Publications by authors named "Lauren Byrne"

32 Publications

Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington's disease.

Sci Rep 2021 Feb 10;11(1):3481. Epub 2021 Feb 10.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington's disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.
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http://dx.doi.org/10.1038/s41598-021-83000-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876124PMC
February 2021

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease.

Sci Transl Med 2020 12;12(574)

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London WC1B 5EH, UK.

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)-mutant huntingtin (mHTT) and neurofilament light (NfL)-are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.
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http://dx.doi.org/10.1126/scitranslmed.abc2888DOI Listing
December 2020

Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease.

J Neurosci 2021 Jan 11;41(4):780-796. Epub 2020 Dec 11.

Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32828

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin () gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons. Changes in CSF mutant huntingtin (mHTT) are being used as an exploratory endpoint in HTT lowering clinical trials for the treatment of Huntington disease (HD). Recently, it was demonstrated that intrathecal administration of a HTT lowering agent leads to dose-dependent reduction of CSF mHTT in HD patients. However, little is known about how HTT, an intracellular protein, reaches the extracellular space and ultimately the CSF. Our findings that HTT enters CSF by both passive release and active secretion followed by glymphatic clearance may have significant implications for interpretation of treatment-induced changes of CSF mHTT in clinical trials for HD.
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http://dx.doi.org/10.1523/JNEUROSCI.1865-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842749PMC
January 2021

From Medical School to Residency: Transitions During the COVID-19 Pandemic.

J Grad Med Educ 2020 Aug;12(4):507-511

Background: The start of a new academic year in graduate medical education will mark a transition for postgraduate year 1 (PGY-1) residents from medical school into residency. The relocation of individuals has significant implications given the COVID-19 pandemic and variability of the outbreak across the United States, but little is known about the extent of the geographic relocation taking place.

Objective: We reported historical trends of PGY-1 residents staying in-state and those starting residency from out-of-state to quantify the geographic movement of individuals beginning residency training each year.

Methods: We analyzed historical data collected by the Accreditation Council for Graduate Medical Education in academic years 2016-2017, 2017-2018, and 2018-2019, comparing the locations of medical school and residency programs for PGY-1 residents to determine the number of matriculants from in-state medical schools and out-of-state medical schools. International medical school graduates (IMGs) were shown separately in the analysis and then combined with out-of-state matriculants. US citizens who trained abroad were counted among IMGs.

Results: The total number of PGY-1s increased by 10.3% during the 3-year time period, from 29 338 to 32 348. When combined, IMGs and USMGs transitioning from one state or country to another state accounted for approximately 72% of PGY-1s each year. Approximately 63% of USMGs matriculated to a residency program in a new state, and IMGs made up 24.6% to 23.1% of PGY-1s over the 3-year period.

Conclusions: Each year brings a substantial amount of movement among PGY-1s that highlights the need for policies and procedures specific to the COVID-19 pandemic.
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http://dx.doi.org/10.4300/JGME-D-20-00627.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450753PMC
August 2020

Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntington's disease.

PLoS One 2020 17;15(8):e0233820. Epub 2020 Aug 17.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible means of exploring the pathobiology of Huntington's disease (HD) in vivo. The endo-lysosomal/autophagy system is dysfunctional in HD, potentially contributing to disease pathogenesis and representing a potential target for therapeutic intervention. Several endo-lysosomal proteins have shown promise as biomarkers in other neurodegenerative diseases; however, they have yet to be fully explored in HD. We performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 healthy controls. Using generalised linear models controlling for age and CAG, none of the 18 proteins measured displayed significant differences in concentration between HD patients and controls. This was affirmed by principal component analysis, in which no significant difference across disease stage was found in any of the three components representing lysosomal hydrolases, binding/transfer proteins and innate immune system/peripheral proteins. However, several proteins were associated with measures of disease severity and cognition: most notably amyloid precursor protein, which displayed strong correlations with composite Unified Huntington's Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We conclude that although endo-lysosomal proteins are unlikely to have value as disease state CSF biomarkers for Huntington's disease, several proteins demonstrate associations with clinical severity, thus warranting further, targeted exploration and validation in larger, longitudinal samples.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430717PMC
October 2020

Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.

