Characterizing the distinct structural changes associated with self-reported knee injury among individuals with incident knee osteoarthritis: Data from the osteoarthritis initiative.

Abstract: We aimed to characterize the agreement between distinct structural changes on magnetic resonance (MR) imaging and self-reported injury in the 12 months leading to incident common or accelerated knee osteoarthritis (KOA). We conducted a descriptive study using data from baseline and the first 4 annual visits of the Osteoarthritis Initiative. Knees had no radiographic KOA at baseline (Kellgren-Lawrence [KL]<2). We classified two groups: (1) accelerated KOA: a knee developed advanced-stage KOA (KL = 3 or 4) within 48 months and (2) common KOA: a knee increased in radiographic severity (excluding those with accelerated KOA). Adults were 1:1 matched based on sex. The index visit was when a person met the accelerated or common KOA criteria. We limited our sample to people with MR images and self-reported injury data at index visit and year prior. Among 226 people, we found fair agreement between self-reported injuries and distinct structural changes (kappa = 0.24 to 0.31). Most distinct structural changes were medial meniscal pathology. No distinct structural changes (e.g., root or radial tears) appeared to differ between adults who reported or did not report an injury; except, all subchondral fractures occurred in adults who developed accelerated KOA and reported an injury. While there is fair agreement between self-reported knee injuries and distinct structural changes, there is some discordance. Self-reported injury may represent a different construct from distinct structural changes that occur after joint trauma. Clin. Anat. 31:330-334, 2018. © 2018 Wiley Periodicals, Inc.

knee injuries
osteoarthritis
magnetic resonance imaging
meniscus
self report


Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups.

Abstract: Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.

immunotherapy
hepatocellular carcinoma
hepatobiliary cancer
molecular oncology


Sustaining nursing programs in the face of budget cuts and faculty shortages.

Abstract: When asked what their major problems are, many nursing deans would state that they are very concerned about budget cuts and faculty shortages. Yet, there is little, if anything in the literature describing how administrators are dealing with these problems. This article describes three strategies that we employed to address these issues. The first strategy, our home hospital program, involves qualified hospital staff serving as clinical instructors. The second strategy, a collaborative on-line doctor of nursing practice program, reduces the number of courses our faculty must teach, while ensuring adequate numbers of students. Lastly, differential fees is a strategy whereby students enrolled in high-cost educational programs (e.g., nursing) pay greater fees but reap supportive benefits that increase their success in the program. These strategies have allowed us to enhance our educational programs despite budget cuts and faculty shortages.

D002017:Budgets
D005181:Faculty, Nursing
D005249:Fees and Charges
D018803:Models, Economic
D012579:Schools, Nursing

Faculty shortage
Differential fees
Clinical partnership
Collaborative program
Funding
Nursing faculty


CAMTA1 is a useful immunohistochemical marker for diagnosing epithelioid haemangioendothelioma.

Abstract:
AIMS
The diagnosis of epithelioid haemangioendothelioma (EHE) is usually straightforward, based on characteristic histological features. However, it is sometimes difficult to differentiate EHE from a variety of other tumours with epithelioid morphology. The WW domain-containing transcription regulator 1-calmodulin-binding transcription activator 1 (WWTR1-CAMTA1) fusion gene, resulting in the overexpression of CAMTA1, is demonstrated in approximately 90% of EHEs, and the yes-associated protein 1-transcription factor E3 (YAP1-TFE3) fusion gene, associated with the strong and diffuse nuclear expression of TFE3, is present in another small subset of EHEs. The aim of our study was to examine CAMTA1 expression in EHEs and a variety of other tumours to evaluate its diagnostic utility, and to analyse TFE3 expression status in EHEs.

METHODS AND RESULTS
Immunohistochemistry was performed on 16 EHEs, including five cases with CAMTA1 rearrangement and 276 non-EHE tumours. Fourteen of 16 EHEs and only one case of ductal carcinoma of the breast were positive for CAMTA1 and its expression was focal and weak in the latter (sensitivity 87.5%, specificity 99.6%). TFE3 expression was expressed focally and weakly in three (19%) EHEs (two with the CAMTA1 rearrangement).

CONCLUSIONS
Nuclear CAMTA1 expression is sensitive and highly specific for EHE and can be applied to diagnostic immunohistochemistry in epithelioid tumours.

Shibuya|Ryo|R| Matsuyama|Atsuji|A| Shiba|Eisuke|E| Harada|Hiroshi|H| Yabuki|Kei|K| Hisaoka|Masanori|M|


Prostate tumour overexpressed-1 promotes tumourigenicity in human breast cancer via activation of Wnt/β-catenin signalling.

Abstract: Breast cancer is the most common malignancy in females. The presence of cancer stem cells (CSCs) is the main cause of local and distant tumour recurrence and is associated with poor outcome in breast cancer. However, the molecular mechanisms underlying the maintenance of CSCs remain largely unknown. This study demonstrates that prostate tumour overexpressed-1 (PTOV1) enhances the CSC population and augments the tumourigenicity of breast cancer cells both in vitro and in vivo. Moreover, PTOV1 suppresses transcription of Dickkopf-1 (DKK1) by recruiting histone deacetylases and subsequently reducing DKK1 promoter histone acetylation, followed by activation of Wnt/β-catenin signalling. Restoration of DKK1 expression in PTOV1-overexpressing cells counteracts the effects of PTOV1 on Wnt/β-catenin activation and the CSC population. Collectively, these results suggest that PTOV1 positively regulates the Wnt/β-catenin signalling pathway and enhances tumourigenicity in breast cancer; this novel mechanism may represent a therapeutic target for breast cancer. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cui|Yanmei|Y| Ma|Weifeng|W| Lei|Fangyong|F| Li|Qingyuan|Q| Su|Yanhong|Y| Lin|Xi|X| Lin|Chuyong|C| Zhang|Xin|X| Ye|Liping|L| Wu|Shu|S| Li|Jun|J| Yuan|Zhongyu|Z| Song|Libing|L|

D015972:Gene Expression Regulation, Neoplastic

D036341:Intercellular Signaling Peptides and Proteins

D023041:Xenograft Model Antitumor Assays

tumourigenicity
breast cancer
Wnt/β-catenin signalling
cancer stem cells
PTOV1


Detection of 10 sweeteners in various foods by liquid chromatography/tandem mass spectrometry.

Abstract: The analytical method for sweeteners in various food matrixes is very important for food quality control and regulation enforcement. A simple and rapid method for the simultaneous determination of 10 sweeteners [acesulfame potassium (ACS-K), aspartame (ASP), cyclamate (CYC), dulcin (DUL), glycyrrhizic acid (GA), neotame (NEO), neohesperidin dihydrochalcone (NHDC), saccharin (SAC), sucralose (SCL), and stevioside (STV)] in various foods by liquid chromatography/tandem mass chromatography (LC-MS/MS) was developed. The chromatographic separation was performed on a Phenomenex Luna Phenyl-Hexyl (5 μm, 4.6 mm × 150 mm) column with gradient elution of 10 mM ammonium acetate in water and 10 mM ammonium acetate in methanol. The recoveries of the 10 sweeteners were between 75% and 120%, and the coefficients of variation were less than 20%. The limits of quantification were 0.5 μg/kg for NHDC and SCL. For the other sweeteners, the limits of quantification were 0.1 μg/kg. Compared to the traditional high-performance liquid chromatography method, the LC-MS/MS method could provide better sensitivity, higher throughput, enhanced specificity, and more sweeteners analyzed in a single run. The samples included 27 beverages (16 alcoholic and 11 nonalcoholic beverages) and 15 pickled foods (1 pickled pepper, 3 candies, and 11 candied fruits). Two remanufactured wines were found to contain 7.2, 8.5 μg/g SAC and 126.5, 123 μg/g CYC, respectively. ACS-K, ASP, SCL, and NEO were detected in five beverages and drinks. The pickled peppers and candied fruits were found to contain SAC, GA, CYC, ASP, STV, NEO, and ACS-K. The wine with sweeteners detected was remanufactured wine, not naturally fermented wine. Therefore, the ingredient label for the sweeteners of remanufactured wine should be regulated by the proper authority for inspection of sweeteners.

Sweeteners
Beverages
Pickled peppers
Candied fruit
LC–MS/MS


Correlates of depression among Black girls exposed to violence.

Abstract: Depression rates for youth remanded to juvenile detention is double that of the general population and Black girls are especially vulnerable. A dearth of literature analyzes the factors that are correlated with depression among system-involved Black girls, ages 12-17 years old. We utilized personal agency to examine the relationship between risk factors (i.e., abuse history, and fear of condom negotiation) and protective factors (i.e., condom self-efficacy, and perceived social support) that might correlate with depression among Black girls exposed to violence. Findings indicate that fear of condom negotiation, abuse history and low condom self-efficacy are correlated with depressive symptomology while self-esteem and perceived social support are protective factors that may serve as a buffer against girls' feelings of helplessness and hopelessness. The findings of this study suggest several implications for prevention and intervention efforts to reduce the depression-related risks among justice-involved Black females, including strategies that promote healing within their social support networks.

depression
Black girls
mental health
trauma


The Heterogeneity of Skewness in T2W-Based Radiomics Predicts the Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Abstract: Our study aimed to investigate whether radiomics on MRI sequences can differentiate responder (R) and non-responder (NR) patients based on the tumour regression grade (TRG) assigned after surgical resection in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT). Eighty-five patients undergoing primary staging with MRI were retrospectively evaluated, and 40 patients were finally selected. The ROIs were manually outlined in the tumour site on T2w sequences in the oblique-axial plane. Based on the TRG, patients were grouped as having either a complete or a partial response (TRG = (0,1), n = 15). NR patients had a minimal or poor nCRT response (TRG = (2,3), n = 25). Eighty-four local first-order radiomic features (RFs) were extracted from tumour ROIs. Only single RFs were investigated. Each feature was selected using univariate analysis guided by a one-tailed Wilcoxon rank-sum. ROC curve analysis was performed, using AUC computation and the Youden index (YI) for sensitivity and specificity. The RF measuring the heterogeneity of local skewness of T2w values from tumour ROIs differentiated Rs and NRs with a p-value ≈ 10-5; AUC = 0.90 (95%CI, 0.73-0.96); and YI = 0.68, corresponding to 80% sensitivity and 88% specificity. In conclusion, higher heterogeneity in skewness maps of the baseline tumour correlated with a greater benefit from nCRT.


A fusogenic dengue virus-derived peptide enhances antitumor efficacy of an antibody-ribonuclease fusion protein targeting the EGF receptor.

