Early immune stimulation and childhood acute lymphoblastic leukemia in Costa Rica: A comparison of statistical approaches.

Abstract:
BACKGROUND
Although epidemiologic studies suggest that early immune stimulation is protective against childhood leukemia, evidence for this relationship is equivocal for Hispanic children, who are disproportionately affected by this disease. The complex biological processes underlying immune stimulation and leukemogenesis may benefit from novel statistical approaches that account for mixed exposures and their nonlinear interactions. In this study, we utilized targeted machine learning and traditional statistical methods to investigate the association of multiple measures of early immune stimulation with acute lymphoblastic leukemia (ALL) in Costa Rican children.

MATERIALS AND METHODS
We used data from a population-based case-control study conducted in Costa Rica (2001-2003). Cases of ALL (n = 240) were diagnosed in 1995-2000 (age >1 year and <15 years at diagnosis) and were identified through the National Cancer Registry and National Children's Hospital. Population controls (n = 578) were frequency-matched to cases by birth year and drawn from the National Birth Registry. Data on surrogate measures of early immune stimulation were collected through in-home interviews. We fitted multivariable models, utilizing targeted causal inference (varimpact), unconditional logistic regression, and latent class analysis (LCA).

RESULTS
In varimpact analysis, contact with any pet [risk difference (RD) = -0.17, 95% CI: -0.25, -0.10)] or any farm animal (RD = -0.07, 95% CI: -0.13, 0.00) and allergies (RD = -0.08, 95% CI: -0.17, 0.01) were associated with a reduced risk of ALL, whereas experiencing a fever longer than one week was associated with an increased risk (RD = 0.23, 95% CI: 0.12, 0.33). In unconditional logistic regression models, contact with any pet or farm animal and a complete vaccination scheme were inversely associated with odds of ALL (OR = 0.44, 95% CI: 0.31, 0.62; OR = 0.66, 95% CI: 0.49, 0.90; OR = 0.45, 95% CI: 0.24, 0.83; respectively), whereas experiencing a fever longer than one week was positively associated with ALL (OR = 2.44, 95% CI: 1.61, 3.70). Two-class and three-class LCA revealed a group with elevated risk for ALL whose exposure profile was mainly characterized by reduced exposure to pets and farm animals.

CONCLUSIONS
Using distinct statistical approaches, we observed that exposure to pets and farm animals was inversely associated with ALL risk, whereas having a fever longer than one week (a putative proxy of severe infection) was associated with an increased risk. For multifactorial diseases such as childhood leukemia, we recommend estimating the joint effects of multiple exposures by applying diverse statistical methods and interpreting their results together. Overall, we found support for the hypothesis that early immune stimulation offers protection against childhood ALL.

Figueroa|Sophia Colombari|SC|
Kennedy|Chris J|CJ|
Wesseling|Catharina|C|
Wiemels|Joseph M|JM|
Morimoto|Libby|L|
Mora|Ana M|AM|

D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma

Early immune stimulation
Acute lymphoblastic leukemia
Costa Rica
Hispanic children
Machine learning
Childhood cancer


Blood pressure lowering medication initiation and fracture risk: a SWAN pharmacoepidemiology study.

Abstract:
We examined the fracture risk after initiation of blood pressure-lowering drugs compared with initiation of antidepressants. Multivariable regression models demonstrated an increased risk of fracture among women initiating a blood pressure-lowering medication (HR 1.73, 95% CI 1.02-2.95). This is likely related to an increased risk of falls.

PURPOSE
Initiation of blood pressure-lowering drugs has been associated with fractures in several studies, presumably due to an increase in the risk of falls. However, these studies used self-controlled designs without active comparators. We examined the risk of fractures after initiation of blood pressure lowering drugs compared with initiation of antidepressants.

METHODS
Women participants in the Study of Women Across the Nation (SWAN) were potentially eligible if they initiated blood pressure-lowering or antidepressant drugs during follow-up. To reduce the risk of confounding, we estimated a propensity score that included potential confounders including age, menopausal status, osteoporosis, and osteoporosis medication use. The propensity score was used to match subjects in both groups and we then constructed multivariable logistic regression models comparing the risk of any fracture. Sensitivity analyses assessed a limited range of fractures less likely related to trauma.

RESULTS
Among the 3302 potentially eligible women participating in the SWAN cohort, we were able to propensity-score match 289 women who initiated a blood pressure-lowering medication with 289 who initiated an antidepressant. Multivariable logistic regression models demonstrated an increased risk of fracture among women initiating a blood pressure lowering medication (OR 1.74, 95% CI 1.02-2.95). After excluding fractures of the digits and face, the results were similar (OR 1.57, 95% CI 0.88-2.81).

CONCLUSIONS
There was evidence of an increased risk in fractures among women initiating blood pressure-lowering medications compared to those initiating antidepressants. This is likely related to an increased risk of falling.

Solomon|Daniel H|DH|
Ruppert|Kristine|K|
Kazlauskaite|Rasa|R|
Finkelstein|Joel S|JS|
Habel|Laurel A|LA|

D000058:Accidental Falls
D000928:Antidepressive Agents
D000959:Antihypertensive Agents
D001794:Blood Pressure
D015331:Cohort Studies
D005260:Female
D050723:Fractures, Bone
D006801:Humans
D016015:Logistic Models
D008875:Middle Aged
D010024:Osteoporosis
D017891:Pharmacoepidemiology
D057216:Propensity Score
D018570:Risk Assessment
D012307:Risk Factors
D014481:United States

Fractures
Antihypertensive drugs
Epidemiology


Disease course of lung oligometastatic colorectal cancer treated with stereotactic body radiotherapy.

Abstract:
PURPOSE
Stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) has been shown to increase survival rates in oligometastatic disease (OMD), but local control of colorectal metastases remains poor. We aimed to explore the natural course of oligometastatic colorectal cancer and to investigate how SBRT of lung metastases can delay the progression to polymetastatic disease (PMD).

METHODS
107 lung oligometastases in 38 patients were treated with SBRT at a single institution. The median number of treated lesions was 2 (range 1-5). Time to PMD (ttPMD) was defined as the time from SBRT to the occurrence of >5 new metastases. Genetic biomarkers such as EGFR, KRAS, NRAS, BRAF, and microsatellite instability were investigated as predictive factors for response rates.

RESULTS
Median follow-up was 28 months. At median follow-up, 7 patients were free from disease and 31 had progression: 18 patients had sequential oligometastatic disease (SOMD) and 13 polymetastatic progression. All SOMD cases received a second SBRT course. Median progression-free survival (PFS) was 7 months (range 4-9 months); median ttPMD was 25.8 months (range 12-39 months) with 1‑ and 2‑year PFS rates of 62.5% and 53.4%, respectively. 1‑ and 2‑year local PFS (LPFS) rates were 91.5% and 80%, respectively. At univariate analysis, BRAF wildtype correlated with better LPFS (p = 0.003), SOMD after primary SBRT was associated with longer cancer-specific survival (p = 0.031). Median overall survival (OS) was 39.5 months (range 26-64 months) and 2‑year OS was 71.1%.

CONCLUSION
The present results support local ablative treatment of lung metastases using SBRT in oligometastatic colorectal cancer patients, as it can delay the transition to PMD. Patients who progressed as SOMD maintained a survival advantage compared to those who developed PMD.

D000368:Aged
D000369:Aged, 80 and over
D015179:Colorectal Neoplasms
D018450:Disease Progression
D005260:Female
D005500:Follow-Up Studies
D006801:Humans
D053208:Kaplan-Meier Estimate
D008175:Lung Neoplasms
D008297:Male
D008875:Middle Aged
D000077982:Progression-Free Survival
D016634:Radiosurgery
D012189:Retrospective Studies
D016896:Treatment Outcome

Stereotactic ablative radiotherapy
SABR
Polymetastatic disease
Gastrointestinal cancer
Metatases directed therapy


The challenging interplay between rheumatoid arthritis, ageing and comorbidities.

Abstract:
BACKGROUND
The incidence of rheumatoid arthritis (RA) is expected to increase over the next 10 years in the European Union because of the increasing proportion of elderly people. As both RA and ageing are associated with emerging comorbidities such as cardiovascular disease, malignancies and osteoporosis, these factors will have a profound effect on the management of RA. In addition, both increasing age and comorbidities may independently alter commonly used RA-specific outcome measures.

DISCUSSION
Age-related decline in immune cell functions (immunosenescence), such as a decrease in T-cell function, may contribute to the development of RA, as well as comorbidity. The chronic immune stimulation that occurs in RA may also lead to premature ageing and comorbidity. The interplay between RA, ageing and (emerging) comorbidities is interesting but complex. Cardiovascular disease, lung disease, malignancies, bone and muscle wasting and neuropsychiatric disease all occur more frequently in RA patients as compared to the general population. It is unclear how RA should be managed in 'today's world of multiple comorbidities'. Evidence that treatment of RA improves comorbidities is currently lacking, although some promising indirect observations are available. On the other hand, there is limited evidence that medication regularly prescribed for comorbidities, such as statins, might improve RA disease activity. Both ageing and comorbidity have an independent effect on commonly used outcome measures in the RA field, such as the Health Assessment Questionnaire (HAQ) and the clinical disease activity index (CDAI). Prospective studies, that also account for the presence of comorbidity in (elderly) RA patients are therefore urgently needed. To address gaps in knowledge, future research should focus on the complex interdependencies between RA, ageing and comorbidity. In addition, these findings should be integrated into daily clinical practice by developing and testing integrated and coordinated health care services. Adaptation of management recommendations is likely required. The elderly RA patient who also deals with (emerging) comorbidities presents a unique challenge to treating clinicians. A paradigm shift from disease-centered to goal-oriented approach is needed to develop adequate health care services for these patients.

Rheumatoid arthritis
Ageing
Comorbidity
Elderly
Multimorbidity


Ovarian cavity fluid of the viviparous surfperch Neoditrema ransonnetii suppresses the spontaneous cytotoxic activity of head-kidney leucocytes against xenogeneic targets.

Abstract: In this study, the effect of ovarian cavity fluid (OCF) from a surfperch Neoditrema ransonnetii on the cytotoxic activity of leucocytes was investigated. In an assay targeting RTG-2, a cell line derived from rainbow trout Oncorhynchus mykiss gonads, leucocytes from both the spleen and head kidney showed spontaneous killing activity. Pre-incubation with OCF significantly suppressed the cytotoxic activity of head-kidney leucocytes towards RTG-2. This suppressive activity was due to the presence of low molecular-mass materials. These results suggest that OCF plays significant roles in pregnancy by its ability to modulate cytotoxicity with maternal leucocytes.

Yokozawa|N|N| Nakamura|O|O| Saito|E|E| Tsutsui|S|S|

viviparity cytotoxicity RTG-2 immunosuppression okitango


Emergency department blood alcohol level associates with injury factors and six-month outcome after uncomplicated mild traumatic brain injury.

