared BA fractions after an overnight fast and following a standard meal. Results The T2DM group had higher baseline glucose (P Conclusion The post-prandial bile acid response is elevated in obese patients with T2DM compared to matched normoglycaemic individuals.

This paper is concerned with the volatility modeling of a set of South African Rand (ZAR) exchange rates. We investigate the quasi-maximum-likelihood (QML) estimator based on the Kalman filter and explore how well a choice of stochastic volatility (SV) models fits the data. We note that a data set from a developing country is used. The main results are: (1) the SV model parameter estimates are in line with those reported from the analysis of high-frequency data for developed countries; (2) the SV models we considered, along with their corresponding QML estimators, fit the data well; (3) using the range return instead of the absolute return as a volatility proxy produces QML estimates that are both less biased and less variable; (4) although the log range of the ZAR exchange rates has a distribution that is quite far from normal, the corresponding QML estimator has a superior performance when compared with the log absolute return.

The morbidity and mortality conference (MMC) remains a central activity within the departments of our academic healthcare institutions. It is deeply rooted in the premise that we can learn from our mistakes, thereby improving the care we provide. Recent advances in our understanding of medical error and quality improvement have challenged the value of traditional models of MMC. As a result the purpose of MMC has become clouded and ill-defined: Is it an educational conference that promotes mastery of clinical acumen, or is it a venue to drive quality improvement by addressing systems-based issues in delivering care? Or can it serve both purposes?Review of the history of MMC, the literature, and critical application of education theory demonstrates the source of the confusion and the challenges in viewing it through the exclusive lens of either education or quality improvement. Application of experiential learning theory helps resolve this discord showing how the conference facilitates the development of clinical mastery while informing quality improvement programs about important and relevant systems-based issues.Building on this, we present a model for MMC involving five essential elements: case-based involving an adverse patient event, anonymity for participants, expert guided critical analysis, reframing understanding of the case presentation and related systems-based factors, and projection to practice change. This model builds on previously described models, is grounded in the literature, and helps clarify its role from both the educational and the quality improvement perspectives.

Background Competency-based medical education has not advanced residency training as much as many observers expected. Some medical educators now advocate reorienting competency-based approaches to focus on a resident's ability to do authentic clinical work. Objective To develop descriptions of clinical work for which internal medicine residents must gain proficiency to deliver meaningful patient care (for example, "Admit and manage a medical inpatient with a new acute problem"). Design A modified Delphi process involving clinical experts followed by a conference of educational experts. Setting The Royal College of Physicians and Surgeons of Canada. Participants In phase 1 of the project, members of the Specialty Committee for Internal Medicine participated in a modified Delphi process to identify activities in internal medicine that represent the scope of the specialty. In phase 2 of the project, 5 experts who were scholars and leaders in competency-based medical education reviewed the results. Measurements Phase 1 identified important activities, revised descriptions to improve accuracy and avoid overlap, and assigned activities to stages of training. Phase 2 compared proposed activity descriptions with published guidelines for their development and application in medical education. Results The project identified 29 activities that qualify as entrustable professional activities. The project also produced a detailed description of each activity and guidelines for using them to assess residents. Limitation These activities reflect the practice patterns of the developers and may not fully represent internal medicine practice in Canada. Conclusion Identification of these activities is expected to facilitate modification of training and assessment programs for medical residents so that programs focus less on isolated skills and more on integrated tasks. Primary funding source Southeastern Ontario Academic Medical Organization Endowed Scholarship and Education Fund and Queen's University Department of Medicine Innovation Fund.