Abstract: Due to its frequent overexpression in a variety of solid tumors the epidermal growth factor receptor (EGFR) is a well-established target for therapeutic interventions in epithelial cancers. In order to target EGFR in head and neck cancer, we have generated a ribonuclease (RNase) fusion protein comprising a humanized anti-EGFR antibody single-chain Fv fragment (scFv) and Ranpirnase, an RNase from Rana pipiens. Fusion of Ranpirnase to the N-terminus of the scFv via a flexible glycine-serine linker (G4S)3 resulted in very poor cytotoxicity of the fusion protein. As endosomal accumulation and lysosomal degradation have been reported to diminish the antitumor efficacy of ribonuclease or toxin-based immunoagents, we explored a fusion peptide from dengue virus that has been reported to be involved in the endosomal escape of the virus. This peptide was introduced as a linker between Ranpirnase and the scFv moiety. The modified immunoRNase exhibited exceptionally high cytotoxicity toward EGFR-expressing head and neck cell lines without affecting specificity. These results indicate that endosomal entrapment needs to be considered for Ranpirnase-based immunoagents and might be overcome by the use of tailored transduction domains from viral proteins.

Kiesgen|Stefan|S|
Liebers|Nora|N|
Cremer|Martin|M|
Arnold|Ulrich|U|
Weber|Tobias|T|
Keller|Armin|A|
Herold-Mende|Christel|C|
Dyckhoff|Gerhard|G|
Jäger|Dirk|D|
Kontermann|Roland E|RE|
Arndt|Michaela A E|MA|
Krauss|Jürgen|J|

D000970:Antineoplastic Agents
D045744:Cell Line, Tumor
D002470:Cell Survival
D003716:Dengue Virus
D066246:ErbB Receptors
D006801:Humans
D011993:Recombinant Fusion Proteins
D012260:Ribonucleases
D057127:Single-Chain Antibodies

EGFR
Ranpirnase
dengue virus
endosomal escape
immunoRNase


Isolation and purification of diastereoisomeric flavonolignans from silymarin by binary-column recycling preparative high-performance liquid chromatography.

Abstract: Silymarin extracted from Silybum marianum (L.) Gaertn consists of a large number of flavonolignans, of which diastereoisomeric flavonolignans including silybin A and silybin B, and isosilybin A and isosilybin B are the main bioactive components, whose preparation from the crude extracts is still a difficult task. In this work, binary-column recycling preparative high-performance liquid chromatography systems without sample loop trapping, where two columns were switched alternately via one or two six-port switching valves, were established and successfully applied to the isolation and purification of the four diastereoisomeric flavonolignans from silymarin. The proposed system showed significant advantages over conventional preparative high-performance liquid chromatography with a single column in increasing efficiency and reducing the cost. To obtain the same amounts of products, the proposed system spends only one tenth of the time that the conventional system spends, and needs only one eleventh of the solvent that the conventional system consumes. Using the proposed system, the four diastereoisomers were successfully isolated from silymarin with purities over 98%.

Zhao|Weiquan|W| Yang|Guang|G| Zhong|Fanyi|F| Yang|Nan|N| Zhao|Xin|X| Qi|Yunpeng|Y| Fan|Guorong|G|

D002851:Chromatography, High Pressure Liquid

Flavonolignan
Silymarin
Column switching
Recycling preparative chromatography


Epicardial Ablation of Ventricular Tachycardia.

Abstract: Epicardial mapping and ablation via a percutaneous subxiphoid technique has been instrumental in improving the working understanding of complex myocardial scars in various arrhythmogenic substrates. Endocardial ablation alone may not be sufficient in patients with ischemic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, and Chagas disease to prevent recurrent ventricular tachycardia. Multiple observational studies have demonstrated greater freedom from recurrence with adjunctive epicardial ablation compared with endocardial ablation alone. While epicardial ablation is performed predominantly at tertiary referral centers, knowledge of the technical approach, clinical indications, and potential complications is imperative to maximizing clinical success and patient safety. In 1996, Sosa and colleagues modified the pericardiocentesis technique to enable percutaneous access to the pericardial space for mapping and catheter ablation of ventricular tachycardia.1 Originally developed for patients with epicardial scarring due to chagasic cardiomyopathy and patients with ischemic cardiomyopathy refractory to endocardial ablationm,2,3 this approach has since become an essential part of the armamentarium for the treatment of ventricular tachycardia. Myocardial scars are three-dimensionally complex with varying degrees of transmurality, and the ability to map and ablate the epicardial surface has contributed to a greater understanding of scar-related VT in postinfarction cardiomyopathy and nonischemic substrates including idiopathic dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, and chagasic cardiomyopathy. In this review, we highlight the percutaneous approach and discuss clinical indications and potential complications.

epicardial ablation ventricular tachycardia


A new microarray platform for whole-genome expression profiling of Mycobacterium tuberculosis.

Abstract: Microarrays have allowed gene expression profiling to progress from the gene level to the genome level, and oligonucleotide microarrays have become the platform of choice for large-scale, targeted gene expression studies. cDNA arrays and spotted oligonucleotide arrays have gradually given way to in situ synthesized oligonucleotide-based DNA microarrays for whole-genome expression profiling. With the identification of new coding and regulatory sequences, it is imperative that microarrays be updated to enable more complete expression profiling of genomes. We report here a new in situ synthesized oligonucleotide-based microarray platform for Mycobacterium tuberculosis that has been updated for the latest genome information and incorporates hitherto unannotated genes with described biological functions. This microarray has greater coverage of mycobacterial genes than any other array reported to date. We have also evaluated different labeled-target preparation methods and hybridization conditions for this new microarray to obtain high quality data and reproducible results. The new design has been rigorously validated for its specificity and performance using samples isolated from mycobacteria grown under different environment conditions. Further, the quality of the generated data has been compared with published data and is superior to that obtained using spotted oligonucleotide microarrays.

D020411:Oligonucleotide Array Sequence Analysis

Microarray
M. tuberculosis
RNA amplification
Whole genome expression profiling


Surge Capacity of Hospitals in Emergencies and Disasters With a Preparedness Approach: A Systematic Review.

Abstract:
OBJECTIVE
Surge capacity is one of the most important components of hospital preparedness for responding to emergencies and disasters. The ability to provide health and medical care during a sudden increase in the number of patients or victims of disasters is a main concern of hospitals. We aimed to perform a systematic review of hospital surge capacity in emergencies and disasters with a preparedness approach.

METHODS
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The key words "surge," "surge capacity," "preparedness," "hospital emergency department," "hospital," "surge capability," "emergency," "hazard," "disaster," "catastrophe," "crisis," and "tragedy" were used in combination with the Boolean operators OR and AND. The Google Scholar, ISI Web of Science, Science Direct, PubMed, Scopus, Ovid, Pro Quest, and Wiley databases were searched.

RESULTS
A total of 1008 articles were extracted and 17 articles were selected for final review of surge capacity based on the objective of the study. Seventeen studies (1 randomized controlled trial, 2 qualitative studies, and 14 cross-sectional studies) investigated the surge capacity of hospitals in emergencies and disasters to evaluate the best evidence to date. The results of selected articles indicated that there are various ways to increase the capacity of hospitals in 4 domains: staff, stuff, structure, and system.

CONCLUSION
Surge capacity is a basic element of disaster preparedness programs. Results of the current study could help health field managers in hospitals to prepare for capacity-building based on surge capacity components to improve and promote hospital preparedness programs. (Disaster Med Public Health Preparedness. 2017;11:612-620).

Sheikhbardsiri|Hojjat|H|
Raeisi|Ahmad Reza|AR|
Nekoei-Moghadam|Mahmood|M|
Rezaei|Fatemeh|F|

surge capacity
hospital
emergency
disaster
preparedness


Interactions of HIV and drugs of abuse: the importance of glia, neural progenitors, and host genetic factors.

Abstract: Considerable insight has been gained into the comorbid, interactive effects of HIV and drug abuse in the brain using experimental models. This review, which considers opiates, methamphetamine, and cocaine, emphasizes the importance of host genetics and glial plasticity in driving the pathogenic neuron remodeling underlying neuro-acquired immunodeficiency syndrome and drug abuse comorbidity. Clinical findings are less concordant than experimental work, and the response of individuals to HIV and to drug abuse can vary tremendously. Host-genetic variability is important in determining viral tropism, neuropathogenesis, drug responses, and addictive behavior. However, genetic differences alone cannot account for individual variability in the brain "connectome." Environment and experience are critical determinants in the evolution of synaptic circuitry throughout life. Neurons and glia both exercise control over determinants of synaptic plasticity that are disrupted by HIV and drug abuse. Perivascular macrophages, microglia, and to a lesser extent astroglia can harbor the infection. Uninfected bystanders, especially astroglia, propagate and amplify inflammatory signals. Drug abuse by itself derails neuronal and glial function, and the outcome of chronic exposure is maladaptive plasticity. The negative consequences of coexposure to HIV and drug abuse are determined by numerous factors including genetics, sex, age, and multidrug exposure. Glia and some neurons are generated throughout life, and their progenitors appear to be targets of HIV and opiates/psychostimulants. The chronic nature of HIV and drug abuse appears to result in sustained alterations in the maturation and fate of neural progenitors, which may affect the balance of glial populations within multiple brain regions.

Methamphetamine
Cocaine
Chemokine (C–C motif) receptor 5 (CCR5)
Drug/substance abuse
Gene polymorphisms
Neural stem cells
Neurogenesis/gliogenesis
Neuroimmunology
Neuropathology
Neuropharmacology
μ opioid receptor (OPRM1)


Prehospital ketamine administration to pediatric trauma patients with head injuries in combat theaters.

Abstract:
BACKGROUND
Head injuries frequently occur in combat. Tactical Combat Casualty Care (TCCC) guidelines recommend pre-hospital use of ketamine for analgesia. Yet the use of this medication in patients with head injuries remains controversial, particularly among pediatric patients. We compare survival to hospital discharge rates among pediatric head injury subjects who received prehospital ketamine versus those who did not.

METHODS
We queried the Department of Defense Trauma Registry (DODTR) for all pediatric (<18 years of age) subjects from January 2007 to January 2016. We performed a sub-analysis of subjects with an abbreviated injury severity score for the head of 3 (serious) or higher and at least one documented Glasgow Coma Score (GCS) ≤13.

RESULTS
Of the 3439 pediatric patients within our dataset, 555 subjects met inclusion criteria for head injury - 36 (6.5%) received prehospital ketamine versus 519 (93.5%) who did not. There was no significant difference noted between groups regarding median age (10 versus 8, p = 0.259), percent male gender (72.2% versus 76.3%, p = 0.579), mechanism of injury (p = 0.143), median composite injury scores (22 versus 20, p = 0.082), median ventilator-free days (28 versus 27, p = 0.068), median ICU-free days (27.5 versus 27, p = 0.767), median hospital days (3.5 versus 4, p = 0.876) or survival to discharge (66.7% versus 70.7%, p = 0.607).

CONCLUSIONS
Within this data set, we were unable to detect any differences in mortality among pediatric head trauma subjects administered ketamine compared to subjects not receiving this medication in the prehospital setting.

Hill|Guyon J|GJ|
April|Michael D|MD|
Maddry|Joseph K|JK|
Schauer|Steven G|SG|

D059030:United States Department of Defense

Prehospital Ketamine Pediatric Trauma Head TBI


Schwannoma-A Rare Subepithelial Lesion of the Colon.

