Parkinson-Associated SNCA Enhancer Variants Revealed by Open Chromatin in Mouse Dopamine Neurons.

The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of Parkinson disease (PD), and modulation of risk by common variants in PD has been well established through genome-wide association studies (GWASs). We acquired open chromatin signatures of purified embryonic mouse MB DA neurons because we anticipated that a fraction of PD-associated genetic variation might mediate the variants' effects within this neuronal population. Correlation with >2,300 putative enhancers assayed in mice revealed enrichment for MB cis-regulatory elements (CREs), and these data were reinforced by transgenic analyses of six additional sequences in zebrafish and mice. One CRE, within intron 4 of the familial PD gene SNCA, directed reporter expression in catecholaminergic neurons from transgenic mice and zebrafish. Sequencing of this CRE in 986 individuals with PD and 992 controls revealed two common variants associated with elevated PD risk. To assess potential mechanisms of action, we screened >16,000 proteins for DNA binding capacity and identified a subset whose binding is impacted by these enhancer variants. Additional genotyping across the SNCA locus identified a single PD-associated haplotype, containing the minor alleles of both of the aforementioned PD-risk variants. Our work posits a model for how common variation at SNCA might modulate PD risk and highlights the value of cell-context-dependent guided searches for functional non-coding variation.

Association of Tripartite Motif Containing 11 rs564309 With Tau Pathology in Progressive Supranuclear Palsy.

BACKGROUND: Intronic variant rs564309 in tripartite motif containing 11 (TRIM11) is associated with clinical phenotypic differences in progressive supranuclear palsy (PSP), whereby the minor allele (A) is more common in atypical PSP than typical PSP (PSP-Richardson's syndrome). However, rs564309 has not been investigated relative to neuropathological outcomes. OBJECTIVE: Evaluate the association of rs564309 with the neuropathologically assessed severity of tau pathology, as measured by semi-quantitative scores for neurofibrillary tangles, tufted astrocytes, neuropil threads, and oligodendroglial coiled bodies. METHODS: 797 neuropathologically confirmed PSP cases were genotyped for TRIM11 rs564309 and assessed for tau pathology across 20 neuroanatomical regions. Tau pathology measures and age at death were examined for association with TRIM11 rs564309-A using multivariable linear regression models. RESULTS: TRIM11 rs564309-A was associated with increased neurofibrillary tangles pathology (P = 0.050), but was not significantly associated with age at death, neuropil threads, coiled bodies, or tufted astrocytes tau pathology scores. CONCLUSIONS: TRIM11 rs564309 may influence burden of neurofibrillary tangles tau pathology in PSP; further study is warranted. © 2020 International Parkinson and Movement Disorder Society.

Creation of a score to predict risk of high conscious sedation requirements in patients undergoing endoscopy.

BACKGROUND AND AIMS: The administration of intravenous conscious sedation to patients undergoing GI endoscopy carries a risk of cardiopulmonary adverse events. Our study aim was to create a score that stratifies the risk of occurrence of either high-dose conscious sedation requirements or a failed procedure. METHODS: Patients receiving endoscopy via endoscopist-directed conscious sedation were included. The primary outcome was occurrence of sedation failure, which was defined as one of the following: (1) high-dose sedation, (2) the need for benzodiazepine/narcotic reversal agents, (3) nurse-documented poor patient tolerance to the procedure, or (4) aborted procedure. High-dose sedation was defined as >10 mg of midazolam and/or >200 µg of fentanyl or the meperidine equivalent. Patients with sedation failure (n = 488) were matched to controls (n = 976) without a sedation failure by endoscopist and endoscopy date. RESULTS: Significant associations with sedation failure were identified for age, sex, nonclonazepam benzodiazepine use, opioid use, and procedure type (EGD, colonoscopy, or both). Based on these 5 variables, we created the high conscious sedation requirements (HCSR) score, which predicted the risk of sedation failure with an area under the curve of 0.70. Compared with the patients with a risk score of 0, risk of a sedation failure was highest for patients with a score ≥3.5 (odds ratio, 17.31; P = 2 × 10-14). Estimated area under the curve of the HCSR score was 0.68 (95% confidence interval, 0.63-0.72) in a validation series of 250 cases and 250 controls. CONCLUSIONS: The HCSR risk score, based on 5 key patient and procedure characteristics, can function as a useful tool for physicians when discussing sedation options with patients before endoscopy.

