Errors encountered in the diagnostic pathway: A prospective single-institution study.

BACKGROUND: Biopsy specimens go through a diagnostic pathway before a pathology report is rendered for the clinician. Errors can occur at any step in this pathway. METHODS: A 1-year prospective study was conducted at a single academic institution to identify and characterize errors that occurred in the diagnostic pathway from the clinic to the dermatopathology lab. RESULTS: A total of 25 662 specimens were processed and 190 errors were recorded (an error rate of 0.7%). The most common errors were an incorrect biopsy site (n = 65), incorrect data entry of a correct diagnosis (n = 25), and specimen mix-up (n = 23). There were 17 diagnostic errors. Errors most often occurred in the pre-analytical phase (n = 128). The clinician was responsible for 34.2% of errors, the dermatopathologist for 23.7%, and the histotechnician for 18.9%. Slips were the most common type of human error (n = 156). CONCLUSION: The most common error involved an incorrect biopsy site at the clinical stage. Over two-thirds of errors occurred before the slide reached the dermatopathologist. Diagnostic errors (analytical phase) rarely occurred, and when they did occur, the clinician was most likely to discover the error. Examining and addressing common laboratory errors help to reduce their incidence and lead to quality improvement in dermatopathology.

An in-depth Comparison of the Pediatric and Adult Urinary N-glycomes.

We performed an in-depth characterization and comparison of the pediatric and adult urinary glycomes using a nanoLC-MS/MS based glycomics method, which included normal healthy pediatric (1-10 years, n = 21) and adult (21-50 years, n = 22) individuals. A total of 116 N-glycan compositions were identified, and 46 of them could be reproducibly quantified. We performed quantitative comparisons of the 46 glycan compositions between different age and sex groups. The results showed significant quantitative changes between the pediatric and adult cohorts. The pediatric urinary N-glycome was found to contain a higher level of high-mannose (HM), asialylated/afucosylated glycans (excluding HM), neutral fucosylated and agalactosylated glycans, and a lower level of trisialylated glycans compared with the adult. We further analyzed gender-associated glycan changes in the pediatric and adult group, respectively. In the pediatric group, there was almost no difference of glycan levels between males and females. In adult, the majority of glycans were more abundant in males than females, except the high-mannose and tetrasialylated glycans. These findings highlight the importance to consider age-matching and adult sex-matching for urinary glycan studies. The identified normal pediatric and adult urinary glycomes can serve as a baseline reference for comparisons to other disease states affected by glycosylation.

Betamethasone Dipropionate Nanocrystals: Investigation, Feasibility and In Vitro Evaluation.

Corticosteroids, such as betamethasone dipropionate (BMD), have been the mainstay in topical therapy as potent glucocorticoid receptor agonist with immune suppression, anti-proliferative, and anti-inflammatory effects. Moreover, they have poor skin penetration, which is a hurdle against its potential therapeutic benefits. In present investigation, nanocrystals as carrier for effective topical delivery of BMD were explored using wet milling as technique and polysorbate 80 as a non-ionic stabilizer. Upon optimizing different process parameters, promising results were observed at stabilizer concentration of 0.9% w/v having particle size analysis (PSA) and PDI as 284 nm and 0.299, respectively. These results were supported by the FTIR and PXRD spectra of BMD-API and BMD nanocrystals, suggesting strong crystal lattice structure of BMD being reduced due to milling. The reduction in particle morphology was evident from the FESEM images. The optimized batch of BMD nanocrystals was incorporated into Carbopol gel base, showing pH 6.2 ± 0.2 and viscosity 87.00 ± 5.2 Pa s at 25°C. A drug diffusion study using Franz diffusion cell proclaimed around ~86% BMD release from nanogel across the membrane. Also, it was observed that the BMD permeation across the skin was 2.39-fold higher with marketed formulation in contrast to BMD nanogel, suggesting prolonged drug release. The skin permeation flux with nanogel was at a much lower rate along with ~50.27% drug retention in different strata of skin, resulting in retention of drug nanocrystals. Thus, in nutshell the prolonged drug release from nanogel would fulfill the aim of once a day application and would aid in reducing the adverse events associated with repeated drug applications.