Abstract: Schwannoma is a benign tumor arising from Schwann cells that form the neural sheath. Primary schwannoma of the colon is rare and a few cases have been reported. We report a case of schwannoma of the colon and present the differential diagnosis that must be considered in the evaluation of colonic subepithelial lesions.

Barbeiro|Sandra|S| Martins|Catarina|C| Gonçalves|Cláudia|C| Arroja|Bruno|B| Canhoto|Manuela|M| Silva|Filipe|F| Cotrim|Isabel|I| Amado|Cristina|C| Eliseu|Liliana|L| Vasconcelos|Helena|H|

Colon Endosonography Immunohistochemistry Neurilemmoma


HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants.

Abstract: The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in treatment-naive patients, and DTG has selected for a small number of resistant viruses in treatment-naive patients. However, some patients who had viruses with substitutions selected by RAL and EVG responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI cabotegravir (CAB), which is in late-stage clinical trials, has been shown to select for novel resistant mutants in vitro Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of compound 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.

Smith|Steven J|SJ|
Zhao|Xue Zhi|XZ|
Passos|Dario Oliveira|DO|
Lyumkis|Dmitry|D|
Burke|Terrence R|TR|
Hughes|Stephen H|SH|0000-0002-9176-4377

integrase
inhibitor
drug resistance
human immunodeficiency virus
replication capacity


Microbiological and biochemical spoilage of smoke-dried fishes sold in West African open markets.

Abstract: Proximate composition and microbiological characteristics of pre-dried Chrysichthys nigrodigitatus and Pseudotolithus typus were studied over a period of 4weeks to determine the health risks associated with delayed consumption. All analyses were conducted using standard microbiological and chemical methods. Results showed a general decline in microbiological safety and nutritive characteristics of both fish species over time, with an observed increase in microbial loads over time. Aspergillus flavus was also present on both species which makes consumption of the fishes hazardous to the health of consumers due to its ability to produce carcinogenic aflatoxins. In order to minimise the health risks to consumers, it is recommended that smoke-dried fishes be consumed with minimal delay and cooked properly before consumption. The findings of this study will prove important in the development of more stringent regulations regarding food safety in Nigeria.

Smoke-dried
Fish
Proximate composition
Microbial loads
Food safety
Shelf-life


The dorsal hippocampus is required for the formation of long-term duration memories in rats.

Abstract: Interval timing-the perception of durations mainly in seconds or minutes-is a ubiquitous behavior in organisms. Animal studies have suggested that the hippocampus plays an essential role in duration memory; however, the memory processes involved are unclear. To clarify the role of the dorsal hippocampus in the acquisition of long-term duration memories, we adapted the "time-shift paradigm" to a peak-interval procedure. After a sufficient number of training with an initial target duration (20 s), the rats underwent "shift sessions" with a new target duration (40 s) under a muscimol (0.5 µg per side) infusion into the bilateral dorsal hippocampus. The memory of the new target duration was then tested in drug-free "probe sessions," including trials in which no lever presses were reinforced. In the probe sessions, the mean response rate distribution of the muscimol group was located leftward to the control group, but these two response rate distributions were superimposed on the standardized time axis, suggesting a scalar property. In the session-by-session analysis, the mean peak time (an index of timing accuracy) of the muscimol group was lower than that of the control group in the probe sessions, but not in the shift sessions. These findings suggest that the dorsal hippocampus is required for the formation of long-term duration memories within the range of interval timing.

dorsal hippocampus
time-shift paradigm
interval timing
long-term memory
peak interval
short-term memory
time perception


Disruption of a neural microcircuit in the rod pathway of the mammalian retina by diabetes mellitus.

Abstract: Diabetes leads to dysfunction of the neural retina before and independent of classical microvascular diabetic retinopathy, but previous studies have failed to demonstrate which neurons and circuits are affected at the earliest stages. Here, using patch-clamp recording and two-photon Ca(2+) imaging in rat retinal slices, we investigated diabetes-evoked changes in a microcircuit consisting of rod bipolar cells and their dyad postsynaptic targets, AII and A17 amacrine cells, which play an essential role in processing scotopic visual signals. AII amacrines forward their signals to ON- and OFF-cone bipolar cells and A17 amacrines provide GABAergic feedback inhibition to rod bipolar cells. Whereas Ca(2+)-permeable AMPA receptors mediate input from rod bipolar cells to both AII and A17 amacrines, diabetes changes the synaptic receptors on A17, but not AII amacrine cells. This was expressed as a change in pharmacological properties and single-channel conductance of the synaptic receptors, consistent with an upregulation of the AMPA receptor GluA2 subunit and reduced Ca(2+) permeability. In addition, two-photon imaging revealed reduced agonist-evoked influx of Ca(2+) in dendritic varicosities of A17 amacrine cells from diabetic compared with normal animals. Because Ca(2+)-permeable receptors in A17 amacrine cells mediate synaptic release of GABA, the reduced Ca(2+) permeability of these receptors in diabetic animals leads to reduced release of GABA, followed by disinhibition and increased release of glutamate from rod bipolar cells. This perturbation of neuron and microcircuit dynamics can explain the decreased dynamic range and sensitivity of scotopic vision that has been observed in diabetes.

retina
diabetes
amacrine cells
calcium-permeable AMPA receptors


A Quest of Great Importance-Developing a Broad Spectrum Escherichia coli Phage Collection.

Abstract: Shigella ssp. and enterotoxigenic Escherichia coli are the most common etiological agents of diarrheal diseases in malnourished children under five years of age in developing countries. The ever-growing issue of antibiotic resistance and the potential negative impact of antibiotic use on infant commensal microbiota are significant challenges to current therapeutic approaches. Bacteriophages (or phages) represent an alternative treatment that can be used to treat specific bacterial infections. In the present study, we screened water samples from both environmental and industrial sources for phages capable of infecting E. coli laboratory strains within our collection. Nineteen phages were isolatedand tested for their ability to infect strains within the ECOR collection and E. coli O157:H7 Δstx. Furthermore, since coliphages have been reported to cross-infect certain Shigella spp., we also evaluated the ability of the nineteen phages to infect a representative Shigella sonnei strain from our collection. Based on having distinct (although overlapping in some cases) host ranges, ten phage isolates were selected for genome sequence and morphological characterization. Together, these ten selected phages were shown to infect most of the ECOR library, with 61 of the 72 strains infected by at least one phage from our collection. Genome analysis of the ten phages allowed classification into five previously described genetic subgroups plus one previously underrepresented subgroup.

Kaczorowska|Joanna|J|
Casey|Eoghan|E|
Neve|Horst|H|0000-0003-0295-2016
Franz|Charles M A P|CMAP|
Noben|Jean-Paul|JP|0000-0003-3368-5686
Lugli|Gabriele A|GA|
Ventura|Marco|M|
Sinderen|Douwe van|DV|
Mahony|Jennifer|J|

D003090:Coliphages
D004926:Escherichia coli
D019453:Escherichia coli O157
D014644:Genetic Variation
D016679:Genome, Viral
D058507:Host Specificity
D040901:Proteomics
D012760:Shigella
D014764:Viral Proteins
D014871:Water Microbiology

Escherichia coli
Shigella ssp.
bacteriophage
host range
phage therapy


Edible processed insects from e-commerce: Food safety with a focus on the Bacillus cereus group.

Abstract: Edible insects are increasing in popularity as a trendy new food item in many countries worldwide. However, little information is available regarding the associated foodborne pathogens, in particular, the spore-forming bacteria that may be present in these processed foods. In this study, mealworms, crickets, mole crickets and silkworms that are widely available online were investigated for microbial quality traits. Whereas water activity and pH results revealed a stable product, microbiota characterisation highlighted wide variability among the analysed insect species. Among the microbial targets considered in this study, total viable count, total aerobic spores and Bacillus cereus count were the most suitable for describing the food safety and microbial quality of these products. Endospore-forming bacteria ascribed to the B. cereus group were identified with genetic methods and putative virulence patterns. Three major clusters were delineated according to the phylogenetic analysis of the B. cereus group: B. cereus, B. thuringiensis and B. cytotoxicus, with virulence patterns particular to the enterotoxin genes found in each cluster. This work represents a first step in the hazard identification of B. cereus group bacteria isolated from edible insects. The presented results should also be considered with respect to domestic handling and rehydration of such products prior to consumption.

Fasolato|Luca|L| Cardazzo|Barbara|B| Carraro|Lisa|L| Fontana|Federico|F| Novelli|Enrico|E| Balzan|Stefania|S|

E-commerce
Bacillus cereus group
Edible insects
Spore-forming bacteria
Ready-to-eat


A novel sensitive laccase biosensor using gold nanoparticles and poly L-arginine to detect catechol in natural water.

Abstract: In this study, the simple, green, and fast layer-by-layer modification of the glassy carbon electrode was mainly performed by electrodeposition of gold nanoparticles and then, poly-l-arginine, and finally, laccase was covalently bonded to poly-l-arginine using glutaraldehyde. This type of fabrication is used for the first time for catechol detection, which provides a bioelectrocatalytic cycle for electron transport in the presence of laccase that results in sensitive and fast detection of catechol. The scanning electron microscopy, Fourier-transform infrared spectroscopy, and electrochemical studies were performed to confirm successful immobilization of the enzyme. The biosensor response was linear in a wide range of catechol trace concentrations, 24.90-274.00 nM, with the detection limit of 18.00 nM. Values of Km , α, n, and Ks for the immobilized enzyme were calculated to be 1.25 × 10-2  µM, 0.56, 3.19, and 0.28 Sec-1 , respectively. It was examined in real sample successfully confirming it is capable of measuring catechol in natural water.

laccase
biosensor
poly l-arginine
catechol
AuNPs


Breast cancer cases of female patients under 35 years of age in Togo: A series of 158 cases.

