Jack Wiedrick

MicroRNAs in Human Cerebrospinal Fluid as Biomarkers for Alzheimer’s Disease

BACKGROUND Currently available biomarkers of Alzheimers disease (AD) include cerebrospinal fluid (CSF) protein analysis and amyloid PET imaging, each of which has limitations. The discovery of extracellular microRNAs (miRNAs) in CSF raises the possibility that miRNA may serve as novel biomarkers of AD. OBJECTIVE Investigate miRNAs in CSF obtained from living donors as biomarkers for AD. METHODS We profiled miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays. Replicate studies performed on a subset of 32 of the original CSF samples verified 20 high confidence miRNAs. Stringent data analysis using a four-step statistical selection process including log-rank and receiver operating characteristic (ROC) tests, followed by random forest tests, identified 16 additional miRNAs that discriminate AD from controls. Multimarker modeling evaluated linear combinations of these miRNAs via best-subsets logistic regression, and computed area under the ROC (AUC) curve ascertained classification performance. The influence of ApoE genotype on miRNA biomarker performance was also evaluated. RESULTS We discovered 36 miRNAs that discriminate AD from control CSF. 20 of these retested in replicate studies verified differential expression between AD and controls. Stringent statistical analysis also identified these 20 miRNAs, and 16 additional miRNA candidates. Top-performing linear combinations of 3 and 4 miRNAs have AUC of 0.80-0.82. Addition of ApoE genotype to the model improved performance, i.e., AUC of 3 miRNA plus ApoE4 improves to 0.84. CONCLUSIONS CSF miRNAs can discriminate AD from controls. Combining miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE genotype improves classification.

Comparison of multiple methods to measure maternal fat mass in late gestation

BACKGROUND Measurements of maternal fat mass (FM) are important for studies of maternal and fetal health. Common methods of estimating FM have not been previously compared in pregnancy with measurements using more complete body composition models. OBJECTIVES The goal of this pilot study was to compare multiple methods that estimate FM, including 2-, 3- and 4-compartment models in pregnant women at term, and to determine how these measures compare with FM by dual-energy X-ray absorptiometry (DXA) 2 wk postpartum. DESIGN Forty-one healthy pregnant women with prepregnancy body mass index (in kg/m(2)) 19 to 46 underwent skinfold thickness (SFT), bioelectrical impedance analysis (BIA), body density (Db) via air displacement plethysmography (ADP), and deuterium dilution of total body water (TBW) with and without adjustments for gestational age using van Raaij (VRJ) equations at 37-38 wk of gestation and 2 wk postpartum to derive 8 estimates of maternal FM. Deming regression analysis and Bland-Altman plots were used to compare methods of FM assessment. RESULTS Systematic differences in FM estimates were found. Methods for FM estimates from lowest to highest were 4-compartment, DXA, TBW(VRJ), 3-compartment, Db(VRJ), BIA, air displacement plethysmography body density, and SFT ranging from a mean ± SD of 29.5 ± 13.2 kg via 4-compartment to 39.1 ± 11.7 kg via SFT. Compared with postpartum DXA values, Deming regressions revealed no substantial departures from trend lines in maternal FM in late pregnancy for any of the methods. The 4-compartment method showed substantial negative (underestimating) constant bias, and the air displacement plethysmography body density and SFT methods showed positive (overestimating) constant bias. ADP via Db(VRJ)and 3-compartment methods had the highest precision; BIA had the lowest. CONCLUSIONS ADP that uses gestational age-specific equations may provide a reasonable and practical measurement of maternal FM across a spectrum of body weights in late pregnancy. SFT would be acceptable for use in larger studies. This trial was registered at clinicaltrials.gov as NCT02586714.

MIF and D-DT are potential disease severity modifiers in male MS subjects

Significance The biological processes that are involved in the progression of multiple sclerosis (MS) are far from complete. Macrophage migration inhibitory factor (MIF) and its homolog, D-dopachrome tautomerase (D-DT), are immunoregulatory cytokines known to be involved in the worsening of various autoimmune disorders. We demonstrate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers. In addition, we show that MIF or D-DT deficiency ameliorates the disease severity of the murine model of MS. Our data suggest that targeting CD74, the common receptor for MIF and D-DT, with therapies such as partial MHC class II constructs could be therapeutically beneficial for inhibiting MS clinical progression in selected patients. Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a −794CATT5–8 microsatellite repeat and a −173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.

