Outcomes in accommodative esotropia with a high AC/A ratio.

PURPOSE: The purpose of this retrospective cohort study was to report the outcomes of high AC/A ratio accommodative esotropia (AET) among children. METHODS: The medical records of all children <19 years diagnosed with accommodative esotropia and a high AC/A ratio while residing in Olmsted County, Minnesota, from January 1, 1975, through December 31, 2004, were retrospectively reviewed. RESULTS: A total of 512 patients were diagnosed with AET during the 30-year study period, of which 395 (77.1%) had fully accommodative ET, 117 (22.8%) had partially accommodative ET and 106 (20.5%) had a high AC/A ratio. Of the 93 (87.7 %) high AC/A patients managed with bifocals, 50 (53.8 %) discontinued their use after a mean of 58.7 (range: 5.6-229) months. The Kaplan-Meier rate of discontinuing bifocals was 24.5% at 3 years, 36.4% at 5 years, and 61.4% at 10 years. Patients who discontinued bifocals were more likely to have had strabismus surgery (44% vs 18.6%, p = 0.009) than those who did not discontinue bifocals. The high AC/A patients managed with bifocals achieved similar stereoacuity outcomes to those who did not wear bifocals (p = 0.65) and were no more likely to require surgery (p = 0.13). CONCLUSION: Among this cohort of children with accommodative esotropia and a high AC/A ratio, bifocal use was discontinued in the majority of children within 10 years, and more commonly among those who underwent strabismus surgery. The use of bifocals was not associated with a higher likelihood of undergoing surgery or enhanced stereopsis compared to those who did not use them.

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.

Ipsilateral gaze deviation as a risk factor for surgical overcorrection in two-muscle surgery for unilateral superior oblique palsy.

PURPOSE: To investigate the angle of deviation in various gaze positions as a risk factor for overcorrection of moderate-angle unilateral trochlear nerve palsies treated with two-muscle surgery. METHODS: The medical records of consecutive patients with presumed unilateral moderate-angle trochlear nerve palsy who underwent two-muscle surgery were retrospectively reviewed. Patients with overcorrection, defined as reversal of hyperdeviation by prism alternate cover testing at distance (straight ahead) or near measured at 6 weeks, were compared to non-overcorrected patients for their preoperative torsion and ocular alignment at near and distance. RESULTS: A total of 45 patients (age range, 12-77 years; 24 [53%] males) with deviation ranging from 14Δ to 25Δ in primary position underwent two-muscle surgery, of whom 8 (18%) experienced surgical overcorrection by 6 weeks' follow-up. The preoperative angle of deviation was similar between overcorrected and non-overcorrected patients for eight of nine cardinal distance positions and near gaze; however, patients with smaller deviations in ipsilateral gaze were more likely to be overcorrected with two-muscle surgery (8.5 vs 16.0 [P = 0.029]). Cut point analysis determined that an ipsilateral gaze of ≤9Δ was significantly associated with overcorrection. Greater lateral incomitance also trended toward overcorrection (15.0 vs 9.0 [P = 0.059]). Torsion was not a clinically significant indicator of overcorrection (3.5 vs 6 [P = 0.083]). CONCLUSIONS: A preoperative ipsilateral angle of ≤9Δ was associated with overcorrection in patients undergoing two-muscle surgery for moderate angle unilateral trochlear nerve palsies.

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.

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.

Cost Analysis of R-CHOP Versus Dose-Adjusted R-EPOCH in Treatment of Diffuse Large B-Cell Lymphoma with High-Risk Features.

Dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA.R-EPOCH) is used for upfront treatment of high-risk diffuse large B cell lymphoma (DLBCL). In this study, we compared the outcomes in patients with high-risk DLBCL who received frontline rituximab, cycophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or DA.R-EPOCH immunochemotherapy. Outcomes and treatment-related cost were analyzed. DLBCL with one of the following features were included in the study: MYC ± BCL2 or BCL6 rearrangement by FISH or MYC overexpression by immunohistochemistry, Ki67 index ≥ 80% or nongerminal center immunophenotype, tumor measuring ≥5 cm and NCCN- IPI score ≥4. A total of 80 patients were treated with R-CHOP (n = 52, 65%) or DA.R-EPOCH (n = 28, 35%), with a median follow-up of 11.2 months (range: 0.7-151.3 months). The hazard ratios (HRs) for progression-free survival and overall survival were 0.79 [95% confidence interval (CI) 0.28%-2.29%, p = 0.67] and 0.86 (95% CI 0.26%-2.78%, p = 0.80), respectively for DA.R-EPOCH compared to R-CHOP. The total mean cost was USD106,940 ± USD39,351 and USD58,509 ± 24,588 for DA.R-EPOCH and R-CHOP respectively (p < 0.001). In our analysis, DA.R-EPOCH resulted comparable clinical outcomes and increased treatment-related expenses compared to R-CHOP in high-risk DLBCL.

Association between contact sports participation and chronic traumatic encephalopathy: a retrospective cohort study.

Chronic traumatic encephalopathy is a debilitating neurodegenerative disorder associated with repetitive traumatic brain injuries often sustained through prior contact sport participation. The frequency of this disorder in a diverse population, including amateur athletes, is unknown. Primary historical obituary and yearbook records were queried for 2566 autopsy cases in the Mayo Clinic Tissue Registry resulting in identification of 300 former athletes and 450 non-athletes. In these cases, neocortical tissue was screened for tau pathology with immunohistochemistry, including pathology consistent with chronic traumatic encephalopathy, blinded to exposure or demographic information. Using research infrastructure of the Rochester Epidemiology Project, a comprehensive and established medical records-linkage system of care providers in southern Minnesota and western Wisconsin, medical diagnostic billing codes pertaining to head trauma, dementia, movement disorders, substance abuse disorders and psychiatric disorders were recorded for cases and controls in a blinded manner. A total of 42 individuals had pathology consistent with, or features of, chronic traumatic encephalopathy. It was more frequent in athletes compared to non-athletes (27 cases versus 15 cases) and was largely observed in men (except for one woman). For contact sports, American football had the highest frequency of chronic traumatic encephalopathy pathology (15% of cases) and an odds ratio of 2.62 (P-value = 0.005). Cases with chronic traumatic encephalopathy pathology had higher frequencies of antemortem clinical features of dementia, psychosis, movement disorders and alcohol abuse compared to cases without chronic traumatic encephalopathy pathology. Understanding the frequency of chronic traumatic encephalopathy pathology in a large autopsy cohort with diverse exposure backgrounds provides a baseline for future prospective studies assessing the epidemiology and public health impact of chronic traumatic encephalopathy and sports-related repetitive head trauma.

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.

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.

Hepatic iron overload identified by magnetic resonance imaging-based T2* is a predictor of non-diagnostic elastography.

BACKGROUND: Magnetic resonance elastography (MRE) is a non-invasive test used to assess liver stiffness and fibrosis in chronic liver disease, which includes systemic iron overload. However, iron deposition by itself is associated with technical failure of MRE of the liver which necessitates the use of invasive liver biopsy as an alternative monitoring method for these patients. T2*-weighted magnetic resonance imaging (T2*) is a reliable modality to asses for hepatic as well as total body iron overload. Therefore, we aimed to determine a cutoff value on the T2* reading at which MRE would no longer provide accurate stiffness measurements in patients with iron overload. METHODS: Ninety-five patients with iron overload who underwent MRE at our institution, between 2010 and 2017 were reviewed retrospectively. We compared T2* values between patients with adequate elastography (N=63) versus those with non-diagnostic elastography (N=32). We additionally examined the ability of T2* to predict the likelihood of non-diagnostic elastography by estimating area under the ROC curve (AUC). RESULTS: T2* was significantly different between patients with and without an adequate elastography (P<0.0001) and predicted occurrence of non-diagnostic elastography with an AUC of 0.95. All patients with a non-diagnostic elastography had a T2* value below 20 milliseconds (ms), and correspondingly 55% of the patients with a T2* value below 20 ms had a non-diagnostic elastography. The subgroups of patients with a T2* value ≤10, ≤8, and ≤6 ms, had a higher likelihood of non-diagnostic elastography (87%, 92%, and 95%, respectively). CONCLUSIONS: T2* can be used to accurately predict which patients are most likely to have a non-diagnostic elastography reading. T2* of 20 ms or lower reflects a higher likelihood of non-diagnostic elastography.

