Lipids as Emerging Biomarkers in Neurodegenerative Diseases.

Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.

Secondary Structure Characterization of Glucagon Products by Circular Dichroism and Nuclear Magnetic Resonance Spectroscopy.

Glucagon, a 29-amino acid polypeptide hormone, is an essential therapeutic agent used in the emergency treatment of hypoglycemia. However, glucagon is inherently unstable in aqueous solution. While glucagon equilibrates between unordered and the secondary α-helix state in solution, it can quickly transform into a different secondary ß-sheet-rich amyloid-like fibril/oligomer structure under various conditions. Since changes in the secondary structure of glucagon can cause significant impacts, structure analysis is necessary and essential to assess the safety of the product. This study analyzed the secondary structure of glucagon products at the release and at the expiry using circular dichroism spectroscopy (CD) and 2D Nuclear Overhauser effect spectroscopy (2D NOESY). In order to also determine if structural differences exist between glucagon produced through different manufacturing processes, synthetic and recombinant glucagon products were used and compared. The CD results indicated that for all release and expired glucagon products, the structure compositions were 14 to 16% α-helix, 17 to 19% ß-strand, 14 to 15% Turn, and 53 to 54% Unordered. This was consistent with the 2D NOESY analysis which showed that both products had an approximate α-helix composition of 14 to 17%. Overall, there were no significant differences in terms of the secondary structure between synthetic and recombinant glucagon products both at the release and at the expiry.

Surgery Performed by Supervised Trainees Does not Affect Outcome in First Metatarsophalangeal Joint (MTPJ) Arthrodesis.

First metatarsophalangeal joint (MTPJ) arthrodesis is an index procedure for orthopedic trainees in the United Kingdom. There is an absence of evidence as to the outcome of surgery when performed by supervised trainees. The aim of this study is to compare the incidence of fusion, complication rate and radiographic outcomes in first MTPJ arthrodesis performed by supervised orthopedic trainees with consultants. This is a retrospective cohort study of 117 patients undergoing first MTPJ arthrodesis from August 2015 to December 2017 in our institute for hallux valgus (HV) deformity with first MPTJ arthrosis or for hallux rigidus. Patients were followed to a minimum of 1-year postsurgery and were given an open appointment thereafter. In the hallux rigidus group, there was no significant difference between the complication rate (p = .477), incidence of fusion (p = .663), postoperatively HVA (p = .763), and postoperative intermetatarsal angle (p = .539) between trainees and consultants. There was a significant difference in mean tourniquet time (p = .563) between trainees and consultants. In the hallux valgus group, there was no significant difference in the complication rate (p = .519), incidence of fusion (p = .786), tourniquet time (p = .075), postoperative HVA (p = .423), and postoperative intermetatarsal angle (p = .143) between the trainees and consultants. This is the first MTPJ fusion series that demonstrates good results can be achieved by supervised trainees performing the procedure. This would suggest that first MTPJ arthrodesis remains an opportunity for trainees to continue learning to perform under supervision whilst ensuring no change in outcome for the patient.

Mechanisms of Persistence of the Ammonia-Oxidizing Bacteria Nitrosomonas to the Biocide Free Nitrous Acid.

Free nitrous acid (FNA) exerts a broad range of antimicrobial effects on bacteria, although susceptibility varies considerably among microorganisms. Among nitrifiers found in activated sludge of wastewater treatment processes (WWTPs), nitrite-oxidizing bacteria (NOB) are more susceptible to FNA compared to ammonia-oxidizing bacteria (AOB). This selective inhibition of NOB over AOB in WWTPs bypasses nitrate production and improves the efficiency and costs of the nitrogen removal process in both the activated sludge and anaerobic ammonium oxidation (Anammox) system. However, the molecular mechanisms governing this atypical tolerance of AOB to FNA have yet to be understood. Herein we investigate the varying effects of the antimicrobial FNA on activated sludge containing AOB and NOB using an integrated metagenomics and label-free quantitative sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) metaproteomic approach. The Nitrosomonas genus of AOB, on exposure to FNA, maintains internal homeostasis by upregulating a number of known oxidative stress enzymes, such as pteridine reductase and dihydrolipoyl dehydrogenase. Denitrifying enzymes were upregulated on exposure to FNA, suggesting the detoxification of nitrite to nitric oxide. Interestingly, proteins involved in stress response mechanisms, such as DNA and protein repair enzymes, phage prevention proteins, and iron transport proteins, were upregulated on exposure to FNA. In addition enzymes involved in energy generation were also upregulated on exposure to FNA. The total proteins specifically derived from the NOB genus Nitrobacter was low and, as such, did not allow for the elucidation of the response mechanism to FNA exposure. These findings give us an understanding of the adaptive mechanisms of tolerance within the AOB Nitrosomonas to the biocidal agent FNA.