A Randomized, Controlled Pilot Trial Comparing Platelet-Rich Plasma to Topical Minoxidil Foam for Treatment of Androgenic Alopecia in Women.

BACKGROUND: Androgenic alopecia (AGA) is a common hair loss disorder. Studies have demonstrated successful treatment with platelet-rich plasma (PRP) in men, but studies in women are few. OBJECTIVE: To evaluate PRP in the treatment of AGA in women, compared with topical minoxidil. MATERIALS AND METHODS: Twenty women with AGA received topical minoxidil for 12 weeks and injectable PRP for 12 weeks in a randomized crossover design with an 8-week washout between treatments. Standardized TrichoScan analysis and quality-of-life questionnaires were assessed at baseline and 12-week follow-up for each treatment. RESULTS: After PRP, significant increases from baseline to Week 12 in TrichoScan analysis hair count (p = .002) and vellus hair density (p = .009) occurred. However, minoxidil resulted in significant increases in hair count (p < .001), vellus hair density (p = .03), terminal hair density (p = .004), and cumulative thickness (p = .004). Several quality of life responses improved from baseline to Week 12 after PRP treatment, whereas no improvements were noted after minoxidil. CONCLUSION: Platelet-rich plasma is an effective treatment for hair regrowth in female AGA, although not as effective as minoxidil. However, the improved quality of life responses after PRP, but not minoxidil, suggest a potential overall greater degree of satisfaction with PRP. LEVELS OF EVIDENCE: I. CLINICAL TRIAL REGISTRATION: NCT03488108.

Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology.

INTRODUCTION: The cytoprotective PTEN-induced kinase 1 (PINK1)-parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65-Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis. METHODS: Morphology, levels, and distribution of the mitophagy tag pS65-Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models. RESULTS: Analyses revealed significant increases of pS65-Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho-tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co-localization of pS65-Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed. DISCUSSION: Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease.

Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease.

INTRODUCTION: Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases. METHODS: We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin-5 (CLDN5) and occludin (OCLN), and major AD-related molecules (amyloid beta [Aß40], Aß42, tau, p-tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA. RESULTS: Higher levels of soluble tau, insoluble p-tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aß40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels. DISCUSSION: Refining the molecular mechanisms connecting tau, Aß, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.

Mortality and Cerebrovascular Events After Heart Rhythm Disorder Management Procedures.

BACKGROUND: Recognition of rates and causes of hard, patient-centered outcomes of death and cerebrovascular events (CVEs) after heart rhythm disorder management (HRDM) procedures is an essential step for the development of quality improvement programs in electrophysiology laboratories. Our primary aim was to assess and characterize death and CVEs (stroke or transient ischemic attack) after HRDM procedures over a 17-year period. METHODS: We performed a retrospective cohort study of all patients undergoing HRDM procedures between January 2000 and November 2016 at the Mayo Clinic. Patients from all 3 tertiary academic centers (Rochester, Phoenix, and Jacksonville) were included in the study. All in-hospital deaths and CVEs after HRDM procedures were identified and were further characterized as directly or indirectly related to the HRDM procedure. Subgroup analysis of death and CVE rates was performed for ablation, device implantation, electrophysiology study, lead extraction, and defibrillation threshold testing procedures. RESULTS: A total of 48 913 patients (age, 65.7±6.6 years; 64% male) who underwent a total of 62 065 HRDM procedures were included in the study. The overall mortality and CVE rates in the cohort were 0.36% (95% confidence interval [CI], 0.31-0.42) and 0.12% (95% CI, 0.09-0.16), respectively. Patients undergoing lead extraction had the highest overall mortality rate at 1.9% (95% CI, 1.34-2.61) and CVE rate at 0.62% (95% CI, 0.32-1.07). Among patients undergoing HRDM procedures, 48% of deaths directly related to the HDRM procedure were among patients undergoing device implantation procedures. Overall, cardiac tamponade was the most frequent direct cause of death (40%), and infection was the most common indirect cause of death (29%). The overall 30-day mortality rate was 0.76%, with the highest being in lead extraction procedures (3.08%), followed by device implantation procedures (0.94%). CONCLUSIONS: Half of the deaths directly related to an HRDM procedure were among the patients undergoing device implantation procedures, with cardiac tamponade being the most common cause of death. This highlights the importance of the development of protocols for the quick identification and management of cardiac tamponade even in procedures typically believed to be lower risk such as device implantation.