Abstract: Breast cancer in young female patients represents a public health problem in developing countries. The objectives of the study were to study the epidemiological and histological characteristics of breast cancer in female patients under 35 years of age. This was a retrospective analytical study of a series of 158 cases of breast cancer in female patients under 35 years of age, conducted at the University Teaching Hospital of Lomé between 2000 and 2015. A total of 158 cases were collected, representing 36.2% (436) of all breast cancer cases. The average age of the patients was 30.9 years (range, 16-35 years). A family history of breast cancer at the 1st or 2nd degree was identified in 13.9% of cases. Genetic mutation studies were carried out for 7 patients, 5 of which revealed mutations (4 BRCA1 and 1 BRCA2). According to the locus, the cancer was located preferentially in the left breast in 88 cases (55.7%). Malignant mammary lesions were epithelial tumors (n=144 cases, 91.1%), infiltrating (n=125 cases, 79.1%) and non-infiltrating (n=19 cases, 12.0%). The other histological groups consisted of 8 cases of sarcomas (5 cases of angiosarcoma, 2 cases of fibrosarcoma and 1 case of Kaposi's sarcoma), 5 cases of lymphomas and one case of melanoma. Not otherwise specified infiltrating ductal carcinomas were SBR II and III in 43.2 and 35.2% of cases, respectively. The tumors classified as T4 were the most frequent (30.4%). Regarding the lymph node status, lymph node metastasis was noted in 22.8% of cases. Studies of hormone receptors were carried out in 23 patients and were positive for 11 patients: Estrogen receptor (ER)+plus progesterone receptor (PR)+(7 patients), ER+PR-(4 patients). Of the aforementioned 8 cases of sarcoma, 5 were angiosarcoma. The lymphomas were predominantly Burkitt's type for 4 cases. Mammary ultrasonography was performed in 45.6% of the patients and 54.4% underwent the combined ultrasonography and mammography. Ultrasound identified one or more sign of malignancy in 67 patients (42.4%), and combined ultrasonography and mammography classified 51.9% of lesions in BIRADS 4 and 5. The incidence of breast cancer in young Togolese patients is high. It is a disease distinguished by a delay in diagnosis, which contributes to the high number of cases that initially diagnosed at an advanced stage, particularly the high histo-prognosis grades of infiltrating ductal carcinoma. These results indicate a genetic origin; therefore, a thorough investigation into genetic mutations should be carried. In addition, further collaborative studies are required to verify these results.

Darré|Tchin|T|
Tchaou|Mazamaesso|M|
Folligan|Koué|K|
Amadou|Abdoulatif|A|
N'Timon|Bidamin|B|
Sonhaye|Lantam|L|
Aboubakari|Abdoul-Samadou|AS|
Amégbor|Koffi|K|
Akpadza|Koffi|K|
Napo Koura|Gado|G|

Togo
carcinoma
Africa
cancer breast
cancer registry
immunohistochemistry


Primitive Neuroectodermal Tumor of the Vulva in an Adolescent Girl.

Abstract: Extraskeletal primitive neuroectodermal tumor (PNET) is rare and that affecting the female genital tract is extremely rare. We report the case of a 17-year-old girl who presented with swelling of the clitorus. She underwent excision and histopathology was PNET. She received chemotherapy and radiation and achieved complete remission. However, she relapsed locally and systemically soon, progressed and died.

Narayanan|Geetha|G|
Rajan|Varun|V|
Puthusseri|Jaisankar|J|
Kattoor|Jayasree|J|
Soman|Lali V|LV|


UNDR ROVER - a fast and accurate variant caller for targeted DNA sequencing.

Abstract:
BACKGROUND
Previously, we described ROVER, a DNA variant caller which identifies genetic variants from PCR-targeted massively parallel sequencing (MPS) datasets generated by the Hi-Plex protocol. ROVER permits stringent filtering of sequencing chemistry-induced errors by requiring reported variants to appear in both reads of overlapping pairs above certain thresholds of occurrence. ROVER was developed in tandem with Hi-Plex and has been used successfully to screen for genetic mutations in the breast cancer predisposition gene PALB2. ROVER is applied to MPS data in BAM format and, therefore, relies on sequence reads being mapped to a reference genome. In this paper, we describe an improvement to ROVER, called UNDR ROVER (Unmapped primer-Directed ROVER), which accepts MPS data in FASTQ format, avoiding the need for a computationally expensive mapping stage. It does so by taking advantage of the location-specific nature of PCR-targeted MPS data.

RESULTS
The UNDR ROVER algorithm achieves the same stringent variant calling as its predecessor with a significant runtime performance improvement. In one indicative sequencing experiment, UNDR ROVER (in its fastest mode) required 8-fold less sequential computation time than the ROVER pipeline and 13-fold less sequential computation time than a variant calling pipeline based on the popular GATK tool. UNDR ROVER is implemented in Python and runs on all popular POSIX-like operating systems (Linux, OS X). It requires as input a tab-delimited format file containing primer sequence information, a FASTA format file containing the reference genome sequence, and paired FASTQ files containing sequence reads. Primer sequences at the 5' end of reads associate read-pairs with their targeted amplicon and, thus, their expected corresponding coordinates in the reference genome. The primer-intervening sequence of each read is compared against the reference sequence from the same location and variants are identified using the same algorithm as ROVER. Specifically, for a variant to be 'called' it must appear at the same location in both of the overlapping reads above user-defined thresholds of minimum number of reads and proportion of reads.

CONCLUSIONS
UNDR ROVER provides the same rapid and accurate genetic variant calling as its predecessor with greatly reduced computational costs.

Park|Daniel J|DJ|
Li|Roger|R|
Lau|Edmund|E|
Georgeson|Peter|P|
Nguyen-Dumont|Tú|T|
Pope|Bernard J|BJ|

ROVER
Massively parallel sequencing
Hi-Plex
Variant calling
PCR-MPS
Targeted sequencing


Left upper pulmonary vein connected to the persistent left superior vena cava and the left atrium.

Abstract: Persistent left superior vena cava (PLSVC) is the most common anomalous thoracic venous drainage. A PLSVC usually drains into the right atrium through a dilated coronary sinus. It is rare that a PLSVC flows directly into the left atrium, and even rarer that it connects to the left upper pulmonary vein (LUPV). We report a case, wherein the LUPV connected to both the PLSVC and the left atrium.

Maki|Ryunosuke|R| Miyajima|Masahiro|M| Mishina|Taijiro|T| Watanabe|Atsushi|A|

Partial anomalous pulmonary venous connection


The Perioperative Surgical Home: Improving the Value and Quality of Care in Total Joint Replacement.

Abstract:
PURPOSE OF REVIEW
The perioperative surgical home (PSH) is a patient-centered, physician-led, multidisciplinary care pathway developed to deliver value-based care based on shared decision-making. Physician and hospital reimbursement will be tied to providing quality care at lower cost, and the PSH model has been used in providing care to patients undergoing lower extremity arthroplasty. The purpose of this review is to discuss the rationale, definition, development, current state, and future direction of the PSH.

RECENT FINDINGS
The PSH model guides the patient throughout the pre and perioperative process and into the postoperative phase. It has been shown in multiple studies to decrease length of stay, improve functional outcomes, allow more home discharges, and lower costs. There is no increase in complications or readmission rates. The PSH pathway is a safe and effective method of providing value-based care to patients undergoing hip and knee arthroplasty.

Chimento|George F|GF|
Thomas|Leslie C|LC|

Perioperative surgical home
Value-based care
Arthroplasty
Outcomes
Bundled payments, readmission


Erythema multiforme-like eruption associated with plant-induced allergic contact dermatitis in a pediatric patient: A case report.

Abstract: An 11-year-old boy presented to the emergency department 5 days after playing in the forest. His initial eruption, consistent with allergic contact dermatitis to poison ivy, progressed into target lesions involving his extremities, palms, upper trunk, and face, consistent with an erythema multiforme-like eruption. This report details the case and reviews the literature concerning this atypical and potentially underreported complication of plant-induced allergic contact dermatitis.

allergic contact dermatitis
contact dermatitis
erythema multiforme
phytodermatitis
plant-induced dermatitis


The De Winter-like electrocardiogram pattern in inferior and lateral leads associated with left circumflex coronary artery occlusion.

Abstract: The aim of this report was to investigate coronary artery occlusion related to De Winter-like electrocardiogram (ECG) pattern. A patient admitted to Zhongshan Hospital who was diagnosed with acute coronary syndrome with De Winter-like ECG pattern was reviewed in our case report. In this case, we found that a De Winter-like ECG change in the inferior and lateral leads was associated with left circumflex coronary artery occlusion. After a timely reperfusion therapy, the symptom was obviously alleviated with a normalization of upsloping ST-segment. Doctors should be aware that De Winter-like ECG changes can also predict acute occlusion in any coronary artery, not only in the left anterior descending artery and right coronary artery but also in the left circumflex coronary artery.

Chen|Qingxing|Q| Zou|Tian|T| Pang|Yang|Y| Ling|Yunlong|Y| Zhu|Wenqing|W|

Coronary artery occlusion
De Winter syndrome


Top-Level Design of a Normalized Chinese Clinical Terminology: An Integrated Application of National and International Data Standards and Terminologies.

Abstract: This work describes the design and building of a Chinese clinical terminology (called CCTS). The terminology is similar to an ontology, and will promote the use of Chinese clinical data, such as indexing, retrieval and exchange. The terminology is a TOPL concept framework, which integrates hierarchical structures of Chinese and interenational reference terminology standards for health. Our framework includes 14 subtrees, 2286 classes and 65 relationships.

Sun|Haixia|H| Ji|Yujing|Y| Deng|Panpan|P| Li|Junlian|J| Ren|Huiling|H| Shen|Liu|L| Feng|Ming|M| Wang|Yi|Y|

D012015:Reference Standards
D018875:Vocabulary, Controlled

Electronic Health Records
Reference Standards
Vocabulary


Outcomes of revascularization treatment in immature dog's teeth.

Abstract:
AIM
The purpose of the current study was to examine the success rate of a revascularization treatment protocol involving canal space disinfection using copious irrigation, a triantibiotic dressing, and induction of a blood clot matrix in immature dog's teeth.

MATERIALS AND METHODS
Thirty-six immature mongrel dog's teeth were divided into two experimental and two control groups. The experimental groups included a necrotic-infected group (n = 20) and a vital group (n = 10). In the group with the necrotic-infected teeth, periapical lesions were induced, and disinfection of the canals was carried out using copious irrigation and a triple antibiotic medication (metronidazole, ciprofloxacin, and tetracycline). Subsequently, the periapical tissues were irritated to initiate bleeding, producing a blood clot. A double seal of the coronal access was then placed. In the vital group, the pulp was aseptically removed before the canal was irrigated and periapical tissues irritated to induce bleeding. The same protocol as that used for the necrotic-infected group was used to seal the coronal access. In the positive control group (n = 3), after pulp removal, sterile sponges soaked in plaque suspension were placed in the pulp chambers of the teeth, after which the chambers were sealed. In the negative control group (n = 3), one untouched 1st premolar tooth in each dog was assigned and left to develop naturally. Radiographic and histological findings were evaluated at 3 and 6 months. Data analysis was performed using Fisher's exact test.

RESULTS
The necrotic-infected group radiographically demonstrated apical healing and apical closure in 70% of the cases and thickening of the walls in 40% after 6 months. The vital group showed apical closure in 77% and thickened walls in 44% of the cases after 3 months. Histological findings confirmed the radiographic findings. No significant difference was observed between the two groups (P > 0.05).

CONCLUSIONS
If necrotic-infected canals are effectively disinfected and treated according to the protocol, the ensuing revascularization response is similar to that of vital immature teeth.

Khademi|Abbas Ali|AA|
Dianat|Omid|O|
Mahjour|Faranak|F|
Razavi|Seyed Mohammad|SM|
Younessian|Farnaz|F|

treatment
immature teeth
animal model
dog's tooth
pulp revascularization
root canal
trauma


Native α-Synuclein, 3-Nitrotyrosine Proteins, and Patterns of Nitro-α-Synuclein-Immunoreactive Inclusions in Saliva and Submandibulary Gland in Parkinson's Disease.