Arthroscopic mechanical chondroplasty of the knee is beneficial for treatment of focal cartilage lesions in the absence of concurrent pathology

Background: Articular cartilage lacks the ability for intrinsic repair after acute injury, and focal articular cartilage lesions cause significant morbidity worldwide. Arthroscopic debridement (chondroplasty) represents the majority of cartilage procedures of the knee; however, limited data exist regarding outcomes after chondroplasty performed in isolation of concurrent procedures or not as a primary treatment for osteoarthritis (OA). Hypothesis: Arthroscopic mechanical chondroplasty is beneficial for patients with a focal cartilage lesion of the knee in the absence of meniscal pathology or OA. Study Design: Case series; Level of evidence, 4. Methods: Potential participants were identified by querying billing data from a 3-year period in a single-surgeon practice, and eligible patients were verified to meet inclusion criteria through electronic medical record review. OA was quantified through Kellgren-Lawrence (KL) scoring. Subjective patient-reported outcome (PRO) scores, including International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), Tegner, Lysholm, and Veterans RAND 12-Item Health Survey (VR-12), were collected preoperatively and at follow-up intervals. International Cartilage Repair Society (ICRS) grade and lesion size were determined at arthroscopy. Linear regression was used to determine the effect of baseline score on final follow-up score. Correlated regression equations were used to assess the relationship of covariates and change in PRO scores. Results: Fifty-three of 86 (62%) eligible participants completed postoperative questionnaires at an average of 31.5 months (range, 11.5-57 months). The mean patient age was 37.3 ± 9.7 years and mean body mass index (BMI) was 27.7 ± 5.6 kg/m2; 33 (62%) participants were women. The mean treated lesion size was 3.3 ± 1.9 cm2, of these, 36 (68%) were ICRS grade 2 or 3, and 42 (79%) patients had a KL score of 0 to −2. On average, the cohort demonstrated significant improvement from baseline for almost all PRO scores. Regression analysis of change in score versus baseline indicated participants with lower preoperative scores gained more benefit from chondroplasty. Correlated regression equations showed KL score >0 and male sex had a consistent positive effect on change in PRO scores, high ICRS grade had a consistent negative effect, and lesion size, age, and obesity had no effect. Eight patients (15%) required further surgical intervention within the follow-up period. Conclusion: The clinical efficacy of chondroplasty for repair of focal cartilage defects of the knee has not been studied in isolation from concurrent orthopaedic procedures. Our data show that arthroscopic mechanical chondroplasty is beneficial to patients, and response to surgical intervention is correlated with baseline PRO scores, sex, ICRS grade, and KL score.

Vaginal birth after cesarean: neonatal outcomes and United States birth setting

BACKGROUND: Women who seek vaginal birth after cesarean delivery may find limited in‐hospital options. Increasing numbers of women in the United States are delivering by vaginal birth after cesarean delivery out‐of‐hospital. Little is known about neonatal outcomes among those who deliver by vaginal birth after cesarean delivery in‐ vs out‐of‐hospital. OBJECTIVE: The purpose of this study was to compare neonatal outcomes between women who deliver via vaginal birth after cesarean delivery in‐hospital vs out‐of‐hospital (home and freestanding birth center). STUDY DESIGN: We conducted a retrospective cohort study using 2007–2010 linked United States birth and death records to compare singleton, term, vertex, nonanomolous, and liveborn neonates who delivered by vaginal birth after cesarean delivery in‐ or out‐of‐hospital. Descriptive statistics and multivariate regression analyses were conducted to estimate unadjusted, absolute, and relative birth‐setting risk differences. Analyses were stratified by parity and history of vaginal birth. Sensitivity analyses that involved 3 transfer status scenarios were conducted. RESULTS: Of women in the United States with a history of cesarean delivery (n=1,138,813), only a small proportion delivered by vaginal birth after cesarean delivery with the subsequent pregnancy (n=109,970; 9.65%). The proportion of home vaginal birth after cesarean delivery births increased from 1.78–2.45%. A pattern of increased neonatal morbidity was noted in unadjusted analysis (neonatal seizures, Apgar score <7 or <4, neonatal seizures), with higher morbidity noted in the out‐of‐hospital setting (neonatal seizures, 23 [0.02%] vs 6 [0.19%; P<.001]; Apgar score <7, 2859 [2.68%] vs 139 [4.42%; P<.001; Apgar score <4, 431 [0.4%] vs 23 [0.73; P=.01]). A similar, but nonsignificant, pattern of increased risk was observed for neonatal death and ventilator support among those neonates who were born in the out‐of‐hospital setting. Multivariate regression estimated that neonates who were born in an out‐of‐hospital setting had higher odds of poor outcomes (neonatal seizures [adjusted odds ratio, 8.53; 95% confidence interval, 2.87–25.4); Apgar score <7 [adjusted odds ratio, 1.62; 95% confidence interval, 1.35–1.96]; Apgar score <4 [adjusted odds ratio, 1.77; 95% confidence interval, 1.12–2.79]). Although the odds of neonatal death (adjusted odds ratio, 2.1; 95% confidence interval, 0.73–6.05; P=.18) and ventilator support (adjusted odds ratio, 1.36; 95% confidence interval, 0.75–2.46) appeared to be increased in out‐of‐hospital settings, findings did not reach statistical significance. Women birthing their second child by vaginal birth after cesarean delivery in out‐of‐hospital settings had higher odds of neonatal morbidity and death compared with women of higher parity. Women who had not birthed vaginally prior to out‐of‐hospital vaginal birth after cesarean delivery had higher odds of neonatal morbidity and mortality compared with women who had birthed vaginally prior to out‐of‐hospital vaginal birth after cesarean delivery. Sensitivity analyses generated distributions of plausible alternative estimates by outcome. CONCLUSION: Fewer than 1 in 10 women in the United States with a previous cesarean delivery delivered by vaginal birth after cesarean delivery in any setting, and increasing proportions of these women delivered in an out‐of‐hospital setting. Adverse outcomes were more frequent for neonates who were born in an out‐of‐hospital setting, with risk concentrated among women birthing their second child and women without a history of vaginal birth. This information urgently signals the need to increase availability of in‐hospital vaginal birth after cesarean delivery and suggests that there may be benefit associated with increasing options that support physiologic birth and may prevent primary cesarean delivery safely. Results may inform evidence‐based recommendations for birthplace among women who seek vaginal birth after cesarean delivery.