Outcomes of Unilateral Cataracts in Infants and Toddlers 7 to 24 Months of Age: Toddler Aphakia and Pseudophakia Study (TAPS).

PURPOSE: To evaluate outcomes of unilateral cataract surgery in children 7 to 24 months of age. DESIGN: Retrospective case series at 10 Infant Aphakia Treatment Study (IATS) sites. PARTICIPANTS: The Toddler Aphakia and Pseudophakia Study is a registry of children treated by surgeons who participated in the IATS. METHODS: Children underwent unilateral cataract surgery with or without intraocular lens (IOL) placement during the IATS enrollment years of 2004 and 2010. MAIN OUTCOME MEASURES: Intraoperative complications, adverse events (AEs), visual acuity, and strabismus. RESULTS: Fifty-six children were included with a mean postoperative follow-up of 47.6 months. Median age at cataract surgery was 13.9 months (range, 7.2-22.9). Ninety-two percent received a primary IOL. Intraoperative complications occurred in 4 patients (7%). At 5 years of age, visual acuity of treated eyes was very good (≥20/40) in 11% and poor (≤20/200) in 44%. Adverse events were identified in 24%, with a 4% incidence of glaucoma suspect. An additional unplanned intraocular surgery occurred in 14% of children. Neither AEs nor intraocular reoperations were more common for children with surgery at 7 to 12 months of age than for those who underwent surgery at 13 to 24 months of age (AE rate, 21% vs. 25% [P = 0.60]; reoperation rate, 13% vs. 16% [P = 1.00]). CONCLUSIONS: Although most children underwent IOL implantation concurrent with unilateral cataract removal, the incidence of complications, reoperations, and glaucoma was low when surgery was performed between 7 and 24 months of age and compared favorably with same-site IATS data for infants undergoing surgery before 7 months of age. Our study showed that IOL implantation is relatively safe in children older than 6 months and younger than 2 years.

Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis.

As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146.

Serum Electrolyte Levels and Outcomes in Patients Hospitalized with Hepatic Encephalopathy.

INTRODUCTION AND AIMS: Serum electrolyte derangements are common in patients with decompensated cirrhosis hospitalized for hepatic encephalopathy. There are limited data describing the association between electrolyte levels and outcomes in hepatic encephalopathy. We assessed the association between initial serum electrolyte values and outcomes in patients with hepatic encephalopathy. MATERIAL AND METHODS: A total of 385 consecutive patients hospitalized with encephalopathy were included in the study. Baseline electrolyte levels (sodium, potassium, chloride, bicarbonate, calcium and phosphorus) were measured at the time of admission and assessed for association with outcomes, which included survival, admission to the intensive care unit, requirement for mechanical ventilation, and length of hospital stay. P-values ≤ 0.0083 were considered significant after adjustment for multiple testing. RESULTS: In unadjusted analysis, significant associations were identified regarding both bicarbonate and phosphorus (admission to intensive care unit), and calcium (mechanical ventilation); however these findings weakened and no longer approached statistical significance when adjusting for confounding variables. No other significant associations between serum electrolyte measurements and outcomes were observed. CONCLUSIONS: Our findings suggest that in patients hospitalized with encephalopathy, serum electrolyte measurements are not strong predictors of patient outcome.

Nontuberculous Mycobacterial Infections of the Upper Extremity: 15-Year Experience at a Tertiary Care Medical Center.

