Stress-induced symptom exacerbation: Stress increases voiding frequency, somatic sensitivity, and urinary bladder NGF and BDNF expression in mice with subthreshold cyclophosphamide (CYP).

Symptom exacerbation due to stress is prevalent in many disease states, including functional disorders of the urinary bladder (e.g., overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS)); however, the mechanisms underlying the effects of stress on micturition reflex function are unclear. In this study we designed and evaluated a stress-induced symptom exacerbation (SISE) mouse model that demonstrates increased urinary frequency and somatic (pelvic and hindpaw) sensitivity. Cyclophosphamide (CYP) (35 mg/kg; i.p., every 48 hours for a total of 4 doses) or 7 days of repeated variate stress (RVS) did not alter urinary bladder function or somatic sensitivity; however, both CYP alone and RVS alone significantly (p ≤ 0.01) decreased weight gain and increased serum corticosterone. CYP treatment when combined with RVS for 7 days (CYP+RVS) significantly (p ≤ 0.01) increased serum corticosterone, urinary frequency and somatic sensitivity and decreased weight gain. CYP+RVS exposure in mice significantly (p ≤ 0.01) increased (2.6-fold) voiding frequency as we determined using conscious, open-outlet cystometry. CYP+RVS significantly (p ≤ 0.05) increased baseline, threshold, and peak micturition pressures. We also evaluated the expression of NGF, BDNF, CXC chemokines and IL-6 in urinary bladder in CYP alone, RVS alone and CYP+RVS mouse cohorts. Although all treatments or exposures increased urinary bladder NGF, BDNF, CXC and IL-6 content, CYP+RVS produced the largest increase in all inflammatory mediators examined. These results demonstrated that CYP alone or RVS alone creates a change in the inflammatory environment of the urinary bladder but does not result in a change in bladder function or somatic sensitivity until CYP is combined with RVS (CYP+RVS). The SISE model of CYP+RVS will be useful to develop testable hypotheses addressing underlying mechanisms where psychological stress exacerbates symptoms in functional bladder disorders leading to identification of targets and potential treatments.

Repeated variate stress increased voiding frequency and altered TrpV1 and TrpV4 transcript expression in lower urinary tract (LUT) pathways in female mice.

Psychological stress is associated with urinary bladder dysfunction (e.g., increased voiding frequency, urgency and pelvic pain); however, the mechanisms underlying the effects of stress on urinary bladder function are unknown. Transient receptor potential (TRP) channels (vanilloid family) may be potential targets for intervention due to their distribution in the LUT and role in pain. Here, we examine a model of repeated variate stress (RVS) of 2 week (wk) or 4 wk duration in female mice and its effects on bladder function, anxiety-like behavior, and TRPV transcript expression in urinary bladder and lumbosacral spinal cord and associated dorsal root ganglia (DRG). Using continuous infusion, open-outlet cystometry in conscious mice, RVS significantly (p ≤ 0.05) decreased infused volume and intermicturition interval. Bladder pressures (threshold, average, minimum, and maximum pressures) were unchanged with RVS. Quantitative PCR demonstrated significant (p ≤ 0.05) changes in TrpV1 and TrpV4 mRNA expression between control and RVS cohorts in the urothelium, lumbosacral spinal cord, and DRG. Future directions will examine the contribution of TRP channels on bladder function, somatic sensation and anxiety-like behavior following RVS.

Imatinib Mesylate Reduces Voiding Frequency in Female Mice With Acute Cyclophosphamide-Induced Cystitis.