Development and characterization of pluronic lecithin organogel containing fluocinolone acetonide.

The rabble-rousing skin condition can be conventionally treated, but due to some demerits, there is a need to find a novel approach with an appropriate release profile. The research work narrates the optimization of the topical delivery system of Fluocinolone acetonide loaded in pluronic lecithin organogel. The preliminary studies were carried out and, the ternary phase diagram was established by Chemix school version 3.60. The formulation was optimized by taking a different concentration of polymers as independent and viscosity and drug release (6 h) as dependent variables by applying 32 full factorial design. The optimized batch was further compared with marketed preparation and also kept for the stability study. The release profile of the optimized batch exhibited a sustained release of up to 6 h (77.00%). It gave ex vivo drug release up to 6 h (90.64%) which is more prolonged than marketed preparation and, cutaneous disposition was found to be higher. Besides, the texture analysis was compared to that of the marketed formulation of the drug. However, the proof of the effectiveness of the formulated pluronic lecithin organogel will require further in vivo study for future aspects. In a nutshell, the proposed formulation of fluocinolone acetonide is the simplest and promising dosage form for the treatment of psoriasis.

Prevalence of Asthma and Allergies and Risk of Relapse in Childhood Nephrotic Syndrome: Insight into Nephrotic Syndrome Cohort.

OBJECTIVE: To determine the lifetime prevalence of allergies in childhood nephrotic syndrome, the seasonality of presentation and relapses, and the impact of allergies on subsequent relapses. STUDY DESIGN: In a longitudinal cohort of children with nephrotic syndrome (ages 1-18 years), assessment for allergic diseases was conducted using the validated and modified version of the International Study of Asthma and Allergies in Childhood questionnaire at enrollment. Outcomes included frequently relapsing nephrotic syndrome, relapse rates, and the relapse-free duration after initial steroid therapy. RESULTS: Among 277 participants, the majority were male (65%) with a median age of 3.7 years (IQR 2.8-5.8) at presentation. A total of 64% reported lifetime allergies with 20% having asthma, 33% wheezing, 27% eczema, and 24% rhinitis. Over 3.3 years of follow-up, presence of asthma and allergies was not associated with frequently relapsing nephrotic syndrome (OR 1.20; 95% CI 0.60, 2.40), higher relapse rates (relative risk 0.95; 95% CI 0.71, 1.27), or risk of first relapse (hazard ratio 1.10; 95% CI 0.83, 1.47) compared with those with no history of allergic diseases. There was also no seasonal variation evident at initial presentation or frequency of relapses. CONCLUSIONS: Two-thirds of children with nephrotic syndrome at presentation have allergic symptoms and asthma; however, neither are associated with an increased frequency of relapses.

The link between depression and performance on the Symbol Digit Modalities Test: Mechanisms and clinical significance.

OBJECTIVE: To determine the mechanism and clinical significance of depression-related differences in performance on the Symbol Digit Modalities Test (SDMT). METHODS: The influence of depression on two versions of a computerized SDMT (i.e. fixed versus variable code) was assessed. Both versions involve processing speed, but the fixed c-SDMT also encompasses incidental visual memory. RESULTS: Depression was associated with a 19.06% slowing on the variable ( p = 0.002) and an 8.10% slowing on the fixed ( p = 0.219) c-SDMT. CONCLUSION: Depression-associated differences in performance on the SDMT appear linked more to a reduction in processing speed than a decline in incidental visual memory and exceed the 10% threshold considered clinically significant.

Taking the tester out of the SDMT: A proof of concept fully automated approach to assessing processing speed in people with MS.