Lancet Neurol 2020 06 26;19(6):502-512. Epub 2020 May 26.

Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK; Dementia Research Institute at University College London, London, UK. Electronic address:

Background: Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset.

Methods: We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR <0·05 deemed a significant result.

Findings: Data were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29·0 years (SD 5·6) and 29·1 years (5·7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23·6 years (SD 5·8) from predicted onset (FDR 0·22-0·87 for cognitive measures, 0·31-0·91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0·03), but this did not appear to be closely related to predicted years to onset (FDR=0·54). There were no group differences in other brain imaging measures (FDR >0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0·0001, =0·01, and =0·03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0·0001).

Interpretation: We report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact.

Funding: Wellcome Trust, CHDI Foundation.
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http://dx.doi.org/10.1016/S1474-4422(20)30143-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254065PMC
June 2020

Characterizing White Matter in Huntington's Disease.

Mov Disord Clin Pract 2020 Jan 28;7(1):52-60. Epub 2019 Nov 28.

University College London Huntington's Disease Centre, Department of Neurodegenerative Disease University College London Queen Square Institute of Neurology, University College London London United Kingdom.

Background: Investigating early white matter (WM) change in Huntington's disease (HD) can improve our understanding of the way in which disease spreads from the striatum.

Objectives: We provide a detailed characterization of pathology-related WM change in HD. We first examined WM microstructure using diffusion-weighted imaging and then investigated both underlying biological properties of WM and products of WM damage including iron, myelin plus neurofilament light, a biofluid marker of axonal degeneration-in parallel with the mutant huntingtin protein.

Methods: We examined WM change in HD gene carriers from the HD-CSFcohort, baseline visit. We used standard-diffusion magnetic resonance imaging to measure metrics including fractional anisotropy, a marker of WM integrity, and diffusivity; a novel diffusion model (neurite orientation dispersion and density imaging) to measure axonal density and organization; T1-weighted and T2-weighted structural magnetic resonance imaging images to derive proxy iron content and myelin-contrast measures; and biofluid concentrations of neurofilament light (in cerebrospinal fluid (CSF) and plasma) and mutant huntingtin protein (in CSF).

Results: HD gene carriers displayed reduced fractional anisotropy and increased diffusivity when compared with controls, both of which were also associated with disease progression, CSF, and mutant huntingtin protein levels. HD gene carriers also displayed proxy measures of reduced myelin contrast and iron in the striatum.

Conclusion: Collectively, these findings present a more complete characterization of HD-related microstructural brain changes. The correlation between reduced fractional anisotropy, increased axonal orientation, and biofluid markers suggest that axonal breakdown is associated with increased WM degeneration, whereas higher quantitative T2 signal and lower myelin-contrast may indicate a process of demyelination limited to the striatum.
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http://dx.doi.org/10.1002/mdc3.12866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962665PMC
January 2020

A pilot study of a novel, incentivised mHealth technology to monitor the vaccine supply chain in rural Zambia.

Pan Afr Med J 2019 22;33:50. Epub 2019 May 22.

Department of Emergency Medicine, University of Sydney, Sydney, Australia.

Introduction: The World Health Organization estimates that up to half of vaccines are wasted, however only a minority of mHealth programs in Africa have been directed at vaccine supply chain optimisation. We piloted a novel mHealth solution dependent only on short message services (SMS) technology that allowed workers in rural health centres in Zambia to report vaccine stock levels directly to an online platform. Small airtime incentives were offered to encourage users to engage with the system, as well as weekly reminder messages asking for stock updates.

Methods: The primary outcome measured was the percentage-of-doses-tracked, calculated over the study period. Each vaccine box was randomly allocated to offer either a standard or double airtime incentive and either weekly or daily reminders, in a 2 x 2 design; ANOVA was used to calculate if any of these factors affected time-to-reply.

Results: Over the study period, the total percentage-of-doses-tracked was 39.9%. Within the subset of users who sent at least one message to the platform, the percentage-of-doses-tracked was 93.8%. There was no significant difference in average time-to-reply between the standard airtime incentive and double airtime incentive groups, nor was there a significant difference between the standard reminder and daily follow-up reminder groups.