Lamina propria interstitial cells that express the tyrosine kinase receptor, platelet-derived growth factor receptor alpha (PDGFRα) may play a role in urinary sensory signaling. Imatinib mesylate, also referred to as imatinib, is a tyrosine kinase inhibitor that can inhibit PDGFRα and has been widely used in urological research. We evaluated the functional effects of imatinib administration (via oral gavage or intravesical infusion) with two different experimental designs (prevention and treatment), in a cyclophosphamide (CYP)-induced cystitis (acute, intermediate, and chronic), male and female rodent model using conscious cystometry and somatic sensitivity testing. Imatinib significantly (0.0001 ≤ p ≤ 0.05) decreased voiding frequency and increased bladder capacity in acute CYP-induced cystitis, by the prevention (females) and treatment (females and males) designs. Imatinib was not effective in preventing or treating intermediate or chronic CYP-induced cystitis in either sex. Interestingly, in the prevention experiments, imatinib administration increased (0.0001 ≤ p ≤ 0.01) voiding frequency and decreased bladder capacity in control mice. However, in the treatment experiments, imatinib administration decreased (0.01 ≤ p ≤ 0.05) voiding frequency and increased bladder capacity in control mice. Bladder function improvements observed with imatinib treatment in acute CYP-induced cystitis mice remained and additionally improved with a second dose of imatinib 24 hours after CYP treatment. Imatinib administration did not affect pelvic somatic sensitivity in female mice with acute CYP-induced cystitis. Our studies suggest that (1) imatinib improves bladder function in mice with acute CYP-induced cystitis with a prevention and treatment design and (2) interstitial cells may be a useful target to improve bladder function in cystitis.

Imatinib Mesylate Reduces Neurotrophic Factors and pERK and pAKT Expression in Urinary Bladder of Female Mice With Cyclophosphamide-Induced Cystitis.

Imatinib mesylate is a tyrosine kinase inhibitor that inhibits platelet-derived growth factor receptor (PDGFR)-α, -ß, stem cell factor receptor (c-KIT), and BCR-ABL. PDGFRα is expressed in a subset of interstitial cells in the lamina propria (LP) and detrusor muscle of the urinary bladder. PDGFRα + interstitial cells may contribute to bladder dysfunction conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) or overactive bladder (OAB). We have previously demonstrated that imatinib prevention via oral gavage or treatment via intravesical infusion improves urinary bladder function in mice with acute (4 hour, h) cyclophosphamide (CYP)-induced cystitis. Here, we investigate potential underlying mechanisms mediating the bladder functional improvement by imatinib using a prevention or treatment experimental design. Using qRT-PCR and ELISAs, we examined inflammatory mediators (NGF, VEGF, BDNF, CCL2, IL-6) previously shown to affect bladder function in CYP-induced cystitis. We also examined the distribution of phosphorylated (p) ERK and pAKT expression in the LP with immunohistochemistry. Imatinib prevention significantly (0.0001 ≤ p ≤ 0.05) reduced expression for all mediators examined except NGF, whereas imatinib treatment was without effect. Imatinib prevention and treatment significantly (0.0001 ≤ p ≤ 0.05) reduced pERK and pAKT expression in the upper LP (U. LP) and deeper LP (D. LP) in female mice with 4 h CYP-induced cystitis. Although we have previously demonstrated that imatinib prevention or treatment improves bladder function in mice with cystitis, the current studies suggest that reductions in inflammatory mediators contribute to prevention benefits of imatinib but not the treatment benefits of imatinib. Differential effects of imatinib prevention or treatment on inflammatory mediators may be influenced by the route and frequency of imatinib administration and may also suggest other mechanisms (e.g., changes in transepithelial resistance of the urothelium) through which imatinib may affect urinary bladder function following CYP-induced cystitis.

Effects of pharmacological neurotrophin receptor inhibition on bladder function in female mice with cyclophosphamide-induced cystitis.

Interstitial cystitis/bladder pain syndrome is a chronic inflammatory pelvic pain syndrome of unknown etiology characterized by a number of lower urinary tract symptoms, including increased urinary urgency and frequency, bladder discomfort, decreased bladder capacity, and pelvic pain. While its etiology remains unknown, a large body of evidence suggests a role for changes in neurotrophin signaling, particularly that of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Here, we evaluated the effects of pharmacological inhibition of the NGF receptor TrkA, BDNF receptor TrkB, and pan-neurotrophin receptor p75NTR on bladder function in acute (4-hour) and chronic (8-day) mouse models of cyclophosphamide (CYP)-induced cystitis. TrkA inhibition via ARRY-954 significantly increased intermicturition interval and bladder capacity in control and acute and chronic CYP-treatment conditions. TrkB inhibition via ANA-12 significantly increased intermicturition interval and bladder capacity in acute, but not chronic, CYP-treatment conditions. Interestingly, intermicturition interval and bladder capacity significantly increased following p75NTR inhibition via LM11A-31 in the acute CYP-treatment condition, but decreased in the chronic condition, potentially due to compensatory changes in neurotrophin signaling or increased urothelial barrier dysfunction in the chronic condition. Our findings demonstrate that these receptors represent additional potent therapeutic targets in mice with cystitis and may be useful in the treatment of interstitial cystitis and other inflammatory disorders of the bladder.