Abstract: The relationship between blood alcohol level (BAL) and mild traumatic brain injury (mTBI) remains in need of improved characterization. Adult patients suffering mTBI without intracranial pathology on computed tomography (CT) from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot study with emergency department (ED) Glasgow Coma Scale (GCS) 13-15 and recorded blood alcohol level (BAL) were extracted. BAL≥80-mg/dl was set as proxy for excessive use. Multivariable regression was performed for patients with six-month Glasgow Outcome Scale-Extended (GOSE; functional recovery) and Wechsler Adult Intelligence Scale Processing Speed Index Composite Score (WAIS-PSI; nonverbal processing speed), using BAL≥80-mg/dl and <80-mg/dl cohorts, adjusting for demographic/injury factors. Overall, 107 patients were aged 42.7±16.8-years, 67.3%-male, and 80.4%-Caucasian; 65.4% had BAL=0-mg/dl, 4.6% BAL<80-mg/dl, and 30.0% BAL≥80-mg/dl (range 100-440-mg/dl). BAL differed across loss of consciousness (LOC; none: median 0-mg/dl [interquartile range (IQR) 0-0], <30-min: 0-mg/dl [0-43], ≥30-min: 224-mg/dl [50-269], unknown: 108-mg/dl [0-232]; p=0.002). GCS<15 associated with higher BAL (19-mg/dl [0-204] vs. 0-mg/dl [0-20]; p=0.013). On univariate analysis, BAL≥80-mg/dl associated with less-than-full functional recovery (GOSE≤7; 38.1% vs. 11.5%; p=0.025) and lower WAIS-PSI (92.4±12.7, 30th-percentile vs. 105.1±11.7, 63rd-percentile; p<0.001). On multivariable regression BAL≥80-mg/dl demonstrated an odds ratio of 8.05 (95% CI [1.35-47.92]; p=0.022) for GOSE≤7 and an adjusted mean decrease of 8.88-points (95% CI [0.67-17.09]; p=0.035) on WAIS-PSI. Day-of-injury BAL>80-mg/dl after uncomplicated mTBI was associated with decreased GCS score and prolongation of reported LOC. BAL may be a biomarker for impaired return to baseline function and decreased nonverbal processing speed at six-months postinjury. Future confirmatory studies are needed.

Yue|John K|JK|
Ngwenya|Laura B|LB|
Upadhyayula|Pavan S|PS|
Deng|Hansen|H|
Winkler|Ethan A|EA|
Burke|John F|JF|
Lee|Young M|YM|
Robinson|Caitlin K|CK|
Ferguson|Adam R|AR|
Lingsma|Hester F|HF|
Cnossen|Maryse C|MC|
Pirracchio|Romain|R|
Korley|Frederick K|FK|
Vassar|Mary J|MJ|
Yuh|Esther L|EL|
Mukherjee|Pratik|P|
Gordon|Wayne A|WA|
Valadka|Alex B|AB|
Okonkwo|David O|DO|
Manley|Geoffrey T|GT|
|||

D000328:Adult
D000067401:Blood Alcohol Content
D000070642:Brain Injuries, Traumatic
D004636:Emergency Service, Hospital
D005260:Female
D015600:Glasgow Coma Scale
D023261:Glasgow Outcome Scale
D006801:Humans
D008297:Male
D008875:Middle Aged
D010865:Pilot Projects
D011446:Prospective Studies
D020127:Recovery of Function
D014057:Tomography, X-Ray Computed
D014474:Unconsciousness
D014888:Wechsler Scales

Blood alcohol level
Injury factors
Mild traumatic brain injury
Nonverbal processing speed
Functional outcome


E-cigarettes in ENT: what do we need to know?

Abstract:
BACKGROUND
E-cigarette use in the UK is increasing and we are commonly encountering patients in the ENT clinic who are e-cigarette smokers. Currently, there is no regulatory body or licensing for e-cigarettes. This means that the contents, and therefore potential carcinogenic and toxic risks, can vary greatly from product to product. Patients are starting to ask about the risks of e-cigarettes and their use in smoking cessation.

OBJECTIVES
This review aimed to examine the regulations, trends, and carcinogenic and health risks of e-cigarettes, and summarise the evidence for their use in smoking cessation. It also aimed to provide a general awareness regarding the advice and information that can be safely given to patients.

D066300:Electronic Nicotine Delivery Systems

Carcinogens
Smoking Cessation
Electronic Cigarettes
Nicotine


Cortisol and politics: variance in voting behavior is predicted by baseline cortisol levels.

Abstract: Participation in electoral politics is affected by a host of social and demographics variables, but there is growing evidence that biological predispositions may also play a role in behavior related to political involvement. We examined the role of individual variation in hypothalamic-pituitary-adrenal (HPA) stress axis parameters in explaining differences in self-reported and actual participation in political activities. Self-reported political activity, religious participation, and verified voting activity in U.S. national elections were collected from 105 participants, who were subsequently exposed to a standardized (nonpolitical) psychosocial stressor. We demonstrated that lower baseline salivary cortisol in the late afternoon was significantly associated with increased actual voting frequency in six national elections, but not with self-reported non-voting political activity. Baseline cortisol predicted significant variation in voting behavior above and beyond variation accounted for by traditional demographic variables (particularly age of participant in our sample). Participation in religious activity was weakly (and negatively) associated with baseline cortisol. Our results suggest that HPA-mediated characteristics of social, cognitive, and emotional processes may exert an influence on a trait as complex as voting behavior, and that cortisol is a better predictor of actual voting behavior, as opposed to self-reported political activity.

French|Jeffrey A|JA|
Smith|Kevin B|KB|
Alford|John R|JR|
Guck|Adam|A|
Birnie|Andrew K|AK|
Hibbing|John R|JR|

Cortisol
Politics
Voting behavior
Stress


Zearalenone Affect the Intestinal Villi Associated with the Distribution and the Expression of Ghrelin and Proliferating Cell Nuclear Antigen in Weaned Gilts.

Abstract: This study explored and investigated how zearalenone (ZEA) affects the morphology of small intestine and the distribution and expression of ghrelin and proliferating cell nuclear antigen (PCNA) in the small intestine of weaned gilts. A total of 20 weaned gilts (42-day-old, D × L × Y, weighing 12.84 ± 0.26 kg) were divided into the control and ZEA groups (ZEA at 1.04 mg/kg in diet) in a 35-d study. Histological observations of the small intestines revealed that villus injuries of the duodenum, jejunum and ileum, such as atrophy, retardation and branching dysfunction, were observed in the ZEA treatment. The villi branch of the ileum in the ZEA group was obviously decreased compared to that of the ileum, jejunum and duodenum, and the number of lymphoid nodules of the ileum was increased. Additionally, the effect of ZEA (1.04 mg/kg) was decreased by the immunoreactivity and distribution of ghrelin and PCNA in the duodenal and jejunal mucosal epithelial cells. Interestingly, ZEA increased the immunoreactivity of ghrelin in the ileal mucosal epithelial cells and decreased the immunoreactivity expression of PCNA in the gland epithelium of the small intestine. In conclusion, ZEA (1.04 mg/kg) had adverse effects on the development and the absorptive capacity of the villi of the intestines; yet, the small intestine could resist or ameliorate the adverse effects of ZEA by changing the autocrine of ghrelin in intestinal epithelial cells.

Zhang|Quanwei|Q| Huang|Libo|L| Leng|Bo|B| Li|Yang|Y| Jiao|Ning|N| Jiang|Shuzhen|S| Yang|Weiren|W| Yuan|Xuejun|X|0000-0002-7028-6732

zearalenone
ghrelin
weaned gilt
PCNA
intestinal morphology


No need to hide in caves: shelter-seeking behavior of surface and cave ecomorphs of Asellus aquaticus (Isopoda: Crustacea).

Abstract: Shelter-seeking is a vital behavior for stress reduction and survival in a range of animals. It comes at the cost of reduced foraging, mate finding, dispersal and territoriality, and is expected to reflect the trade-off between fitness costs and benefits. One way to test this hypothesis is to compare shelter-seeking behavior in surface habitats and in caves where external threat factors are largely reduced. We did so using the freshwater isopod Asellus aquaticus from the Postojna-Planina Cave System and surrounding surface waters. Animals from two distinct, replicated pairs of surface and cave populations were individually offered a choice between shelter and open area. The thigmotatic sensation of a transparent plastic plate was the only stimulus that could trigger the sheltering behavior. Video recordings showed a clear reduction of shelter-seeking behavior in the cave ecomorph in one population pair (Pivka). There were no changes in the other population pair (Rak), where the behavioral response had a much higher variance. Our results were partly in agreement with the hypothesis that shelter-seeking behavior should be selected against in an environment with reduced external threats. It is nevertheless too early for generalizations as the results in the second population pair were inconclusive. Additionally, we showed that for benthic walkers like A. aquaticus the use of rough substrate is crucial to obtain unbiased behavioral responses. Results of some previous studies using smooth glass or plastic substratum could be affected by unnatural behavior of animals constantly trying to find firm contact with the ground.

Fišer|Žiga|Ž| Prevorčnik|Simona|S| Lozej|Nina|N| Trontelj|Peter|P|

cave
shelter-seeking behavior
non-parallel evolution
substrate preference
thigmotaxis


Interleukin-12: Functional activities and implications for disease.

Abstract: Interleukin-12 (IL-12) was the first member of the IL-12 family of cytokines to be identified and has therefore become its eponym. It is a heterodimeric protein of two subunits (p35, p40) secreted by phagocytic cells in response to pathogens and mainly acts through STAT4 to induce IFN-γ production in T and NK cells. IFN-γ in turn mediates proinflammatory functions and activates T-bet. As IL-12 engages in TH1 development, it is believed to represent an important link between innate and adaptive immunity. Following its identification and the finding of its association to TH1 commitment, great hopes were placed in IL-12 to become a target for therapeutic applications in multiple settings of autoimmunity and cancer. Though, the discovery of the related members of the IL-12 family and several rather disappointing attempts to translate experimental results into clinical practice, have relativized these hopes. Nevertheless, IL-12 remains a cytokine of outstanding importance with lots of unresolved questions. In this review, we will first briefly depict the biochemistry of the cytokine, its receptor and the related signal transduction, before summarizing the regulation of IL-12 production and its biological functions. We will then describe the current knowledge about the implication of IL-12 in different murine disease models as well as in the corresponding human conditions and comment on possible consequences for future clinical applications.

IL-12
Cytokines
STAT4
Autoimmunity
Immunology
T(H)1 cells


A proposed Clino-radio-pathological Risk Scoring System (CRiSS) for prediction and management of inguinal lymph-nodes metastasis in squamous cell carcinoma of the penis.

Abstract:
OBJECTIVE
To develop a risk scoring system for prediction of inguinal lymph-node involvement and to suggest a management strategy according to the risk groups based on clinical, radiological and pathological parameters in squamous cell carcinoma (SCC) of penis.

MATERIALS AND METHODS
A retrospective analysis of all patients of SCC penis from 2014 to 2020 at our institute was done. The patients were divided into derivation cohort (2014 to 2019) and validation cohort (2019 to 2020). A total of 10 predictors were analysed in univariate analysis and those found significant were further subjected to multivariate analysis to derive regression coefficient for each. CRiSS scores were assigned based on the coefficients and three groups were created which were correlated with nodal metastasis. The predictive accuracy of the model was assessed by ROC analysis of the derivation cohort and validation cohort.

RESULTS
A total of 102 patients were identified in derivation cohort and 23 patients in validation cohort. Size of the primary >3cm, ulceroinfiltrative growth, involving shaft, ultrasound size of lymph-nodes >1cm, loss of fatty hila, moderate and poor differentiation, and lypmphovascular/perineural invasion were independent predictors of inguinal lymphnode metastasis in multivariate analysis. CRiSS could achieve AUROC of .910 and .887 in derivation and validation cohort respectively. The rate of metastatic lymphadenopathy was 0%, 41.4%, and 89.5% in low, intermediate, and high-risk groups respectively.

CONCLUSIONS
CRiSS can effectively predict inguinal lymph-node metastasis in SCC penis. We suggest a management strategy based on risk groups that will avoid morbidity of groin dissection in many patients.