Conclusion: This pilot study found that in an active subgroup of health workers, an incentivised mHealth solution was able to collect tracking data for 93.8% of doses. More research is needed to identify methods to encourage healthcare workers to engage in timely stock reporting practices.
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http://dx.doi.org/10.11604/pamj.2019.33.50.16318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689832PMC
September 2019

The Positive Effects of Accreditation on Graduate Medical Education Programs in Singapore.

J Grad Med Educ 2019 Aug;11(4 Suppl):213-217

Background: There is worldwide interest in assessing the impact of accreditation systems to quantify their benefits to medical education and, through this, health care at the local and global levels.

Objective: We analyzed ACGME-I Resident Survey data from Singapore for 2011-2018 to assess the impact of accreditation on residents' evaluations of their programs.

Methods: We focused on 7 questions from the annual Resident Survey, which would be affected by accreditation compliance, along with a single global rating of respondents' overall perception of their program. We assessed for differences among specialty groupings (medical, surgical, and hospital-based) and Singapore's 3 health care systems. Repeated measures analysis of variance procedures was used to assess trends across time for the combined 8 items and each individual item.

Results: Analysis of the combined items showed significant improvement over the 7 years Singaporean programs had accreditation. There were no effects for specialty type or sponsoring institution. Analyses of individual questions showed 6 of 8 were significant for improvement. For the individual question related to duty hour compliance, there was a significant interaction between time and specialty, suggesting medical specialties showed greater improvement across time compared to surgical and hospital-based specialties.

Conclusions: Implementation of accreditation in Singapore provided educational and clinical learning environment infrastructure not present prior to 2010, with the benefits of this reflected in residents' perceptions of their learning environment. Future assessments of the effects of accreditation might add stakeholder interviews to more fully describe its value and impact.
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http://dx.doi.org/10.4300/JGME-D-19-00429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697308PMC
August 2019

Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI.

Eur J Neurosci 2019 06 19;49(12):1632-1639. Epub 2019 Feb 19.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.

Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross-sectional study comparing people with early stage Huntington's disease with age- and gender-matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub-arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter-group differences with Wilcoxon rank-sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTTCAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics - that is, one that would justify dose-adjustments of intrathecal drugs - is unlikely to exist in Huntington's disease.
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http://dx.doi.org/10.1111/ejn.14356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618296PMC
June 2019

Paediatrician's guide to epigenetics.

Arch Dis Child 2019 03 17;104(3):297-301. Epub 2019 Jan 17.

University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.

Epigenetic regulation of gene expression is critical for normal development. Dysregulation of the epigenome can lead to the development and progression of a number of diseases relevant to paediatricians, including disorders of genomic imprinting and malignancies. It has long been recognised that early life events have implications for future disease risk, and epigenetic modifications may play a role in this, although further high-quality research is needed to better understand the underlying mechanisms. Research in the field of epigenetics will contribute to a greater understanding of growth, development and disease; however, paediatricians need to be able to interpret such research critically, in order to use the potential advances brought about through epigenetic studies while appreciating their limitations.
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http://dx.doi.org/10.1136/archdischild-2018-316054DOI Listing
March 2019

Should Artificial Intelligence Augment Medical Decision Making? The Case for an Autonomy Algorithm.

AMA J Ethics 2018 09 1;20(9):E902-910. Epub 2018 Sep 1.

An emergency department physician affiliated with the University of Sydney in Australia.

A significant proportion of elderly and psychiatric patients do not have the capacity to make health care decisions. We suggest that machine learning technologies could be harnessed to integrate data mined from electronic health records (EHRs) and social media in order to estimate the confidence of the prediction that a patient would consent to a given treatment. We call this process, which takes data about patients as input and derives a confidence estimate for a particular patient's predicted health care-related decision as an output, the . We suggest that the proposed algorithm would result in more accurate predictions than existing methods, which are resource intensive and consider only small patient cohorts. This algorithm could become a valuable tool in medical decision-making processes, augmenting the capacity of all people to make health care decisions in difficult situations.
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http://dx.doi.org/10.1001/amajethics.2018.902DOI Listing
September 2018

Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington's disease.

Sci Transl Med 2018 09;10(458)

Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, UK.

Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.
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http://dx.doi.org/10.1126/scitranslmed.aat7108DOI Listing
September 2018

Biofluid Biomarkers in Huntington's Disease.

Methods Mol Biol 2018 ;1780:329-396

Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.

Huntington's disease (HD) is a chronic progressive neurodegenerative condition where new markers of disease progression are needed. So far no disease-modifying interventions have been found, and few interventions have been proven to alleviate symptoms. This may be partially explained by the lack of reliable indicators of disease severity, progression, and phenotype.Biofluid biomarkers may bring advantages in addition to clinical measures, such as reliability, reproducibility, price, accuracy, and direct quantification of pathobiological processes at the molecular level; and in addition to empowering clinical trials, they have the potential to generate useful hypotheses for new drug development.In this chapter we review biofluid biomarker reports in HD, emphasizing those we feel are likely to be closest to clinical applicability.
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http://dx.doi.org/10.1007/978-1-4939-7825-0_17DOI Listing
February 2019

Relationships Between the ACGME Resident and Faculty Surveys and Program Pass Rates on the ABIM Internal Medicine Certification Examination.

Acad Med 2018 08;93(8):1205-1211

K.D. Holt is special projects analyst, Accreditation Council for Graduate Medical Education (ACGME), Chicago, Illinois, and staff scientist, University of Rochester Medical Center, Rochester, New York. R.S. Miller is senior vice president of applications and data analysis, ACGME, Chicago, Illinois. J. Vasilias is executive director, Review Committee for Internal Medicine, ACGME, Chicago, Illinois. L.M. Byrne is director of data analytics, quality, and reporting, ACGME, Chicago, Illinois. C. Cable is chair, Review Committee for Internal Medicine, ACGME, Chicago, Illinois, and faculty member, Hematology-Oncology Program, Scott and White Memorial Hospital, Temple, Texas. L. Grosso is vice president of psychometrics, American Board of Internal Medicine (ABIM), Philadelphia, Pennsylvania. L.M. Bellini is vice dean for academic affairs, University of Pennsylvania, Philadelphia, Pennsylvania. F.S. McDonald is senior vice president of academic and medical affairs, ABIM, Philadelphia, Pennsylvania.

Purpose: The Accreditation Council for Graduate Medical Education (ACGME) has surveyed residents since 2003, and faculty since 2012. Surveys are designed to assess program functioning and specify areas for improvement. The purpose of this study was to assess the association of the ACGME's resident and faculty surveys with residency-program-specific performance on the American Board of Internal Medicine (ABIM) certification exam.

Method: Data were available from residents and faculty in 375 U.S. ACGME-accredited internal medicine programs from the 2012-2013, 2013-2014, and 2014-2015 academic years. Analysis of variance and correlations were used to examine the relationship between noncompliance with ACGME program requirements as assessed by the resident and faculty surveys, and ABIM program pass rates.

Results: Noncompliance reported on the resident and faculty surveys was highest for programs not meeting the ACGME program requirement of an 80% pass rate on the ABIM certification examination. This relationship was significant for overall noncompliance, both within the resident (P < .001) and faculty (P < .05) surveys, for many areas within the two surveys (correlations ranged between -.07 and -.25, and P values ranged between .20 and < .001), and for the highest levels of noncompliance across areas of the resident (P < .001) and faculty (P < .04) surveys.

Conclusions: ACGME resident and faculty surveys were significantly associated with ABIM program pass rates, supporting the importance of these surveys within the ACGME's Next Accreditation System.
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http://dx.doi.org/10.1097/ACM.0000000000002228DOI Listing
August 2018

Cerebrospinal fluid neurogranin and TREM2 in Huntington's disease.

Sci Rep 2018 03 9;8(1):4260. Epub 2018 Mar 9.

Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.