Oropharyngeal and tongue exercises (myofunctional therapy) for snoring: a systematic review and meta-analysis.

PURPOSE: Oropharyngeal and tongue exercises (myofunctional therapy) have been shown to improve obstructive sleep apnea. However, to our knowledge, a systematic review has not been performed for snoring. The study objective is to perform a systematic review, with a meta-analysis, dedicated to snoring outcomes after myofunctional therapy. METHODS: PubMed/MEDLINE and three other databases were searched through November 25, 2017. Two authors independently searched the literature. Eligibility (1) patients: children or adults with snoring, (2) intervention: oropharyngeal and/or tongue exercises, (3) comparison: pre and post-treatment data for snoring, (4) outcomes: snoring frequency and snoring intensity, (5) study design: publications of all study designs. RESULTS: A total of 483 articles were screened, 56 were downloaded in their full text form, and nine studies reported outcomes related to snoring. There were a total of 211 patients (all adults) in these studies. The snoring intensity was reduced by 51% in 80 patients from pre-therapy to post-therapy visual analog scale values of 8.2 ± 2.1 (95% CI 7.7, 8.7) to 4.0 ± 3.7 (95% CI 3.2, 4.8). Berlin questionnaire snoring intensity reduced by 36% in 34 patients from 2.5 ± 1.0 (95% CI 2.2, 2.8) to 1.6 ± 0.8 (95% CI 1.3, 1.9). Finally, time spent snoring during sleep was reduced by 31% in 60 patients from 26.3 ± 18.7% (95% CI 21.6, 31.0) to 18.1 ± 20.5% (95% CI 12.9, 23.3) of total sleep time. CONCLUSIONS: This systematic review demonstrated that myofunctional therapy has reduced snoring in adults based on both subjective questionnaires and objective sleep studies.

Enlarging premaxillary mass: A unique manifestation of extranodal diffuse B-cell lymphoma.

Lymphomas are the most common nonepithelial malignancy in the head and neck region. Among these, non-Hodgkin Lymphoma (NHL) is the most prevalent, and diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype. NHL is known for its propensity for extranodal involvement, which can affect any anatomical location. The presence of perineural spread is frequently encountered in head and neck malignancies, including lymphomas. We report a case of a 40-year-old male with an enlarging infraorbital facial mass with associated erythema, pain, and paresthesia, which was subsequently found to be extranodal DLBCL with retrograde perineural spread along the infraorbital nerve.

Isolated torsion of fallopian tube with associated torsed paratubal cystadenofibroma: A case report.

Cystadenofibromas (CAF) and adenofibromas (AF) are rare benign gynecologic neoplasms of epithelial origin. They can be composed predominantly of solid fibrous tissue, adenofibromas, or contain cystic components, as seen in cystadenofibromas; which can be further classified by their epithelial cell type (serous, mucinous, etc.). They most commonly arise from the ovary; however, CAF/AF associated with the fallopian tube have also been reported. CAF/AF is typically asymptomatic and found incidentally. Like other adnexal and ovarian masses, patients are at increased risk of ovarian/adnexal torsion, with increasing risk with lesion size. Herein, we present the case of a patient with isolated torsion of a fallopian tube with associated torsed paratubal serous cystadenofibroma. To our knowledge, this is the first reported case of isolated torsion of a fallopian tube with associated para-tubal cystadenofibroma.

A massive retroperitoneal mature teratoma from a "burned-out" testicular teratoma and seminoma.