Patel|Keval N|KN|
Bhirud|Chirag|C|
Dipin|J|J|
Nandy|Kunal|K|
Venugopal|Vivek|V|
Salunke|Abhijeet|A|
Pandya|Shashank J|SJ|

D002294:Carcinoma, Squamous Cell
D016022:Case-Control Studies
D019468:Disease Management
D005500:Follow-Up Studies
D006801:Humans
D007264:Inguinal Canal
D008197:Lymph Node Excision
D008198:Lymph Nodes
D008207:Lymphatic Metastasis
D008297:Male
D008875:Middle Aged
D010412:Penile Neoplasms
D011379:Prognosis
D012189:Retrospective Studies
D012307:Risk Factors

Inguinal lymph-nodes metastasis
Cancer of penis
Scoring methods


Acute Respiratory Distress Syndrome Induced by White Smoke Inhalation: a Potential Animal Model For Evaluating Pathological Changes and Underlying Mechanisms.

Abstract:
BACKGROUND/AIMS
White smoke inhalation (WSI) is an uncommon but potentially deadly cause of acute respiratory distress syndrome (ARDS). However, no clinical treatment protocol has been established for the treatment of WSI-induced ARDS. Therefore, it is necessary to investigate the effects of WSI in ARDS and the mechanisms underlying the effects of WSI to determine a novel therapeutic target.

METHODS
On the basis of the duration of continued inhalation of white smoke (3 min, 5 min, and 7 min), rats were divided into three groups (WSI-3 min, WSI-5 min, and WSI-7 min). The survival rate, pathological change, and computed tomography (CT) score were evaluated to determine the modeling conditions. In the established WSI-5 min models, evaluations were performed to evaluate the following: arterial blood gas levels, lung wet/dry weight ratio, the expression of inflammatory cytokines, and the effect of NF-κB signaling pathway.

RESULTS
The survival rate of rats at 72 h post-WSI in the WSI-3 min, WSI-5 min, and WSI-7 min groups was 83.33%, 75%, and 25%, respectively. Results from evaluation of H&E staining, CT scan, arterial blood gas levels, and lung wet/dry weight ratio suggest that the pathological changes in the rat in the WSI-5 min and WSI-7 min groups are very similar to those in patients with ARDS induced by WSI. Additionally, the expression of INF-γ, TGF-β1, TNF-α, and IL-1β were increased, and the NF-κB signaling pathway was activated in the WSI-5 min group.

CONCLUSION
The rat model of WSI-5 min can be used as a WSI-induced ALI model for further experiments. The NF-κB signaling pathway may be a potential therapeutic target for the treatment of WSI- induced ARDS.

Cui|Pei|P| Feng|Xiaoyan|X| Zhu|Feng|F| Yao|Yongming|Y| Xiao|Shichu|S| Gong|Zhenyu|Z| Xin|Haiming|H| Zhan|Qiu|Q| Yang|Fuwang|F| Deng|Chunjiang|C| Tang|Zhiping|Z| Tong|Yalin|Y| Xia|Zhaofan|Z|

Acute respiratory distress syndrome
White smoke inhalation
Animal model
Therapeutic target
NF-κB


Transfemoral Transcatheter Aortic Valve Replacement for Mixed Aortic Valve Disease in Child's Class C Liver Disease Prior to Orthotopic Liver Transplantation: A Case Report.

Abstract: The American Association for the Study of Liver Diseases practice guidelines list severe cardiac disease as a contraindication to liver transplantation. Transcatheter aortic valve replacement has been shown to decrease all-cause mortality in patients with severe aortic stenosis who are not considered candidates for surgical aortic valve replacement. We report our experience of liver transplantation in a patient with severe aortic stenosis and moderate aortic insufficiency who underwent transcatheter aortic valve replacement with Child-Pugh Class C disease at a Model For End-Stage Liver Disease score of 29. The patient had a difficult post procedure course that was successfully medically managed. After liver transplantation the patient was discharged to home on postoperative day 11. The combination of cardiac disease and end stage liver disease is challenging but these patients can have a successful outcome despite very severe illness.

Wilkey|Barbara J|BJ|
Hanson|Ross|R|
Reece|T Brett|TB|
Forman|Lisa|L|
Burton|James R|JR|
Messenger|John C|JC|
Kim|Michael S|MS|
Cleveland|Joseph C|JC|
Fiegel|Matt J|MJ|
Nydam|Trevor L|TL|
Mandell|M Susan|MS|

D065626:Non-alcoholic Fatty Liver Disease

D065467:Transcatheter Aortic Valve Replacement

aortic valve replacement
cardiac anesthesia
cardiac surgery
coagulopathy
heparin
platelet function


High-throughput assessment of mutations generated by genome editing in induced pluripotent stem cells by high-resolution melting analysis.

Abstract:
BACKGROUND AND AIMS
Genome editing of induced pluripotent stem cells (iPSCs) holds great potential for both disease modeling and regenerative medicine. Although clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 provides an efficient and precise genome editing tool, iPSCs are especially difficult to transfect, resulting in a small percentage of cells carrying the desired correction. A high-throughput method to identify edited clones is required to reduce the time and costs of such an approach.

METHODS
Here we assess high-resolution melting analysis (HRMA), a simple and efficient real-time polymerase chain reaction-based method, and compare it with more commonly used assays.

RESULTS AND CONCLUSIONS
Our data show that HRMA is a robust and highly sensitive method, allowing the cost-effective and time-saving screening of genome-edited iPSCs. Samples can be prepared directly from 96-well microtiter plates for high-throughput analysis, and amplicons can be further analyzed with downstream techniques for further confirmation, if needed.

Pham|Quang T|QT|
Raad|Suleen|S|
Mangahas|Chenicka-Lyn|CL|
M'Callum|Marie-Agnès|MA|
Raggi|Claudia|C|
Paganelli|Massimiliano|M|

genome editing
induced pluripotent stem cells
CRISPR-Cas9
human iPSCs


Modulation of calcium oxalate dihydrate growth by phosphorylated osteopontin peptides.

Abstract: Osteopontin (OPN) is a significant component of kidney stone matrix and a key modulator of stone formation. Here, we investigated the effects of different phosphorylated states of a synthesized peptide of OPN (the ASARM peptide; acidic, serine- and aspartate-rich motif) on calcium oxalate dihydrate (COD) crystals, a major mineral phase of kidney stones. In vitro, phosphorylated OPN-ASARM peptides strongly inhibited COD crystal growth in solution as compared to the nonphosphorylated state, with increasing inhibitory potency correlating with the degree of peptide phosphorylation. Scanning electron microscopy revealed that the inhibition from the phosphopeptides resulted in distinctive, rosette-like crystal aggregates called spherulites. The OPN-ASARM peptides preferentially bound and specifically inhibited the {1 1 0} crystallographic faces of COD, as identified by combining atomic force microscopy and computational simulation approaches. These {1 1 0} surfaces of COD have high lattice calcium occupancy (exposure), providing preferential binding sites for the highly acidic peptides; binding and inhibition by OPN-ASARM peptides at the {1 1 0} faces led to crystal aggregation and intergrowth. The crystal spherulite formations obtained in vitro when using the most phosphorylated form of OPN-ASARM peptide at a high concentration, resembled crystal morphologies observed in vivo in a rat model of urolithiasis, in which crystal deposits in the kidney contain abundant OPN as revealed by immunogold labeling. A mechanistic model for spherulite formation is proposed based on the symmetry and crystallographic structure of COD, where the phosphate groups of OPN-ASARM bind to calcium atoms at [1 1 1] step risers on the COD {1 1 0} surface, inducing the periodic emergence of new COD crystals to form spherulites.

Chien|Yung-Ching|YC|
Mansouri|Ahmad|A|
Jiang|Wenge|W|
Khan|Saeed R|SR|
Gray|Jeffrey J|JJ|
McKee|Marc D|MD|

Calcium oxalate dihydrate
Osteopontin
Kidney stones
Crystal growth
Electron microscopy
Atomic force microscopy
Urolithiasis
Biomineralization
Computer modeling


Australian Assassins, Part I: A review of the Assassin Spiders (Araneae, Archaeidae) of mid-eastern Australia.

Abstract: The Assassin Spiders of the family Archaeidae are an ancient and iconic lineage of basal araneomorph spiders, characterised by a specialised araneophagic ecology and unique, 'pelican-like' cephalic morphology. Found throughout the rainforests, wet sclerophyll forests and mesic heathlands of south-western, south-eastern and north-eastern Australia, the genus Austrarchaea Forster & Platnick, 1984 includes a diverse assemblage of relictual, largely short-range endemic species. With recent dedicated field surveys and significant advances in our understanding of archaeid biology and ecology, numerous new species of assassin spiders have been discovered in the montane sub-tropical and warm-temperate closed forests of mid-eastern Australia, including several rare or enigmatic taxa and species of conservation concern. This fauna is revised and 17 new species are described from south-eastern Queensland and eastern New South Wales: Austrarchaea alanisp. n., Austrarchaea aleenaesp. n., Austrarchaea binfordaesp. n., Austrarchaea christopherisp. n., Austrarchaea clyneaesp. n., Austrarchaea cunninghamisp. n., Austrarchaea dianneaesp. n., Austrarchaea harmsisp. n., Austrarchaea helenaesp. n., Austrarchaea judyaesp. n., Austrarchaea mascordisp. n., Austrarchaea mcguiganaesp. n., Austrarchaea milledgeisp. n., Austrarchaea monteithisp. n., Austrarchaea platnickorumsp. n., Austrarchaea ravenisp. n. and Austrarchaea smithaesp. n. Adult specimens of the type species, Austrarchaea nodosa (Forster, 1956) are redescribed from the Lamington Plateau, south-eastern Queensland, and distinguished from the sympatric species Austrarchaea dianneaesp. n. A key to species and a molecular phylogenetic analysis of COI and COII mtDNA sequences complement the species-level taxonomy, with maps, habitat photos, natural history information and conservation assessments provided for all species.

rainforest
new species
conservation
taxonomy
Palpimanoidea
cytochrome c oxidase
mitochondrial DNA


Pyrolysis of de-oiled yeast biomass of Rhodotorula mucilaginosa IIPL32: Kinetics and thermodynamic parameters using thermogravimetric analysis.

Abstract: The increasing demand for natural resources has highlighted the need to search for unutilized carbon resource that satisfy the demand and pose a minor threat to the environment. Yeast is a microbe with large industrial applications, and the biomass leftover after fermentation needs utilization for achieving increased efficiency. De-oiled yeast biomass (DYB), the residue after yeast lipid extraction, has not yet been evaluated for its potential application in the pyrolysis process. The present study was performed to understand its detailed pyrolysis kinetics. The observed activation energy (87-216 KJ/mol), random nucleation mechanism, pre-exponential factor (7.87 × 1031-3.24 × 1031/min), and thermodynamic profile showed the DYB pyrolysis process to be feasible. .

Banerjee|Ayan|A|
Vithusha|T|T|
Krishna|Bhavya B|BB|
Kumar|Jitendra|J|
Bhaskar|Thallada|T|
Ghosh|Debashish|D|

De-oiled yeast
Thermodynamics
Thermogravimetric analysis
Pyrolysis kinetics
Biorefinery


Validation of contemporary stroke and bleeding risk stratification scores in non-anticoagulated Chinese patients with atrial fibrillation.