Biomarkers of Huntington's disease (HD) in cerebrospinal fluid (CSF) could be of value in elucidating the biology of this genetic neurodegenerative disease, as well as in the development of novel therapeutics. Deranged synaptic and immune function have been reported in HD, and concentrations of the synaptic protein neurogranin and the microglial protein TREM2 are increased in other neurodegenerative diseases. We therefore used ELISAs to quantify neurogranin and TREM2 in CSF samples from HD mutation carriers and controls. CSF neurogranin concentration was not significantly altered in HD compared to controls, nor was it significantly associated with disease burden score, total functional capacity or motor score. An apparent increase in CSF TREM2 in manifest HD was determined to be due to increasing TREM2 with age. After age adjustment, there was no significant alteration of TREM2 in either HD group, nor any association with motor, functional or cognitive score, or brain volume quantified by MRI. Both analyses were well-powered, and sample size calculations indicated that several thousand samples per group would be needed to prove that disease-associated alterations do in fact exist. We conclude that neither neurogranin nor TREM2 is a useful biofluid biomarker for disease processes in Huntington's disease.
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http://dx.doi.org/10.1038/s41598-018-21788-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844906PMC
March 2018

Neurofilament light protein in blood predicts regional atrophy in Huntington disease.

Neurology 2018 02 24;90(8):e717-e723. Epub 2018 Jan 24.

From the Huntington's Disease Research Centre (E.B.J., L.M.B., S.G., F.B.R., S.J.T., R.I.S., E.J.W.), UCL Institute of Neurology, London, UK; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Institut du Cerveau et de la Moelle épinière (A.D.), Sorbonne Universités, UPMC University Paris 06, UMRS 1127, INSERM, U 1127, CNRS, UMR 7225; APHP (A.D.), Genetics Department, Pitié-Salpêtrière University Hospital, Paris, France; Centre for Molecular Medicine and Therapeutics (B.R.L.), University of British Columbia, Vancouver, BC, Canada; Department of Neurology (R.A.R.), Leiden University, the Netherlands; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, Queen Square, London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; and UK Dementia Research Institute (H.Z.), London, UK.

Objective: Neurofilament light (NfL) protein in blood plasma has been proposed as a prognostic biomarker of neurodegeneration in a number of conditions, including Huntington disease (HD). This study investigates the regional distribution of NfL-associated neural pathology in HD gene expansion carriers.

Methods: We examined associations between NfL measured in plasma and regionally specific atrophy in cross-sectional (n = 198) and longitudinal (n = 177) data in HD gene expansion carriers from the international multisite TRACK-HD study. Using voxel-based morphometry, we measured associations between baseline NfL levels and both baseline gray matter and white matter volume; and longitudinal change in gray matter and white matter over the subsequent 3 years in HD gene expansion carriers.

Results: After controlling for demographics, associations between increased NfL levels and reduced brain volume were seen in cortical and subcortical gray matter and within the white matter. After also controlling for known predictors of disease progression (age and CAG repeat length), associations were limited to the caudate and putamen. Longitudinally, NfL predicted subsequent occipital gray matter atrophy and widespread white matter reduction, both before and after correction for other predictors of disease progression.

Conclusions: These findings highlight the value of NfL as a dynamic marker of brain atrophy and, more generally, provide further evidence of the strong association between plasma NfL level, a candidate blood biomarker, and pathologic neuronal change.
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http://dx.doi.org/10.1212/WNL.0000000000005005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818166PMC
February 2018

Validation of Ultrasensitive Mutant Huntingtin Detection in Human Cerebrospinal Fluid by Single Molecule Counting Immunoassay.

J Huntingtons Dis 2017 ;6(4):349-361

IRBM Science Park, Pomezia, Rome, Italy.

Background: The measurement of disease-relevant biomarkers has become a major component of clinical trial design, but in the absence of rigorous clinical and analytical validation of detection methodology, interpretation of results may be misleading. In Huntington's disease (HD), measurement of the concentration of mutant huntingtin protein (mHTT) in cerebrospinal fluid (CSF) of patients may serve as both a disease progression biomarker and a pharmacodynamic readout for HTT-lowering therapeutic approaches. We recently published the quantification of mHTT levels in HD patient CSF by a novel ultrasensitive immunoassay-based technology and here analytically validate it for use.

Objective: This work aims to analytically and clinically validate our ultrasensitive assay for mHTT measurement in human HD CSF, for application as a pharmacodynamic biomarker of CNS mHTT lowering in clinical trials.