(Headache 2010;50:357-373) Objective.— To describe the pharmacokinetic and safety profiles of sumatriptan 85 mg formulated with RT Technology (RT) and naproxen sodium 500 mg in a fixed-dose combination tablet (sumatriptan/naproxen sodium) that targets both serotonergic dysmodulation and inflammation in migraine. Methods.— Six open-label, crossover studies were conducted in healthy volunteers (Studies 1, 2, 3, 4, 5) or patients with migraine (Study 6). Results.— Consistently across studies, naproxen administered as a component of sumatriptan/naproxen sodium demonstrated a delayed-release profile similar to that of an enteric-coated product. Naproxen from the combination tablet showed a delayed time to peak plasma concentration and lower peak plasma concentration while exposures (area under the plasma concentration–time curve) were similar. The peak plasma concentration for naproxen was approximately 36% lower and the time to peak plasma concentration approximately 4 hours later when naproxen was administered as sumatriptan/naproxen sodium compared with a single naproxen sodium 550 mg tablet. Sumatriptan peak plasma concentration and area under the plasma concentration–time curve after administration of sumatriptan/naproxen sodium (containing sumatriptan 85 mg) were comparable to those after administration of a commercially available sumatriptan 100 mg (RT) tablet. Sumatriptan time to peak plasma concentration occurred, on average, 30 minutes earlier with sumatriptan/naproxen sodium compared with sumatriptan 100 mg (RT). No clinically significant differences between sumatriptan/naproxen sodium and sumatriptan tablets 100 mg (RT) were identified with respect to electrocardiograms, blood pressure, or heart rate. In addition, food had no significant effect on the bioavailability of naproxen or sumatriptan after administration of sumatriptan/naproxen sodium but slightly delayed the time to peak plasma concentration of sumatriptan by approximately 40 minutes. The pharmacokinetics of sumatriptan and naproxen did not differ according to whether sumatriptan/naproxen sodium was administered during a migraine attack or a migraine-free period. The pharmacokinetics of 2 sumatriptan/naproxen sodium tablets administered 2 hours apart were consistent with the pharmacokinetic predictions from a single dose of the combination tablet. The adverse-event profile of the sumatriptan/naproxen sodium combination tablet did not appear to differ from that of the individual components of the same or similar dosage strengths administered alone or in combination. In addition, the incidence of adverse events with 2 sumatriptan/naproxen sodium tablets administered 2 hours apart was lower than that with the single dose. Conclusion.— The combination tablet of sumatriptan/naproxen sodium has unique pharmacokinetic properties. The rapid absorption of sumatriptan with the delayed-release properties of naproxen sodium from sumatriptan/naproxen sodium might contribute to its therapeutic advantage over monotherapy with either component. No clinically meaningful effects of food, administration during a migraine attack, or administration of a second tablet (2 hours after initial dose) on the pharmacokinetics or safety of sumatriptan/naproxen sodium were observed.

A comprehensive and systematic study of overall termination rate coefficients, k t , in low-conversion radical (homo)polymerization of methyl methacrylate and styrene is presented. Values of k t were determined by gravimetric analysis of steady-state experiments, employing 2,2'-azoisobutyronitrile as initiator. The values delivered by this simple method were found to be in qualitative and quantitative agreement with those from more modern and sophisticated techniques for measuring k t . Accordingly, correlations for bulk, low-conversion k t as a function of temperature are given for each monomer. The effects of initiator concentration, c I , and temperature on bulk k t were studied in a controlled way for both monomers. Additionally, ethyl benzene was used as solvent in order to investigate rigorously the effect of monomer concentration, c M , on styrene k t . The trends found by these systematic studies were considered in the light of what is known about the chain-length dependence of termination. Styrene's behavior was always found to be qualitatively in accord with expectation, although the variations of k t with c I and c M were not as strong as should be the case. However its activation energy, 15 kJ · mol- 1 , is shown to be almost perfectly in agreement with theory. Methyl methacrylate, on the other hand, is recalcitrant in that its overall k t does not make manifest the chain-length dependent termination that has been directly measured by other techniques. Possible reasons for these discrepancies are discussed, as are reasons for the difference in values between k t for the two monomers. On the latter topic it is concluded likely that the chain-length dependence of termination at short chain lengths is primarily responsible for styrene having k t that is higher by a factor of about 3, with there also being a contribution that arises from styrene's slower propagation.

The distributional properties of returns data have important implications for financial models and are of particular importance in risk-scenario simulation, volatility prediction and in the event of financial crisis. We present simple time-series models that capture the heteroskedasticity of financial time series and incorporate the effect of using heavy-tailed distributions. These models allow for time-varying volatility, which is an important extension of the conventional methodology. The models are an augmentation of the GARCH class of models, but allow for conditionally normal inverse Gaussian and variance gamma distributed errors. As in previous studies, this new approach permits a distinction between conditional heteroskedasticity and a conditionally leptokurtic distribution, but, compared with the well-known GARCH-t model, it allows us to capture the asymmetric behaviour observed in actual returns series. The practical applicability of the models is confirmed by implementing a fitting procedure to a carefully chosen set of South African stock price returns.

In the field of membrane biology, perhaps one of the most controversial concepts in recent years has been the enigmatic membrane microdomain, the cholesterol- and glycosphingolipid-rich lipid raft.