Abstract:
BACKGROUND
Risk stratification schemes assessing stroke and thromboembolism (stroke/TE) and bleeding relating to atrial fibrillation (AF) have largely been derived and validated in Western populations. We assessed risk factors that constitute scores for assessing stroke/TE (CHADS2, CHA2DS2-VASc) and bleeding (HAS-BLED), and the predictive value of these scores in a large cohort of Chinese patients with AF.

METHODS AND RESULTS
We studied 1034 AF patients (27.1% female, median age 75; 85.6% non-anticoagulated) with mean follow-up of 1.9 years. On multivariate analysis, vascular disease was independently associated with stroke/TE in non-anticoagulated patients (p=0.04). In patients with a CHADS2 or CHA2DS2-VASc score=1, the rate of stroke/TE was 2.9% and 0.9% respectively, but in patients at "high risk" (scores ≥ 2), this rate was 4.6% and 4.5%, respectively. The c-statistics for predicting stroke/TE with CHADS2 and CHA2DS2-VASc were 0.58 (p=0.109) and 0.72 (p<0.001), respectively. Compared to CHADS2, the use of CHA2DS2-VASc would result in a Net Reclassification Improvement (NRI) of 16.6% (p=0.009) and an Integrated Discrimination Improvement (IDI) of 1.1% (p=0.002). Cumulative survival of the patients with a CHA2DS2-VASc score≥2 was decreased compared to those with a CHA2DS2-VASc score 0-1 (p<0.001), but the CHADS2 was not predictive of mortality. There was an increased risk of major bleeding with increasing HAS-BLED score (c-statistic 0.61, 95% CI: 0.51-0.71, p=0.042).

CONCLUSIONS
Vascular disease was a strong independent predictor of stroke/TE in Chinese patients with AF. The CHA2DS2-VASc score performed better than CHADS2 in predicting stroke/TE in this Chinese AF population. Cumulative survival of the patients at high risk with the CHA2DS2-VASc score (but not using CHADS2) was significantly decreased.

Guo|Yutao|Y|
Apostolakis|Stavros|S|
Blann|Andrew D|AD|
Wang|Haijun|H|
Zhao|Xiaoning|X|
Zhang|Yu|Y|
Zhang|Dexian|D|
Ma|Jingling|J|
Wang|Yutang|Y|
Lip|Gregory Y H|GY|

Stroke
Bleeding
Atrial fibrillation
Chinese population
Risk assessment


Parametric response mapping on chest computed tomography associates with clinical and functional parameters in chronic obstructive pulmonary disease.

Abstract:
BACKGROUND
In the search for specific phenotypes of chronic obstructive pulmonary disease (COPD) computed tomography (CT) derived Parametric Response Mapping (PRM) has been introduced. This study evaluates the association between PRM and currently available biomarkers of disease severity in COPD.

METHODS
Smokers with and without COPD were characterized based on questionnaires, pulmonary function tests, body plethysmography, and low-dose chest CT scanning. PRM was used to calculate the amount of emphysema (PRMEmph) and non-emphysematous air trapping (i.e. functional small airway disease, PRMfSAD). PRM was first compared with other biomarkers for emphysema (Perc15) and air trapping (E/I-ratioMLD). Consequently, linear regression models were utilized to study associations of PRM measurements with clinical parameters.

RESULTS
166 participants were included with a mean ± SD age of 50.5 ± 17.7 years. Both PRMEmph and PRMfSAD were more strongly correlated with lung function parameters as compared to Perc15 and E/I-ratioMLD. PRMEmph and PRMfSAD were higher in COPD participants than non-COPD participants (14.0% vs. 1.1%, and 31.6% vs. 8.2%, respectively, both p < 0.001) and increased with increasing GOLD stage (all p < 0.001). Multivariate analysis showed that PRMfSAD was mainly associated with total lung capacity (TLC) (β = -7.90, p < 0.001), alveolar volume (VA) (β = 7.79, p < 0.001), and residual volume (β = 6.78, p < 0.001), whilst PRMEmph was primarily associated with Kco (β = 8.95, p < 0.001), VA (β = -6.21, p < 0.001), and TLC (β = 6.20, p < 0.001).

CONCLUSIONS
PRM strongly associates with the presence and severity of COPD. PRM therefore appears to be a valuable tool in differentiating COPD phenotypes.

Pompe|Esther|E|
Galbán|Craig J|CJ|
Ross|Brian D|BD|
Koenderman|Leo|L|
Ten Hacken|Nick Ht|NH|
Postma|Dirkje S|DS|
van den Berge|Maarten|M|
de Jong|Pim A|PA|
Lammers|Jan-Willem J|JJ|
Mohamed Hoesein|Firdaus Aa|FA|

D029424:Pulmonary Disease, Chronic Obstructive

Parametric response mapping
Computed tomography
Phenotypes
Copd
Emphysema
Small airway disease


Effectiveness of a multifaceted intervention to improve emergency department care of low back pain: a stepped-wedge, cluster-randomised trial.

Abstract:
BACKGROUND
Overuse of lumbar imaging is common in the emergency department (ED). Few trials have examined interventions to address this. We evaluated the effectiveness of a multifaceted intervention to implement guideline recommendations for low back pain in the emergency department.

METHODS
We conducted a stepped-wedge, cluster-randomised trial in four EDs in New South Wales, Australia. After a 13-month control phase of usual care, the EDs received a multifaceted intervention to support guideline-endorsed care in a random order, based on a computer-generated random sequence, every 4 weeks over a 4-month period. All sites were followed up for at least 3 months. The primary outcome was the proportion of low back pain presentations receiving lumbar imaging. Secondary healthcare utilisation outcomes included prescriptions of opioid and non-opioid pain medicines, inpatient admissions, length of ED stay, specialist referrals and re-presentations. Clinician beliefs and knowledge about low back pain care were measured before and after the intervention. Patient-reported pain, disability, quality of life and satisfaction were measured at 1, 2 and 4 weeks post ED presentation.

RESULTS
A total of 269 ED clinicians and 4625 episodes of care for low back pain (4491 patients) were included. The data did not provide clear evidence that the intervention reduced lumbar imaging (OR 0.77; 95% CI 0.47 to 1.26; p=0.29). It did reduce opioid use (OR 0.57; 95% CI 0.38 to 0.85; p=0.006) and improved clinicians' beliefs (mean difference (MD), 2.85; 95% CI 1.85 to 3.85; p<0.001; on a scale from 9 to 45) and knowledge about low back pain care (MD, 0.48; 95% CI 0.13 to 0.83; p<0.01; on a scale from 0 to 11). There was no difference in pain scores at 1-week follow-up (MD, 0.04; 95% CI -1.00 to 1.08; p=0.94; on a scale from 0 to 10). A similar trend was observed for all other patient-reported outcomes and time points. This study found no effect on the other secondary healthcare utilisation outcomes.

CONCLUSION
It is uncertain if a multifaceted intervention to implement guideline recommendations for low back pain care decreased lumbar imaging in the ED; however, it did reduce opioid prescriptions without adversely affecting patient outcomes. Trial registration number ACTRN12617001160325.

D004636:Emergency Service, Hospital
D004638:Emergency Treatment
D006760:Hospitalization
D006801:Humans
D017116:Low Back Pain
D011788:Quality of Life

emergency department
continuing education
continuing professional development
implementation science


Structural Basis of Clade-specific Engagement of SAMHD1 (Sterile α Motif and Histidine/Aspartate-containing Protein 1) Restriction Factors by Lentiviral Viral Protein X (Vpx) Virulence Factors.

Abstract: Sterile α motif (SAM) and histidine/aspartate (HD)-containing protein 1 (SAMHD1) restricts human/simian immunodeficiency virus infection in certain cell types and is counteracted by the virulence factor Vpx. Current evidence indicates that Vpx recruits SAMHD1 to the Cullin4-Ring Finger E3 ubiquitin ligase (CRL4) by facilitating an interaction between SAMHD1 and the substrate receptor DDB1- and Cullin4-associated factor 1 (DCAF1), thereby targeting SAMHD1 for proteasome-dependent down-regulation. Host-pathogen co-evolution and positive selection at the interfaces of host-pathogen complexes are associated with sequence divergence and varying functional consequences. Two alternative interaction interfaces are used by SAMHD1 and Vpx: the SAMHD1 N-terminal tail and the adjacent SAM domain or the C-terminal tail proceeding the HD domain are targeted by different Vpx variants in a unique fashion. In contrast, the C-terminal WD40 domain of DCAF1 interfaces similarly with the two above complexes. Comprehensive biochemical and structural biology approaches permitted us to delineate details of clade-specific recognition of SAMHD1 by lentiviral Vpx proteins. We show that not only the SAM domain but also the N-terminal tail engages in the DCAF1-Vpx interaction. Furthermore, we show that changing the single Ser-52 in human SAMHD1 to Phe, the residue found in SAMHD1 of Red-capped monkey and Mandrill, allows it to be recognized by Vpx proteins of simian viruses infecting those primate species, which normally does not target wild type human SAMHD1 for degradation.

Wu|Ying|Y|
Koharudin|Leonardus M I|LMI|
Mehrens|Jennifer|J|
DeLucia|Maria|M|
Byeon|Chang-Hyeok|CH|
Byeon|In-Ja L|IL|
Calero|Guillermo|G|
Ahn|Jinwoo|J|
Gronenborn|Angela M|AM|

D000076106:SAM Domain and HD Domain-Containing Protein 1

D054334:Viral Regulatory and Accessory Proteins

SAM domain and HD domain-containing protein 1 (SAMHD1)


A high ratio of IC31(®) adjuvant to antigen is necessary for H4 TB vaccine immunomodulation.

Abstract: A tuberculosis (TB) vaccine consisting of a recombinant fusion protein (H4) and a novel TLR9 adjuvant (IC31) is in clinical development. To better understand the H4-IC31 ratio, we measured the binding capacity of IC31 for H4 protein and immunized mice with formulations that contained limiting to excess ratios of IC31 to H4. An immunomodulated H4-specific IFNγ response was only observed when IC31 was present in excess of H4. Since TLR expression is species-specific and the vaccine is intended to boost BCG-primed immunity, we questioned whether data in mice would translate to humans. To address this question, we used the fresh human Whole Blood (hWB) recovered from BCG-vaccinated subjects to screen H4-IC31 formulations. We found IC31 modulation in hWB to be quite distinct from the TLR4-Adjuvant. Unlike TLR4-Adjuvant, IC31 formulations did not induce the pro-inflammatory cytokine TNFα, but modulated a robust H4-specific IFNγ response after 12 d of culture. We then re-stimulated the fresh hWB of 5 BCG-primed subjects with formulations that had excess or limiting IC31 binding for H4 protein and again found that an immunomodulated H4-specific IFNγ response needed an excess of IC31. Finally, we monitored the zeta (ζ) potential of H4-IC31 formulations and found that the overall charge of H4-IC31 particles changes from negative to positive once IC31 is in greater than 9-fold excess. Using two diverse yet mutually supportive approaches, we confirm the need for an excess of IC31 adjuvant in H4 TB vaccine formulations and suggest surface potential may be an important factor.

Aboutorabian|Sepideh|S|
Hakimi|Jalil|J|
Boudet|Florence|F|
Montano|Sandrine|S|
Dookie|Annie|A|
Roque|Cristopher|C|
Ausar|Salvador F|SF|
Rahman|Nausheen|N|
Brookes|Roger H|RH|

IC31®, Valneva Adjuvant consisting of KLK and ODN1a

KLK, Antimicrobial peptide H-KLKL5KLK-OH

TLR4-Adjuvant, TLR4A combined with an aluminum salt adjuvant


Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer.