Methods: The single molecule counting (SMC) assay is an ultrasensitive bead-based immunoassay where upon specific recognition, dye-labeled antibodies are excited by a confocal laser and emit fluorescent light as a readout. The detection of mHTT by this technology was clinically validated following established Food and Drug Administration and European Medicine Agency guidelines.

Results: The SMC assay was demonstrated to be accurate, precise, specific, and reproducible. While no matrix influence was detected, a list of interfering substances was compiled as a guideline for proper collection and storage of patient CSF samples. In addition, a set of recommendations on result interpretation is provided.

Conclusions: This SMC assay is a robust and ultrasensitive method for the relative quantification of mHTT in human CSF.
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http://dx.doi.org/10.3233/JHD-170269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757651PMC
July 2018

Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis.

Lancet Neurol 2017 08 7;16(8):601-609. Epub 2017 Jun 7.

UCL Institute of Neurology, London, UK. Electronic address:

Background: Blood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease.

Methods: We did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF.

Findings: Baseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r=-0·374, p<0·0001; Stroop word reading r=-0·248, p=0·0033), total functional capacity (r=-0·289, p=0·0264), and brain atrophy (caudate r=0·178, p=0·0087; whole-brain r=0·602, p<0·0001; grey matter r=0·518, p<0·0001; white matter r=0·588, p<0·0001; and ventricular expansion r=-0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48-7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0·868, p<0·0001).

Interpretation: NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.

Funding: Medical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.
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http://dx.doi.org/10.1016/S1474-4422(17)30124-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507767PMC
August 2017

The Impact of Systematic Point-of-Care Ultrasound on Management of Patients in a Resource-Limited Setting.

Am J Trop Med Hyg 2017 Feb 19;96(2):488-492. Epub 2016 Dec 19.

Augusta University, Augusta, Georgia.

Although target point-of-care (POC) ultrasonography has been shown to benefit patients in resource-limited settings, it is not clear whether a systematic POC ultrasound assessment in these settings can also lead to similar changes in patient management. A predefined systematic set of POC ultrasound scans were performed on inpatients at a tertiary referral hospital in Tanzania to see if this resulted in changes to patient management. Of the 55 patients scanned, an abnormality was detected in 75% ( = 41), and a change in patient management was recommended or implemented on the basis of POC ultrasound findings in 53% ( = 29). The main impact was earlier initiation of treatment due to more rapid and accurate diagnosis. Further research is warranted to determine whether systematic POC ultrasonography would result in improved patient outcomes in resource-limited settings.
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http://dx.doi.org/10.4269/ajtmh.16-0201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303058PMC
February 2017

Cerebrospinal Fluid Inflammatory Biomarkers Reflect Clinical Severity in Huntington's Disease.

PLoS One 2016;11(9):e0163479. Epub 2016 Sep 22.

Huntington's Disease Centre, Institute of Neurology, University College London, London, United Kingdom.

Introduction: Immune system activation is involved in Huntington's disease (HD) pathogenesis and biomarkers for this process could be relevant to study the disease and characterise the therapeutic response to specific interventions. We aimed to study inflammatory cytokines and microglial markers in the CSF of HD patients.

Methods: CSF TNF-α, IL-1β, IL-6, IL-8, YKL-40, chitotriosidase, total tau and neurofilament light chain (NFL) from 23 mutation carriers and 14 healthy controls were assayed.

Results: CSF TNF-α and IL-1β were below the limit of detection. Mutation carriers had higher YKL-40 (p = 0.003), chitotriosidase (p = 0.015) and IL-6 (p = 0.041) than controls. YKL-40 significantly correlated with disease stage (p = 0.007), UHDRS total functional capacity score (r = -0.46, p = 0.016), and UHDRS total motor score (r = 0.59, p = 4.5*10-4) after adjustment for age.

Conclusion: YKL-40 levels in CSF may, after further study, come to have a role as biomarkers for some aspects of HD. Further investigation is needed to support our exploratory findings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033331PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163479PLOS
September 2016

Experience of implementing a National pre-hospital Code Red bleeding protocol in Scotland.

Injury 2017 Jan 11;48(1):41-46. Epub 2016 Sep 11.

Scottish National Blood Transfusion Service, 21 Ellen's Glen Rd, Edinburgh EH17 7QT, UK; Department of Transfusion Medicine, Ninewells Hospital, Dundee DD2 1UB, UK.