Monoclonal antibody utilization characteristics in patients with multiple myeloma.

This study analyzed 91 multiple myeloma patients who received two monoclonal antibodies, Daratumumab and Elotuzumab, over a year and report the adverse event profile, infusion practices and utilization of these drugs in the real world. All current reported data on monoclonal antibodies is from clinical trials, without any real-world experience. Patients from Mayo Clinic Florida or Arizona diagnosed with relapsed or refractory multiple myeloma who were treated with Daratumumab or Elotuzumab alone or in combination between 1 January 2016 and 31 December 2016 were included in the analysis. Daratumumab-treated patients (n = 78) were more heavily pre-treated than that in published clinical trials, whereas the elotuzumab patient (n = 13) profile was similar to that published before. Infusion time was on average 2 hours less than the prescribing guidelines and premedication use varied noticeably after the initial monoclonal antibody infusion, with an overall decrease over time. We noted higher than reported haematologic adverse events, especially neutropenia and fewer non-haematologic adverse events. 91.7% infusion-related reactions were observed during the first monoclonal antibody infusion, with a subsequent decrease. All infusion-related reactions were grade 2 or less, and none of the patients discontinued treatment due to infusion-related reactions. Baseline allergy profile or laboratory tests were not associated with the likelihood of developing monoclonal antibody-related infusion-related reactions. The real-world safety profile of monoclonal antibodies showed varying adverse event patterns than those reported in previous clinical trials. The infusion-related reaction patterns were similar to previous reports. Despite changes in premedication regimens safety was maintained in succeeding infusions. Such treatment utilization data is vital to broaden our knowledge of approved therapeutic agents and maximize their benefits for patients.

Evaluating the Efficacy, Safety, and Tolerability of the Combination of Tazarotene, Azelaic Acid, Tacrolimus, and Zinc Oxide for the Treatment of Melasma: A Pilot Study.

Background: Melasma is a common hyperpigmentation disorder of the skin. Combination therapy of topical retinoids, corticosteroids, and hydroquinone has been effective in treating melasma, but long-term use is limited by corticosteroid atrophy and exogenous ochronosis. The aim of this pilot study (NCT02730819) was to determine the efficacy, safety, and tolerability of a novel composition (2013-MCN-333) comprising tazarotene 0.075%, azelaic acid 20%, tacrolimus 0.1%, and (microfine) zinc oxide 10% for the treatment of melasma. Methods: Sixteen patients with moderate-to-severe melasma were treated daily with sunscreen and 2013-MCN-333 for 20 weeks. Primary outcome measure was change in Melasma Area and Severity Index (MASI) score. Results: Twenty-five percent of patients met the primary endpoint of a MASI score of less than eight points at Week 20. MASI score also decreased significantly from baseline (median: 18.9 points) through Week 4 (median: 17.3 points; p=0.006), Week 12 (median: 16.0 points; p=0.001), and Week 20 (median: 13.3 points; p=0.001). Treatment-related adverse events were mild, most of which decreased or resolved over the course of the study. Limitations: The small sample size and nonblinded nature of treatment intervention are potential limitations. Conclusion: Our results suggest daily 2013-MCN-333 could potentially be an effective, safe, and tolerable treatment for moderate-to-severe melasma.