Abstract: Seven years after the launch of the European Paediatric Medicine Regulation, limited progress in paediatric oncology drug development remains a major concern amongst stakeholders - academics, industry, regulatory authorities, parents, patients and caregivers. Restricted increases in early phase paediatric oncology trials, legal requirements and regulatory pressure to propose early Paediatric Investigation Plans (PIPs), missed opportunities to explore new drugs potentially relevant for paediatric malignancies, lack of innovative trial designs and no new incentives to develop drugs against specific paediatric targets are some unmet needs. Better access to new anti-cancer drugs for paediatric clinical studies and improved collaboration between stakeholders are essential. The Cancer Drug Development Forum (CDDF), previously Biotherapy Development Association (BDA), with Innovative Therapy for Children with Cancer Consortium (ITCC), European Society for Paediatric Oncology (SIOPE) and European Network for Cancer Research in Children and Adolescents (ENCCA) has created a unique Paediatric Oncology Platform, involving multiple stakeholders and the European Union (EU) Commission, with an urgent remit to improve paediatric oncology drug development. The Paediatric Oncology Platform proposes to recommend immediate changes in the implementation of the Regulation and set the framework for its 2017 revision; initiatives to incentivise drug development against specific paediatric oncology targets, and repositioning of drugs not developed in adults. Underpinning these changes is a strategy for mechanism of action and biology driven selection and prioritisation of potential paediatric indications rather than the current process based on adult cancer indications. Pre-competitive research and drug prioritisation, early portfolio evaluation, cross-industry cooperation and multi-compound/sponsor trials are being explored, from which guidance for innovative trial designs will be provided.

Vassal|Gilles|G|
Rousseau|Raphaël|R|
Blanc|Patricia|P|
Moreno|Lucas|L|
Bode|Gerlind|G|
Schwoch|Stefan|S|
Schrappe|Martin|M|
Skolnik|Jeffrey|J|
Bergman|Lothar|L|
Bradley-Garelik|Mary Brigid|MB|
Saha|Vaskar|V|
Pearson|Andy|A|
Zwierzina|Heinz|H|

Paediatric oncology
Drug development
Paediatric Investigation Plan
Long-term follow up
Precompetitive development
Regulatory framework


Left atrial size and function: role in prognosis.

Abstract: The author examines the ability of left atrial size and function to predict cardiovascular outcomes. Data are sufficient to recommend evaluation of left atrial volume in certain populations, and although analysis of atrial reservoir, conduit, and booster pump function trails in that regard, the gap is rapidly closing. In this state-of-the-art paper, the author reviews the methods used to assess left atrial size and function and discusses their role in predicting cardiovascular events in general and referral populations and in patients with atrial fibrillation, cardiomyopathy, ischemic heart disease, and valvular heart disease.

cardiovascular outcomes
left atrial volume
left atrial function


Disparities in insulin resistance between black and white adults in the United States: The role of lifespan stress exposure.

Abstract:
BACKGROUND
Disparities in insulin resistance between Black and White adults in the United States are well documented, yet relatively little is known about the psychosocial or biological antecedents of these inequities. The current study examined childhood adversity and contemporaneous psychosocial stressors in adulthood as possible mediators of the racial disparity in insulin resistance. Inflammatory and hypothalamic-pituitary adrenal (HPA) axis mechanisms implicated in associations between lifespan stress exposure and insulin resistance were also considered.

METHODS
Data were derived from the biomarker component of the Midlife in the United States Study (N = 1170, 20% Black, 56% female, Mean age = 54.7 years, SD = 11.6). A homeostatic model assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Twelve risk factors relating to household dysfunction, socioeconomic disadvantage, and maltreatment were sum scored to index childhood adversity. Measures of adult stress included socioeconomic adversity, major stressful events, everyday discrimination, and lifetime discrimination.

RESULTS
Levels of insulin resistance were higher among Black than White adults. Childhood adversity was positively associated with HOMA-IR, and attenuated 18% of the race difference. Measures of adult stress mediated 33% of the association between childhood adversity and HOMA-IR, and accounted for an additional 47% of the race difference. Higher inflammation and lower nocturnal cortisol both played an important role in mediating the association between stress exposure and HOMA-IR.

CONCLUSIONS
Findings are consistent with prior research showing that childhood adversity and adult stress are salient predictors of glucose metabolism, and extend this work by showing that lifespan stress exposures attenuate a significant portion of the Black-White disparity in HOMA-IR. Results also suggest stress effects on insulin resistance through inflammatory and HPA-axis pathways.

Fuller-Rowell|Thomas E|TE|
Homandberg|Lydia K|LK|
Curtis|David S|DS|
Tsenkova|Vera K|VK|
Williams|David R|DR|
Ryff|Carol D|CD|

Insulin resistance
Inflammation
Cortisol
Adult psychosocial stress
Adverse childhood experiences
Health inequalities


An interfaith dialogue with Sir William Osler: crossing the divide of COVID-19 pandemic.

Abstract: With the recent COVID-19 pandemic and George Floyd protests, the USA (US) has become extensively polarized across social and political divides. The COVID-19 pandemic has left tens of thousands dead and several million American citizens without work. Furthermore, the months of quarantine and uncertainty with the COVID-19 virus impacted the economic stability and health of Americans. In recent weeks, the divides have only deepened with the death of George Floyd from police brutality, which ushered in worldwide protests addressing racial, social, and law enforcement issues for minority groups. Both developments have ushered in unprecedented challenges for addressing social disparities while controlling the spread and devastation of the COVID-19 pandemic. With social media and mass communication, polarization between opposing groups has only deepened the divide. An inclusive dialogue that recognizes the intellectual and interpersonal boundaries of opposing groups would provide an avenue towards mutual understanding and further collaboration towards a common goal and solution. A physician that exemplified many aspects interfaith dialogue in his clinical practice and personal life was the late Sir William Osler. This will be accomplished through a fictional dialogue between Sir William Osler and Dr. Mark Webb.

Interfaith
Sir William Osler
and dialogue
medicine
religion


Pediatric tongue laceration repair using 2-octyl cyanoacrylate (dermabond(®)).

Abstract:
BACKGROUND
Tongue lacerations provide a challenge for emergency physicians, especially in the case of pediatric patients. Traditional wound closure typically involves local anesthesia or procedural sedation in children, which is time consuming and often anxiety provoking for providers, patients, and parents. 2-Octyl cyanoacrylate (Dermabond(®); Ethicon, Inc., Sommerville, NJ) has been used in the context of the emergency department for successful repair of lacerations, however, is not marketed for use on mucosal or intraoral surfaces. This case report describes an alternative manner of tongue laceration repair by the use of 2-octyl cyanoacrylate.

OBJECTIVE
2-Octyl cyanoacrylate is generally not indicated for intraoral use. Our case demonstrates a situation in which it was used safely and effectively to repair a tongue laceration.

CASE REPORT
A 7-year-old boy presented to the emergency department after sustaining a large tongue laceration requiring repair. The boy's parent refused traditional wound repair with suturing due to concerns regarding the pain of local anesthesia administration, as well as risks posed by procedural sedation. The wound was repaired using the tissue adhesive 2-octyl cyanoacrylate. The patient tolerated the procedure well and there were no complications in the patient's course. Good cosmetic results were achieved using this method.

CONCLUSIONS
Tongue lacerations and other intraoral lacerations are challenging to repair, especially in pediatric patients. The use of tissue adhesives such as 2-octyl cyanoacrylate is very likely safe and may provide an expedient manner in which to repair such lesions with good cosmetic results.

tongue laceration repair
2-octyl cyanoacrylate
Dermabond(®)
tissue adhesive
intraoral laceration repair


Adipose Tissue-Derived Stem Cells: Immunomodulatory Effects and Therapeutic Potential.

Abstract: Adipose-derived stem cells (ASCs) can self-renew and differentiate along multiple cell lineages. ASCs are also potently anti-inflammatory due to their inherent ability to regulate the immune system by secreting anti-inflammatory cytokines and growth factors that play a crucial role in the pathology of many diseases, including multiple sclerosis, diabetes mellitus, Crohn's, SLE, and graft-versus-host disease. The immunomodulatory effects and mechanisms of action of ASCs on pathological conditions are reviewed here.

D045164:Mesenchymal Stem Cell Transplantation

adipose-derived stem cells
cytokines
mechanisms of action
immune cells
immunological disease
stromal vascular fraction


Proton Pumping and Non-Pumping Terminal Respiratory Oxidases: Active Sites Intermediates of These Molecular Machines and Their Derivatives.

Abstract: Terminal respiratory oxidases are highly efficient molecular machines. These most important bioenergetic membrane enzymes transform the energy of chemical bonds released during the transfer of electrons along the respiratory chains of eukaryotes and prokaryotes from cytochromes or quinols to molecular oxygen into a transmembrane proton gradient. They participate in regulatory cascades and physiological anti-stress reactions in multicellular organisms. They also allow microorganisms to adapt to low-oxygen conditions, survive in chemically aggressive environments and acquire antibiotic resistance. To date, three-dimensional structures with atomic resolution of members of all major groups of terminal respiratory oxidases, heme-copper oxidases, and bd-type cytochromes, have been obtained. These groups of enzymes have different origins and a wide range of functional significance in cells. At the same time, all of them are united by a catalytic reaction of four-electron reduction in oxygen into water which proceeds without the formation and release of potentially dangerous ROS from active sites. The review analyzes recent structural and functional studies of oxygen reduction intermediates in the active sites of terminal respiratory oxidases, the features of catalytic cycles, and the properties of the active sites of these enzymes.

proton pump
cytochromes
cytochrome oxidase
electrogenic mechanisms
membrane proteins
reactive oxygen species
terminal oxidases


Tetradecanoic Acids With Anti-Virulence Properties Increase the Pathogenicity of Pseudomonas aeruginosa in a Murine Cutaneous Infection Model.

Abstract: Blocking virulence is a promising alternative to counteract Pseudomonas aeruginosa infections. In this regard, the phenomenon of cell-cell communication by quorum sensing (QS) is an important anti-virulence target. In this field, fatty acids (FA) have gained notoriety for their role as autoinducers, as well as anti-virulence molecules in vitro, like some saturated FA (SAFA). In this study, we analyzed the anti-virulence activity of SAFA with 12 to18 carbon atoms and compared their effect with the putative autoinducer cis-2-decenoic acid (CDA). The effect of SAFA on six QS-regulated virulence factors and on the secretion of the exoenzyme ExoU was evaluated. In addition, a murine cutaneous infection model was used to determine their influence on the establishment and damage caused by P. aeruginosa PA14. Dodecanoic (lauric, C12:0) and tetradecanoic (myristic, C14:0) acids (SAFA C12-14) reduced the production of pyocyanin by 35-58% at 40 and 1,000 µM, while CDA inhibited it 62% at a 3.1 µM concentration. Moreover, the SAFA C12-14 reduced swarming by 90% without affecting biofilm formation. In contrast, CDA reduced the biofilm by 57% at 3 µM but did not affect swarming. Furthermore, lauric and myristic acids abolished ExoU secretion at 100 and 50 µM respectively, while CDA reduced it by ≈ 92% at 100 µM. Remarkably, the coadministration of myristic acid (200 and 1,000 µM) with P. aeruginosa PA14 induced greater damage and reduced survival of the animals up to 50%, whereas CDA to 500 µM reduced the damage without affecting the viability of the PA14 strain. Hence, our results show that SAFA C12-14 and CDA have a role in regulation of P. aeruginosa virulence, although their inhibition/activation molecular mechanisms are different in complex environments such as in vivo systems.