A novel homozygous synonymous variant further expands the phenotypic spectrum of POLR3A-related pathologies.

Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.

The Lived Experiences of Adults with Multiple Sclerosis.

Multiple sclerosis (MS), a chronic, often disabling, nervous system disease, affects over 2.3 million people worldwide. This research examined the lived experiences of 46 community-dwelling adults with MS. We conducted five focus groups that covered topics such as diagnosis, decision-making regarding MS treatment, learning about and paying for assistance, and unmet needs. Focus group transcripts were qualitatively analyzed to identify overarching themes. Participants described how MS affects both current and future physical and financial security, how they often feel unheard or misunderstood by loved ones and healthcare providers, and how MS support organizations provide a vital collaborative and compassionate environment. Our findings reflect the importance of MS support organizations, and the incorporation of social workers in MS care teams, as they can foster communication and empathy between parties, provide psycho- social treatment, and link patients to needed services.

Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS).

Stress causes symptom exacerbation in functional disorders of the urinary bladder. However, the potential mediators and underlying mechanisms of stress effects on micturition reflex function are unknown. We have characterized PACAP (Adcyap1) and PAC1 receptor (Adcyap1r1) signaling in stress-induced urinary bladder dysfunction in mice. We determined PACAP and PAC1 transcripts and protein expressions in the urinary bladder and lumbosacral dorsal root ganglia (DRG) and spinal cord in repeated variate stress (RVS) or control mouse (handling only) groups. RVS in mice significantly (p ≤ 0.01) increased serum corticosterone and urinary bladder NGF content and decreased weight gain. PACAP and PAC1 mRNA and protein were differentially regulated in lower urinary tract tissues with changes observed in lumbosacral DRG and spinal cord but not in urinary bladder. RVS exposure in mice significantly (p ≤ 0.01) increased (2.5-fold) voiding frequency as determined using conscious cystometry. Intrabladder administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly (p ≤ 0.01) increased infused volume (1.5-2.7-fold) to elicit a micturition event and increased the intercontraction interval (i.e., decreased voiding frequency) in mice exposed to RVS and in control mice, but changes were smaller in magnitude in control mice. We also evaluated the effect of PAC1 blockade at the level of the urinary bladder on pelvic sensitivity in RVS or control mouse groups using von Frey filament testing. Intrabladder administration of PACAP(6-38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity following RVS. PACAP/receptor signaling in the CNS and PNS contributes to increased voiding frequency and pelvic sensitivity following RVS and may represent a potential target for therapeutic intervention.

TRPV4 blockade reduces voiding frequency, ATP release, and pelvic sensitivity in mice with chronic urothelial overexpression of NGF.

Transient receptor potential vanilloid family member 4 (TRPV4) transcript and protein expression increased in the urinary bladder and lumbosacral dorsal root ganglia of transgenic mice with chronic urothelial overexpression of nerve growth factor (NGF-OE). We evaluated the functional role of TRPV4 in bladder function with open-outlet cystometry, void spot assays, and natural voiding (Urovoid) assays with the TRPV4 antagonist HC-067047 (1 µM) or vehicle in NGF-OE and littermate wild-type (WT) mice. Blockade of TRPV4 at the level of the urinary bladder significantly (P ≤ 0.01) increased the intercontraction interval (2.2-fold) and void volume (2.6-fold) and decreased nonvoiding contractions (3.0-fold) in NGF-OE mice, with lesser effects (1.3-fold increase in the intercontraction interval and 1.3-fold increase in the void volume) in WT mice. Similar effects of TRPV4 blockade on bladder function in NGF-OE mice were demonstrated with natural voiding assays. Intravesical administration of HC-067047 (1 µM) significantly (P ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in littermate WT mice. Blockade of urinary bladder TRPV4 or intravesical infusion of brefeldin A significantly (P ≤ 0.01) reduced (2-fold) luminal ATP release from the urinary bladder in NGF-OE and littermate WT mice. The results of the present study suggest that TRPV4 contributes to luminal ATP release from the urinary bladder and increased voiding frequency and pelvic sensitivity in NGF-OE mice.

Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson-Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann-Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome.

Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment. Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS. Design, Setting, and Participants: Cohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018. Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications. Main Outcomes and Measures: The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients. Results: Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04). Conclusions and Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.

Survey of plasma proteins in children with progeria pre-therapy and on-therapy with lonafarnib.

BackgroundHutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare, fatal, segmental premature aging syndrome caused by the aberrant lamin A protein, progerin. The protein farnesyltransferase inhibitor, lonafarnib, ameliorates some aspects of cardiovascular and bone disease.MethodsWe performed a prospective longitudinal survey of plasma proteins in 24 children with HGPS (an estimated 10% of the world's population at the time) at baseline and on lonafarnib therapy, compared with age- and gender-matched controls using a multi-analyte, microsphere-based immunofluorescent assay.ResultsThe mean levels for 23/66 (34.8%) proteins were significantly lower and 7/66 (10.6%) were significantly higher in HGPS samples compared with those in controls (P≤0.05). Six proteins whose concentrations were initially lower normalized with lonafarnib therapy: interleukins 1α, 7, and 13, beta-2 microglobulin, C-reactive protein, and myoglobin. Alpha-2 macroglobulin, a protease inhibitor associated with stroke, was elevated at baseline and subsequently normalized with lonafarnib therapy.ConclusionThis is the first study to employ a multi-analyte array platform in HGPS. Novel potential biomarkers identified in this study should be further validated by correlations with clinical disease status, especially proteins associated with cardiovascular disease and those that normalized with lonafarnib therapy.

A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels. METHODS AND RESULTS: We report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide-one producing severe HGPS and one mild HGPS. The proband possessed an intermediate phenotype. The mosaicism was initially discovered when Sanger sequencing showed a c.1968+2T>A mutation in blood DNA and a c.1968+2T>C in DNA from cultured fibroblasts. Deep sequencing of DNA from the proband's blood revealed 4.7% c.1968+2T>C mutation, and 41.3% c.1968+2T>A mutation. CONCLUSIONS: We hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease.

Conservative management for postprostatectomy urinary incontinence.