Abstract: Background. Salivary α-synuclein (aSyn) and its nitrated form, or 3-nitrotyrosine-α-synuclein (3-NT-αSyn), hold promise as biomarkers for idiopathic Parkinson's disease (IPD). Nitrative stress that is characterized by an excess of 3-nitrotyrosine proteins (3-NT-proteins) has been proposed as a pathogenic mechanism in IPD. The objective is to study the pathological role of native αSyn, 3-NT-αSyn, and 3-NT-proteins in the saliva and submandibulary glands of patients with IPD. Methods. The salivary and serum αSyn and 3-NT-proteins concentration is evaluated with ELISA in patients and controls. Correlations of αSyn and 3-NT-proteins content with clinical features of the disease are examined. Immunohistochemical 3-NT-αSyn expression in submandibulary gland sections is analyzed. Results. (a) Salivary concentration and saliva/serum ratios of native αSyn and 3-NT-proteins are similar in patients and controls; (b) salivary αSyn and 3-NT-proteins do not correlate with any clinical feature; and (c) three patterns of 3-NT-αSyn-positive inclusions are observed on histological sections: rounded "Lewy-type" aggregates of 10-25 µm in diameter, coarse deposits with varied morphology, and spheroid inclusions or bodies of 3-5 µm in diameter. "Lewy-type" and coarse inclusions are observed in the interlobular connective tissue of the gland, and small-sized bodies are located within the cytoplasm of duct cells. "Lewy-type" inclusions are only observed in patients, and the remaining patterns of inclusions are observed in both the patients and controls. Conclusions. The patients' saliva presents a similar concentration of native αSyn and 3-nitrotyrosine-proteins than that of the controls, and no correlations with clinical features are found. These findings preclude the utility of native αSyn in the saliva as a biomarker, and they indicate the absence of nitrative stress in the saliva and serum of patients. As regards nitrated αSyn, "Lewy-type" inclusions expressing 3-NT-αSyn are observed in the patients, not the controls-a novel finding that suggests that a biopsy of the submandibulary gland, if proven safe, could be a useful technique for diagnosing IPD. Finally, to our knowledge, this is also the first description of 3-NT-αSyn-immunoreactive intracytoplasmic bodies in cells that are located outside the nervous system. These intracytoplasmic bodies are present in duct cells of submandibulary gland sections from all subjects regardless of their pathology, and they can represent an aging or involutional change. Further immunostaining studies with different antibodies and larger samples are needed to validate the data.

α-synuclein
saliva
parkinson
nitration
nitrative stress
lewy-type


Enhancement of dissolution rate through eutectic mixture and solid solution of posaconazole and benznidazole.

Abstract: Benznidazole (BNZ), the only commercialized antichagasic drug, and the antifungal compound posaconazole (PCZ) have shown synergistic action in the therapy of Chagas disease, however both active pharmaceutical ingredients (APIs) exhibit low aqueous solubility potentially limiting their bioavailability and therapeutic efficacy. In this paper, we report for the first time the formation of a eutectic mixture as well as an amorphous solid solution of PCZ and BNZ (at the same characteristic ratio of 80:20wt%), which provided enhanced solubility and dissolution rate for both APIs. This eutectic system was characterized by DSC and the melting points obtained were used for the construction of a phase diagram. The preservation of the characteristic PXRD patterns and the IR spectra of the parent APIs, and the visualization of a characteristic eutectic lamellar crystalline microstructure using Confocal Raman Microscopy confirm this system as a true eutectic mixture. The PXRD result also confirms the amorphous nature of the prepared solid solution. Theoretical chemical analyses indicate the predominance of π-stacking interactions in the amorphous solid solution, whereas an electrostatic interaction between the APIs is responsible for maintaining the alternating lamellar crystalline microstructure in the eutectic mixture. Both the eutectic mixture and the amorphous solid solution happen to have a characteristic PCZ to BNZ ratio similar to that of their pharmacological doses for treating Chagas disease, thus providing a unique therapeutic combination dose with enhanced apparent solubility and dissolution rate.

de Medeiros Vieira|Amanda Carla Quintas|ACQ|

Chagas disease
Amorphous solid solution
Eutectic system
Apparent solubility
Acetonitrile (PubChem CID: 6342)
Benznidazole (PubChem CID: 31593)
Ethyl alcohol (PubChem CID: 702)
Posaconazole (PubChem CID: 468595)
Trypanosoma cruzi


Membrane Poration Mechanisms at the Cell-Nanostructure Interface.

Abstract: 3D vertical nanostructures have become one of the most significant methods for interfacing cells and the nanoscale and for accessing significant intracellular functionalities such as membrane potential. As this intracellular access can be induced by means of diverse cellular membrane poration mechanisms, it is important to investigate in detail the cell condition after membrane rupture for assessing the real effects of the poration techniques on the biological environment. Indeed, differences of the membrane dynamics and reshaping have not been observed yet when the membrane-nanostructure system is locally perturbed by, for instance, diverse membrane breakage events. In this work, new insights are provided into the membrane dynamics in case of two different poration approaches, optoacoustic- and electro-poration, both mediated by the same 3D nanostructures. The experimental results offer a detailed overview on the different poration processes in terms of electrical recordings and membrane conformation.

Dipalo|Michele|M|0000-0002-1823-8231
Caprettini|Valeria|V|
Bruno|Giulia|G|
Caliendo|Fabio|F|
Garma|Leonardo D|LD|
Melle|Giovanni|G|
Dukhinova|Marina|M|
Siciliano|Velia|V|
Santoro|Francesca|F|
De Angelis|Francesco|F|

electrophysiology
electroporation
membrane deformation
plasmonic optoporation
scanning electron microscopy


Imagery rescripting and eye movement desensitisation and reprocessing for treatment of adults with childhood trauma-related post-traumatic stress disorder: IREM study design.

Abstract:
BACKGROUND
Post-traumatic stress disorder (PTSD) that originates from childhood trauma experiences can develop into a chronic condition that has lasting effects on an individual's functioning and quality of life. While there are evidence-based guidelines for treating adult onset PTSD, treatments for adults with childhood trauma-related PTSD (Ch-PTSD) are varied and subject to ongoing debate. This study will test the effectiveness of two trauma-focused treatments, imagery rescripting (ImRs) and eye movement desensitisation and reprocessing (EMDR) in participants with Ch-PTSD. Both have been found effective in treatment of adult PTSD or mixed onset PTSD and previous research indicates they are well-tolerated treatments. However, we know less about their effectiveness for treating Ch-PTSD or their underlying working mechanisms.

METHODS
IREM is an international multicentre randomised controlled trial involving seven sites across Australia, Germany and the Netherlands. We aim to recruit 142 participants (minimum of n = 20 per site), who will be randomly assigned to treatment condition. Assessments will be conducted before treatment until 1-year follow-up. Assessments before and after the waitlist will assess change in time only. The primary outcome measure is change in PTSD symptom severity from pre-treatment to 8-weeks post-treatment. Secondary outcome measures include change in severity of depression, anger, trauma-related cognitions, guilt, shame, dissociation and quality of life. Underlying mechanisms of treatment will be assessed on changes in vividness, valence and encapsulated belief of a worst trauma memory. Additional sub-studies will include qualitative investigation of treatment experiences from the participant and therapists' perspective, changes in memory and the impact of treatment fidelity on outcome measures.

DISCUSSION
The primary aims of this study are to compare the effectiveness of EMDR and ImRs in treating Ch-PTSD and to investigate the underlying working mechanisms of the two treatments. The large-scale international design will make a significant contribution to our understanding of how these treatments address the needs of individuals with Ch-PTSD and therefore, potentially improve their effectiveness.

TRIAL REGISTRATION
Australian New Zealand Clinical Trials Registry ACTRN12614000750684 . Registered 16 July 2014.

Boterhoven de Haan|Katrina L|KL|
Lee|Christopher W|CW|
Fassbinder|Eva|E|
Voncken|Marisol J|MJ|
Meewisse|Mariel|M|
Van Es|Saskia M|SM|
Menninga|Simone|S|
Kousemaker|Margriet|M|
Arntz|Arnoud|A|

D057169:Eye Movement Desensitization Reprocessing

Eye movement desensitisation and reprocessing


B-1a B cells regulate T cell differentiation associated with pregnancy disturbances.

Abstract: DURING PREGNANCY, THE MATERNAL IMMUNE SYSTEM FACES A DOUBLE DILEMMA: tolerate the growing semi-allogeneic fetus and at the same time protect the mother and the progeny against pathogens. This requires a fine and extremely regulated equilibrium between immune activation and tolerance. As professional antigen presenting cells, B cells and in particular B-1a B cells, can activate or tolerize T cells and thus participate in the generation or regulation of the immune response. B-1a B cells were involved in the humoral immune response leading to pre-eclampsia, one of the main medical complications during pregnancy. Here we demonstrated that B-1a B cells are additionally involved in cellular immune mechanisms associated with pregnancy complications. Using a mouse model of pregnancy disturbances, we showed that B-1a B cells from animals suffering pregnancy disturbances but not from those developing normal pregnancies induce the differentiation of naïve T cells into Th17 and Th1 cells. This differential role of B-1a B cells during pregnancy seems to be associated with the co-stimulatory molecule CD86 as normal pregnant mice showed lower percentages of CD86 expressing B-1a B cells as compared to pregnant mice developing pregnancy disturbances or to non-pregnant animals. Our data bring to light a new and not explored role of B-1a B cells in the context of pregnancy.

Muzzio|Damián Oscar|DO|
Soldati|Rocío|R|
Rolle|Luise|L|
Zygmunt|Marek|M|
Zenclussen|Ana Claudia|AC|
Jensen|Federico|F|


Solar Radiation as an Isolated Environmental Factor in an Experimental Mesocosm Approach for Studying Photosynthetic Acclimation of Macrocystis pyrifera (Ochrophyta).

Abstract: Solar radiation effects on the ecophysiology and biochemical responses of the brown macroalga Macrocystis pyrifera (L.) C. Agardh were evaluated using a mesocosm approach in Southern Chile. Treatments with different radiation attenuations were simulated with three vertical attenuation coefficients: (1) total (Kd = 0.8 m-1), (2) attenuated (Kd = 1.2 m-1), and (3) low (Kd = 1.6 m-1) radiation levels. Nutrient concentration and temperature did not show differences under the three light conditions. Photosynthetic activity was estimated by in vivo chlorophyll a (Chla) fluorescence under the three light treatments as an isolated physical factor in both in situ solar radiation in the field. This was achieved using a pulse amplitude-modulated (PAM) fluorometera-Diving PAM (in situ). Photosynthetic activity and biochemical composition were measured in winter during two daily cycles (1DC and 2DC) in different parts of the thalli of the plant: (1) canopy zone, (2) middle zone, and (3) down zone, associated with different depths in the mesocosm system. Nevertheless, the in situ electron transport rate (ETR  ) was higher in the exposed thalli of the canopy zone, independent of the light treatment conditions. The concentration of phenolic compounds (PC) increases in the down zone in the first daily cycle, and it was higher in the middle zone in the second daily cycle. The Chla increased in the morning time under total and attenuated radiation in the first daily cycle. Solar radiation increasing at midday prompted the photoinhibition of photosynthesis in the canopy zone but also an increase in productivity and phenol content. Therefore, light attenuation in the water column drove key differences in the photo-physiological responses of M. pyrifera, with the highest productivity occurring in thalli positioned in the canopy zone when exposed to solar irradiance.

