Association Between Orthostatic Hypotension and Dementia in Patients With Parkinson Disease and Multiple System Atrophy.

BACKGROUND AND OBJECTIVES: Orthostatic hypotension (OH) increases dementia risk in patients with Parkinson disease (PD), although the underlying mechanisms and whether a similar association between OH and cognitive impairment exists in other synucleinopathies remain unknown. The aim is to evaluate the association between OH and dementia risk in patients with PD, and cognitive impairment risk in patients with multiple system atrophy (MSA), and to explore relevant clinical and neuropathologic factors to understand underlying pathogenic mechanisms. METHODS: This is a retrospective cohort study. Medical records throughout the entire disease course of consecutive patients with neuropathology-confirmed PD and MSA from the Queen Square Brain Bank were systematically reviewed. Time of onset and severity of OH-related symptoms were documented, and their association with other clinical and neuropathologic variables was evaluated. Dementia risk for patients with PD and cognitive impairment risk for patients with MSA were estimated using multivariable hazard regression. RESULTS: One hundred thirty-two patients with PD and 137 with MSA were included. Patients with MSA developed OH more frequently, earlier in the disease course and with more severe symptoms. Cumulative dementia prevalence was higher in patients with PD. Multivariable adjusted regression models showed that early OH, but not its symptom severity, increased dementia risk in patients with PD by 14% per year (hazard ratio [HR] = 0.86; 95% CI, 0.80-0.93) and cognitive impairment risk in patients with MSA by 41% per year (HR = 0.59; 95% CI, 0.42-0.83). Early OH was not associated with increased α-synuclein, ß-amyloid, tau, Alzheimer, or cerebrovascular pathologies. No significant associations were found between severity of OH symptoms and other clinical or neuropathologic variables. DISCUSSION: Early OH, but not its symptom severity, increases the risk of cognitive impairment in patients with PD and MSA. OH is not associated with more extensive Lewy, ß-amyloid, tau, Alzheimer, or cerebrovascular pathologies. It is likely that OH contributes to cognitive impairment in patients with PD and MSA by hypoxia-induced nonspecific neurodegeneration. Further research should evaluate whether improving brain perfusion by treating OH may modify the risk of dementia in these conditions.

Tuberactinomycin antibiotics: Biosynthesis, anti-mycobacterial action, and mechanisms of resistance.

The tuberactinomycins are a family of cyclic peptide ribosome-targeting antibiotics with a long history of use as essential second-line treatments for drug-resistant tuberculosis. Beginning with the identification of viomycin in the early 1950s, this mini-review briefly describes tuberactinomycin structures and biosynthesis, as well as their past and present application in the treatment of tuberculosis caused by infection with Mycobacterium tuberculosis. More recent studies are also discussed that have revealed details of tuberactinomycin action on the ribosome as well as resistance mechanisms that have emerged since their introduction into the clinic. Finally, future applications of these drugs are considered in the context of their recent removal from the World Health Organization's List of Essential Medicines.

Secular Trends in Risk Profiles Among Adults With Cardiovascular Disease in the United States.