BACKGROUND: Urinary incontinence is common after radical prostatectomy and can also occur in some circumstances after transurethral resection of the prostate (TURP). Conservative management includes pelvic floor muscle training with or without biofeedback, electrical stimulation, extra-corporeal magnetic innervation (ExMI), compression devices (penile clamps), lifestyle changes, or a combination of methods. OBJECTIVES: To determine the effectiveness of conservative management for urinary incontinence up to 12 months after transurethral, suprapubic, laparoscopic, radical retropubic or perineal prostatectomy, including any single conservative therapy or any combination of conservative therapies. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register (5 February 2014), CENTRAL (2014, Issue 1), EMBASE (January 2010 to Week 3 2014), CINAHL (January 1982 to 18 January 2014), ClinicalTrials.gov and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (both searched 29 January 2014), and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials evaluating conservative interventions for urinary continence in men after prostatectomy. DATA COLLECTION AND ANALYSIS: Two or more review authors assessed the methodological quality of the trials and abstracted data. We tried to contact several authors of included studies to obtain extra information. MAIN RESULTS: Fifty trials met the inclusion criteria, 45 in men after radical prostatectomy, four trials after TURP and one trial after either operation. The trials included 4717 men of whom 2736 had an active conservative intervention. There was considerable variation in the interventions, populations and outcome measures. Data were not available for many of the pre-stated outcomes. Men's symptoms improved over time irrespective of management.There was no evidence from eight trials that pelvic floor muscle training with or without biofeedback was better than control for men who had urinary incontinence up to 12 months after radical prostatectomy; the quality of the evidence was judged to be moderate (for example 57% with urinary incontinence in the intervention group versus 62% in the control group, risk ratio (RR) for incontinence after 12 months 0.85, 95% confidence interval (CI) 0.60 to 1.22). One large multi-centre trial of one-to-one therapy showed no difference in any urinary or quality of life outcome measures and had narrow CIs. It seems unlikely that men benefit from one-to-one PFMT therapy after TURP. Individual small trials provided data to suggest that electrical stimulation, external magnetic innervation, or combinations of treatments might be beneficial but the evidence was limited. Amongst trials of conservative treatment for all men after radical prostatectomy, aimed at both treatment and prevention, there was moderate evidence of an overall benefit from pelvic floor muscle training versus control management in terms of reduction of urinary incontinence (for example 10% with urinary incontinence after one year in the intervention groups versus 32% in the control groups, RR for urinary incontinence 0.32, 95% CI 0.20 to 0.51). However, this finding was not supported by other data from pad tests. The findings should be treated with caution because the risk of bias assessment showed methodological limitations. Men in one trial were more satisfied with one type of external compression device, which had the lowest urine loss, compared to two others or no treatment. The effect of other conservative interventions such as lifestyle changes remained undetermined as no trials involving these interventions were identified. AUTHORS' CONCLUSIONS: The value of the various approaches to conservative management of postprostatectomy incontinence after radical prostatectomy remains uncertain. The evidence is conflicting and therefore rigorous, adequately powered randomised controlled trials (RCTs) which abide by the principles and recommendations of the CONSORT statement are still needed to obtain a definitive answer. The trials should be robustly designed to answer specific well constructed research questions and include outcomes which are important from the patient's perspective in decision making and are also relevant to the healthcare professionals. Long-term incontinence may be managed by an external penile clamp, but there are safety problems.

Professional development and exposure to geriatrics: medical student perspectives from narrative journals.

Teaching professionalism is an important goal in American medical education. With the aging of the U.S. population, it is critical to understand how medical students develop professional behaviors when caring for older adults. Exposure to geriatrics and older patients can enhance students' professional development with patients of all ages and across different specialties. Medical students learn explicit and implicit messages during their education. In addition to helping to evaluate curricula, reflective journaling encourages individual development and helps in revealing how medical students become professionals. In this study, medical student volunteers described their responses to new geriatrics content in their curriculum, encounters with older patients in clinical settings, and their evolving physician identities. Multidisciplinary team analysis elicited 10 themes regarding: evaluation of geriatrics within the curriculum, recognition of geriatrics principles, and attitudes regarding aging and professional development over time. This article focuses on the impact of geriatrics exposure on students' professional development, revealing ways that students think about professionalism and older patients. Medical educators should consider journaling to help foster and gauge students' professional development.

Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. METHODS AND RESULTS: We generated Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. CONCLUSIONS: This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.

Theoretical and empirical dimensions of the Aberdeen Glaucoma Questionnaire: a cross sectional survey and principal component analysis.