Cost-Utility of Routine Testing in Chronic Urticaria/Angioedema: A Cohort Study.

BACKGROUND: Chronic urticaria/angioedema (CUA) guidelines recommend limiting tests to diagnose and assess prognosis, activity, and severity. Routine testing in CUA might substantially increase cost of disease without benefiting outcome. OBJECTIVE: To evaluate the utility of tests in CUA and how they influence the cost of disease. METHODS: We reviewed 725 electronic medical records of patients who were evaluated for CUA between 2010 and 2018 at a tertiary care center. The sample was gathered through the search of International Classification of Diseases Ninth and Tenth Revision codes pertaining to CUA. Analyses were made to evaluate changes in outcome for patients on whom at least 1 test was performed to evaluate CUA, the costs generated by these tests, and the tendencies to order specific tests from 2010 through 2018. RESULTS: Of 725 patients (age median, 47 years; women, 73.1%), 543 (74.8%) had at least 1 test performed. Tests had an elevated percentage of normal results (>90%). Five patients (0.9%) had a change in outcome and 8 patients were given a different diagnosis (0.1% each). Evaluation, management, and tests accounted for most of the costs. Costs remain similar between 2010-2014 (mean, $569) and 2015-2018 (mean, $569). CONCLUSIONS: In CUA, tests rarely uncover underlying conditions or lead to changes in management and outcome, but they substantially increase the costs generated by the disease. Adherence to current recommendations to limit testing might help in reducing the financial burden of CUA and improve delivery of care.

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.

Incidence and Ocular Features of Pediatric Myasthenias.

PURPOSE: To report the incidence, demographics, and ocular findings of children with myasthenia. DESIGN: Retrospective cohort study. METHODS: The medical records of all children (<19 years) examined at Mayo Clinic with any form of myasthenia from January 1 1966, through December 31, 2015, were retrospectively reviewed. RESULTS: A total of 364 children were evaluated during the study period, of which 6 children were residents of the Olmsted County at the time of their diagnosis, yielding an annual age- and sex-adjusted incidence of 0.35 per 100 000 <19 years, or 1 in 285 714 <19 years. The incidence of juvenile myasthenia gravis (JMG) and congenital myasthenic syndrome (CMS) was 0.12 and 0.23 per 100 000, respectively. Of the 364 study children, 217 (59.6%) had JMG, 141 (38.7%) had CMS, and 6 (1.7%) had Lambert-Eaton syndrome, diagnosed at a median age of 13.5, 5.1, and 12.6 years, respectively. A majority of the JMG and CMS patients had ocular involvement (90.3% and 85.1%, respectively), including ptosis and ocular movement deficits. Among children with at least 1 year of follow-up (JMG; median, 7.1 years, CMS; median, 7.0 years), improvement was seen in 88.8% of JMG patients (complete remission in 31.3%) and in 58.3% of CMS patients. CONCLUSION: Although relatively rare, myasthenia gravis in children has 2 predominant forms, CMS and JMG, both of which commonly have ocular involvement. Improvement is more likely in children with the juvenile form.

Delay to Colectomy and Survival for Patients Diagnosed with Colon Cancer.

Background: A long wait-time for colectomy for colon cancer should theoretically affect survival but, to date, the association between delay to colectomy and survival remains unresolved. Methods: We studied 4,685 patients who underwent a colectomy for colon cancer between 1990 and 2012. Wait-time was defined as the number of days between diagnosis and colectomy. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. Results: The number of patients in the wait-time group of 1-21 days was 3,529 (75.3%), 22-42 days was 842 (18.0%), 43-84 days was 253 (5.4%), and >84 days was 61 (1.3%). When compared to patients undergoing surgery in the first week after diagnosis, there was no increased risk of death until wait time >84 days (HR = 1.47; 95% CI, 1.02-2.11; p =.038). Patients in the wait time >84 day group tended to be older, traveled further for colectomy, and had tumors with a lower histologic grade. Conclusions: Colectomy for colon cancer performed up to 3 months following diagnosis is not associated with adverse long-term survival. These data provide a framework to address concerns over prolonged wait-times and direct efforts for timely surgery in patients with colon cancer.