BACKGROUND: Documenting trends in risk factors among individuals with cardiovascular disease (CVD) may inform policy and secondary prevention initiatives. OBJECTIVES: This study aimed to examine 20-year trends in risk profiles among U.S. adults with CVD and any racial/ethnic disparities. METHODS: In this serial cross-sectional analysis of 6,335 adults with self-reported CVD participating in the National Health and Nutrition Examination Survey from 1999 through 2018, we calculated age- and sex-adjusted proportions with ideal risk factor attainment. RESULTS: The proportions with ideal hemoglobin A1c (<7% if diabetes or <5.7% if not) and body mass index (<25 kg/m2) worsened from 58.7% (95% CI: 55.2%-62.1%) to 52.4% (95% CI: 48.2%-56.6%) and 23.9% (95% CI: 21.5%-26.4%) to 18.2% (95% CI: 15.6%-21.2%) from 1999-2002 to 2015-2018, respectively. After initial improvement, the proportion with blood pressure <130/80 mm Hg declined from 52.1% (95% CI: 48.9%-55.4%) in 2007-2010 to 48.6% (95% CI: 44.2%-52.7%) in 2015-2018. The proportion with non-high-density lipoprotein cholesterol levels <100 mg/dL increased from 7.3% (95% CI: 5.6%-9.5%) in 1999-2002 to 30.3% (95% CI: 25.7%-35.5%) in 2015-2018. The proportions with ideal smoking, physical activity, and diet profiles were unchanged over time, and in 2015-2018 were 77.8% (95% CI: 73.6%-81.4%), 22.4% (95% CI: 19.3%-25.9%), and 1.3% (95% CI: 0.7%-2.6%). Worsening trends were observed in Hispanic adults for cholesterol, and in Black adults for smoking (both P < 0.05 for nonlinear and linear trends). Persistently lower ideal risk factor attainment was observed for blood pressure in Black adults and for hemoglobin A1c levels in Asian adults compared with White adults (all P < 0.05 for differences). CONCLUSIONS: Trends in cardiovascular risk factor profiles in U.S. adults with CVD were suboptimal from 1999 through 2018, with persistent racial/ethnic disparities.

50S subunit recognition and modification by the Mycobacterium tuberculosis ribosomal RNA methyltransferase TlyA.

Changes in bacterial ribosomal RNA (rRNA) methylation status can alter the activity of diverse groups of ribosome-targeting antibiotics. These modifications are typically incorporated by a single methyltransferase that acts on one nucleotide target and rRNA methylation directly prevents drug binding, thereby conferring drug resistance. Loss of intrinsic methylation can also result in antibiotic resistance. For example, Mycobacterium tuberculosis becomes sensitized to tuberactinomycin antibiotics, such as capreomycin and viomycin, due to the action of the intrinsic methyltransferase TlyA. TlyA is unique among antibiotic resistance-associated methyltransferases as it has dual 16S and 23S rRNA substrate specificity and can incorporate cytidine-2'-O-methylations within two structurally distinct contexts. Here, we report the structure of a mycobacterial 50S subunit-TlyA complex trapped in a postcatalytic state with a S-adenosyl-L-methionine analog using single-particle cryogenic electron microscopy. Together with complementary functional analyses, this structure reveals critical roles in 23S rRNA substrate recognition for conserved residues across an interaction surface that spans both TlyA domains. These interactions position the TlyA active site over the target nucleotide C2144, which is flipped from 23S Helix 69 in a process stabilized by stacking of TlyA residue Phe157 on the adjacent A2143. Base flipping may thus be a common strategy among rRNA methyltransferase enzymes, even in cases where the target site is accessible without such structural reorganization. Finally, functional studies with 30S subunit suggest that the same TlyA interaction surface is employed to recognize this second substrate, but with distinct dependencies on essential conserved residues.

Trends in user ratings and reviews of a popular yet inaccurate blood pressure-measuring smartphone app.

Objective: To understand whether user reviews of Instant Blood Pressure (IBP), an inaccurate, unregulated BP-measuring app reflected IBP's inaccuracy, to understand drivers for high and low ratings, and to understand if disclaimers prevented medical use. Materials and Methods: All iTunes app reviews for IBP v1.2.3 were downloaded and assessed for themes by two reviewers. Summary statistics for themes were tabulated with their associated star ratings. Results: Common themes included perceived accuracy (42% of all reviews, star rating mean 4.8, median 5), inaccuracy (10%, 2.0, 1), and convenience (34%, 4.7, 5). Nine percent documented IBP use in medical conditions (4.6, 5), and 2% mentioned IBP's disclaimer (2.7, 3). Discussion: User reviews and ratings of a popular, inaccurate BP-measuring app were positive and uncommonly commented on its inaccuracy. Disclaimers attempting to prevent medical use of the app were ineffective. These findings support the need for more rigorous regulatory review of apps prior to their release.

Giant Cell Tumor of Bone Presenting as Left Posteromedial Chest Wall Tumor.