BACKGROUND: To develop patient-reported outcome instruments, statistical techniques (e.g., principal components analysis; PCA) are used to examine correlations among items and identify interrelated item subsets (empirical factors). However, interpretation and labelling of empirical factors is a subjective process, lacking precision or conceptual basis. We report a novel and reproducible method for mapping between theoretical and empirical factor structures. We illustrate the method using the pilot Aberdeen Glaucoma Questionnaire (AGQ), a new measure of glaucoma-related disability developed using the International Classification of Functioning and Disability (ICF) as a theoretical framework and tested in a sample representing the spectrum of glaucoma severity. METHODS: We used the ICF to code AGQ item content before mailing the AGQ to a UK sample (N = 1349) selected to represent people with a risk factor for glaucoma and people with glaucoma across a range of severity. Reflecting uncertainty in the theoretical framework (items with multiple ICF codes), an exploratory PCA was conducted. The theoretical structure informed our interpretation of the empirical structure and guided the selection of theoretically-derived factor labels. We also explored the discrimination of the AGQ across glaucoma severity groups. RESULTS: 656 (49%) completed questionnaires were returned. The data yielded a 7-factor solution with a simple structure (using cut-off point of a loading of 0.5) that together accounted for 63% of variance in the scores. The mapping process resulted in allocation of the following theoretically-derived factor labels: 1) Seeing Functions: Participation; 2) Moving Around & Communication; 3) Emotional Functions; 4) Walking Around Obstacles; 5) Light; 6) Seeing Functions: Domestic & Social Life; 7) Mobility. Using the seven factor scores as independent variables in a discriminant function analysis, the AGQ scores resulted in correct glaucoma severity grading of 32.5% of participants (p < 0.001). CONCLUSIONS: This paper addresses a methodological gap in the application of classical test theory (CTT) techniques, such as PCA, in instrument development. Labels for empirically-derived factors are often selected intuitively whereas they can inform existing bodies of knowledge if selected on the basis of theoretical construct labels, which are more explicitly defined and which relate to each other in ways that are evidence based.

Medical students' recognition and application of geriatrics principles in a new curriculum.

Given the aging U.S. population, it is imperative that medical students recognize and apply geriatrics principles. To address this need, in 2006, the Warren Alpert Medical School of Brown University integrated geriatrics content into a new medical school curriculum. Preclinical and clinical medical students submitted written reflective journals in response to prompts regarding the geriatrics content of the new medical school curriculum, including their didactic and clinical experiences. An interdisciplinary team used a structured qualitative approach to identify themes, including the recognition and application of geriatrics principles. Thirty medical student journalers submitted 405 journal entries. Themes regarding students' emerging understanding of geriatrics principles included a growing understanding of geriatrics principles, recognition of the importance of psychosocial factors and patient preferences in caring for older adults, recognition of the complexities of treating older adults and application of geriatric principles to clinical situations, and understanding of physicians' roles in managing the care of older adults. Medical student reflective journaling allows medical educators to obtain timely feedback on curricular innovations and helps illuminate the process by which medical students learn to recognize and apply core geriatrics principles.

Developing the specifications of an open angle glaucoma screening intervention in the United Kingdom: a Delphi approach.

BACKGROUND: Glaucoma is a leading cause of blindness. Early detection is advocated but there is insufficient evidence from randomized controlled trials (RCTs) to inform health policy on population screening. Primarily, there is no agreed screening intervention. For a screening programme, agreement is required on the screening tests to be used, either individually or in combination, the person to deliver the test and the location where testing should take place. This study aimed to use ophthalmologists (who were experienced glaucoma subspecialists), optometrists, ophthalmic nurses and patients to develop a reduced set of potential screening tests and testing arrangements that could then be explored in depth in a further study of their feasibility for evaluation in a glaucoma screening RCT. METHODS: A two-round Delphi survey involving 38 participants was conducted. Materials were developed from a prior evidence synthesis. For round one, after some initial priming questions in four domains, specialists were asked to nominate three screening interventions, the intervention being a combination of the four domains; target population, (age and higher risk groups), site, screening test and test operator (provider). More than 250 screening interventions were identified. For round two, responses were condensed into 72 interventions and each was rated by participants on a 0-10 scale in terms of feasibility. RESULTS: Using a cut-off of a median rating of feasibility of ≥5.5 as evidence of agreement of intervention feasibility, six interventions were identified from round 2. These were initiating screening at age 50, with a combination of two or three screening tests (varying combinations of tonometry/measures of visual function/optic nerve damage) organized in a community setting with an ophthalmic trained technical assistant delivering the tests. An alternative intervention was a 'glaucoma risk score' ascertained by questionnaire. The advisory panel recommended that further exploration of the feasibility of screening higher risk populations and detailed specification of the screening tests was required. CONCLUSIONS: With systematic use of expert opinions, a shortlist of potential screening interventions was identified. Views of users, service providers and cost-effectiveness modeling are now required to identify a feasible intervention to evaluate in a future glaucoma screening trial.