Celis-Plá|Paula S M|PSM|
Kappes|José Luis|JL|
Figueroa|Félix L|FL|
Pereda|Sandra V|SV|
Villegas|Karina|K|
Altamirano|Robinson|R|
Hernández-González|María Carmen|MC|
Buschmann|Alejandro H|AH|

mesocosm approach
Macrocystis pyrifera
phenolic compounds
brown algae
dayle cycle experiments
in vivo chlorophyll a fluorescence
photosynthetic pigments


Development and pilot testing of the treatment and education approach for childhood-onset lupus (TEACH): a cognitive behavioral treatment.

Abstract:
BACKGROUND
To develop and test the feasibility and initial effectiveness of the Treatment and Education Approach for Childhood-onset Lupus (TEACH) protocol, a 6-session cognitive behavioral therapy (CBT) intervention for adolescents and young adults (AYA) with childhood-onset systemic lupus erythematosus (cSLE).

METHODS
Females with cSLE (n = 14; ages 13-19 years, M = 16.21 years) presenting to a pediatric rheumatology clinic subsequently completed the protocol, which was iteratively modified based on participant/interventionist feedback. Upon intervention completion, participants provided qualitative data on feasibility, acceptability, potential modifications, and perceived effectiveness of the program via a semi-structured interview, which was analyzed for shared themes. Participants also completed measures of fatigue, psychological distress, and pain intensity before and after the intervention. Nonparametric statistics were conducted to examine changes in outcome measures following the intervention.

RESULTS
During the study, several protocol modifications were employed to better address the unique needs of individuals with cSLE (e.g., separate content for adolescents versus young adults). Results suggest that TEACH is feasible, acceptable, and potentially effective in the management of cSLE symptoms. Following the intervention, there was a statistically significant reduction in fatigue (Z = - 2.81, p < .01) and depressive symptoms (Z = - 2.69, p < .01). Reductions in pain and anxiety symptoms were marginal.

CONCLUSIONS
TEACH, a tailored CBT protocol for AYA with cSLE, is a feasible and potentially effective intervention for the management of fatigue and depressive symptoms. Future directions include testing the protocol in a larger controlled study.

Cunningham|Natoshia R|NR|
Fussner|Lauren M|LM|
Moorman|Erin|E|
Avar Aydin|Pinar O|PO|
Brunner|Hermine I|HI|
Kashikar-Zuck|Susmita|S|

Childhood-onset
Lupus
Cognitive behavioral therapy (CBT)
Fatigue
Pain
Depressive symptoms


Male-specific contributions to the Brazilian population of Espirito Santo.

Abstract: Y chromosome markers have been widely studied due to their various applications in the fields of forensic and evolutionary genetics. In this study, 35 Y-SNPs and 17 Y-STRs were genotyped in 253 males from the State of Espirito Santo, Brazil. A total of 18 haplogroups and 243 haplotypes were detected; the haplogroup and haplotype diversities were 0.7794 and 0.9997, respectively. Genetic distance analysis using the Y-STR data showed no statistically significant differences between Espirito Santo and other admixed populations from Brazil. The classification of paternal lineages based on haplogroups showed a predominant European contribution (85.88%), followed by African (11.37%) and Amerindian (2.75%) contributions.

de F Figueiredo|Raquel|R|
Ambrosio|Isabela B|IB|
Braganholi|Danilo F|DF|
Chemale|Gustavo|G|
Martins|Joyce A|JA|
Gomes|Veronica|V|
Gusmão|Leonor|L|
Cicarelli|Regina M B|RM|

Y chromosome
Brazil
Y-SNP haplogroup
Y-STR haplotype


Lamina propria: The connective tissue of rat urinary bladder mucosa.

Abstract: To describe and illustrate the structure of the propria, the bladder of adult rats was fixed in controlled conditions of distension and examined by light and electron microscopy. The lamina propria, ~50 µm thick in the distended bladder, consists of a superficial part (the cellular component), adjacent to the urothelium, rich in nerves, capillaries, fibroblasts and thin bundles of collagen, and a deep, thicker part (the fibrous component), adjacent to the detrusor, rich in large collagen fibres and with few fibroblasts. In the cellular part there is an extensive plexus of afferent nerve fibers and a dense capillary network (with numerous pericytes), lying close to the urothelium, that is unique to the bladder. The main resident cells are fibroblasts, adhering to each other at the end of laminar extensions without forming specialized junctions. The deep part of the lamina propria is made of thick collagen fibers, interwoven and crisscrossing each other, with a few fibroblasts in the interstitial spaces between them. In summary, the superficial part of the lamina propria has most of the bladder afferent nerves, contains many fibroblasts and has a network of suburothelial capillaries. The deep part as a whole forms an ovoid balloon of woven fibrous material that is acted upon by the detrusor musculature attached to its outer surface. The lamina propria is a strong fibrous barrier between urothelium and musculature. The abundance of collagen points to the main role for its fibroblasts, that is, the production of collagen fibrils, assisting the mechanical role of the lamina propria.

connective tissue
urinary bladder
mucosa
fibroblasts
pericytes
lamina propria (tunica propria)


Prognostic Impact of AJCC/UICC 8th Edition New Staging Rules in Oropharyngeal Squamous Cell Carcinoma.

Abstract:
INTRODUCTION
The purpose of this study was to test whether the 8th edition of the AJCC/UICC TNM staging system (UICC) precisely differentiates between stages and reflects disease outcome in human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC).

PATIENTS AND METHODS
OPSCC patients that were diagnosed between 2000 and 2016 were included in this analysis and HPV status was determined by combined DNA and p16 testing. Stratification was done according to 7th and 8th UICC staging rules. Incidence trends of HPV-associated tumorigenesis, 5-year overall survival (OS) according to tumor stages as well as the influence of therapy and prognostic factors toward the outcome were calculated using Kaplan-Meier method and Cox proportional-hazards model.

RESULTS
A significant increase [2000; n = 8/39 (21%)-2015; n = 17/32 (53%); p = 0.002] in HPV-associated OPSCC was seen in the observation period. Together, 150/599 (25.0%) of the patients had HPV-driven OPSCC and 64.7% of curative treatments in all OPSCC patients included upfront surgery of the primary and the neck. 7th edition staging rules led to no discrimination in all respective four UICC stages in HPV OPSCC underlining the need for new staging rules. However, only discrimination between stages I vs. II and III vs. IV was significant in our patients with HPV-OPSCC (94.4 vs. 77.5%; p = 0.031 and 63.9 vs. 25.0%; p = 0.013), and stages II vs. III did not differ in OS rates (p = 0.257), when applying the new staging rules. For HPV-negative OPSCC, significant outcome differences were only seen between UICC stages III vs. IV (57.6 vs. 35.2%; p = 0.012).

DISCUSSION
While the 7th edition of UICC shows invalid discrimination between stages, the 8th edition is more suitable for HPV-associated carcinoma. Due to lack of differentiation between stages II and III further adaption is essential.

Würdemann|Nora|N|
Wagner|Steffen|S|
Sharma|Shachi Jenny|SJ|
Prigge|Elena-Sophie|ES|
Reuschenbach|Miriam|M|
Gattenlöhner|Stefan|S|
Klussmann|Jens Peter|JP|
Wittekindt|Claus|C|

human papilloma virus
surgery
UICC 7
UICC 8
head and neck cancer
oropharyngeal cancer
prognosis


Is subvalvular repair worthwhile in severe ischemic mitral regurgitation? Subanalysis of the Papillary Muscle Approximation trial.

Abstract:
OBJECTIVE
The symmetry of mitral valve tethering and regional left ventricle wall dysfunction are reported to play a fundamental role in the outcomes and long-term durability of surgical repair in ischemic mitral regurgitation (IMR). We recently demonstrated in a randomized clinical trial (the Papillary Muscle Approximation trial) the superiority of papillary muscle approximation (PMA) in combination with standard restrictive annuloplasty (RA) in severe IMR over annuloplasty alone in terms of adverse left ventricular remodeling and mitral regurgitation (MR) recurrence. This approach, however, failed to produce a survival advantage and was still plagued by a high incidence of reoperation. We therefore performed a subanalysis of the PMA trial on the basis of preoperative parameters to elucidate the value of subvalvular surgery in certain subcategories of patients with the aim of creating a decisional algorithm on the best operative strategy.

METHODS
We performed a subanalysis of PMA trial, evaluating 96 patients with severe IMR and eligible for myocardial revascularization randomized to PMA + RA (n = 48) versus RA alone (n = 48) in association with coronary artery bypass grafting. Endpoints included left ventricular remodeling, MR recurrence, overall mortality, reoperation, and a composite cardiac endpoint (cardiac death, stroke, reintervention, hospitalization for heart failure, or New York Heart Association class worsening). Stratification variables were preoperative symmetry of mitral valve tethering and regional wall motion abnormality.

RESULTS
PMA improved ventricular remodeling and recurrence of MR in both preoperative symmetric and asymmetric tethering and in case of inferior wall dyskinesia but did not produce an additional benefit in anterolateral wall dysfunction.

CONCLUSIONS
Preoperative symmetric and asymmetric tethering and isolated inferior wall dyskinesia are an indication for subvalvular apparatus surgery in IMR.

Nappi|Francesco|F| Spadaccio|Cristiano|C| Nenna|Antonio|A| Lusini|Mario|M| Fraldi|Massimiliano|M| Acar|Christophe|C| Chello|Massimo|M|

ischemic mitral regurgitation
mitral regurgitation
papillary muscle
approximation
annuloplasty
ventricular remodeling


Measurement of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydro-guanosine in cerebrospinal fluid by ultra performance liquid chromatography-tandem mass spectrometry.

Abstract: Increased levels of nucleosides modified by oxidation in human cerebrospinal fluid (CSF) have several times been reported in Alzheimer patients and patients suffering from Parkinson's disease. The focus has especially been on nucleosides containing the 8-hydroxylation of guanine. Only few reports on quantification of the ribonucleoside 8-oxo-7,8-dihydro-guanosine (8oxoGuo) in CSF have been published, whereas more have been published on the quantification of the deoxy-ribonucleoside 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodGuo). The reports on the quantification of 8oxodGuo concentrations in CSF report absolute concentrations varying by a factor >105 in healthy humans. This could indicate that there is a serious specificity problem in some of the methods. In this paper an isotope-dilution UPLC-MS/MS method with high specificity and sensitivity for the quantification of 8oxoGuo and 8oxodGuo in CSF is presented. LLOQ for the two analytes is determined to 4pM and 2pM, respectively. The calibration curves has been tested to be linear in the range from 4 to 3,000pM for 8oxoGuo and between 2 and 3,000pM for 8oxodGuo. Using a weighting factor of 1/x the correlation coefficient "r" for both analytes is >0.999.