PURPOSE: To present our experience with culture-positive, nontuberculous mycobacterial infections (NTMI) of the upper extremity and to compare the clinical features and outcomes of treatment among immunocompetent and immunocompromised patients. METHODS: All patients at our medical center diagnosed with NTMI of the upper extremity from December 1, 2000, through December 31, 2015, were included. We performed a retrospective analysis of patient demographic characteristics, delay to diagnosis, risk factors, clinical presentation, specific location, diagnostic testing, treatment regimens, and outcomes. These variables were compared between immunocompetent and immunocompromised patients. RESULTS: Forty-four patients were identified with culture-positive NTMI of the upper extremity. Of the patients, 27 (61%) were men (median age, 59 years [range, 23-83 years]). Twenty (45%) patients were immunocompromised. Immunocompromised patients had fewer known inoculation injuries compared with immunocompetent patients (45% vs 92%). A significant difference existed in the treatment regimens selected for immunocompetent versus immunocompromised patients: immunocompetent patients were more often treated with both antibiotics and surgery (88% vs 50%), whereas immunocompromised patients were more often treated with antibiotics alone (45% vs 4%). Overall, 24% experienced treatment failure and 9% died. Outcomes were relatively similar between immunocompetent and immunocompromised patients. A shorter delay to diagnosis was associated with a lower failure rate. CONCLUSIONS: Diagnosis of upper-extremity NTMI is often delayed because of indolent presentation and lack of clinical suspicion. The clinical presentation, diagnostic delay, and diagnostic testing results are similar between immunocompetent and immunocompromised patients. Although treatment varied significantly between patient groups, outcomes were similar. Timely diagnosis has the greatest impact on patient outcome. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Trends in Sexual Function After Breast Cancer Surgery.

PURPOSE: Sexual dysfunction is assumed to be common, but understudied, in breast cancer patients. Herein, we use the validated female sexual functioning index (FSFI) to evaluate changes in female sexual function after breast cancer surgery. METHODS: The FSFI assesses sexual function in six domains (desire, arousal, lubrication, orgasm, satisfaction, pain) on a 36-point scale, with scores >26.6 indicating better sexual function. We identified 226 women with unilateral breast cancer undergoing surgery at our institution from June 2010-January 2015. All completed the FSFI preoperatively and at a median of 13 months postoperatively. We quantified declines in FSFI scores and considered p-values <0.05 statistically significant. RESULTS: Overall, 119 women had breast-conserving surgery (BCS), 40 had unilateral mastectomy (UM), and 67 had UM plus contralateral prophylactic mastectomy (CPM). All women had similar baseline FSFI scores (medians: BCS, 26.3; UM, 25.2; UM+CPM, 23.7; p = 0.23). At follow-up, sexual function had declined significantly in BCS (23.5; p < 0.001) and UM (17.4; p = 0.010), but was unchanged in UM+CPM (22.8; p = 0.74) women. Interestingly, all women maintained their desire for sex (p = 0.17). BCS and UM women demonstrated significant declines in all other subscale domains (all p < 0.045). UM+CPM women demonstrated no decline in any subscale domain, yet did not exhibit superior sexual function to those having UM or BCS (medians: BCS, 23.5; UM, 17.4; UM+CPM, 22.8; p = 0.21). CONCLUSIONS: Baseline sexual dysfunction exists in women diagnosed with breast cancer. Surgery negatively impacts sexual function. Patients who choose mastectomy do not exhibit superior sexual function over those having BCS at 13 months following surgery.

Regional analysis and genetic association of nigrostriatal degeneration in Lewy body disease.

BACKGROUND: A number of genetic loci are associated with risk for Parkinson's disease (PD) based on genome-wide association studies; however, the relationship between genetic variants and nigrostriatal degeneration, which is the structural correlate of parkinsonism, has not been reported. OBJECTIVES: We quantified nigrostriatal dopaminergic integrity with image analysis of putaminal tyrosine hydroxylase immunoreactivity in 492 brains with Lewy body disease and used this pathologic endophenotype to explore possible association with PD genetic variants. METHODS: The study cases had Lewy-related pathology and variable degrees of nigrostriatal degeneration. They were assigned to one of the following clinical subgroups according to their predominant clinical syndrome: parkinsonism-predominant, parkinsonism+dementia, and dementia-predominant. In addition to putaminal tyrosine hydroxylase immunoreactivity, semiquantitative scoring was used to assess substantia nigra neuronal loss. A total of 29 PD genetic risk variants were genotyped on each case. RESULTS: When compared with controls, tyrosine hydroxylase immunoreactivity was reduced in Lewy body cases in the dorsolateral (79%) and ventromedial (57%) putamen. The dorsolateral region was better preserved in dementia-predominant cases than in cases with parkinsonism. Dorsolateral putaminal tyrosine hydroxylase immunoreactivity correlated with neuronal loss in the ventrolateral substantia nigra. Genetic analyses showed no significant association of PD risk variants with putaminal tyrosine hydroxylase immunoreactivity. CONCLUSIONS: The results confirm regional differences in putaminal dopaminergic degeneration and vulnerability of nigrostriatal pathway in Lewy body disorders with parkinsonism. The lack of association with PD genetic risk variants suggests that they may not be associated with quantitative endophenotypes of nigrostriatal degeneration, but more likely related to the risk of disease per se. © 2017 International Parkinson and Movement Disorder Society.