Juárez-Rodríguez|Martha María|MM|
Cortes-López|Humberto|H|
García-Contreras|Rodolfo|R|
González-Pedrajo|Bertha|B|
Díaz-Guerrero|Miguel|M|
Martínez-Vázquez|Mariano|M|
Rivera-Chávez|José Alberto|JA|
Soto-Hernández|Ramón Marcos|RM|
Castillo-Juárez|Israel|I|

Pseudomonas aeruginosa
quorum sensing
anti-virulence activity
myristic acid
animal model
lauric acid
saturated fatty acids
type III secretion system


Exploring the selective vulnerability in Alzheimer disease using tissue specific variant analysis.

Abstract: The selective vulnerability of distinct regions of the brain is a critical factor in neurodegenerative disorders. In Alzheimer's disease (AD), neurons in hippocampus situated in medial temporal lobe are immensely damaged. Identifying tissue-specific variants is essential in order to perceive the selective vulnerability in AD. In current work, we aligned mRNA-seq data with HG19/HG38 genomic assembly and identified specific variations present in temporal, frontal and other lobes of the AD using sequence alignment map tools. We compared the results with the genome-wide association and gene expression quantitative trait loci studies of the various neurological disorders. We also distinguished variants and epitranscriptomic modifications through the RNA-modification database and evaluated the variant effect in the coding/UTR regions. In addition, we developed genetic and functional interaction networks to understand the relationship between predicted vulnerable variations and differentially expressed genes. We found that genes involved in gliogenesis, intermediate filament organization are altered in the temporal lobe. Oxidative phosphorylation, and calcium ion homeostasis are modified in the frontal lobe, and protein degradation, apoptotic signaling are altered in other lobes. From this study, we propose that disruption of glial cell structural integrity, defective gliogenesis, and failure in glia-neuron communication are the primary factors for selective vulnerability.

Akila Parvathy Dharshini|S|S|
Taguchi|Y-H|YH|
Michael Gromiha|M|M|

D020413:3' Untranslated Regions
D000544:Alzheimer Disease
D001921:Brain
D006801:Humans
D053858:Metabolic Networks and Pathways
D009928:Organ Specificity
D020641:Polymorphism, Single Nucleotide
D040641:Quantitative Trait Loci
D059467:Transcriptome

Alzheimer's disease
Epitranscriptome
Age-related macular degeneration
Amyotrophic lateral sclerosis
Reactive oxygen species
Sequence alignment/map


Intercellular Adhesion Molecule-1 (ICAM-1) and ICAM-2 Differentially Contribute to Peripheral Activation and CNS Entry of Autoaggressive Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis.

Abstract: In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), myelin-specific T cells are activated in the periphery and differentiate in T helper (Th) 1 and Th17 effector cells, which cross the blood-brain barrier (BBB) to reach the central nervous system (CNS), where they induce neuroinflammation. Here, we explored the role of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in the activation of naïve myelin-specific T cells and in the subsequent migration of differentiated encephalitogenic Th1 and Th17 cells across the BBB in vitro and in vivo. While on antigen-presenting cells ICAM-1, but not ICAM-2 was required for the activation of naïve CD4+ T cells, endothelial ICAM-1 and ICAM-2 mediated both Th1 and Th17 cell migration across the BBB. ICAM-1/-2-deficient mice developed ameliorated typical and atypical EAE transferred by encephalitogenic Th1 and Th17 cells, respectively. Our study underscores important yet cell-specific contributions for ICAM-1 and ICAM-2 in EAE pathogenesis.

Haghayegh Jahromi|Neda|N|
Marchetti|Luca|L|
Moalli|Federica|F|
Duc|Donovan|D|
Basso|Camilla|C|
Tardent|Heidi|H|
Kaba|Elisa|E|
Deutsch|Urban|U|
Pot|Caroline|C|
Sallusto|Federica|F|
Stein|Jens V|JV|
Engelhardt|Britta|B|

D057705:Transendothelial and Transepithelial Migration


Transcription Factor and lncRNA Regulatory Networks Identify Key Elements in Lung Adenocarcinoma.

Abstract: Lung cancer is the second most commonly diagnosed carcinoma and is the leading cause of cancer death. Although significant progress has been made towards its understanding and treatment, unraveling the complexities of lung cancer is still hampered by a lack of comprehensive knowledge on the mechanisms underlying the disease. High-throughput and multidimensional genomic data have shed new light on cancer biology. In this study, we developed a network-based approach integrating somatic mutations, the transcriptome, DNA methylation, and protein-DNA interactions to reveal the key regulators in lung adenocarcinoma (LUAD). By combining Bayesian network analysis with tissue-specific transcription factor (TF) and targeted gene interactions, we inferred 15 disease-related core regulatory networks in co-expression gene modules associated with LUAD. Through target gene set enrichment analysis, we identified a set of key TFs, including known cancer genes that potentially regulate the disease networks. These TFs were significantly enriched in multiple cancer-related pathways. Specifically, our results suggest that hepatitis viruses may contribute to lung carcinogenesis, highlighting the need for further investigations into the roles that viruses play in treating lung cancer. Additionally, 13 putative regulatory long non-coding RNAs (lncRNAs), including three that are known to be associated with lung cancer, and nine novel lncRNAs were revealed by our study. These lncRNAs and their target genes exhibited high interaction potentials and demonstrated significant expression correlations between normal lung and LUAD tissues. We further extended our study to include 16 solid-tissue tumor types and determined that the majority of these lncRNAs have putative regulatory roles in multiple cancers, with a few showing lung-cancer specific regulations. Our study provides a comprehensive investigation of transcription factor and lncRNA regulation in the context of LUAD regulatory networks and yields new insights into the regulatory mechanisms underlying LUAD. The novel key regulatory elements discovered by our research offer new targets for rational drug design and accompanying therapeutic strategies.

Li|Dan|D|
Yang|William|W|
Zhang|Jialing|J|
Yang|Jack Y|JY|
Guan|Renchu|R|
Yang|Mary Qu|MQ|

transcription factor
network
cancer
long non-coding RNA
gene regulation
systems biology


Leachability and adverse effects of coal fly ash: A review.

Abstract: Coal fly ash (CFA) is a valuable industrial solid waste, but conventional methods used for its disposal can lead to serious and long-lasting environmental issues. The study of technologies for CFA recycling has been of major concern, while the harm caused by CFA is only partially understood, limiting its reuse. In this review, the basic physico-chemical properties of CFA are introduced, followed by a systematic summary and discussion of the leachability of CFA via different leaching methods and the chemical speciation of some typical metal elements in CFA, which is related to its harmful effects. The specific harm that CFA causes to humans, wild animals, and plants and the study status of magnetic property of CFA are presented. Because of the pervasive concerns of many people, the utilisation of CFA in the USA and Europe and an economic and environmental analysis of its disposal is provided and discussed. Finally, some possible directions for future research involving CFA are proposed.

Wang|Nannan|N| Sun|Xiyu|X| Zhao|Qiang|Q| Yang|Ying|Y| Wang|Peng|P|

Leachability
Coal fly ash
Environmental pollution
Metal/metalloid elements
Radiation


Sensitive detection of 2,4,6-trinitrotoluene utilizing fluorescent sensor from carbon dots and reusable magnetic core-shell nanomaterial.

Abstract: Carbon dots have been a promising nano-carbon material with many advantages, and attracted many more attentions. This study designed a new chemosensor integrating the strong fluorescent property of carbon dots and the magnetism of amino-functionalized magnetic core-shell nanomaterial, Fe@SiO2-NH2 for determination of 2,4,6-trinitrotoluene (TNT). In this system, fluorescent carbon dots interacted with amino groups on the surface of amino-functionalized magnetic core-shell nanomaterial leading to fluorescence quenching of carbon dots, appearance of TNT competitively replaced of carbon dots on the surface of the magnetic material through forming a Meisenheimer complex. This sensor exhibits excellent selectivity and sensitivity for TNT, and which provided a good dynamic linear range for TNT from 10 to 2000 ng mL-1. The experiments demonstrate a low detection limit of 2.15 ng mL-1. The intra-day precisions for 25, 100 and 500 ng mL-1 were 4.6, 2.3 and 0.5% (RSD, n = 6), inter-day precisions for 25, 100 and 500 ng mL-1 were 4.2, 2.5 and 0.9% (RSD, n = 6), respectively. The developed sensor was validated with river water, dust, and soil samples, and the achieved spiked recoveries were immensely satisfied from 98.1% to 102.0%. The Fe@SiO2-NH2 possessed excellent reusability. This sensor exhibits that it is simple, sensitive and selective, and will be a vital analytical tool for TNT in many fields.

Liu|Yongli|Y| Zhou|Qingxiang|Q| Wu|Yalin|Y| Li|Shuangying|S| Sun|Yi|Y| Sheng|Xueying|X| Zhan|Yali|Y| Zhao|Jingyi|J| Guo|Jinghan|J| Zhou|Boyao|B|

Amino-functionalized magnetic core-shell nanomaterial


Cytokine regulation by MAPK activated kinase 2 in keratinocytes exposed to sulfur mustard.

Abstract: Uncontrolled inflammation contributes to cutaneous damage following exposure to the warfare agent bis(2-chloroethyl) sulfide (sulfur mustard, SM). Activation of the p38 mitogen activated protein kinase (MAPK) precedes SM-induced cytokine secretion in normal human epidermal keratinocytes (NHEKs). This study examined the role of p38-regulated MAPK activated kinase 2 (MK2) during this process. Time course analysis studies using NHEK cells exposed to 200μM SM demonstrated rapid MK2 activation via phosphorylation that occurred within 15 min. p38 activation was necessary for MK2 phosphorylation as determined by studies using the p38 inhibitor SB203580. To compare the role of p38 and MK2 during SM-induced cytokine secretion, small interfering RNA (siRNA) targeting these proteins was utilized. TNF-α, IL-1β, IL-6 and IL-8 secretion was evaluated 24h postexposure, while mRNA changes were quantified after 8h. TNF-α, IL-6 and IL-8 up regulation at the protein and mRNA level was observed following SM exposure. IL-1β secretion was also elevated despite unchanged mRNA levels. p38 knockdown reduced SM-induced secretion of all the cytokines examined, whereas significant reduction in SM-induced cytokine secretion was only observed with TNF-α and IL-6 following MK2 knockdown. Our observations demonstrate potential activation of other p38 targets in addition to MK2 during SM-induced cytokine secretion.

Yego|E Chepchumba K|EC|
Dillman|James F|JF|

D047908:Intracellular Signaling Peptides and Proteins

D048051:p38 Mitogen-Activated Protein Kinases

granulocyte–macrophage colony stimulating factor

P P P P P P P P P P P P P P P P P U U U U U U U U U U U U U U U M M M U U U U M U M M U U M U U M U U U U U U U U U U P U U


Cold agglutinin disease following SARS-CoV-2 and Mycoplasma pneumoniae co-infections.

Abstract: SARS-CoV-2 and other respiratory co-infections may occur. As Mycoplasma pneumoniae and various viruses can cause cold agglutinin disease (CAD), the presence of CAD in COVID-19 patients should indicate the need of investigations for those pathogens.


Effectiveness and safety of herbal medicine for cancer-related fatigue in lung cancer survivors: A systematic review and meta-analysis.