Germ cell tumors are the most common nonhematologic malignancy of young men which often present with metastasis to the retroperitoneum, however a primary retroperitoneal mass should also be considered. The case presented herein reports a 42-year-old male presenting with a massive heterogenous retroperitoneal mass determined to be a mature cystic teratoma. Further investigation revealed a multifocal right testicular mass containing both a viable pure seminoma and a fibrous scar demonstrating germ cell neoplasia in situ thus representing the rare phenomenon of a "burned-out" mixed germ cell testicular tumor. When the radiologist is faced with a large retroperitoneal fat-containing mass, the differential includes a renal angiomyolipoma, liposarcoma, or germ cell tumor (whether primary or secondary). If pathology reveals a germ cell tumor, it is imperative to perform a thorough evaluation of the gonads, as it is much more common for a retroperitoneal germ cell tumor to be a metastasis from the gonads, rather than primary in origin.

The association of atherosclerotic cardiovascular disease and statin use with inflammation and treatment outcomes in tuberculosis.

Tuberculosis (TB) and atherosclerotic cardiovascular disease (ASCVD) have a close epidemiological and pathogenetic overlap. Thus, it becomes essential to understand the relationship between ASCVD and TB outcomes. From our retrospective cohort on drug-susceptible TB patients at the National Taiwan University Hospital, we assessed the association of pre-existing ASCVD (coronary artery disease (CAD) and atherothrombotic stroke (ATS)) with 9-month all-cause and infection-related mortality and the extent of mediation by systemic inflammatory markers. We determined the effect of pre-existing ASCVD on 2-month sputum microbiological status. Among ASCVD patients, we assessed the association of statin use on mortality. Nine-month all-cause mortality was higher in CAD patients with prior acute myocardial infarction (CAD+AMI+) (adjusted HR 2.01, 95%CI 1.38-3.00) and ATS patients (aHR 2.79, 95%CI 1.92-4.07) and similarly, for infection-related mortality was higher in CAD+AMI+ (aHR 1.95, 95%CI 1.17-3.24) and ATS (aHR 2.04, 95%CI 1.19-3.46) after adjusting for confounding factors. Pre-existing CAD (AMI- or AMI+) or ATS did not change sputum culture conversion or sputum smear AFB positivity at 2 months. The CAD+AMI+ group had significantly higher levels of CRP at TB diagnosis in the multivariable linear regression analysis (Adjusted B(SE) 1.24(0.62)). CRP mediated 66% (P = 0.048) and 25% (P = 0.033) of the association all-cause mortality with CAD+AMI- and CAD+AMI+, respectively. In summary, patients with ASCVD have higher hazards of 9-month all-cause and infection-related mortality, with elevated serum inflammation mediating one to three-quarters of this association when adjusted for confounders. Statin use was associated with lower all-cause mortality among patients with ASCVD.

Best practices for high data-rate macromolecular crystallography (HDRMX).

In macromolecular crystallography, higher flux, smaller beams, and faster detectors open the door to experiments with very large numbers of very small samples that can reveal polymorphs and dynamics but require re-engineering of approaches to the clustering of images both at synchrotrons and XFELs (X-ray free electron lasers). The need for the management of orders of magnitude more images and limitations of file systems favor a transition from simple one-file-per-image systems such as CBF to image container systems such as HDF5. This further increases the load on computers and networks and requires a re-examination of the presentation of metadata. In this paper, we discuss three important components of this problem-improved approaches to the clustering of images to better support experiments on polymorphs and dynamics, recent and upcoming changes in metadata for Eiger images, and software to rapidly validate images in the revised Eiger format.

Long-term Results for Maxillomandibular Advancement to Treat Obstructive Sleep Apnea: A Meta-analysis.