Identification of Hip BMD Loss and Fracture Risk Markers Through Population-Based Serum Proteomics.

Serum proteomics analysis may lead to the discovery of novel osteoporosis biomarkers. The Osteoporotic Fractures in Men (MrOS) study comprises men ≥65 years old in the US who have had repeated BMD measures and have been followed for incident fracture. High‐throughput quantitative proteomic analysis was performed on baseline fasting serum samples from non‐Hispanic white men using a multidimensional approach coupling liquid chromatography, ion‐mobility separation, and mass spectrometry (LC‐IMS‐MS). We followed the participants for a mean of 4.6 years for changes in femoral neck bone mineral density (BMD) and for incident hip fracture. Change in BMD was determined from mixed effects regression models taking age and weight into account. Participants were categorized into three groups: BMD maintenance (no decline; estimated change ≥0 g/cm2, n = 453); expected loss (estimated change 0 to 1 SD below the estimated mean change, –0.034 g/cm2 for femoral neck, n = 1184); and accelerated loss (estimated change ≥1 SD below mean change, n = 237). Differential abundance values of 3946 peptides were summarized by meta‐analysis to determine differential abundance of each of 339 corresponding proteins for accelerated BMD loss versus maintenance. Using this meta‐analytic standardized fold change at cutoffs of ≥1.1 or ≤0.9 (p < 0.10), 20 proteins were associated with accelerated BMD loss. Associations of those 20 proteins with incident hip fracture were tested using Cox proportional hazards models with age and BMI adjustment in 2473 men. Five proteins were associated with incident hip fracture (HR between 1.29 and 1.41 per SD increase in estimated protein abundance). Some proteins have been previously associated with fracture risk (eg, CD14 and SHBG), whereas others have roles in cellular senescence and aging (B2MG and TIMP1) and complement activation and innate immunity (CO7, CO9, CFAD). These findings may inform development of biomarkers for future research in bone biology and fracture prediction.

Quantification of nutritive sucking among preterm and full-term infants

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Effectiveness of testosterone therapy for masculinizing voice in transgender patients: A meta-analytic review