Abstract: Approximately half of lung cancer patients (LCP) receiving chemotherapy are experiencing cancer-related fatigue (CRF). In East Asia, herbal medicines (HMs) have been used as tonics due to their anti-fatigue effect. This systematic review evaluated the effectiveness and safety of HMs for CRF in LCP. We comprehensively searched 12 electronic medical databases to search randomized controlled trials (RCTs) and quasi-RCTs investigating HMs for CRF in LCP, published up to September 2019. The primary outcome was the fatigue severity. Secondary outcomes included patients' quality of life (QOL), activities of daily life (ADL), and incidence of adverse events. Cochrane's risk of bias tool assessed the methodological quality of included RCTs. The risk ratio or mean difference was estimated with 95% confidence intervals by performing a meta-analysis. Twelve RCTs with 861 participants were included. Compared to conventional medicine alone, HM combined with conventional medicine significantly improved fatigue level, QOL, and ADL. As monotherapy, HM significantly improved ADL compared with megestrol. No serious HM-related adverse events were reported. Limited evidence suggests that HM could be effective and safe for CRF in LCP. However, further high-quality RCTs are needed to confirm these findings owing to the small number and low methodological quality of the included studies.

D016032:Randomized Controlled Trials as Topic

herbal medicine
fatigue
systematic review
lung neoplasms


SARS-CoV-2 Fulminant Myocarditis.

Abstract: An 18-year-old male without prior medical history developed fulminant myocarditis concomitant to severe COVID-19 pneumonia, which was confirmed using serial cardiac magnetic resonance. This may have important diagnostic, monitoring, and pathogenic implications. (Level of Difficulty: Intermediate.).

Garot|Jérôme|J| Amour|Julien|J| Pezel|Théo|T| Dermoch|Firas|F| Messadaa|Kamel|K| Felten|Marie-Louise|ML| Raymond|Valérie|V| Baubillier|Eric|E| Sanguineti|Francesca|F| Garot|Philippe|P|

LVEF, left ventricular ejection fraction

SARS-CoV-19, severe acute respiratory syndrome-coronavirus-2019


Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology.

Abstract: Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.

Baschal|Erin E|EE|0000-0002-8936-434X
Terhune|Elizabeth A|EA|
Wethey|Cambria I|CI|
Baschal|Robin M|RM|
Robinson|Kandice D|KD|
Cuevas|Melissa T|MT|
Pradhan|Shreyash|S|
Sutphin|Brittan S|BS|
Taylor|Matthew R G|MRG|
Gowan|Katherine|K|
Pearson|Chad G|CG|0000-0003-1915-6593
Niswander|Lee A|LA|
Jones|Kenneth L|KL|
Miller|Nancy H|NH|

idiopathic scoliosis
extracellular matrix
exome sequencing
cilia
actin cytoskeleton
microtubules


Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD-L1.

Abstract: Mounting evidence suggests that cancer stemness and immunosuppression are related, but the underlying mechanisms behind these are not clear. We previously reported that the stress granule-associated protein G3BP2 is involved in the regulation of tumor-initiating (stem) cells. In this study we show that this protein also upregulates the immune checkpoint molecule PD-L1 under conditions of stress in breast and glioblastoma cancer cells, revealing a previously-unknown connection between stemness programs, stress responses and immune checkpoint control. We also identified a significant correlation between G3BP2 and PD-L1 co-expression in tumor tissues from cancer patients. To assess the targetability of G3BP2, we employed a small molecule (C108) that binds G3BP2 and interferes with the stress response. Tumors treated with C108 had increased CD8 T cell proliferation and infiltration. Moreover, treatment of breast tumor-bearing mice with C108 resulted in a significant survival benefit and long-term cures. Cancer cells treated with C108 or cancer cells with genetically repressed G3BP2 had decreased PD-L1 expression due to enhanced mRNA degradation. Our study provides a compelling mechanism linking stress granule formation and immune checkpoint program of cancer, suggesting this link may provide new opportunities for improving anti-cancer immunotherapy.

stress granules
PD-L1
immunosuppression
stress granule-associated protein G3BP2
a small molecule C108


The Prevalence and Concurrent Pathogenic Mutations of KRAS  in Northeast Chinese Non-small-cell Lung Cancer Patients.

Abstract:
Objective
KRAS mutation is one of important driver genes in non-small-cell lung cancer (NSCLC) and the patients with KRAS  mutations benefit from the inhibitor AMG510. However, the frequency, concurrent pathogenic mutations, and clinical characteristic of KRAS  is unknown in the NSCLC population of Northeast China.

Methods
The retrospective analysis was derived from 431 NSCLC patients in Jilin Cancer Hospital between January 2018 and June 2019. The mutation frequency and concurrent mutations of KRAS  in tumor or peripheral blood was detected by next-generation sequencing (NGS).

Results
The RAS mutant rate was observed in 10.7% (46/431) of this cohort. All RAS-driver cancers are caused by mutations in the KRAS isoform, while the NRAS and HRAS isoforms were not detected. Among KRAS-mutant patients, 42 (91.3%) showed exon 2 mutation in 12 codon and 13 codon. KRAS  showed a 4.6% (20/431) mutation rate in this cohort and the highest frequency (43.5%, 20/46) in KRAS-mutant-positive patients. There was no difference between tumor tissue and plasma in terms of either KRAS or KRAS  mutation. The most frequent co-occurrence mutations with KRAS  were TP53, followed by PTEN. Furthermore, KRAS  was exclusive with STK11 mutation. KRAS  mutation was associated with age, disease stage, and smoking status (P=0.024; P=0.02; P=0.006), smoking remained an independent factor for KRAS  mutation (P=0.037), and higher mutation frequency in patients older than 60, stage I-III, or smoking in NSCLC (P=0.0151, P=0.0343, P=0.0046, respectively).

Conclusion
KRAS mutation was the only isoforms of RAS family, of these 43.5% harbored the KRAS  subtype in northeastern Chinese NSCLC patients. KRAS  is associated with age, pathological stage and smoking status, more commonly harbored TP53/PTEN mutations, and providing more genome profile for targeted therapy in local clinical practice.

Liu|Yan|Y| Li|Hui|H| Zhu|Jing|J| Zhang|Yang|Y| Liu|Xianhong|X| Li|Rixin|R| Zhang|Qiang|Q| Cheng|Ying|Y|

mutations
non-small-cell lung cancer
next-generation sequencing
tissue
plasma
KRASG12C


Circadian Regulation of Macronutrient Absorption.

Abstract: Various intestinal functions exhibit circadian rhythmicity. Disruptions in these rhythms as in shift workers and transcontinental travelers are associated with intestinal discomfort. Circadian rhythms are controlled at the molecular level by core clock and clock-controlled genes. These clock genes are expressed in intestinal cells, suggesting that they might participate in the circadian regulation of intestinal functions. A major function of the intestine is nutrient absorption. Here, we will review absorption of proteins, carbohydrates, and lipids and circadian regulation of various transporters involved in their absorption. A better understanding of circadian regulation of intestinal absorption might help control several metabolic disorders and attenuate intestinal discomfort associated with disruptions in sleep-wake cycles.

D051246:Glucose Transport Proteins, Facilitative

circadian rhythms
clock genes
glucose transporters
lipid absorption
peptide transporters


Is an opportunistic primary care-based intervention for non-responders to bowel screening feasible and acceptable? A mixed-methods feasibility study in Scotland.

Abstract:
OBJECTIVES
We aimed to test whether a brief, opportunistic intervention in general practice was a feasible and acceptable way to engage with bowel screening non-responders.

DESIGN
This was a feasibility study testing an intervention which comprised a brief conversation during routine consultation, provision of a patient leaflet and instructions to request a replacement faecal occult blood test kit. A mixed-methods approach to evaluation was adopted. Data were collected from proformas completed after each intervention, from the Bowel Screening Centre database and from questionnaires. Semi-structured interviews were carried out. We used descriptive statistics, content and framework analysis to determine intervention feasibility and acceptability.

PARTICIPANTS
Bowel screening non-responders (as defined by the Scottish Bowel Screening Centre) and primary care professionals working in five general practices in Lothian, Scotland.

PRIMARY AND SECONDARY OUTCOME MEASURES
Several predefined feasibility parameters were assessed, including numbers of patients engaging in conversation, requesting a replacement kit and returning it, and willingness of primary care professionals to deliver the intervention.

RESULTS
The intervention was offered to 258 patients in five general practices: 220 (87.0%) engaged with the intervention, 60 (23.3%) requested a new kit, 22 (8.5%) kits were completed and returned. Interviews and questionnaires suggest that the intervention was feasible, acceptable and consistent with an existing health prevention agenda. Reported challenges referred to work-related pressures, time constraints and practice priorities.

CONCLUSIONS
This intervention was acceptable and resulted in a modest increase in non-responders participating in bowel screening, although outlined challenges may affect sustained implementation. The strategy is also aligned with the increasing role of primary care in promoting bowel screening.

Calanzani|Natalia|N|
Cavers|Debbie|D|
Vojt|Gabriele|G|
Orbell|Sheina|S|
Steele|Robert J C|RJC|
Brownlee|Linda|L|
Smith|Steve|S|
Patnick|Julietta|J|
Weller|David|D|
Campbell|Christine|C|

D007722:Health Knowledge, Attitudes, Practice

bowel screening
feasibility studies
general practice
neoplasms


Localization of orexin B and orexin-2 receptor in the rat epididymis.

Abstract: The peptides orexin A (OXA) and orexin B (OXB) derived from the proteolytic cleavage of a common precursor molecule, prepro-orexin, were originally described in the rat hypothalamus. Successively, they have been found in many other brain regions as well as in peripheral organs of mammals and other less evolved animals. The widespread localization of orexins accounts for the multiple activities that they exert in the body, including the regulation of energy homeostasis, feeding, metabolism, sleep and arousal, stress, addiction, and cardiovascular and endocrine functions. Both OXA and OXB peptides bind to two G-coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) receptor, though with different binding affinity. Altered expression/activity of orexins and their receptors has been associated with a large number of human diseases. Though at present evidence highlighted a role for orexins and cognate receptors in mammalian reproduction, their central and/or local effects on gonadal functions remain poorly known. Here, we investigated the localization of OXB and OX2R in the rat epididymis. Immunohistochemical staining of sections from caput, corpus and cauda segments of the organ showed intense signals for both OXB and OX2R in the principal cells of the lining epithelium, while no staining was detected in the other cell types. Negative results were obtained from immunohistochemical analysis of hypothalamic and testicular tissues from OX2R knock-out mice (OX2R-/-) and OX1R/OX2R double knock-out (OX1R-/-; OX2R-/-) mice, thus demonstrating the specificity of the rabbit polyclonal anti-OX2R antibody used in our study. On contrary, the same antibody clearly showed the presence of OX2R in sections from hypothalamus and testis of normal mice and rats which are well known to express the receptor. Thus, our results provide the first definite evidence for the immunohistochemical localization of OXB and OX2R in the principal cells of rat epididymis.

Liguori|Giovanna|G|
Tafuri|Simona|S|
Miyoshi|Chika|C|
Yanagisawa|Masashi|M|
Squillacioti|Caterina|C|
De Pasquale|Valeria|V|
Mirabella|Nicola|N|
Vittoria|Alfredo|A|
Costagliola|Anna|A|

Orexin B
Orexin-2 receptor
Rat
Epididymis


Arum palaestinum poisoning: revenge of the witch.