Quantitative T2 MRI Mapping and 12-Month Follow-up in a Randomized, Blinded, Placebo Controlled Trial of Bone Marrow Aspiration and Concentration for Osteoarthritis of the Knees.

OBJECTIVE: Bone marrow aspiration and concentration (BMAC) is becoming a more common regenerative therapy for musculoskeletal pathology. In our current pilot study, we studied patients with mild-to-moderate bilateral knee osteoarthritis, compared pain at 12-month follow-up between BMAC-injected and saline-injected knees, and examined cartilage appearance measured by magnetic resonance imaging (MRI) T2 quantitative mapping. DESIGN: Twenty-five patients with mild-to-moderate bilateral osteoarthritic knee pain were randomized to receive BMAC into one knee and saline placebo into the other. Bone marrow was aspirated from the iliac crests, concentrated in an automated centrifuge, combined with platelet-poor plasma for knee injection, and compared with saline injection into the contralateral knee. Primary outcome measures were T2 MRI cartilage mapping at 6-month and Visual Analog Scale and Osteoarthritis Research Society International Intermittent and Constant Osteoarthritis Pain scores and radiographs at 12-month follow-up. RESULTS: Constant, intermittent, and overall knee pain remained significantly decreased from baseline at 12-month follow-up (all P ⩽ 0.01), with no apparent difference between BMAC- and saline-treated knees (all P ⩾ 0.54). A similar significant increase from baseline to 12-month follow-up regarding quality of life was observed for both BMAC- and saline-treated knees (all P ⩽ 0.04). T2 quantitative MRI mapping showed no significant changes as a result of treatment. CONCLUSIONS: BMAC is safe to perform and relieves pain from knee arthritis but showed no superiority to saline injection at 12-month follow-up. MRI cartilage sequences failed to show regenerative benefit with single BMAC injection. The mechanisms of action that led to pain relief remain unclear and warrant further studies.

Comparing morbidity rates between wise pattern and standard horizontal elliptical mastectomy incisions in patients undergoing immediate breast reconstruction.

BACKGROUND: Breast cancer patients with ptotic breasts pursuing mastectomy with immediate reconstruction can present challenges. A wise pattern (inverted-T) mastectomy incision (WPM) has been suggested as an alternative to the standard horizontal elliptical mastectomy (EM) to reduce redundant skin and correct ptosis. Herein, we sought to examine the differences in morbidity between the two techniques. METHODS: We performed a retrospective review of women undergoing mastectomy with immediate reconstruction at our institution from June 2007 to January 2016. We compared those undergoing WPM to a control population undergoing EM. Statistical analysis was performed evaluating clinical, pathological, and surgical outcome variables according to patient and per breast. All tests were two-sided with alpha level set at 0.05 for statistical significance. RESULTS: A total of 241 women underwent mastectomy and reconstruction in 421 breasts; 78/241 (32%) had WPM (149 breasts), 163/241 (68%) had EM (272 breasts). Both groups were similar in age, smoking status, diabetes, race, tumor type, and pathologic stage (all P > 0.07). Skin flap necrosis was the most frequently encountered complication, occurring in 58/149 (38.9%) of WPM breasts and in 24/272 (8.9%) of EM breasts (P < 0.0001). There was no difference in the need for revisional procedures between the groups (WPM: 24.1% vs EM: 17.6%, P = 0.207). CONCLUSION: Patients should be counseled WPM is associated with higher rates of skin flap necrosis. However, this does not translate into higher rates of revisional procedures or return to OR.

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.