BACKGROUND: One factor hindering the widespread use of cognitive testing for people with multiple sclerosis (pwMS) is the need for a tester to administer tests. OBJECTIVE: To undertake a proof of concept study assessing the feasibility of a fully automated speech recognition version of the Symbol Digit Modalities Test (auto-SDMT) in detecting abnormalities in processing speed in pwMS. METHODS: A sample of 50 pwMS and 32 matched healthy control (HC) subjects was tested with the auto-SDMT and the Brief International Cognitive Assessment for MS (BICAMS). RESULTS: The percentages of MS participants impaired on the auto-SDMT and the traditional oral SDMT were 34% and 32%, respectively. Excellent convergent validity was found between the two tests (MS: r = -0.806, p < 0.001 and HC: r = -0.629, p < 0.001). The auto-SDMT had a similar sensitivity and specificity to the traditional oral SDMT in predicting overall impairment on the BICAMS. CONCLUSION: The auto-SDMT is a sensitive measure for detecting processing speed deficits in pwMS. The test, the first entirely computer administrated oral response version of the SDMT, uses speech recognition technology, thereby eliminating the need for a human tester. Replication of the results is required in a larger representative sample of pwMS.

Cognitive mediated eye movements during the SDMT reveal the challenges with processing speed faced by people with MS.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is regarded as the cognitive test of choice for people with MS (pwMS). While deficits are linked to impaired processing speed, the mechanisms by which they arise are unclear. Cognitive-mediated eye movements offer one putative explanation. The objective of this study was to determine the association between eye movements and performance on the SDMT. METHODS: Thirty-three people with confirmed MS and 25 matched healthy control subjects (HC) were administered the oral SDMT while eye movements were recorded. RESULTS: Mean SDMT scores were significantly lower in pwMS (p < 0.038). Shorter mean saccade distance in the key area (p = 0.007), more visits to the key area per response (p = 0.014), and more total number of fixations in the test area (p = 0.045) differentiated pwMS from HCs. A hierarchical regression analysis revealed that the number of visits to the key area per response (p < 0.001; ΔR2 = 0.549) and total number of fixations in the test area (p < 0.001; ΔR2 = 0.782) were the most robust predictors of SDMT scores. CONCLUSION: Cognitive-mediated eye movements help elucidate the processing speed challenges confronted by people with MS. Mechanistic insights such as these can potentially help inform new cognitive rehabilitation strategies.

Association of low birth weight and prematurity with clinical outcomes of childhood nephrotic syndrome: a prospective cohort study.

BACKGROUND: Low birth weight (LBW)/prematurity have been proposed as risk factors for the development of kidney disease in adulthood. Whether there is an association between LBW/prematurity and poor renal outcomes in childhood onset nephrotic syndrome remains unknown. METHODS: Children with nephrotic syndrome diagnosed between 1 and 18 years of age were followed prospectively from 1996 to 2016 at The Hospital for Sick Children (N = 377). LBW/prematurity was defined as birth weight < 2500 g or gestational age < 36 weeks. Normal birth weight (NBW) was defined as birth weight ≥ 2500 g. Measures evaluating clinical course of nephrotic syndrome include initial steroid-resistant nephrotic syndrome (SRNS), time to first relapse, and frequently relapsing nephrotic syndrome. Kaplan-Meier survival analysis, logistic regression, and Cox proportional hazards regression were used to determine the association of LBW/prematurity with clinical outcomes. RESULTS: Median birth weights in LBW/premature (n = 46) and NBW (n = 331) children were 2098 g (interquartile range [IQR] 1700-2325 g) and 3317 g (IQR 2977-3685 g), respectively. Odds of having SRNS were 3.78 (95% confidence interval [CI] 1.28-11.21) times higher among LBW/premature children than NBW children. An 8% decrease in odds of developing SRNS was observed for every 100 g increase in birth weight (adjusted odds ratio [OR] 0.92; 95% CI 0.86-0.98). Median time to first relapse did not differ (hazard ratio [HR] 0.89; 95% CI 0.53-1.16). CONCLUSIONS: LBW/premature children were more likely to develop SRNS but did not have a difference in time to first relapse with NBW children. Understanding the impact and mechanism of birth weight and steroid-resistant disease needs further study.

Topical antibiotics in pregnancy: A review of safety profiles.