Impact of an Endoscopic Quality Improvement Program Focused on Adenoma Detection on Sessile Serrated Adenoma/Polyp Detection.

BACKGROUND: Sessile serrated adenomas/polyps (SSA/P) are an under-recognized disease with a unique malignant pathway. Improved endoscopic recognition and pathological interpretation is needed. AIMS: To determine whether an educational intervention that improved adenoma detection rate (ADR) could improve SSA/P detection rate after reclassification of previously termed "hyperplastic" polyps. METHODS: We reanalyzed data from a prospective randomized trial of an educational intervention aimed at increasing ADR. All hyperplastic polyps ≥6 mm reported in a previously published study were rereviewed and reclassified using standardized criteria for serrated lesions. Detection rates of sessile serrated adenomas/polyps and other clinically relevant serrated polyps were calculated in the baseline and post-training phases of the original study. RESULTS: Of 263 available for rereview, 33 (12.5%) were reclassified as SSA/P (N = 32) or traditional serrated adenoma (TSA) (N = 1). Reclassification was more common in the right colon (18 vs. 8%, p = 0.02). Baseline SSA/P detection rate was 0.7% in the untrained group and 1.3% in the trained group. Post-training, the SSA/P detection rate increased to 2.1 and 1.5%, respectively. The clinically relevant serrated polyp detection rate at baseline was 14.2% in the untrained group and 11.3% in the trained group. After the educational intervention, the clinically relevant serrated polyp detection rates increased to 16.5 and 14.8% in the untrained and trained groups, respectively. The estimated odds of an endoscopist detecting either a SSA/P or other clinically relevant serrated polyp during colonoscopy increased by only 3% with the educational intervention (OR 1.03, 95% CI 0.61-1.74, p = 0.91). CONCLUSIONS: Pathological re-interpretation of larger serrated polyps resulted in the reclassification of 12.5% of lesions. Quality improvement methods focused on adenoma detection did not impact SSA/P detection, and thus specific methods for serrated polyp detection are needed.

Timing interval from peri-prostatic block to biopsy impacts procedural pain.

INTRODUCTION: To compare visual analog scale (VAS) pain scores between patients with a 2-minute versus 10-minute delay of peri-prostatic lidocaine injection prior to transrectal ultrasound-guided prostate biopsies (TRUS-bx). MATERIALS AND METHODS: Eighty patients who underwent standard 12-core TRUS-bx by a single surgeon were prospectively randomized into four different treatment arms: bibasilar injection with a 2-minute delay, bibasilar injection plus a single apical injection with a 2-minute delay, bibasilar injection with a 10-minute delay, and bibasilar injection plus a single apical injection with a 10-minute delay. Patients were asked to report their level of pain on the VAS (0-10, with 10 indicating unbearable pain) at the following intervals: probe insertion (baseline), after each core, and post-procedure. The primary outcome measure was mean VAS score across all 12 cores minus baseline VAS score, which we refer to baseline-adjusted mean VAS score. RESULTS: Baseline-adjusted mean VAS score was significantly higher for the 2-minute delay group compared to the 10-minute delay group (mean: -0.7 versus -1.6, p = 0.025). Subset analysis of biopsies 1-3, 4-6, 7-9 and 10-12 also demonstrated higher baseline-adjusted mean VAS scores in the 2-minute delay group (all p ≤ 0.043). CONCLUSIONS: Lower TRUS-bx VAS scores can be achieved by extending the time from lidocaine injection to onset of prostate biopsy from 2 to 10 minutes.

