The missing ingredient: Medical student insights to inform and enhance learner handover.

BACKGROUND: Learner handover (LH) is the passing on of information about students between educators. In light of broad acceptance that LH can improve learner support experiences and performance outcomes, those involved are seeking greater governance to achieve practical, effective handover implementation. Stakeholder consultation can inform and enable the co-creation of meaningful, robust practice guidance. This study sought to address the gap in literature around in-depth learner opinion, a key element so far overlooked. METHODS: This qualitative study (2022) investigated undergraduate medical student perspectives on appropriate tutor information-sharing at the University of Limerick School of Medicine (ULSoM). The findings build upon an educator focus group study published by the authors (2021). Eleven participants were recruited to represent the typical graduate-entry medical school programme population across years 1-4 of study. Their understanding and expectations of "learner handover" were explored qualitatively, using online, individual, semi-structured interviews. Inductive transcript coding and thematic data analysis were applied to illustrate learner insights. FINDINGS: Emergent themes included shared values, individual context and collaborative process, with ideas proposed for specific action around student education, staff training, mental health support, and documented procedures. DISCUSSION: Consent, system transparency, data security and the development of positive handover culture were revealed as current needs. Student perspectives, together existing LH literature and highlighted aspects of educational theory, allowed the creation a new conceptual LH framework as a foundation for practice improvement. CONCLUSION: These findings provide clarity and contextual understanding, mainly from a pre-clinical phase learner standpoint, with pragmatic suggestions to enhance LH appeal.

Mentoring & support practices for final year medical students during a pandemic - 'The covid doctors'.

BACKGROUND: Transition from final-year medical student to newly graduated doctor is challenging with evidence of associated increased patient mortality and medical errors. Previous work suggests tackling preparedness alone does not 'solve' this transition. The current focus on mentoring and support provision during this period and is an under-researched area. The COVID-19 pandemic represents a unique disruptive critical incident in which to examine mentoring and support practices, exposing strengths and weaknesses. The perspectives of this cohort and their implications remains an under-researched area. METHODS: Individual semi-structured interviews were conducted with nine graduate-entry final-year medical students. An inductive latent phenomenological approach explored individual experiences of mentoring and support practices during final-year and transition to professional practice. RESULTS: Three major themes emerged: 1) Mentoring & Support; 2) Clinical Exposure; 3) Graduation & Transition. A journey metaphor was used to aid the description of participants' lived experience of mentoring and support practices during their final year. Final year medical students (FYMs) felt under-supported and found practices inadequate. Reduced clinical exposure yielded unpreparedness and regression, potentially impacting future careers. Positive experiences were variable and unstructured. 'The COVID Doctors', subtheme provided rich insights into shared narratives and identities amongst participants. CONCLUSIONS: This study provides qualitative evidence for perceived inadequate mentoring and support provision for final year medical students at transition during a critical incident (the COVID-19 pandemic). Several themes using the metaphor of a journey explore the lived experience of this unique cohort determining their perceptions on the delivery of their medical education and their identity as 'covid doctors'. There are several implications for this study in a post-pandemic era and for pandemic-preparedness, both rapidly growing areas of research in medical education. Recommendations include updating contingency plans, balancing clinical exposure with patient safety issues, and providing support to 'bottom-up' mentoring practices.

Health-related Internet Use by Caregivers of Children and Adolescents With Cancer.

Caregivers of children with cancer have needs for information and social support related to their child's diagnosis. The internet serves as a resource to help meet these needs. There is growing interest in health-related internet use (HRIU) by caregivers of pediatric patients as the internet rapidly evolves. This survey study describes patterns of internet use by caregivers of children with cancer and examines associations between socioeconomic status and internet use. 114 caregivers participated between 2014 and 2016. The majority (82%) reported frequent general internet use, but fewer (25-54%) reported frequent HRIU. Very few respondents (4%) reported difficulty accessing the internet; those reporting difficulty were more likely to report lower income, public/no insurance, and lower educational attainment. There were no consistent associations between socioeconomic status variables and frequency of HRIU. Less than half (43%) of caregivers reported that their internet use raised questions that they discussed or planned to discuss with the child's nurse or doctor, and only 4% reported having changed medical decisions based on information found on the internet. We conclude that caregivers of children with cancer engage in HRIU, and this is an area for improvement in oncology anticipatory guidance and family-centered care.