Weimann|Allan|A|
Simonsen|Anja Hviid|AH|
Poulsen|Henrik E|HE|

Cerebrospinal fluid
Mass spectrometry
8-Hydroxy-2′-deoxyguanosine
8-Hydroxyguanosine
Liquid chromatography
Oxidative stress


Spatio-temporal patterns in pollination of deceptive Aristolochia rotunda L. (Aristolochiaceae).

Abstract: Pollination success of highly specialised flowers is susceptible to fluctuations of the pollinator fauna. Mediterranean Aristolochia rotunda has deceptive trap flowers exhibiting a highly specialised pollination system. The sole pollinators are kleptoparasitic flies in search of food. This study investigates these pollinators on a spatio-temporal scale and the impact of weather conditions on their availability. Two potential strategies of the plants to cope with pollinator limitation, i.e. autonomous selfing and an increased floral life span, were tested. A total of 6156 flowers were investigated for entrapped pollinators in 10 Croatian populations. Availability of the main pollinator was correlated to meteorological data. Artificial pollination experiments were conducted and the floral life span was recorded in two populations according to pollinator availability. Trachysiphonella ruficeps (Chloropidae) was identified as dominant pollinator, along with less abundant species of Chloropidae, Ceratopogonidae and Milichiidae. Pollinator compositions varied among populations. Weather conditions 15-30 days before pollination had a significant effect on availability of the main pollinator. Flowers were not autonomously selfing, and the floral life span exhibited considerable plasticity depending on pollinator availability. A. rotunda flowers rely on insect pollen vectors. Plants are specialised on a guild of kleptoparasitic flies, rather than on a single species. Pollinator variability may result in differing selection pressures among populations. The availability/abundance of pollinators depends on weather conditions during their larval development. Flowers show a prolonged trapping flower stage that likely increases outcrossing success during periods of pollinator limitation.

Oelschlägel|B|B|
von Tschirnhaus|M|M|
Nuss|M|M|
Nikolić|T|T|
Wanke|S|S|
Dötterl|S|S|
Neinhuis|C|C|

Aristolochia rotunda
floral life span
Chloropidae
pollinator variability
autogamy
deceptive pollination
flower biology


Risk factors of kyphosis recurrence after implant removal in thoracolumbar burst fractures following posterior short-segment fixation.

Abstract:
PURPOSE
Our aim was to evaluate the results of short-segment pedicle instrumentation with screw insertion in the fracture level and find factors predicting kyphosis recurrence in thoracolumbar burst fractures.

METHODS
We retrospectively analysed 122 patients with thoracolumbar burst fracture who were divided into two groups: kyphosis recurrence and no kyphosis recurrence. Pre-operative radiographic data comprising Cobb angle (CA), regional angle, anterior vertebra height (AVH), upper intervertebral angle, vertebral wedge angle (VWA), pre-anteroposterior A/P approach, superior endplate fracture, load-sharing classification (LSC) score and clinical data including age, visual analogue scale (VAS) score, thoracolumbar injury classification and severity score were compared between groups. T test, Pearson's chi-square and multivariate logistic regression were calculated for variables.

RESULTS
CA, VWA and AVH were significantly corrected after surgery. CA changed from 23.7 to 3.0 (p <0.001), VWA from 38.7 to 9.6 (p <0.001) and AVH from 48.8 % to 91.2 % (p <0.001). These parameters were well maintained during the follow-up period with a mild, tolerant loss of correction. Neurological function and pain were significantly improved without deterioration. Age, pre-A/P and pre-AVH < 50 % influenced kyphosis recurrence (p = 0.032, 0.026, 0.011, respectively).

CONCLUSIONS
Short-segment pedicle instrumentation including the fractured vertebra was effective in treating thoracolumbar burst fractures. The loss of correction at follow-up after implant removal was associated with age, A/P ratio and anterior vertebral height < 50 %.

Chen|Jiao-Xiang|JX| Xu|Dao-Liang|DL| Sheng|Sun-Ren|SR| Goswami|Amit|A| Xuan|Jun|J| Jin|Hai-Ming|HM| Chen|Jian|J| Chen|Yu|Y| Zheng|Zeng-Ming|ZM| Chen|Xi-Bang|XB| Wang|Xiang-Yang|XY|

Kyphosi recurrence
Thoracolumbar burst fracture
Anterior vertebra height
Short- segment pedicle instrumentation


Clinically significant traumatic intracranial hemorrhage following minor head trauma in older adults: a retrospective cohort study.

Abstract:
OBJECTIVES
The primary objective of this study was to determine the incidence of clinically significant traumatic intracranial hemorrhage (T-ICH) following minor head trauma in older adults. Secondary objective was to investigate the impact of anticoagulant and antiplatelet therapies on T-ICH incidence.

METHODS
This retrospective cohort study extracted data from electronic patient records. The cohort consisted of patients presenting after a fall and/or head injury and presented to one of five ED between 1st March 2010 and 31st July 2017. Inclusion criteria were age ≥ 65 years old and a minor head trauma defined as an impact to the head without fulfilling criteria for traumatic brain injury.

RESULTS
From the 1,000 electronic medical records evaluated, 311 cases were included. The mean age was 80.1 (SD 7.9) years. One hundred and eighty-nine (189) patients (60.8%) were on an anticoagulant (n = 69), antiplatelet (n = 130) or both (n = 16). Twenty patients (6.4%) developed a clinically significant T-ICH. Anticoagulation and/or antiplatelets therapies were not associated with an increased risk of clinically significant T-ICH in this cohort (Odds ratio (OR) 2.7, 95% CI 0.9-8.3).

CONCLUSIONS
In this cohort of older adults presenting to the ED following minor head trauma, the incidence of clinically significant T-ICH was 6.4%.

O'Brien|Toby|T|
Mitra|Biswadev|B|
Le Sage|Natalie|N|
Tardif|Pier-Alexandre|PA|
Emond|Marcel|M|
D'Astous|Myreille|M|
Mercier|Eric|E|

intracranial hemorrhage
Trauma
anticoagulant
Falls
head Injury
traumatic brain injury
anti-platelet
computed tomography


Prognostic Factors for Cognitive Decline After Intracerebral Hemorrhage.

Abstract:
BACKGROUND AND PURPOSE
Stroke and dementia are closely related, but no prospective study ever focused on poststroke cognitive decline in patients with intracerebral hemorrhage (ICH). We aimed to determine prognostic factors for cognitive decline in patients with ICH.

METHODS
We prospectively included 167 consecutive ICH survivors without preexisting dementia from the Prognosis of Intra-Cerebral Hemorrhage (PITCH) cohort. Median follow-up was 4 years (interquartile range, 2.3-5.4). We explored factors associated with cognitive decline using linear mixed models. Cognitive decline was determined based on repeated mini-mental state examination. We investigated each prognostic factor separately in univariate models. Next, we constructed clinical and radiological multivariable models. In a sensitivity analysis, we excluded patients with preexisting cognitive impairment.

RESULTS
Median age was 64 (interquartile range, 53-75) years, 69 (41%) patients were women, and median mini-mental state examination at 6 months was 27 (interquartile range, 23-29). Overall, 37% of the patients declined during follow-up. Factors associated with cognitive decline in univariate analyses were previous stroke or transient ischemic attack, preexisting cognitive impairment, microbleed presence, severity of white matter hyperintensities, and severity of cortical atrophy. In multivariable analyses, previous stroke or transient ischemic attack (β [SE], -0.55 [0.23]; P<0.05), preexisting cognitive impairment (β [SE], -0.56 [0.25]; P<0.01), and severity of cortical atrophy (β [SE], -0.50 [0.19]; P<0.01) remained independent prognostic factors. In patients without preexisting cognitive impairment (n=139), severity of cortical atrophy (β [SE], -0.38 [0.17]; P<0.05) was the only prognostic factor for future cognitive decline.

CONCLUSIONS
Prognostic factors for cognitive decline after ICH are already present when ICH occurs, suggesting a process of ongoing cognitive impairment instead of new-onset decline induced by the ICH itself.

Benedictus|Marije R|MR|
Hochart|Anaïs|A|
Rossi|Costanza|C|
Boulouis|Gregoire|G|
Hénon|Hilde|H|
van der Flier|Wiesje M|WM|
Cordonnier|Charlotte|C|

stroke
dementia
cerebral hemorrhage
ischemic attack, transient
mild cognitive impairment


Stabilizing l1-norm prediction models by supervised feature grouping.

Abstract: Emerging Electronic Medical Records (EMRs) have reformed the modern healthcare. These records have great potential to be used for building clinical prediction models. However, a problem in using them is their high dimensionality. Since a lot of information may not be relevant for prediction, the underlying complexity of the prediction models may not be high. A popular way to deal with this problem is to employ feature selection. Lasso and l1-norm based feature selection methods have shown promising results. But, in presence of correlated features, these methods select features that change considerably with small changes in data. This prevents clinicians to obtain a stable feature set, which is crucial for clinical decision making. Grouping correlated variables together can improve the stability of feature selection, however, such grouping is usually not known and needs to be estimated for optimal performance. Addressing this problem, we propose a new model that can simultaneously learn the grouping of correlated features and perform stable feature selection. We formulate the model as a constrained optimization problem and provide an efficient solution with guaranteed convergence. Our experiments with both synthetic and real-world datasets show that the proposed model is significantly more stable than Lasso and many existing state-of-the-art shrinkage and classification methods. We further show that in terms of prediction performance, the proposed method consistently outperforms Lasso and other baselines. Our model can be used for selecting stable risk factors for a variety of healthcare problems, so it can assist clinicians toward accurate decision making.

Kamkar|Iman|I|
Gupta|Sunil Kumar|SK|
Phung|Dinh|D|
Venkatesh|Svetha|S|

D057286:Electronic Health Records
D006801:Humans
D008490:Medical Informatics
D015233:Models, Statistical
D000069553:Supervised Machine Learning

Stability
Supervised feature grouping
Feature selection
Lasso


The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits.

Abstract:
AIMS
The present study was aim to explore aging-dependent changes in hippocampal autophagy and apoptosis in a natural aging rat model from adult to old stages and to discover a suitable age for treating neurodegenerative diseases.

METHODS
Wistar rats at 5, 18 and 24months of age were used to mimic the adulthood, initial old, and old phases, respectively. The learning and cognitive ability of the rats was detected by the Morris water maze test. Morphological changes in the hippocampus were observed. Expressions of apoptosis and autophagy-related proteins were examined by Western blot.