Endoscopic mucosal resection: learning curve for large nonpolypoid colorectal neoplasia.

BACKGROUND AND AIMS: Colorectal EMR for nonpolypoid neoplasia achieves better outcomes when performed by expert endoscopists. The time point at which the endoscopist achieves expert level remains to be defined. The objective of this study was to establish a learning curve of colorectal EMR for nonpolypoid neoplasia based on residual tissue on surveillance colonoscopy and adverse event rate. METHODS: Five hundred seventy-eight consecutive patients underwent EMR of colorectal neoplasia by 1 of 3 primary endoscopists between December 2004 and September 2013 in a tertiary academic center. Primary analyses focused on the largest lesion for patients with more than 1 lesion (median age, 69 years; median polyp size, 30 mm; 51% en bloc resection). Data on surveillance colonoscopy were available for 74%. Learning curves were calculated for each of the 3 main outcome measurements: the presence of residual neoplasia on surveillance colonoscopy, endoscopic assessment of incomplete EMR, and the occurrence of an immediate bleeding adverse event. RESULTS: Residual neoplasia on surveillance colonoscopy was present for 23.2% of patients, the rate of endoscopist-assessed incomplete EMR was 27.6%, and immediate bleeding adverse events occurred in 6.9% of patients. Although there was between-endoscopist variability, the overall rates of residual neoplasia and incomplete EMR decreased to below 20% to 25% after 100 EMRs; initial decreases in both rates were observed for earlier EMRs. Immediate bleeding adverse events occurred at a low frequency for each endoscopist across all EMRs. Perforation requiring surgical intervention occurred in 1 patient (0.2%). CONCLUSIONS: This study demonstrated that an unexpectedly high number of 100 colorectal EMR procedures for large nonpolypoid colorectal neoplasia are required to achieve a plateau phase for crucial outcomes.

Proposed prognostic scoring system evaluating risk factors for biochemical recurrence of prostate cancer after salvage radiation therapy.

OBJECTIVE: To update a previously proposed prognostic scoring system that predicts risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer when using additional patients and a PSA value of 0.2 ng/mL and rising as the definition of BCR. PATIENTS AND METHODS: We included 577 patients who received SRT for a rising PSA after radical prostatectomy in this retrospective cohort study. Clinical, pathological, and SRT characteristics were evaluated for association with BCR using relative risks (RRs) from multivariable Cox regression models. RESULTS: With a median follow-up of 5.5 years after SRT, 354 patients (61%) experienced BCR. At 5 years after SRT, 40% of patients were free of BCR. Independent associations with BCR were identified for the PSA level before SRT (RR [doubling]: 1.25, P < 0.001), pathological tumour stage (RR [T3a vs T2] 1.21, P = 0.19; RR [T3b/T4 vs T2] 2.09, P < 0.001; overall P < 0.001), Gleason score (RR [7 vs <7] 1.63, P < 0.001; RR [8-10 vs <7] 2.28, P < 0.001; overall P < 0.001), and surgical margin status (RR [positive vs negative] 0.71, P = 0.003). We combined these four variables to create a prognostic scoring system that predicted BCR risk with a c-index of 0.66. Scores ranged from 0 to 7, and 5-year freedom from BCR for different levels of the score was as follows: Score = 0-1: 66%, Score = 2: 46%, Score = 3: 28%, Score = 4: 19%, and Score = 5-7: 15%. CONCLUSION: We developed a scoring system that provides an estimation of the risk of BCR after SRT. These findings will be useful for patients and physicians in decision making for radiation therapy in the salvage setting.

Pediatric melanomas often mimic benign skin lesions: A retrospective study.