OBJECTIVE: To examine outcomes in the intermediate term (1 to <4 years), long term (4 to <8 years), and very long term (≥8 years) for maxillomandibular advancement (MMA) as treatment for obstructive sleep apnea (OSA). DATA SOURCES: The Cochrane Library, Google Scholar, Embase, Cumulative Index to Nursing and Allied Health, and PubMed/MEDLINE. REVIEW METHODS: Three authors systematically reviewed the international literature through July 26, 2018. RESULTS: A total of 445 studies were screened, and 6 met criteria (120 patients). Thirty-one patients showed a reduction in apnea-hypopnea index (AHI) from a mean 48.3 events/h (95% CI, 42.1-54.5) pre-MMA to 8.4 (95% CI 5.6, 11.2) in the intermediate term. Fifty-four patients showed a reduction in AHI from a mean 65.8 events/h (95% CI, 58.8-72.8) pre-MMA to 7.7 (95% CI 5.9, 9.5) in the long term. Thirty-five showed a reduction in AHI from a mean 53.2 events/h (95% CI 45, 61.4) pre-MMA to 23.1 (95% CI 16.3, 29.9) in the very long term. Improvement in sleepiness was maintained at all follow-up periods. Lowest oxygen saturation improvement was maintained in the long term. CONCLUSION: The current international literature shows that patients with OSA who were treated with MMA maintained improvements in AHI, sleepiness, and lowest oxygen saturation in the long term; however, the mean AHI increased to moderate OSA in the very long term. Definitive generalizations cannot be made, and additional research providing individual patient data for the intermediate term, long term, and very long term is needed.

Double Barrel Nasal Trumpets to Prevent Upper Airway Obstruction after Nasal and Non-Nasal Surgery.

OBJECTIVES: During anesthesia emergence, patients are extubated and the upper airway can become vulnerable to obstruction. Nasal trumpets can help prevent obstruction. However, we have found no manuscript describing how to place nasal trumpets after nasal surgery (septoplasties or septorhinoplasties), likely because (1) the lack of space with nasal splints in place and (2) surgeons may fear that removing the trumpets could displace the splints. The objective of this manuscript is to describe how to place nasal trumpets even with nasal splints in place. MATERIALS AND METHODS: The authors describe techniques (Double Barrel Technique and Modified Double Barrel Technique) that were developed over three years ago and have been used in patients with obstructive sleep apnea (OSA) and other patients who had collapsible or narrow upper airways (i.e., morbidly obese patients). RESULTS: The technique described in the manuscript provides a method for placing one long and one short nasal trumpet in a manner that helps prevent postoperative upper airway obstruction. The modified version describes a method for placing nasal trumpets even when there are nasal splints in place. Over one-hundred patients have had nasal trumpets placed without postoperative oxygen desaturations. CONCLUSIONS: The Double Barrel Technique allows for a safe emergence from anesthesia in patients predisposed to upper airway obstruction (such as in obstructive sleep apnea and morbidly obese patients). To our knowledge, the Modified Double Barrel Technique is the first description for the use of nasal trumpets in patients who had nasal surgery and who have nasal splints in place.

Hyoid surgery alone for obstructive sleep apnea: A systematic review and meta-analysis.

OBJECTIVES/HYPOTHESIS: The primary objective was to determine if sleep study variables (e.g., apnea-hypopnea index [AHI] and lowest oxygen saturation) and quantitative sleepiness data improve following isolated hyoid surgery for obstructive sleep apnea (OSA). STUDY DESIGN: Systematic review and meta-analysis. METHODS: Nine databases, including PubMed, were searched through September 5, 2015. RESULTS: Four hundred ninety-eight studies were screened, 64 were reviewed, and nine studies met inclusion criteria. A total of 101 patients were identified who underwent hyoid surgery alone for treatment of OSA. Subanalyses were performed for: 1) type of surgery, 2) primary versus secondary hyoid surgery, 3) positional versus nonpositional OSA, 4) age, and 5) body mass index. In patients undergoing isolated hyoid surgery, the AHI decreased from a mean ± standard deviation of 37.3 ± 21.1 (95% confidence interval [CI]: 33.1, 41.5) to 23.0 ± 18.6 (95% CI: 19.3, 26.7) events/hour, which correspond to a 38.3% reduction (P < .0001). AHI reduced by 38.3% for hyoid myotomy with suspension, by 50.7% for hyothyroidopexy, and by 7.1% for hyoid expansion. The Epworth Sleepiness Scale decreased by 3.2 points from 10.3 ± 4.9 (95% CI: 8.8, 11.8) to 7.1 ± 4.2 (95% CI: 5.8, 8.4; P = .0027). CONCLUSIONS: Isolated hyoid surgery has reduced OSA severity and improved sleepiness in adults. Hyothyroidopexy provided a 50.7% reduction in AHI, followed by hyoid myotomy with suspension (38.3% reduction in AHI) and hyoid expansion (7.1% reduction in AHI). The current literature lacks high-quality evidence with regard to hyoid surgery, and additional studies are needed to further elucidate the effect of hyoid surgery in OSA. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1702-1708, 2016.