Introduction: The Scottish Transfusion and Laboratory Support in Trauma Group (TLSTG) have introduced a unified National pre-hospital Code Red protocol. This paper reports the results of a study aiming to establish whether current pre-hospital Code Red activation criteria for trauma patients successfully predict need for in hospital transfusion or haemorrhagic death, the current admission coagulation profile and Concentrated Red Cell (CRC): Fresh Frozen Plasma (FFP) ratio being used, and whether use of the protocol leads to increased blood component discards?

Methods: Prospective cohort study. Clinical and transfusion leads for each of Scotland's pre-hospital services and their receiving hospitals agreed to enter data into the study for all trauma patients for whom a pre-hospital Code Red was activated. Outcome data collected included survival 24h after Code Red activation, survival to hospital discharge, death in the Emergency Department and death in hospital.

Results: Between June 1st 2013 and October 31st 2015 there were 53 pre-hospital Code Red activations. Median Injury Severity Score (ISS) was 24 (IQR 14-37) and mortality 38%. 16 patients received pre-hospital blood. The pre-hospital Code Red protocol was sensitive for predicting transfusion or haemorrhagic death (89%). Sensitivity, specificity, positive and negative predictive values of the pre-hospital SBP <90mmHg component were 63%, 33%, 86% and 12%. 19% had an admission prothrombin time >14s and 27% had a fibrinogen <1.5g/L. CRC: FFP ratios did not drop to below 2:1 until 150min after arrival in the ED. 16 red cell units, 33 FFP and 6 platelets were discarded. This was not significantly increased compared to historical data.

Conclusions: A National pre-hospital Code Red protocol is sensitive for predicting transfusion requirement in bleeding trauma patients and does not lead to increased blood component discards. A significant number of patients are coagulopathic and there is a need to improve CRC: FFP ratios and time to transfusion support especially FFP provision. Training clinicians to activate pre-hospital Code Red earlier during the pre-hospital phase may give blood bank more time to thaw and prepare FFP and may improve FFP administration times and ratios so long as components are used upon their availability.
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http://dx.doi.org/10.1016/j.injury.2016.09.020DOI Listing
January 2017

Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease.

J Neurochem 2016 10 20;139(1):22-5. Epub 2016 Sep 20.

Huntington's Disease Centre, Institute of Neurology, University College London, London, UK.

Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre-symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale '99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme-linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p < 0.05. Seventy-six participants were included in this cross-sectional multicenter international pilot study. Age-adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p = 0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r = -0.29, p = 0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r = 0.32, p = 0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age-adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. In the era of novel targeted approaches to Huntington's disease, reliable biomarkers are needed. We quantified Tau protein, a marker of neuronal death, in cerebrospinal fluid and found it was increased in patients with Huntington's disease and predicted motor, cognitive, and functional disability in patients. It is therefore likely to be a biomarker of disease progression, and possibly of therapeutic response. Read the Editorial Highlight for this article on page 9.
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http://dx.doi.org/10.1111/jnc.13719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053298PMC
October 2016

Cerebrospinal Fluid Biomarkers for Huntington's Disease.

J Huntingtons Dis 2016 ;5(1):1-13

Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD.
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http://dx.doi.org/10.3233/JHD-160196DOI Listing
December 2016

CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes.

Curr Biol 2015 Sep 27;25(18):2411-6. Epub 2015 Aug 27.

MRC Centre for Regenerative Medicine, The University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK.