Medications should be used with caution in women of childbearing age who are pregnant, or are contemplating pregnancy. Although topical medications are considered safer than oral or parenteral agents, their safety data in pregnancy must be assessed carefully. The available information on medication use in pregnancy is limited, and not always aided by the FDA pregnancy letter category system. Thus, in this article, we aggregate human studies, animal studies, and pharmacokinetics data to provide recommendations on utilizing topical antibiotics in pregnancy.

Why Sex Matters: A Cognitive Study of People With Multiple Sclerosis.

BACKGROUND: Cognitive dysfunction affects 40% to 70% of people with multiple sclerosis (MS). Sex may influence a person's cognition. Although a few studies have reported greater cognitive deficits in men than women, it is unclear whether specific cognitive domains are more vulnerable than others to the effects of sex or whether cognition is influenced by neurologic or psychiatric variables. METHODS: A chart review was undertaken of 408 people with MS referred to neuropsychological services. Demographic and MS-related variables were extracted from the patients' records. We used the Minimal Assessment of Cognitive Functioning in Multiple Sclerosis for the neuropsychological assessment. Raw test scores were converted to z scores using Canadian regression-based normative means. A general linear model was conducted on the adjusted scores, controlling for age; years of education; disease course; illness duration; and disability, anxiety, and depression scores. RESULTS: Men were more likely than women to have primary progressive MS (χ=6.415, P=0.011). There were no other sex differences with respect to demographic, neurologic, or psychiatric data. Women performed significantly better than men on the California Verbal Learning Test-Second Edition Total Learning index (F=7.846, P=0.006). CONCLUSIONS: An analysis of a large, consecutive sample of people with MS demonstrated that sex, independent of demographic, neurologic, or psychiatric factors, is an important determinant in cognitive impairment, with men being more impaired than women on tests of verbal learning and memory.

Impact of Process Parameters on Particle Size Involved in Media Milling Technique Used for Preparing Clotrimazole Nanocrystals for the Management of Cutaneous Candidiasis.

Clotrimazole is widely used for the management of cutaneous candidiasis infection. The low solubility of clotrimazole and excipient-related topical side effects (of currently available marketed products) cause the compromised efficacy of the therapy with poor patient compliance. In the present investigation, a clotrimazole nanocrystal-based nanogel was developed. Clotrimazole nanocrystals were optimized with studying the impact of individual process parameters of the media milling technique. The optimum level of individual process parameters was considered in the development of optimized batches. A promising result was obtained with a non-ionic stabilizer, polysorbate 80, at a concentration of 1.5%w/v, showing a distinct reduction in the particle size from above 31 µm to 264 nm and a polydispersity index of 0.211 with media milling at 1500 rpm for 6 h. This result was found to be in concordance with the TEM images, revealing a sharp diminution in particle morphology. Powder X-ray diffraction and differential scanning calorimetry results revealed crystallinity of clotrimazole (CTZ) in nanocrystal form. The optimized nanocrystal suspension was formulated into nanogel with carbopol 934, having a viscosity of 86.43 ± 2.06 Pa s at 25°C, which enhanced the ease of application of CTZ nanocrystals topically. A diffusion study showed around 82% of CTZ is transported across the membrane with the flux of 110.07 µg cm-2 h-1. In vivo results of the nanogel revealed improvement in CTZ release with 52% CTZ retention in different strata of the skin. The developed nanogel showed a significant improvement in the eradication of fungal infection within 10 days of application over Candida albicans-induced Wistar rat model. In a nutshell, the CTZ nanocrystal-loaded nanogel could achieve the goal of retaining CTZ in skin layers providing a prolonged effect and was able to treat cutaneous candidiasis in a short span with improved compliance for the candidiasis patients.

Revisiting cognitive reserve and cognition in multiple sclerosis: A closer look at depression.