Giant cell tumor is a relatively uncommon bone tumor rarely originating from the chest wall. Given its proximity to vital structures in the thoracic cavity, treatment options may be challenging. We report the case of a patient with a giant cell tumor of the posterolateral chest wall with invasion of the thoracic spine treated with neoadjuvant denosumab, followed by surgical resection.

User experience of instant blood pressure: exploring reasons for the popularity of an inaccurate mobile health app.

Instant blood pressure (IBP) is a top-selling yet inaccurate blood pressure (BP)-measuring app that underreports elevated BP. Its iTunes app store user ratings and reviews were generally positive. Whether underreporting of elevated BP improves user experience is unknown. Participants enrolled at five clinics estimated their BP, measured their BP with IBP, then completed a user experience survey. Participants were grouped based on how their IBP BP measurements compared to their estimated BP (IBP Lower, IBP Similar, or IBP Higher). Logistic regressions compared odds of rating "agree" or "strongly agree" on survey questions by group. Most participants enjoyed using the app. In the adjusted model, IBP Higher had significantly lower proportions reporting enjoyment and motivation to check BP in the future than IBP Similar. All three groups were comparable in perceived accuracy of IBP and most participants perceived it to be accurate. However, user enjoyment and likelihood of future BP monitoring were negatively associated with higher-than-expected reported systolic BP. These data suggest reassuring app results from an inaccurate BP-measuring app may have improved user experience, which may have led to more positive user reviews and greater sales. Systematic underreporting of elevated BPs may have been a contributor to the app's success. Further studies are needed to confirm whether falsely reassuring output from other mobile health apps improve user experience and drives uptake.

LC-MS/MS quantitation of esophagus disease blood serum glycoproteins by enrichment with hydrazide chemistry and lectin affinity chromatography.

Changes in glycosylation have been shown to have a profound correlation with development/malignancy in many cancer types. Currently, two major enrichment techniques have been widely applied in glycoproteomics, namely, lectin affinity chromatography (LAC)-based and hydrazide chemistry (HC)-based enrichments. Here we report the LC-MS/MS quantitative analyses of human blood serum glycoproteins and glycopeptides associated with esophageal diseases by LAC- and HC-based enrichment. The separate and complementary qualitative and quantitative data analyses of protein glycosylation were performed using both enrichment techniques. Chemometric and statistical evaluations, PCA plots, or ANOVA test, respectively, were employed to determine and confirm candidate cancer-associated glycoprotein/glycopeptide biomarkers. Out of 139, 59 common glycoproteins (42% overlap) were observed in both enrichment techniques. This overlap is very similar to previously published studies. The quantitation and evaluation of significantly changed glycoproteins/glycopeptides are complementary between LAC and HC enrichments. LC-ESI-MS/MS analyses indicated that 7 glycoproteins enriched by LAC and 11 glycoproteins enriched by HC showed significantly different abundances between disease-free and disease cohorts. Multiple reaction monitoring quantitation resulted in 13 glycopeptides by LAC enrichment and 10 glycosylation sites by HC enrichment to be statistically different among disease cohorts.

Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair.

OBJECTIVE: Esophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues. METHODS: We analyzed the expression of genes involved in homologous recombination (HR), nonhomologous end-joining, and nucleotide excision repair (NER) pathways in 12 EAC tumor samples with their matched normal counterparts. These pathways were chosen because they are the main pathways involved in the repair of platinum- or ionizing-radiation-induced damage. In addition, abnormalities in these pathways have not been well characterized in EAC. RESULTS: We identified increased expression of at least one HR gene in eight of the EAC tumor samples. Alterations in the expression of EME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples. In addition, all EAC samples revealed decreased expression of at least one of numerous NER genes including XPC, XPA, DDB2, XPF, and XPG. CONCLUSION: Our study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration of EME1 upregulation in any cancer. These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC.

Assessment of morbidity and mortality after esophagectomy using a modified frailty index.