Since Río-Hortega's description of oligodendrocyte morphologies nearly a century ago, many studies have observed myelin sheath-length diversity between CNS regions. Myelin sheath length directly impacts axonal conduction velocity by influencing the spacing between nodes of Ranvier. Such differences likely affect neural signal coordination and synchronization. What accounts for regional differences in myelin sheath lengths is unknown; are myelin sheath lengths determined solely by axons or do intrinsic properties of different oligodendrocyte precursor cell populations affect length? The prevailing view is that axons provide molecular cues necessary for oligodendrocyte myelination and appropriate sheath lengths. This view is based upon the observation that axon diameters correlate with myelin sheath length, as well as reports that PNS axonal neuregulin-1 type III regulates the initiation and properties of Schwann cell myelin sheaths. However, in the CNS, no such instructive molecules have been shown to be required, and increasing in vitro evidence supports an oligodendrocyte-driven, neuron-independent ability to differentiate and form initial sheaths. We test this alternative signal-independent hypothesis--that variation in internode lengths reflects regional oligodendrocyte-intrinsic properties. Using microfibers, we find that oligodendrocytes have a remarkable ability to self-regulate the formation of compact, multilamellar myelin and generate sheaths of physiological length. Our results show that oligodendrocytes respond to fiber diameters and that spinal cord oligodendrocytes generate longer sheaths than cortical oligodendrocytes on fibers, co-cultures, and explants, revealing that oligodendrocytes have regional identity and generate different sheath lengths that mirror internodes in vivo.
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http://dx.doi.org/10.1016/j.cub.2015.07.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580335PMC
September 2015

Tracking Residents Through Multiple Residency Programs: A Different Approach for Measuring Residents' Rates of Continuing Graduate Medical Education in ACGME-Accredited Programs.

J Grad Med Educ 2010 Dec;2(4):616-23

Background: Increased focus on the number and type of physicians delivering health care in the United States necessitates a better understanding of changes in graduate medical education (GME). Data collected by the Accreditation Council for Graduate Medical Education (ACGME) allow longitudinal tracking of residents, revealing the number and type of residents who continue GME following completion of an initial residency. We examined trends in the percent of graduates pursuing additional clinical education following graduation from ACGME-accredited pipeline specialty programs (specialties leading to initial board certification).

Methods: Using data collected annually by the ACGME, we tracked residents graduating from ACGME-accredited pipeline specialty programs between academic year (AY) 2002-2003 and AY 2006-2007 and those pursuing additional ACGME-accredited training within 2 years. We examined changes in the number of graduates and the percent of graduates continuing GME by specialty, by type of medical school, and overall.

Results: The number of pipeline specialty graduates increased by 1171 (5.3%) between AY 2002-2003 and AY 2006-2007. During the same period, the number of graduates pursuing additional GME increased by 1059 (16.7%). The overall rate of continuing GME increased each year, from 28.5% (6331/22229) in AY 2002-2003 to 31.6% (7390/23400) in AY 2006-2007. Rates differed by specialty and for US medical school graduates (26.4% [3896/14752] in AY 2002-2003 to 31.6% [4718/14941] in AY 2006-2007) versus international medical graduates (35.2% [2118/6023] to 33.8% [2246/6647]).

Conclusion: The number of graduates and the rate of continuing GME increased from AY 2002-2003 to AY 2006-2007. Our findings show a recent increase in the rate of continued training for US medical school graduates compared to international medical graduates. Our results differ from previously reported rates of subspecialization in the literature. Tracking individual residents through residency and fellowship programs provides a better understanding of residents' pathways to practice.
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http://dx.doi.org/10.4300/JGME-D-10-00105.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010950PMC
December 2010

Advanced maternal age as a risk factor for stress urinary incontinence: a review of the literature.

Int Urogynecol J 2012 Apr 8;23(4):395-401. Epub 2011 Sep 8.

Department of Urology, Case Western Reserve University, University Hospitals of Case Medical Center, Cleveland, OH 44106, USA.

The pathophysiology of stress urinary incontinence (SUI) is multifactorial and evidence supports a critical role of pregnancy and vaginal delivery. This review dissects epidemiologic literature to determine the weight of evidence on the role of advanced maternal age (AMA) as a risk factor for the development of subsequent or persistent SUI. We conducted a Medline search using the keywords postpartum, SUI, maternal age, pregnancy, and incontinence. The published literature was critically analyzed. Evidence supports that childbirth trauma contributes to the development and severity of SUI. Yet, there is contradicting evidence as to whether AMA increases the risk. AMA clearly represents an independent risk factor for postpartum SUI. However, long-term studies did not confirm this observation. Whether this finding is suggestive of a true biologic signal that is lost with competing risk factors over time warrants further research.
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http://dx.doi.org/10.1007/s00192-011-1562-5DOI Listing
April 2012