BACKGROUND: The protective effect of cognitive reserve (CR) on cognition in people with multiple sclerosis (PwMS) has been well described. OBJECTIVE: To explore the relationship between aspects of CR, namely, leisure pursuits and depression. METHODS: In a cross-sectional study, a sample of 155 PwMS and 115 healthy controls (HC) underwent cognitive testing with the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery. Leisure activity was retrospectively recorded using the Leisure Activity Scale (LAS). Depression was assessed using the Hospital Anxiety and Depression Scale. RESULTS: PwMS demonstrated greater decreases in leisure activity over time compared to the HC group, particularly in the past year ( p < 0.001). Here, depression accounted for 17% of the variance in determining the level of leisure activity ( p < 0.001). Premorbid IQ and leisure activity within the past year emerged as significant predictors of information processing speed, learning, memory and executive function. After controlling for depression, the influence of leisure activity on cognition was insignificant. CONCLUSION: Depression can cause significant changes in behaviour which can influence indices of CR, such as leisure pursuits. Successfully treating depression may lead to a more active lifestyle thereby offsetting in part the cognitive burden of disease.

Screening Colonoscopy Withdrawal Time Threshold for Adequate Proximal Serrated Polyp Detection Rate.

INTRODUCTION: For adequate adenoma detection rate (ADR), guidelines recommend a mean withdrawal time (MWT) of ≥ 6 min. ADR has been shown to correlate strongly with proximal serrated polyp detection rate (PSP-DR), which is another suggested quality measure for screening colonoscopy. However, the impact of directly measured withdrawal time on PSP-DR has not been rigorously studied. We examined the relationship between MWT to ADR and PSP-DR, with the aim of identifying a functional threshold withdrawal time associated with both increased ADR and PSP-DR. METHODS: This was a retrospective study of endoscopy and pathology data from average-risk screening colonoscopy examinations performed at a large system with six endoscopy laboratories. A natural language processing tool was used to determine polyp location and histology. ADR and PSP-DR were calculated for each endoscopist. MWT was calculated from colonoscopy examinations in which no polyps were resected. RESULTS: In total, 31,558 colonoscopy examinations were performed, of which 10,196 were average-risk screening colonoscopy examinations with cecal intubation and adequate prep by 24 gastroenterologists. When assessing the statistical significance of increasing MWT by minute, the first significant time mark for PSP-DR was at 11 min at a rate of 14.2% (p = 0.01). There was a significant difference comparing aggregated MWT < 11 min compared to ≥ 11 min looking at the rates of adenomas [OR 1.65 (1.09-2.51)] and proximal serrated polyps [OR 1.81 (1.06-3.08)]. While ADR linearly correlated well with MWT (R = 0.76, p < 0.001), the linear relationship with PSP-DR was less robust (R = 0.42, p = 0.043). CONCLUSION: In this large cohort of average-risk screening colonoscopy, a MWT of 11 min resulted in a statistically significant increase in both ADR and PSP-DR. Our data suggest that a longer withdrawal time may be required to meet both quality metrics.

Symptoms of PTSD in Frontline Journalists: A Retrospective Examination of 18 Years of War and Conflict.

OBJECTIVE: The objective of the current study was to determine the frequency and severity of symptoms of posttraumatic stress disorder (PTSD) in journalists covering conflict. METHODS: PTSD data (Impact of Event Scale-Revised) collected over an 18-year period from 684 conflict journalists were analyzed retrospectively for frequency and severity of reexperiencing, avoidance, and arousal symptoms. Conflicts covered were civil wars in the Balkans ( n = 140 journalists), 9/11 attack in New York City ( n = 46), Iraq war ( n = 84), Mexico drug wars ( n = 104), civil war in Syria ( n = 59), Kenya election violence/Al-Shabab terror ( n = 57), state-sanctioned media intimidation in Iran ( n = 114), and the current migration crisis in Europe ( n = 80). RESULTS: The mean age of the sample was 38.59 (SD = 8.35) years, 461 (67%) journalists were men, and the mean duration of conflict work was 13.42 (SD = 7.74) years. The 5 most frequently endorsed symptoms were in the reexperiencing/intrusion category. Mean intrusion (1.31, SD = 0.97), avoidance (1.08, SD = 0.89), and arousal (1.07, SD = 0.96) scores for the entire sample were in the mild range. Being female and less educated independently predicted PTSD symptoms. CONCLUSIONS: PTSD phenomenology in a group of conflict journalists with well over a decade of frontline experience is dominated by reexperiencing symptoms. While symptom severity is for the most part mild, group means can obscure those individuals with significantly more severe difficulties.