BACKGROUND: Childhood melanoma can be misdiagnosed because of its rarity and atypical presentation. OBJECTIVE: We sought to correlate the clinical appearance of pediatric melanomas with Breslow depth and clinical behavior, and to identify diagnostic errors made by dermatologists and nondermatologist physicians. METHODS: This was a retrospective review of Mayo Clinic records of children and young adults 21 years of age or younger with a diagnosis of primary cutaneous melanoma between January 2000 and January 2015. RESULTS: Pediatric melanomas that mimicked benign skin lesions were more often deeper (>1 mm; odds ratio 5.48; P = .002) and had a higher T stage (odds ratio [T2, T3, or T4] 6.28; P = .001) than melanomas with a clinically malignant appearance. Of pediatric melanomas, 66% originally diagnosed as benign melanocytic lesions exhibited changes in size, shape, and color. LIMITATIONS: Sample size and retrospective design are limitations. CONCLUSIONS: Benign-appearing pediatric skin lesions with a history of evolution, bleeding, or ulceration should raise suspicion for melanoma. Melanomas demonstrating these features are associated with a higher Breslow depth and T stage. Although biopsy of all lesions that exhibit change in children is not practical, safe, or desired, close monitoring is recommended.

Stability of increased adenoma detection at colonoscopy. Follow-up of an endoscopic quality improvement program-EQUIP-II.

OBJECTIVES: We recently completed a randomized controlled trial of an endoscopic quality improvement program (EQUIP) that demonstrated an improved adenoma detection rate (ADR) through simple educational interventions. The aim of this study (phase III) is to examine whether the improvement in ADR in the trained endoscopists remained stable with further follow-up. METHODS: We prospectively followed up 15 staff endoscopists who had previously been randomized to a quality improvement intervention. In the current study, we examined an additional 1,200 colonoscopy procedures conducted over a 5-month time period following the original study, referred to as phase III. During this time, all physicians received quarterly ADR and other quality metric feedback, and the previous control group was offered the educational intervention voluntarily. ADRs and adenoma per patient (APP) rates were estimated in the endoscopists who were and were not randomized to EQUIP training and compared with those obtained in phases I and II of the original study. The study was conducted in a tertiary care Academic Medical Center. The study sample comprised 1200 patients undergoing routine colonoscopy. The main outcome measurement was adenoma detection rate. RESULTS: The previously observed increase in ADR in the trained group from 36% in phase I to 47% in phase II was maintained into phase III (46%). The ADR of the untrained group remained unchanged from phase I (36%) to phase II (35%); it was increased only marginally in phase III to 39%, which was still lower than the 46% ADR in the trained group. The trained group had an increase in APP, from 0.72 in Phase I to 0.87 in Phase II and 0.98 in Phase III. For the previously untrained group, there was no change in APP from phase I (0.68) to phase II (0.68), but there was possibly a small increase (to 0.74) in Phase III. CONCLUSIONS: This study provides evidence that improvements in ADR obtained through the endoscopic quality-training program can persist for at least 5 months after completion of the program. It further suggests that a focus on ADR does not lead to a "one and done" phenomenon. The limitations of this study were as follows: single-center setting, and lack of sessile polyp information/standardization.

The incidence and clinical characteristics of adult-onset convergence insufficiency.

OBJECTIVE: The purpose of this study was to describe the clinical characteristics and natural history of convergence insufficiency (CI) in a population-based cohort of adults. DESIGN: Retrospectively reviewed population-based cohort. PARTICIPANTS: Adult (age ≥19 years) residents of Olmsted County, Minnesota. METHODS: The medical records of all adults diagnosed with CI over a 20-year period were reviewed retrospectively. MAIN OUTCOME MEASURES: Clinical characteristics and outcomes for adult-onset CI. RESULTS: A total of 118 adults (annual incidence, 8.44 per 100 000 patients older than 19 years) were diagnosed with CI during the 20-year period, constituting 15.7% of all forms of adult-onset strabismus observed in this population. The median age at diagnosis was 68.5 years (range, 21.7-97.1 years), and 68 (57.6%) were female. The mean initial exodeviation at near was 14.1 prism diopters (PD; range, 1-30 PD) and 1.7 PD (range, 0-10 PD) at distance. The Kaplan-Meier rate of exotropia increasing over time by 7 PD or more at near was 4.2% at 5 years, 13.5% at 10 years, and 24.4% at 20 years. Approximately 88% were managed with prisms, whereas less than 5% underwent surgical correction. CONCLUSIONS: Adult-onset CI included approximately 1 in 6 adults who were newly diagnosed with strabismus in this 20-year cohort. There was a significant increase in incidence with increasing age. Nearly one-fourth had an increase of their near exodeviation of at least 7 PD by 20 years after their diagnosis, and most patients were managed conservatively.