BACKGROUND: Esophagectomy is associated with significant morbidity and mortality. This retrospective study examined use of a modified frailty index as a potential predictor of morbidity and mortality in esophagectomy patients. METHODS: National Surgical Quality Improvement Program Participant Use Files were reviewed for 2005 through 2010. Patients undergoing esophagectomy were selected based on CPT codes. A modified frailty index with 11 variables was used to determine correlation between frailty and postesophagectomy morbidity and mortality. Data were analyzed using χ(2) test and logistic regression. RESULTS: A total of 2,095 patients were included in the analysis. Higher frailty scores were associated with a statistically significant increase in morbidity and mortality. A frailty score of 0, 1, 2, 3, 4, and 5 had associated morbidity rates of 17.9% (142 of 795 patients), 25.1% (178 of 710 patients), 31.4% (126 of 401 patients), 34.4% (48 of 140 patients), 44.4% (16 of 36 patients), and 61.5% (8 of 13 patients), respectively. A frailty score of 0, 1, 2, 3, 4, and 5 had associated mortality rates of 1.8% (14 of 795 patients), 3.8% (27 of 710 patients), 4% (16 of 401 patients), 7.1% (10 of 140 patients), 8.3% (3 of 36 patients), and 23.1% (3 of 13 patients), respectively. When using multivariate logistic regression for mortality comparing age, functional status, prealbumin, emergency surgery, wound class, American Society of Anesthesiologists score, and sex, only age and frailty were statistically significant. The odds ratio was 31.84 for frailty (p = 0.015) and 1.05 (p = 0.001) for age. CONCLUSIONS: Using a large national database, a modified frailty index was shown to correlate with postesophagectomy morbidity and mortality. Such an index may be used to aid in improving risk assessment and patient selection for esophagectomy.

A modified frailty index to assess morbidity and mortality after lobectomy.

BACKGROUND: Frailty has yet to be explored as a risk factor for thoracic surgery. We hypothesized that our modified frailty index (mFI) may be a predictor of morbidity and mortality following lobectomy. MATERIALS: National Surgical Quality Improvement Program (NSQIP) participant use files were reviewed (2005-2010). Patients undergoing lobectomy were identified based on Current Procedural Terminology code 32480. We used an mFI with 11 variables, based on mapping the Canadian Study of Health and Aging Frailty Index to the NSQIP comorbidities. Data were analyzed using χ(2) test, independent sample t-test, Jonckheere-Terpstra test, and logistic regression. RESULTS: Of 1940 open lobectomy patients identified, morbidity and mortality uniformly increased as the mFI increased; 14.9% of patients (75/504) with mFI of 0 had at least one complication, compared with 32% of patients (91/284) with mFI of 0.27 (P < 0.001). An mFI of 0 was associated with a mortality rate of 1% (5/504), compared with 5.6% (16/284) for mFI of 0.27 (P < 0001). Failure to wean from the ventilator, reintubation, surgical site infections, pneumonia, and Clavien 4 and above complications occurred in 1.8% (9/504), 2.6% (13/504), 2.2% (11/504), 5.4% (27/504), and 4.2% (21/504), respectively, in patients with an mFI of 0, compared with 7.4% (21/284), 7% (22/284), 3.2% (9/284), 10.9% (31/284), and 14.4% (41/284), respectively, in patients with mFI of 0.27. CONCLUSIONS: This study demonstrates that the mFI may identify patients at higher risk for morbidity and mortality post-lobectomy. With the aging population, preoperative selection is important in minimizing morbidity and mortality and improving risk stratification for informed decision-making.

Prevalence and resolution of anemia with paraesophageal hernia repair.

BACKGROUND: Paraesophageal hernias may produce a variety of clinical sequelae including anemia and esophagogastric ulcerations or erosions. We examined the prevalence of anemia in patients with paraesophageal hernias and frequency of anemia resolution with hernia repair. METHODS: Patients undergoing paraesophageal hernia repairs from July 1996 to September 2010 were included. Data gathered included age, gender, type of hernia, presence of symptomatic anemia, presence of esophagogastric ulcer/erosion, type of repair, and anemia resolution. RESULTS: One hundred eighty-three patients underwent paraesophageal hernia repair; of these, 68 (37%) were anemic. Of these anemic patients, 39 (57%) were symptomatic from their anemia or specifically referred for anemia, and 20 (29%) had esophagogastric ulceration/erosion. Fifty-eight had documented follow-up. Overall, of these, 35 (60%) had resolution of their anemia. Seventy percent of symptomatic patients had resolution of their anemia, compared to 48% of asymptomatic patients (p = 0.1). Of patients with esophagogastric ulceration/erosion, 85% were symptomatic and 88% had resolution of anemia, compared to 50% of patients without ulceration/erosion (p = 0.015). CONCLUSIONS: Anemia was a common finding in patients with paraesophageal hernia and most patients were symptomatic because of their anemia. Those patients with esophageal or gastric ulceration/erosion were very likely to have symptomatic anemia, and, interestingly, these patients were more likely to have their anemia resolve with paraesophageal hernia repair.