Tutor Uncertainty in Dealing with Unprofessional Behaviours of Medical Students and Residents: a Mixed Methods Study.

BACKGROUND: Despite acknowledgement of medical students' expected professional behaviours and attitudes, there remains widespread reluctance to report students that behave inappropriately. Existing literature focuses on why faculty fail to fail, overlooking the tutors who deal with students day to day. We investigated how tutors address inappropriate behaviours and attitudes in students and residents. METHODS: A mixed methods study was carried out consisting of a survey and two focus groups with tutors. Seventeen tutors from the University of Limerick School of Medicine, Ireland, took part in the survey (n = 22%) and eight tutors participated in two focus groups during the 2018-2019 academic year. RESULTS: Findings suggested that 59% of tutors would take a different approach to addressing unprofessional behaviours witnessed in medical students and residents. A total of 88% of tutors said they intervened on a professionalism issue with 52% saying 'once in a while'. In contrast to the survey, tutors in the focus groups expressed a lack of confidence in addressing some behaviours due to a lack of time, not seeing the outcome of process/remediation etc. Tutors indicated a strong preference for case-based training on assessing professional identity formation (PIF). CONCLUSIONS: We found tutors typically work closely with students on a day-to-day basis managing unprofessionalism issues. Tutors valued regular communication about policies and procedures about appropriate conduct as well as support, advice, and/or oversight from independent members of university staff. This research highlights the need for training designed for busy tutors as a distinct type of medical teacher. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01429-1.

Medical students and clinical placements - a qualitative study of the continuum of professional identity formation.

Background: To explore graduates' perceptions of significant factors affecting professional identity formation (PIF) throughout their graduate medical school education journey and early practice years.Methods: A qualitative study with medical graduates using non-probability sampling. Data collected with graduates via face to face and telephone interviews. Interviews (n = 9) completed with medical graduates of the School of Medicine, University of Limerick.Results: Graduates described their experiences in general practice, during the early patient contact programme and the longitudinal integrated clerkship (LIC) as highly influential. The lasting impact of positive role models was highlighted. The importance of socialisation and entering a community of practice were identified as drivers of professional development. Role modelling and mentorship between students and GP tutors were pivotal as part of early clinical years and clinical LIC. This seemed to have a positive influence on graduate's consideration of general practice as a future career pathway.Conclusion: Professional identity formation occurs for medical students who participate in early patient contact programmes and longitudinal integrated clerkships in GP. Factors such as positive role modelling, good mentorship, communities of practice and a positive learning environment appear to be the main contributors to this process. Experiences as part of longitudinal integrated clerkships are meaningful for graduates, regardless of postgraduate specialisation choices. Educators should acknowledge this when designing medical curricula to ensure that students' professional identity formation is optimally facilitated. Training should be available to support the educators involved in longitudinal integrated clerkships, as they become role models and mentors to students.

Race and socioeconomic status in pediatric allogeneic hematopoietic cell transplantation for nonmalignant conditions.

BACKGROUND: Survival disparities by race/ethnicity and socioeconomic status (SES) are observed in a wide range of pediatric treatment settings including oncology and solid organ transplantation. To date, few studies have examined the effects of race and SES on outcomes in pediatric allogeneic hematopoietic cell transplantation (HCT). We explored whether survival differed by race/ethnicity or SES in children receiving HCT for nonmalignant conditions at a single institution serving a diverse patient population. PROCEDURES: The Kaplan-Meier method was used to estimate overall survival (OS) with the log-rank test for between-group comparisons. Cox proportional hazards models were used to identify risk factors for OS, adjusting for treatment- and disease-related factors. RESULTS: Of 133 subjects, 0 to 21 years, 19% were non-Hispanic (NH) white, 34% were NH black, 40% were Hispanic, and 7% were Asian. Sixty-seven percent of the subjects had public insurance; 49% lived in neighborhoods with poverty rate ≥20%. Primary diagnoses included hemoglobinopathies (56%), bone marrow failure (22%), and other conditions (22%). Median follow-up was 5.8 years (range 0.1-14.5). Analysis revealed no difference in OS by race, insurance type, or neighborhood SES. CONCLUSIONS: Findings from this single-institution study suggest that in pediatric patients undergoing HCT for nonmalignant conditions, treatment at a tertiary care center with a multidisciplinary approach may mitigate drivers of disparities observed in other settings. Additional studies are now needed to further elucidate the complex interrelationships among race, SES, and clinical outcomes for children undergoing HCT.