ABSTRACT Background: Testosterone therapy is the predominant treatment for voice masculinization in transgender patients. Although lowering of voice fundamental frequency (f0) occurs with testosterone therapy, evidence suggests voice and gender identity may not fully align—i.e., voice-gender congruence may not be achieved—with its use. Aim: This meta-analytic review evaluates the effectiveness of testosterone therapy to masculinize voice in transgender patients. Methods: Multiple electronic databases were queried (inclusion dates: from database inception up to October 27, 2017) to identify original research on voice masculinization using testosterone therapy. Nineteen articles were included in this meta-analytic review, which followed PRISMA guidelines. In addition to qualitative analyses, random effects proportion meta-analyses were performed on data related to f0, voice-gender congruence, voice problems, and satisfaction with voice. Results: A meta-analysis on f0 data showed after 1 year of testosterone therapy a combined estimate of 21% of participants (95% confidence interval [CI]: 5%–43%; I2: 59.9%) did not achieve cisgender male normative frequencies (f0 ≤ 131 Hz). Meta-analyses on incomplete voice-gender congruence and voice problems indicated combined estimates of 21% (95% CI: 10%–34%; I2: 0.0%) and 46% (95% CI: 14%–79%; I2: 90.2%), respectively. Regarding incomplete satisfaction with voice, a meta-analysis showed a combined estimate of 16% (95% CI: 7%–28%; I2: 0.0%). Discussion: We found that not all transgender patients using testosterone therapy to masculinize voice should expect f0 lowering to cisgender male normative frequencies after 1 year. The vocal transition may involve voice problems for many patients, and some might not achieve voice-gender congruence without additional, voice-specific intervention. Given these findings, a voice evaluation should occur prior to initiating testosterone therapy and involve counseling on expectations for voice. Transgender patients who pursue voice masculinization may need management from laryngology and speech and language therapy to improve voice-gender congruence, mitigate voice problems, and increase satisfaction with voice.

Evaluation of Multimedia Medication Reconciliation Software: A Randomized Controlled, Single-Blind Trial to Measure Diagnostic Accuracy for Discrepancy Detection

BACKGROUND The Veterans Affairs Portland Healthcare System developed a medication history collection software that displays prescription names and medication images. OBJECTIVE This article measures the frequency of medication discrepancy reporting using the medication history collection software and compares with the frequency of reporting using a paper-based process. This article also determines the accuracy of each method by comparing both strategies to a best possible medication history. STUDY DESIGN Randomized, controlled, single-blind trial. SETTING Three community-based primary care clinics associated with the Veterans Affairs Portland Healthcare System: a 300-bed teaching facility and ambulatory care network serving Veteran soldiers in the Pacific Northwest United States. PARTICIPANTS Of 212 patients with primary care appointments, 209 patients fulfilled the study requirements. INTERVENTION Patients randomized to a software-directed medication history or a paper-based medication history. Randomization and allocation to treatment groups were performed using a computer-based random number generator. Assignments were placed in a sealed envelope and opened after participant consent. The research coordinator did not know or have access to the treatment assignment until the time of presentation. MAIN OUTCOME MEASURES The primary analysis compared the discrepancy detection rates between groups with respect to the health record and a best possible medication history. RESULTS Of 3,500 medications reviewed, we detected 1,435 discrepancies. Forty-six percent of those discrepancies were potentially high risk for causing an adverse drug event. There was no difference in detection rates between treatment arms. Software sensitivity was 83% and specificity was 91%; paper sensitivity was 81% and specificity was 94%. No participants were lost to follow-up. CONCLUSION The medication history collection software is an efficient and scalable method for gathering a medication history and detecting high-risk discrepancies. Although it included medication images, the technology did not improve accuracy over a paper list when compared with a best possible medication history. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02135731.

High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men

The biological perturbations associated with incident mortality are not well elucidated, and there are limited biomarkers for the prediction of mortality. We used a novel high‐throughput proteomics approach to identify serum peptides and proteins associated with 5‐year mortality in community‐dwelling men age ≥65 years who participated in a longitudinal observational study of musculoskeletal aging (Osteoporotic Fractures in Men: MrOS). In a discovery phase, serum specimens collected at baseline in 2473 men were analyzed using liquid chromatography–ion mobility–mass spectrometry, and incident mortality in the subsequent 5 years was ascertained by tri‐annual questionnaire. Rigorous statistical methods were utilized to identify 56 peptides (31 proteins) that were associated with 5‐year mortality. In an independent replication phase, selected reaction monitoring was used to examine 21 of those peptides in baseline serum from 750 additional men; 81% of those peptides remained significantly associated with mortality. Mortality‐associated proteins included a variety involved in inflammation or complement activation; several have been previously linked to mortality (e.g., C‐reactive protein, alpha 1‐antichymotrypsin) and others are not previously known to be associated with mortality. Other novel proteins of interest included pregnancy‐associated plasma protein, VE‐cadherin, leucine‐rich α‐2 glycoprotein 1, vinculin, vitronectin, mast/stem cell growth factor receptor, and Saa4. A panel of peptides improved the predictive value of a commonly used clinical predictor of mortality. Overall, these results suggest that complex inflammatory pathways, and proteins in other pathways, are linked to 5‐year mortality risk. This work may serve to identify novel biomarkers for near‐term mortality.