N-glycan profiling by microchip electrophoresis to differentiate disease states related to esophageal adenocarcinoma.

We report analysis of N-glycans derived from disease-free individuals and patients with Barrett's esophagus, high-grade dysplasia, and esophageal adenocarcinoma by microchip electrophoresis with laser-induced fluorescence detection. Serum samples in 10 µL aliquots are enzymatically treated to cleave the N-glycans that are subsequently reacted with 8-aminopyrene-1,3,6-trisulfonic acid to add charge and a fluorescent label. Separations at 1250 V/cm and over 22 cm yielded efficiencies up to 700,000 plates for the N-glycans and analysis times under 100 s. Principal component analysis (PCA) and analysis of variance (ANOVA) tests of the peak areas and migration times are used to evaluate N-glycan profiles from native and desialylated samples and determine differences among the four sample groups. With microchip electrophoresis, we are able to distinguish the three patient groups from each other and from disease-free individuals.

Venous hemangioma presenting as a superior sulcus tumor.

Non-small cell pulmonary carcinomas represent the majority of tumors located in the superior sulcus. However, only 5% of all non-small cell pulmonary carcinomas present in the superior sulcus. Other causes of superior sulcus tumors include metastatic tumors, hematologic malignancies, infectious causes, and amyloid nodules, as well as other lesions. We report a case in which a venous hemangioma presented as a superior sulcus tumor.

A quantitative investigation of fucosylated serum glycoproteins with application to esophageal adenocarcinoma.

Although glycoproteomic studies provide unique opportunities for cancer research, it has been necessary to develop specific methods for analysis of oncologically interesting glycoproteins. We describe a general, multimethodological approach for quantitative glycoproteomic analysis of fucosylated glycoproteins in human blood serum. A total of 136 putative fucosylated glycoproteins were identified with very high confidence in three clinically relevant sample pools (N=5 for each), with a mean CV of 3.1% observed for replicate analyses. Two samples were collected from subjects diagnosed with esophagus disease states, high-grade dysplasia plus esophageal adenocarcinoma, while the third sample was representative of a disease-free condition. Some glycoproteins, observed to be significantly upregulated in esophageal adenocarcinoma, i.e. more than twofold higher than in the disease-free condition, are briefly discussed. Further investigation will be necessary to validate these findings; however, the method itself is demonstrated to be an effective tool for quantitative glycoproteomics of clinical samples.

A randomized, controlled study of amiodarone for prevention of atrial fibrillation after transthoracic esophagectomy.

OBJECTIVE: Atrial fibrillation is common after esophagectomy. The objective of this study was to determine the efficacy and safety of amiodarone for prevention of atrial fibrillation after transthoracic esophagectomy. METHODS: Eighty patients undergoing transthoracic esophagectomy were randomly, prospectively assigned to receive amiodarone (n = 40) or no prophylaxis (control group, n = 40). Amiodarone-treated patients received the drug by continuous infusion, initiated at the time of induction of anesthesia, at a rate of 0.73 mg/min (43.75 mg/h), and continued for 96 hours (total dose 4200 mg). The primary end point was atrial fibrillation requiring treatment. Secondary end points included any atrial fibrillation lasting longer than 30 seconds and postoperative hospital and intensive care unit stays. RESULTS: There were no significant differences between the amiodarone and control groups in demographic characteristics, comorbid conditions, or preoperative or postoperative use of beta-blockers or calcium-channel blockers. The incidence of atrial fibrillation requiring treatment was lower in the amiodarone group than in the control group (15% vs 40%, P = .02, relative risk reduction 62.5%). There were no significant differences between the amiodarone and control groups in median hospital stay (11 days vs 12 days, P = .31) or median intensive care unit stay (68 hours vs 77 hours, p = .097). There were no significant difference between the groups in the incidences of adverse effects. CONCLUSIONS: Amiodarone prophylaxis significantly reduced the incidence of atrial fibrillation after transthoracic esophagectomy.