Correction: Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

Following publication of this article, the authors noticed an error in the abstract, where they incorrectly stated that: "Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-/--dependent fashion". This has now been corrected to: "Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion". The authors would like to apologise for this error. This has been corrected in both the PDF and HTML versions of the article.

Postpartum depression prevalence and risk factors among Indigenous, non-Indigenous and immigrant women in Canada.

OBJECTIVES: The social position of different minority groups in contemporary societies suggests different risk factors for postpartum depression (PPD). In this study, we used two cut-offs of the Edinburgh Postpartum Depression Scale (EPDS) to examine prevalence and risk factors for PPD among mothers participating in the Canadian Maternity Experiences Survey (MES), and to compare Indigenous, Canadian-born non-Indigenous and immigrant mothers. METHODS: We used cross-sectional nationwide data from the 2006 MES (unweighted N = 6237, weighted N = 74,231) and conducted multivariate logistic regression models for EPDS ≥ 10 and EPDS ≥ 13 to explore risk factors for the total sample of mothers and in each study group. RESULTS: Prevalence (%, 95 % CI) of EPDS ≥ 10 and EPDS ≥ 13 was significantly higher among immigrant (12.2 %, 10.2-14.2 and 24.1 %, 21.5-26.7) and Indigenous (11.1 %, 7.5-14.7 and 21.2 %, 16.5-25.9) compared to Canadian-born non-Indigenous mothers (5.6 %, 4.9-6.3 and 12.9 %, 11.9-13.9). Multivariate analysis of the total sample showed similar risk factors for EPDS ≥ 10 and EPDS ≥ 13 (ethnicity, low education, ≥ low income cut-off, taking antidepressants, experiencing abuse, low social support). Stratification by study group revealed differing risk factors in each group for EPDS ≥ 10 and EPDS ≥ 13. Indigenous mothers had the most distinct risk factors, followed by immigrant mothers. Non-indigenous Canadian-born mothers had risk factors most similar to the total sample. CONCLUSION: Differing prevalence and risk factors for PPD within and across study groups suggest that instead of a universal approach, tailored programs and services to prevent PPD in Indigenous, immigrant and non-Indigenous Canadian-born groups could better protect the mental health of Canadian mothers.

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1ß replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1ß synthesis. Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1ß but direct hippocampal action of IL-1ß causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

What can we learn from problem-based learning tutors at a graduate entry medical school? A mixed method approach.