A Rare Case Report of Bilateral Complex Macrocystic Adrenal Hemorrhage Mimicking Fetal Neuroblastoma.

Fetal and neonatal adrenal glands are large vascular organs, which make them vulnerable to frequent bleeding. Although neonatal adrenal hemorrhage is commonly reported, it is rarely diagnosed on antenatal sonography. We present a rare case of prenatally diagnosed bilateral adrenal hemorrhage, which mimicked antenatal neuroblastoma.

Distraction adds to the cognitive burden in multiple sclerosis.

BACKGROUND: Cognitive dysfunction in multiple sclerosis (MS) causes numerous limitations in activities of daily living. OBJECTIVES: To develop an improved method of cognitive assessment in people with MS using novel real-world distracters. METHODS: A sample of 99 people with MS and 55 demographically matched healthy controls underwent testing with the Minimal Assessment of Cognitive Functioning in Multiple Sclerosis (MACFIMS) and a modified version of the computerized Symbol Digit Modalities Test (c-SDMT). Half of the subjects completed the c-SDMT with built-in real-world distracters and half without. RESULTS: The mean time on the c-SDMT was significantly greater in MS subjects than healthy controls for both distracter ( p = 0.001) and non-distracter ( p < 0.001) versions. Significantly more MS subjects were impaired on the c-SDMT with distracters than the traditional SDMT (47.1% vs 30.3%, p = 0.04). There were no differences in impairment between the c-SDMT with and without distracters (47.1% vs 37.5%, p = 0.34). The distracter version had a sensitivity of 81% and specificity of 88% in detecting global cognitive impairment. CONCLUSIONS: The incorporation of distracters improves the sensitivity of a validated computerized version of the SDMT relative to the non-distracter and traditional versions and offers a quick and easy means of detecting cognitive impairment in people with MS.

Hereditary leiomyomatosis and renal cell cancer syndrome: An update and review.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is a rare genetic disorder that predisposes individuals to multiple cutaneous leiomyomas, renal cell carcinomas, and in women, uterine leiomyomas. Also known as Reed syndrome, it is caused by a germline heterozygous mutation of the fumarate hydratase tumor suppressor gene. HLRCC is associated with significant morbidity because of pain from cutaneous and uterine leiomyomas, the cutaneous pain often of unique character. Although genetic testing is currently considered the criterion standard to diagnose HLRCC, newer immunohistochemistry markers may provide rapid and cost effective alternatives to genetic testing. Because of the potentially aggressive nature of renal cell carcinomas that develop as early as in childhood, close annual cancer surveillance is desirable in individuals with HLRCC. In this review, we offer an update and an approach to the diagnosis, management, and renal cancer surveillance in HLRCC.

Incidence and risk factors of early surgical complications in young renal transplant recipients: A persistent challenge.

There is a paucity of data on the rate of urological and vascular complications in very young children after kidney transplant. We conducted a study on the incidence and risk factors for early post-transplant surgical complications in young recipients (<5 years) over three decades. The primary outcome was any urological or vascular complication within 30 days of transplant, and the secondary outcome was incidence rate of graft failure reported as per 1000 person-years. Risk factors associated with surgical complications were analyzed by logistic regression. There were 22 (26.5%) complications in 21 children with vascular thrombosis being the most common complication. There was no significant difference in the number of complications in period 1 (1985-1994) and period 2 (1995-2014) (P=.1). The incidence rate of graft failure was higher in period 1 (IR 70.8, 95% CI 41.1, 121.9) compared to period 2 (IR 20.7, 95% CI 9.3, 46.0). Cumulative incidence of graft survival at 1, 3, and 5 years' post-transplant was 96.5%, 92.6%, and 90%, respectively, in those without compared to 71%, 65.1%, and 58.6%, respectively, in children with complications. In conclusion, early surgical, especially vascular, complications are quite common in young renal transplant recipients and lead to significantly reduced graft survival.