Comparative glycomic profiling in esophageal adenocarcinoma.

OBJECTIVE: Aberrant glycosylation has been implicated in various types of cancers. Cancerous cells with altered glycosylation of their surface proteins shed such proteins into the circulating fluids. Glycomic profiling of such fluids shows the altered glycosylation. We performed glycomic profiling of serum from patients with no known disease, Barrett's without dysplasia, with high-grade dysplasia, and with esophageal adenocarcinoma in an attempt to delineate distinct differences in glycosylation among these groups. METHODS: Serum samples from patients with Barrett's metaplasia (N = 5), high-grade dysplasia (N = 11), and esophageal adenocarcinoma (N = 50) were collected; samples from 18 healthy volunteers were used as control. Serum N-glycans were enzymatically released and then applied to both C18 Sep-Pak (Waters, Milford, MA) cartridges and activated charcoal cartridges. N-glycans were permethylated and then spotted directly onto a matrix-assisted laser desorption ionization plate. Mass spectra were acquired using the Applied Biosystems 4800 MALDI TOF/TOF Analyzer (Applied Biosystems Inc, Framingham, Mass). The obtained matrix-assisted laser desorption ionization-mass spectrometry data were processed using DataExplorer files (Applied Biosystems Inc) listing m/z values and intensities. RESULTS: The intensities of 98 glycans were significantly different among the 3 groups; 26 of these corresponded to known glycan structures. Pairwise comparisons showed that 8 glycans were significantly different in all 3 pairwise comparisons. CONCLUSION: We demonstrated that comparative glycomic profiling of esophageal adenocarcinoma reveals a subset of glycans that can be selected as candidate biomarkers. These markers can differentiate normal from high-grade dysplasia, normal from esophageal adenocarcinoma, and high-grade dysplasia from esophageal adenocarcinoma. Further validation will be necessary to determine the clinical utility of these glycan biomarkers.

Diffusion lung capacity for carbon monoxide (DLCO) is an independent prognostic factor for long-term survival after curative lung resection for cancer.

INTRODUCTION: We examined the early and late prognostic significance of DLCO and forced expiratory volume in 1 sec (FEV1) in patients who underwent surgical resection of lung cancer. METHODS: From 1997 to 2004, 462 patients underwent successful complete resection of their lung cancer and had full pulmonary function testing including DLCO performed. Mean follow-up was over 5 years (64.8 months--range: 0-158 months). RESULTS: Postoperative 90-day mortality was 2.6% (12/462). At last follow-up, of the remaining 450 patients, 182 patients were alive, 130 had died of cancer, and 138 have died of other causes and did not have recurrent cancer. Mean DLCO values were 69.4%, 66.8%, and 53.9%, respectively. Mean FEV1 values were 81.3%, 78.1%, and 71.5%, respectively. Mean DLCOs and FEV1s between patients who died of cancer versus other causes were significantly different (P < 0.0001 and P = 0.0157). When cause-specific survival was analyzed for both DLCO and FEV1 simultaneously, DLCO had a very significant effect on survival from other causes (HR 0.966, P < 0.0001) when adjusted for FEV1. However, when adjusted by DLCO, FEV1 had no significant effect. A DLCO <40% best predicted decreased survival from causes other than cancer within stage I lung cancers (stage IA HR 0.953, P < 0.0001; stage IB HR 0.968, P < 0.0001). CONCLUSIONS: DLCO was found to be a significant prognostic factor for long-term survival after lung cancer surgery. This may serve as a surrogate for competing morbidities with declining values predicting a higher risk of late non-cancer-related death.