Problem-based learning (PBL) has been adopted by many medical schools as an innovative method to deliver an integrated medical curriculum since its inception at McMaster University (Dornan et al., Med Educ 39(2):163-170, 2005; Finucane et al., Med Educ 35(1):56-61, 2001; Barrows, Tutorials in problem-based learning: A new direction in teaching the health professions, 1984). The student experience in PBL has been explored in detail (Merriam, New Directions for Adult and Continuing Education 89: 3-13, 2001; Azer, Kaohsiung J Med Sci 25(5): 240-249, 2009; Boelens et al., BMC Med Ed 15(1): 84, 2015; Dolmans et al., Med Teach 24(2):173-180, 2002; Lee et al., Med Teach 35(2): e935-e942, 2013) but the tutors who facilitate PBL have valuable insight into how PBL functions and this aspect has not been extensively researched. The integrated curriculum for years 1 and 2 at the Graduate Entry Medical School at the University of Limerick is delivered though problem-based learning (PBL). This programme requires collaborative teamwork between students and the tutors who facilitate small-group tutorial sessions. All PBL tutors at GEMS are medically qualified, with the majority (68%) currently working in clinical practice. METHODS: A mixed-methods approach was adopted, utilising two surveys and follow-up focus groups to fully understand the tutor experience. Thirty-three tutors took part in two online surveys with a response rate of 89%. Thirteen tutors participated in two focus groups. Descriptive analysis was completed on survey data and thematic analysis on focus group discussions which highlighted five main themes. RESULTS: Tutors reported challenges with managing group dynamics, development of confidence in tutoring with experience and a willingness to learn from peers to improve practice. Findings are in keeping with previously published work. Results also identified several less commonly discussed issues impacting student engagement in PBL including the use of mobile device technology, unauthorised access to learning objectives and PBL cases, and the importance and need for professional development amongst tutors, including the impact of tutoring on clinical practice. This study revealed that experienced tutors spend considerable time preparing for PBL tutorials in the basic sciences and that this input is rewarded by the benefits it brings to their clinical practice. CONCLUSIONS: Understanding PBL from the tutor's perspective reveals valuable insights which can inform ongoing tutor development and support. Limited research exists in the area of PBL tutor's experiences which may be of interest to medical educators, clinicians and the wider medical community. Findings highlight the value of shared tutor experiences as a resource that can be capitalised on to benefit both novice and experienced tutors.

Validation of Transient Elastography Cut Points to Assess Advanced Liver Fibrosis in Children and Young Adults: The Boston Children's Hospital Experience.

OBJECTIVE: To derive an optimal liver stiffness measurement cut point to discriminate METAVIR fibrosis stage F4 and to validate both METAVIR fibrosis stage F3-F4 and F4 cut points in a separate cohort. STUDY DESIGN: Patients at Boston Children's Hospital with liver stiffness measurement from 2006 to 2016 and liver biopsy ≤12 months before screening were eligible. Patients enrolled 2006-2011 were used to calibrate liver stiffness measurement cut points and those enrolled 2011-2016 for validation. Diagnostic performance was assessed by receiver operating curve analysis. RESULTS: In total, 267 subjects were enrolled (97 calibration, 170 validation). The cohorts were similar with 54% male, aged 0-29 years (median 13 years), and liver diseases including 21% autoimmune, 19% viral, 11% nonalcoholic fatty liver, 9% cholestatic, and 9% primary sclerosing cholangitis. Cut points to discriminate F3-F4 and F4 were >8.6 kPa and >11.5 kPa with 81% and 84% accuracy, respectively. Applied to the validation cohort, accuracy was 67% and 75%, respectively. In 44 fasted subjects, the accuracy was 73% and 80%, respectively. CONCLUSION: This study validates previously determined liver stiffness measurement cut points of 8.6 kPa and 11.5 kPa to predict METAVIR F3-F4 and F4 fibrosis in children and young adults in separate cohorts. With increasing data on the utility and validity of liver stiffness measurement in children, transient elastography may help identify patients with greater risk of advanced fibrosis and those who need liver biopsy assessment and/or surveillance for the complications of cirrhosis in a variety of liver disorders.

Correlation of Transient Elastography With Severity of Cystic Fibrosis-related Liver Disease.