Levamisole-Adulterated Cocaine Nephrotoxicity: Ultrastructural Features.

OBJECTIVES: The issue of levamisole-adulterated cocaine is emerging as a rapidly growing public health concern due to an increasing number of reports describing its role in cutaneous vasculitis and agranulocytosis. Of note, levamisole is recognized as a contaminant in 69% of the cocaine used within the United States. METHODS: We describe a patient who was a chronic cocaine user and developed systemic vasculitis characterized by polyarthralgia, bullous skin lesions, agranulocytosis, and antineutrophil cytoplasmic antibody-positive rapidly progressive glomerulonephritis. RESULTS: The skin biopsy specimen demonstrated leukocytoclastic vasculitis. The renal biopsy specimen revealed pauci-immune necrotizing and crescentic glomerulonephritis and unusual deposits with medium electron density composed of granules, microspherules, and rare single fibrils on electron microscopy. CONCLUSIONS: The electron microscopic features of levamisole-adulterated cocaine toxicity are novel findings that are presented for the first time, to our knowledge, in this report.

Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis.

CONTEXT: Various drugs affect body weight as a side effect. OBJECTIVE: We conducted this systematic review and meta-analysis to summarize the evidence about commonly prescribed drugs and their association with weight change. DATA SOURCES: MEDLINE, DARE, and the Cochrane Database of Systematic Reviews were searched to identify published systematic reviews as a source for trials. STUDY SELECTION: We included randomized trials that compared an a priori selected list of drugs to placebo and measured weight change. DATA EXTRACTION: We extracted data in duplicate and assessed the methodological quality using the Cochrane risk of bias tool. RESULTS: We included 257 randomized trials (54 different drugs; 84 696 patients enrolled). Weight gain was associated with the use of amitriptyline (1.8 kg), mirtazapine (1.5 kg), olanzapine (2.4 kg), quetiapine (1.1 kg), risperidone (0.8 kg), gabapentin (2.2 kg), tolbutamide (2.8 kg), pioglitazone (2.6 kg), glimepiride (2.1 kg), gliclazide (1.8 kg), glyburide (2.6 kg), glipizide (2.2 kg), sitagliptin (0.55 kg), and nateglinide (0.3 kg). Weight loss was associated with the use of metformin (1.1 kg), acarbose (0.4 kg), miglitol (0.7 kg), pramlintide (2.3 kg), liraglutide (1.7 kg), exenatide (1.2 kg), zonisamide (7.7 kg), topiramate (3.8 kg), bupropion (1.3 kg), and fluoxetine (1.3 kg). For many other remaining drugs (including antihypertensives and antihistamines), the weight change was either statistically nonsignificant or supported by very low-quality evidence. CONCLUSIONS: Several drugs are associated with weight change of varying magnitude. Data are provided to guide the choice of drug when several options exist and institute preemptive weight loss strategies when obesogenic drugs are prescribed.

Using GRADE for evaluating the quality of evidence in hyperbaric oxygen therapy clarifies evidence limitations.

OBJECTIVES: The current evidence rating for hyperbaric oxygen therapy indications uses the American Heart Association system, which mainly depends on the study design. STUDY DESIGN AND SETTING: We systematically reviewed the literature and applied the Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach to the main patient-important outcomes in each indication. RESULTS: We included 17 systematic reviews that synthesized 44 randomized trials and 131 observational studies enrolling 8,145 participants. The quality of evidence for seven indications with category A was high (1), moderate (2), low (2), and very low (2); for 10 indications with category B, it was moderate (1), low (5), and very low (4); and for 1 indication with category C, it was high. The quality of evidence was rated down for the risk of bias and imprecision for most indications and rated up because of large effect size for some indications. Most discrepant ratings were in the indications of decompression illness (C, high), carbon monoxide poisoning (A, very low), and later presentations of idiopathic sudden hearing loss (A, very low). CONCLUSION: The GRADE approach uncovered factors affecting the quality of evidence that were otherwise implicit. Knowing these factors can influence clinicians' confidence in applying hyperbaric oxygen therapy and orient the research agenda.