RESULTS
The adult group (5months) exhibited high levels of autophagy related p-ULK p-ULK-1/ULK-1 ratio, Beclin-1, LC3II and cell survival, maintaining normal learning and cognitive function and integrated hippocampal morphology. The initial old group (18 months) presented a reduced number of neurons and cognitive deficits, and exhibited high levels of apoptosis related Bax/Bcl-2 ratio, Caspase-3 activation and autophagy related p-ULK p-ULK-1/ULK-1 ratio, Beclin-1, LC3II compared to the adult group. The old group (24 months) exhibited a high level of apoptosis related Bax/Bcl-2 ratio, Caspase-3 activation and a low level of autophagy related p-ULK p-ULK-1/ULK-1 ratio, Beclin-1, LC3II compared to its younger group, as well as significant neuronal death and cognitive deficits. The degree of autophagy was generally consistent with its negative regulator, the PI3K/Akt/mTOR axis, in all groups.

CONCLUSION
Our data suggest that cognitive deficits are first observed in the initial old stage. The levels of autophagy and apoptosis tend to be opposite in the adult and old phases. High levels of autophagy and apoptosis coexist in the initial old stage. Our study indicates that up-regulation of autophagy in the initial old phase to anti-cognitive deficits must be further evaluated.

Yu|Yang|Y| Feng|Linjing|L| Li|Junnan|J| Lan|Xiaoxin|X| A|Lixiang|L| Lv|Xiaoyan|X| Zhang|Ming|M| Chen|Li|L|

Autophagy
Apoptosis
Aging
mTOR
Learning and memory decline


Discovery of Age-Related Protein Folding Stability Differences in the Mouse Brain Proteome.

Abstract: Described here is the application of thermodynamic stability measurements to study age-related differences in the folding and stability of proteins in a rodent model of aging. Thermodynamic stability profiles were generated for 809 proteins in brain cell lysates from mice, aged 6 (n = 7) and 18 months (n = 9) using the Stability of Proteins from Rates of Oxidation (SPROX) technique. The biological variability of the protein stability measurements was low and within the experimental error of SPROX. A total of 83 protein hits were detected with age-related stability differences in the brain samples. Remarkably, the large majority of the brain protein hits were destabilized in the old mice, and the hits were enriched in proteins that have slow turnover rates (p < 0.07). Furthermore, 70% of the hits have been previously linked to aging or age-related diseases. These results help validate the use of thermodynamic stability measurements to capture relevant age-related proteomic changes and establish a new biophysical link between these proteins and aging.

Roberts|Julia H|JH|
Liu|Fang|F|
Karnuta|Jaret M|JM|
Fitzgerald|Michael C|MC|

proteomics
aging
SPROX
chemical denaturation
iTRAQ
mass spectrometry


On pattern matching with k mismatches and few don't cares.

Abstract: We consider the problem of pattern matching with k mismatches, where there can be don't care or wild card characters in the pattern. Specifically, given a pattern P of length m and a text T of length n, we want to find all occurrences of P in T that have no more than k mismatches. The pattern can have don't care characters, which match any character. Without don't cares, the best known algorithm for pattern matching with k mismatches has a runtime of [Formula: see text]. With don't cares in the pattern, the best deterministic algorithm has a runtime of O(nk polylog m). Therefore, there is an important gap between the versions with and without don't cares. In this paper we give an algorithm whose runtime increases with the number of don't cares. We define an island to be a maximal length substring of P that does not contain don't cares. Let q be the number of islands in P. We present an algorithm that runs in [Formula: see text] time. If the number of islands q is O(k) this runtime becomes [Formula: see text], which essentially matches the best known runtime for pattern matching with k mismatches without don't cares. If the number of islands q is O(k2), this algorithm is asymptotically faster than the previous best algorithm for pattern matching with k mismatches with don't cares in the pattern.

k mismatches with don’t cares in the pattern

pattern matching with k mismatches and don’t cares


Initial treatment seeking from professional health care providers for eating disorders: A review and synthesis of potential barriers to and facilitators of "first contact".

Abstract: The objective of this study is to provide a comprehensive review of empirical research exploring barriers to and facilitators of initial treatment seeking ("first contact") from professional health care providers by adults and young adults with eating disorders (EDs). A search of databases PsycINFO and MEDLINE using the terms "treatment" and "eating disorder*" yielded 9,468 peer-reviewed articles published from January 1945 to June 2016. Screening identified 31 articles meeting the following criteria: (1) participants were 16 or older and presented with a self-reported or clinically diagnosed ED; (2) studies focused on (a) initial treatment seeking (b) for an ED (c) from professional health care providers; (3) articles were empirical, and (4) peer reviewed. Quantitative studies revealed few consistent correlates of treatment seeking, perhaps because most variables were examined in only one or two investigations. Variables with some degree of predictive utility (i.e., produced significant results in multiple studies) were age (older), ethnicity (nonethnic minority), ED type (anorexia, purging BN), specific ED-related behaviors (i.e., purging), and time spent on a treatment waitlist following referral (less). Although BMI was one of the most investigated variables, it did not predict treatment seeking. Qualitative studies revealed the following perceived barriers: (1) personal feelings of shame/fear, (2) ED-related beliefs/perceptions, (3) lack of access/availability, and (4) aspects of the treatment process. Perceived facilitators included (1) health-related concerns, (2) emotional distress, and (3) social support. Implications for clinical practice and areas for further research are discussed. Results highlight the need for shared definitions and methodologies across studies of treatment seeking.

Regan|Pamela|P|
Cachelin|Fary M|FM|0000-0001-8902-2262
Minnick|Alyssa M|AM|

D010342:Patient Acceptance of Health Care

treatment seeking
eating disorders
review
barriers
health service utilization


Molecular Biology and Evolution of Cancer: From Discovery to Action.

Abstract: Cancer progression is an evolutionary process. During this process, evolving cancer cell populations encounter restrictive ecological niches within the body, such as the primary tumor, circulatory system, and diverse metastatic sites. Efforts to prevent or delay cancer evolution-and progression-require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform cancer biology in new and meaningful ways. We also highlight current challenges to applying these concepts, and propose ways in which incorporating these concepts could identify new therapeutic modes and vulnerabilities in cancer.

Somarelli|Jason A|JA|
Gardner|Heather|H|
Cannataro|Vincent L|VL|
Gunady|Ella F|EF|
Boddy|Amy M|AM|
Johnson|Norman A|NA|
Fisk|Jeffrey Nicholas|JN|
Gaffney|Stephen G|SG|
Chuang|Jeffrey H|JH|
Li|Sheng|S|
Ciccarelli|Francesca D|FD|
Panchenko|Anna R|AR|
Megquier|Kate|K|
Kumar|Sudhir|S|
Dornburg|Alex|A|
DeGregori|James|J|
Townsend|Jeffrey P|JP|

cancer
comparative oncology
fitness landscapes
genomics
metastasis
tumor phylogenetics


Palliative care is not associated with decreased intensity of care: Results of a chart review from a large children's hospital.

Abstract:
BACKGROUND
Palliative care is an important component of pediatric oncology care, especially for children who will not be cured of their disease. However, barriers remain to integration of this service. One barrier is the perception that it indicates "giving up." This study examined if palliative care involvement was associated with a decreased intensity of care at the end of life for children with malignancy at a large academic center with a well-established palliative care program.

PROCEDURE
This is a retrospective chart review that measured intensity of care as the number of emergency department visits, hospital days, and intensive care unit days in the last one and three months of life. The data were compared for patients with and without palliative care involvement and with and without hospice involvement.

RESULTS
Palliative involvement was not associated with a decrease in the intensity of care in the last three months of life. Hospice care was associated with a decreased intensity of care. These results held true in analyses adjusted for age at death, gender, and type of malignancy.

CONCLUSIONS
These data can reassure patients, families, and providers that palliative involvement does not necessitate decreased intensity of care. Patients and families often choose hospice care to decrease the amount of time spent at the hospital and it was associated with meeting that goal.

palliative care
oncology
hospice
treatment intensity


Modernizing Perinatal Substance Use Management.

Abstract: The increase in prescription and illicit opioid use since 2000 has become an urgent public health crisis. While the opioid epidemic spans racial, regional, and socioeconomic divides, women have surfaced as one demographic affected by opioid use and related sequelae. Certain federal and state regulations, secondary to the Child Abuse Prevention and Treatment Act, strip pregnant women with opioid use disorders of the ability to engage autonomously with their health care clinician while simultaneously impeding their ability to achieve and sustain recovery. The purpose of this article is to explore current health policy that impacts pregnant women who use opioids. Recommendations to improve care, broadly, will be highlighted to include access to contraceptive services, universal screening for perinatal substance use, and access to appropriate treatment strategies. Policy modifications to facilitate these recommendations are discussed. The Centers for Disease Control and Prevention Policy Analytical Framework was utilized to derive recommendations. The recommendations are relevant to advanced practice registered nurses and midwives who have the potential to treat substance use in women, to women's health and pediatric registered nurses, and to nursing administrators who are involved in decision-making in obstetric and pediatric settings.

public health
pregnant women
opioid-related disorders


The evaluation and management of patients with LDL-C ≥ 190 mg/dL in a large health care system.

Abstract:
Objectives
Patients with severe hyperlipidemia (low-density lipoprotein-cholesterol (LDL-C) ≥190 mg/dL) have a significantly increased risk of cardiovascular disease (CVD) and are more likely to have familial hypercholesterolemia (FH). We sought to determine how often health care providers recognize the implications of and adjust therapy for an LDL-C ≥190 mg/dL.

Methods
We conducted a retrospective review of patients with an LDL-C measurement in the medical record of a large health care system between November 2015 and June 2016. Patients were restricted to those with LDL-C ≥190 mg/dL and without secondary causes of dyslipidemia, with sensitivity analyses for those with LDL-C ≥220 mg/dL.

Results
Of 27,963 patients, 227 had LDL-C ≥190 mg/dL. Only 21% were on a statin at the time of LDL-C measurement. More than 90% had a follow-up clinic visit, but 41% had no change in treatment. FH was only included in the differential for 14%. The presence/absence of a family history of dyslipidemia, myocardial infarction, and premature CVD were documented in 26%, 29%, and 31%. Only 20.7% and 22.1% had documentation of the presence or absence of tendinous xanthomas or corneal arcus, respectively. Among those without prior specialist care (cardiologist or endocrinologist), only 13% were referred. These measures were only slightly better for those with LDL-C ≥220 mg/dL.

Conclusion
In a large health care system, the possibility of FH was rarely acknowledged in those with residual LDL-C ≥190 mg/dL, few were referred to specialists, and therapeutic adjustments were suboptimal. Additional efforts are required to understand barriers to improving the evaluation and management of patients with LDL-C ≥190 mg/dL.

Jackson|Candace L|CL|
Ahmad|Zahid|Z|
Das|Sandeep R|SR|
Khera|Amit|A|

Hyperlipidemia
Familial hypercholesterolemia
Prevention