OBJECTIVES: The aim of the study was to evaluate whether liver stiffness measurement (LSM), determined by transient elastography, correlates with presence and severity of liver disease in children and young adults with cystic fibrosis (CF). METHODS: Subjects underwent LSM at routine CF visits. Presence and severity of cystic fibrosis liver disease (CFLD) was determined by clinical parameters. Subjects were classified as no CFLD, CFLD without portal hypertension (PHTN), and CFLD with PHTN. LSM was compared with aspartate aminotransferase/platelet ratio index (APRI) as a correlate to severity of CFLD. RESULTS: A total of 249 subjects (53% boys; mean age 14 ±â€Š7 years; 7 [3%] <2 years and 74 [30%] 18-25 years) underwent LSM. Subjects were classified as 158 (64%) with no CFLD, 73 (29%) CFLD without PHTN, and 18 (7%) CFLD with PHTN. The median (interquartile range) LSM was different among the 3 groups: 4.4 (3.8-5.4), 5.1 (4.4-6.3), and 14.1 (8.8-24.8) kPa, respectively, with all pairwise comparisons different from one another (P < 0.0001). Similarly, median (interquartile range) APRI was different in groups 1 and 2 compared with CFLD with PHTN: 0.22 (0.17-0.27), 0.24 (0.17-0.33), and 0.53 (0.24-0.84), respectively (P < 0.01). Analysis of receiver operating characteristics for discriminating CFLD with PHTN from the other groups resulted in cut-points at 6.2 kPa (LSM) and 0.35 (APRI). LSM was superior to APRI in discriminating CFLD with PHTN from other groups, with areas under the curve 0.91 (LSM) versus 0.78 (APRI) (P = 0.05). CONCLUSIONS: Liver stiffness, as determined by transient elastography, correlates with the presence and severity of CFLD. Although APRI provided some information regarding severity of liver disease, LSM performed better than APRI in this population.

Hepatic Inflammation May Influence Liver Stiffness Measurements by Transient Elastography in Children and Young Adults.

OBJECTIVES: Transient elastography (TE) measures liver stiffness to assess fibrosis. Studies in adults have shown that inflammation increases stiffness, leading to an overestimation of fibrosis. We investigated the contribution of inflammation to liver stiffness measurements (LSMs) in children/young adults. METHODS: This was a cohort analysis of children/young adults who underwent TE within 1 year of liver biopsy. Alanine aminotransferase (ALT) was obtained within 30 days of the biopsy and LSM. Fibrosis was assessed by METAVIR stage and inflammation by ALT and Ishak score. Data were stratified into METAVIR F0-F2 versus F3-F4. Change between ALT and LSM over time was also assessed. RESULTS: A total of 154 patients (50% male patients) ages 3 weeks to 24 years (18% <3 years) were studied. Diagnoses included autoimmune (N = 38, 25%), viral (N = 25, 16%), cholestasis (N = 17, 11%), fatty liver (N = 9, 6%), biliary atresia (N = 8, 5%), metabolic (N = 5, 3%), allograft rejection (N = 4, 3%), and other (N = 48, 31%). Thirty-four percent of patients had F3-F4. In patients with F0-F2, the proportion of those with LSM >8.6 kPa increased with increasing ALT (P = 0.002). In patients with F3-F4, there was no association between ALT and LSM (P = 0.17). A correlation between change in ALT and LSM was observed in patients with no/minimal fibrosis and inflammatory liver diseases (r = 0.33). CONCLUSIONS: In children with no/minimal hepatic fibrosis and inflammatory liver disease, high ALT values are associated with LSM in the range typical of advanced fibrosis. However, with more advanced fibrosis, inflammation does not appear to contribute to LSM. Caution must be taken when interpreting LSM for assessing fibrosis severity in the setting of inflammation.

The Natural History of Primary Sclerosing Cholangitis in Children: A Large Single-Center Longitudinal Cohort Study.

OBJECTIVES: Data regarding pediatric primary sclerosing cholangitis (PSC) natural history are limited. We describe a large pediatric PSC cohort with longitudinal follow-up. METHODS: The present study records review of pediatric patients with PSC diagnosed between 1984 and 2014. RESULTS: N = 120 (63% M) ages 1 to 21 years (median 14 years) at diagnosis. 27% (31/113) had autoimmune sclerosing cholangitis (ASC), 24% had exclusive small duct PSC, METAVIR stage was F3-F4 in 41%. Eighty-one percent of patients with PSC had inflammatory bowel disease (IBD); most had ulcerative/indeterminate colitis (72/97), typically pancolitis (40/72). PSC-IBD was more common than ASC-IBD (85% vs 68%, P = 0.03). Median follow-up was 3.7 years (interquartile range [IQR] 1.5, 6.9). Median gamma glutamyl transferase decreased from baseline of 221 U/L (IQR 110, 425) to 104 U/L by 1 year postdiagnosis ([IQR 18,229], P < 0.0001), and then changed little. Mean fibrosis stage at diagnosis was 2.3 ±â€Š1.4 (N = 91), and at 1 to 5 years was 2.6 ±â€Š1.3 (N = 20). Transplant-free survival at 10 year was 89%; there were 6 liver transplants, 2 in patients with small duct PSC and 4 with diffuse large duct PSC. Although the cirrhosis rate was not significantly different in PSC with IBD versus without (22% vs 41%, P = 0.06), the former had a lower rate of liver transplantation (2% vs 18%, P = 0.01). The rate of cirrhosis was lower in patients diagnosed with IBD before PSC (15% vs 31%, P = 0.05). CONCLUSIONS: In this largest reported pediatric PSC cohort, liver transplantation rate at 10 years was lower than that reported in adults. ASC and PSC had similar biochemical abnormalities and degree of fibrosis at diagnosis. PSC that developed after IBD diagnosis had a milder course, possibly reflecting earlier disease detection or milder phenotype.

Comparison of Controlled Attenuation Parameter and Liver Biopsy to Assess Hepatic Steatosis in Pediatric Patients.

OBJECTIVE: To assess whether the degree of steatosis as determined by controlled attenuation parameter (CAP) measurements correlates with that observed on liver biopsies in a single-center pediatric and young adult cohort. STUDY DESIGN: This cross-sectional study included patients undergoing liver biopsy as part of standard clinical care between January 25, 2012, and April 1, 2015, at Boston Children's Hospital. Eligible patients, with a variety of liver diseases, had CAP measurements within 1 year of biopsy. CAP values were compared across histologic steatosis grades using ANOVA. RESULTS: Sixty-nine patients (mean age, 16.0 ± 2.9 years; 62% male) were studied. CAP measurements were obtained at a median of 1.3 months (IQR, 0.5-3.2) after biopsy. Of the 69 subjects, 23 had steatosis on biopsy. Mean CAP value (dB/m) for subjects with no steatosis was 198 ± 37 vs 290 ± 47 for subjects with steatosis (P < .0001). There were statistically significant differences between CAP values in individuals with no steatosis vs mild/moderate steatosis (P < .0001), no steatosis vs marked steatosis (P < .0001), and mild/moderate vs marked steatosis (P = .004). CONCLUSION: This study demonstrated a difference in CAP between no steatosis and steatosis, and between grades of steatosis. CAP may be a useful noninvasive tool to detect hepatic steatosis in children.

Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents.

Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.

Transient elastography may identify Fontan patients with unfavorable hemodynamics and advanced hepatic fibrosis.

BACKGROUND: Transient elastography (TE) offers a noninvasive correlate with the degree of hepatic fibrosis. However, factors other than fibrosis affect liver stiffness. We sought to determine whether hepatic congestion related to hemodynamics in Fontan circulation influences liver stiffness measurement (LSM) assessed by TE. METHODS: We studied 45 subjects with Fontan circulation undergoing cardiac catheterization with or without simultaneous liver biopsy. Subjects underwent TE within 5 days before catheterization. Clinical history, hemodynamic and biopsy data, and hepatic biomarkers were collected. Five subjects who had previously undergone liver biopsy and TE were also included. RESULTS: Median age was 13.1 years (range 2.4-57.8); median time since Fontan was 9.9 years (range 0.1-32.5). No subject had known hepatitis C. Mean LSM for the entire cohort was 21.4 ± 10.8 kPa. Univariate regression analysis using LSM as a continuous outcome variable shows significant correlations with age (R = 0.35, P = .01), time since Fontan (R = 0.41, P = .003), Fontan pressure (R = 0.31, P = .04), cardiac index (R = 0.33, P = .03), pulmonary vascular resistance (R = 0.34, P = .03), systemic arterial oxygen saturation (R = 0.31, P = .04), and platelet count (R = 0.29, P = .05). On multiple regression analysis, Fontan pressure (ß = 0.901, P = .03) and cardiac index (ß = 2.703, P = .02) were significant predictors of LSM with overall model R(2) = 0.206. Univariate analysis shows LSM to be associated with more severe centrilobular fibrosis (P = .05). CONCLUSIONS: Higher LSM is associated with unfavorable Fontan hemodynamics and advanced centrilobular hepatic fibrosis. TE may be a useful tool for identifying Fontan patients who warrant invasive testing.

A role for prolyl hydroxylase domain proteins in hippocampal synaptic plasticity.

Hypoxia-inducible factors (HIFs) are key transcriptional regulators that play a major role in oxygen homeostasis. HIF activity is tightly regulated by oxygen-dependent hydroxylases, which additionally require iron and 2-oxoglutarate as cofactors. Inhibition of these enzymes has become a novel target to modulate the hypoxic response for therapeutic benefit. Inhibition of prolyl-4-hydroxylase domains (PHDs) have been shown to delay neuronal cell death and protect against ischemic injury in the hippocampus. In this study we have examined the effects of prolyl hydroxylase inhibition on synaptic transmission and plasticity in the hippocampus. Field excitatory postsynaptic potentials (fEPSPs) and excitatory postsynaptic currents (EPSCs) were elicited by stimulation of the Schaffer collateral pathway in the CA1 region of the hippocampus. Treatment of rat hippocampal slices with low concentrations (10 µM) of the iron chelator deferosoxamine (DFO) or the 2-oxoglutarate analogue dimethyloxalyl glycine (DMOG) had no effect on fEPSP. In contrast, application of 1 mM DMOG resulted in a significant decrease in fEPSP slope. Antagonism of the NMDA receptor attenuated the effects of DMOG on baseline synaptic signalling. In rat hippocampal slices pretreated with DMOG and DFO the induction of long-term potentiation (LTP) by tetanic stimulation was strongly impaired. Similarly, neuronal knockout of the single PHD family member PHD2 prevented murine hippocampal LTP. Preconditioning of PHD2 deficient hippocampi with either DMOG, DFO, or the PHD specific inhibitor JNJ-42041935, did not further decrease LTP suggesting that DMOG and DFO influences synaptic plasticity primarily by inhibiting PHDs rather than unspecific effects. These findings provide striking evidence for a modulatory role of PHD proteins on synaptic plasticity in the hippocampus.

Plasticity of NMDA receptor-mediated excitatory postsynaptic currents at perforant path inputs to dendrite-targeting interneurons.

Synaptic plasticity of NMDA receptors (NMDARs) has been recently described in a number of brain regions and we have previously characterised LTP and LTD of glutamatergic NMDA receptor-mediated EPSCs (NMDAR-EPSCs) in granule cells of dentate gyrus. The functional significance of NMDAR plasticity at perforant path synapses on hippocampal network activity depends on whether this is a common feature of perforant path synapses on all postsynaptic target cells or if this plasticity occurs only at synapses on principal cells. We recorded NMDAR-EPSCs at medial perforant path synapses on interneurons in dentate gyrus which had significantly slower decay kinetics compared to those recorded in granule cells. NMDAR pharmacology in interneurons was consistent with expression of both GluN2B- and GluN2D-containing receptors. In contrast to previously described high frequency stimulation-induced bidirectional plasticity of NMDAR-EPSCs in granule cells, only LTD of NMDAR-EPSCs was induced in interneurons in our standard experimental conditions. In interneurons, LTD of NMDAR-EPSCs was associated with a loss of sensitivity to a GluN2D-selective antagonist and was inhibited by the actin stabilising agent, jasplakinolide. While LTP of NMDAR-EPSCs can be readily induced in granule cells, this form of plasticity was only observed in interneurons when extracellular calcium was increased above physiological concentrations during HFS or when PKC was directly activated by phorbol ester, suggesting that opposing forms of plasticity at inputs to interneurons and principal cells may act to regulate granule cell dendritic integration and processing.