Abstract: The Arum palaestinum plant is one of the 26 species of the Arum genus of the Araceae family. This plant species is found through the Mediterranean region, Western Asia, and Europe. The leaves and seeds of the plant contain needle-shaped oxalate crystals that can irritate the affected tissue (skin, oral cavity, or GI tract) upon exposure. Up to this date, there is no available literature supporting the epidemiology or the clinical manifestations of poisoning by this plant. We retrospectively reviewed all Arum palaestinum exposures to children younger than 18 years of age reported to the Israel National Poison Information Center during 2017 from the IPIC computerized data system. We extracted demographic data and clinical data from those digital files. We reviewed the files of 53 patients' files and found slight male predominance (58% vs. 42%), and the age of exposure ranged from 9 month to 15 years. The main site of exposure was at home in most cases (47%) followed by outdoor exposure in 40% of the cases. In 66% of the cases, minor clinical manifestations were reported, mainly erythema and mouth irritation, agitation, and drooling. Asymptomatic patients composed 34% of the cases. In 17% of the cases, patients were recommended to visit an ambulatory facility, and other 15% of the cases were referred to the emergency department. There were no cases of severe poisoning, upper airways compromise, or death.Conclusion: Poisoning by Arum palaestinum is one of the most common pediatric plant poisoning in Israel. Our study supports with clinical data for the first time that this poisoning is self-limited, confined to the affected mucosa, and most likely does not necessitate any intervention. What is Known • A. palaestinum poisoning is one of the most common pediatric plant poisoning in Israel. • The leaves and seeds of the plant contain needle-shaped oxalates crystals. What is New • Pediatric exposure to A. palaestinum usually causes only mild and self-limited poisoning. • Expectant observation is the preferred management of such exposure.

Maree|Aus|A| Hashavya|Saar|S| Gross|Itai|I| Asaf|Yaakov|Y| Bentur|Yedidia|Y|

Arum palaestinum
Plants
Araceae
Pediatric poisoning
Toxicology


Effects of dietary Antrodia cinnamomea fermented product supplementation on metabolism pathways of antioxidant, inflammatory, and lipid metabolism pathways-a potential crosstalk.

Abstract:
OBJECTIVE
This study was conducted to fathom the underlying mechanisms of nutrition intervention and redox sensitive transcription factors regulated by Antrodia cinnamomea fermented product (FAC) dietary supplementation in broiler chickens.

METHODS
Four hundreds d-old broilers (41±0.5 g/bird) assigned to 5 groups were examined after consuming control diet, or control diet replaced with 5% wheat bran (WB), 10% WB, 5% FAC, and 10% FAC. Liver mRNA expression of antioxidant, inflammatory and lipid metabolism pathways were analyzed. Prostaglandin E2 (PGE2) concentration in each group were tested in the chicken peripheral blood mononuclear cells (cPBMCs) of 35-d old broilers to represent the stress level of the chickens. Furthermore, these cells were stimulated with 2,2'-Azobis(2-amidinopropane) dihydrochloride (AAPH) and lipopolysaccharide (LPS) to evaluate the cell stress tolerance by measuring cell viability and oxidative species.

RESULTS
Heme oxygenase-1, glutathione S-transferase, glutamate-cysteine ligase, catalytic subunit, and superoxide dismutase, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) that regulates the above antioxidant genes were all up-regulated significantly in FAC groups. Reactive oxygen species modulator protein 1 and NADPH oxygenase 1 were both rather down-regulated in 10% FAC group as comparison with two WB groups. Despite expressing higher level than control group, birds receiving diet containing FAC had significantly lower expression level in nuclear factor-kappa B (NF-κB) and other genes (inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β, nucleotide-binding domain, leucine-richcontaining family, pyrin domain-containing-3, and cyclooxygenase 2) involving in inflammatory pathways. Additionally, except for 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase that showed relatively higher in both groups, the WB, lipoprotein lipase, Acetyl-CoA carboxylase, fatty acid synthase, fatty acid binding protein, fatty acid desaturase 2 and peroxisome proliferator-activated receptor alpha genes were expressed at higher levels in 10% FAC group. In support of above results, promoted Nrf2 and inhibited NF-κB nuclear translocation in chicken liver were found in FAC containing groups. H2O2 and NO levels induced by LPS and AAPH in cPBMCs were compromised in FAC containing diet. In 35-d-old birds, PGE2 production in cPBMCs was also suppressed by the FAC diet.

CONCLUSION
FAC may promote Nrf2 antioxidant pathway and positively regulate lipid metabolism, both are potential inhibitor of NF-κB inflammatory pathway.

Lee|M T|MT|
Lin|W C|WC|
Lin|L J|LJ|
Wang|S Y|SY|
Chang|S C|SC|
Lee|T T|TT|

Nuclear Factor (Erythroid-derived 2)-like 2 (Nrf2)


The complete mitochondrial genome of Babylonia borneensis (Gastropoda: Neogastropoda: Buccinidae).

Abstract: The complete mitochondrial genome sequence of the Babylonia borneensis is reported for the first time in this study. The length of genome was 15 556 bp, including 13 protein-coding genes, 2 ribosomal RNA genes and 22 transfer RNA genes. The nucleotide composition of the mitogenome showed AT-rich feature, with the AT content of 68.2%. Comparison of the identity of the B. borneensis mitogenome with B. areolata, B. lani and B. lutosa was 87.5%, 87.4% and 86.9%, respectively. The construction of phylogenetic tree showed high bootstrap support value. Babylonia borneensis grouped together with other Babylons and the lineages of Buccinidae was strongly supported. In this study, our results could provide a further understanding in the phylogenetic relationships of the Neogastropoda.

Sung|Chia-Hsuan|CH| Tseng|Chen-Te|CT| Wang|Liang-Jong|LJ| Li|Yu-Chi|YC| Lu|Jenn-Kan|JK|

Babylonia borneensis
Neogastropoda
mitogenome
mitochondria


Case Report: Autoimmune Encephalitis Associated With Anti-glutamic Acid Decarboxylase Antibodies: A Pediatric Case Series.

Abstract: Background: Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients, including stiff person syndrome, cerebellar ataxia, refractory epilepsy, and limbic and extralimbic encephalitis. There have been some case reports and investigations regarding anti-GAD65 antibody-associated encephalitis in adult populations, but pediatric cases are rare. We retrospectively analyzed the clinical data of three anti-GAD65 antibody-positive patients to explore the diversity and clinical features of anti-GAD65 antibody-associated pediatric autoimmune encephalitis. Methods: The clinical data of a series of three patients positive for anti-GAD65 antibody were retrospectively analyzed. GAD65 antibodies were determined in serum and CSF using a cell-based assay. Results: All three patients were female, and the onset ages were 4 years and 9 months, 6 years, and 16 years old. Their clinical phenotypes included autoimmune limbic encephalitis, extralimbic encephalitis, and encephalitis combining limbic and extralimbic encephalitis. The clinical symptoms included seizures, memory deficits, drowsiness, dysautonomia, and headache. All patients had abnormal carinal MRI and EEG. All patients received immunotherapy and had transiently good responsiveness, but one patient then experienced relapse. In follow-up, one patient with extralimbic encephalitis recovered completely, while two patients with limbic involvement had poor outcomes with refractory focal epilepsy. Conclusion: In addition to limbic encephalitis, extralimbic encephalitis is also an important phenotype in patients who are positive for anti-GAD65 antibodies. Early diagnosis and immunotherapy can improve the symptoms. However, patients with limbic encephalitis often have refractory epilepsy in the chronic phase and have a poor long-term outcome.

Ren|Changhong|C| Ren|Haitao|H| Ren|Xiaotun|X| Zhang|Weihua|W| Li|Jiuwei|J| Dai|Lifang|L| Guan|Hongzhi|H| Fang|Fang|F|

autoimmune encephalitis
pediatric
extralimbic encephalitis
limbic encephalitis
anti-glutamic acid decarboxylase 65


A descriptive study on the adjacent segment degeneration related signs following a lumbar fusion procedure.

Abstract:
Background
Adjacent segment degeneration (ASD) is a frequent complication following vertebral fusion procedures and is defined as the condition where patients recover after the initial procedure but develop compatible symptoms with radiological injuries in the segments adjacent to the fused ones at a later stage. The objective of the study was to describe the frequency and analysis of ASD related signs following a lumbar fusion procedure.

Methods
Observational descriptive retrospective study on patients with degenerative or instability conditions, operated on by posterolateral or circumferential lumbar fusion procedure. Pedicle screws, interbody peek cages (polyether-ether-ketone) and autologous bone graft were used. Clinical (pain and disability) and radiological (instability, rotation, disc height loss, radiological degeneration evaluated by X-ray and MR) variables were analysed.

Results
Postoperative disc height loss was observed in 159 free discs among 112 patients (42.6%) (95% CI: 36.4-48.8%). Anterior or posterior slippage (anterolisthesis or retrolisthesis) at the end of the follow-up period was observed in 33 patients (12.5%). Upper segment rotation increased in the postoperative period in 36 patients (13.6%). Radiological disc degeneration was observed in 107 discs among 72 patients, being more frequent in the immediate upper disc with grade 2 and 3 changes at the end of follow-up in 48 discs from 35 patients (13.6%) (95% CI: 13.4-23.1%). Radiological ASD signs were observed in 151 patients (57.4%; 95% CI: 51.2-63.6%) and 53 of them (20.2%; 95% CI: 15.1-25.2%) who also showed clinical ASD symptoms (clinical and radiological ASD). Degeneration changes with degrees IV and V shown by a preoperative and magnetic resonance (MR) study at end of the follow-up period performed in 73 patients (27.7%), were observed in 46 discs among 32 patients (43.8%) (95% CI: 31.8-55.9%).

Conclusions
Radiological ASD signs evaluated in every free disc following a lumbar fusion procedure are observed with a variable frequency. All free discs after fusion were assessed as they could indicate mechanisms of compensation of lordosis loss and should be taken into consideration in a prospective revision surgery.

Ramírez-Villaescusa|José|J|
López-Torres Hidalgo|Jesús|J|
Ruiz-Picazo|David|D|
Martín-Benlloch|Antonio|A|

lumbar fusion
Adjacent segment degeneration (ASD)
radiological signs


Attachment of a migrated MitraClip to the left ventricular apex: A novel case report.

Abstract: Herein, we report a novel case of emergency surgical mitral valve replacement for severe mitral valve regurgitation (MR) following MitraClip implantation (Abbott Laboratories, Chicago, IL, USA). Recurrent MR was caused because of the migration of the clip due to the destruction of the mitral valve leaflets with Staphylococcus aureus infective endocarditis. Intra-operative transesophageal echocardiography revealed that the clip was stuck to the left ventricular apex. Although the device could not be removed surgically, surgical repair of the valve enabled the patient to recover without any further complications.

Nagai|Mirei|M|0000-0002-2383-1400 Kurokawa|Satoshi|S| Ozaki|Makoto|M| Nomura|Minoru|M|

D019918:Heart Valve Prosthesis Implantation

infective endocarditis
transesophageal echocardiography
mitral regurgitation


Dietary niche and the evolution of cranial morphology in birds.

Abstract: Cranial morphology in birds is thought to be shaped by adaptive evolution for foraging performance. This understanding of ecomorphological evolution is supported by observations of avian island radiations, such as Darwin's finches, which display rapid evolution of skull shape in response to food resource availability and a strong fit between cranial phenotype and trophic ecology. However, a recent analysis of larger clades has suggested that diet is not necessarily a primary driver of cranial shape and that phylogeny and allometry are more significant factors in skull evolution. We use phenome-scale morphometric data across the breadth of extant bird diversity to test the influence of diet and foraging behaviour in shaping cranial evolution. We demonstrate that these trophic characters are significant but very weak predictors of cranial form at this scale. However, dietary groups exhibit significantly different rates of morphological evolution across multiple cranial regions. Granivores and nectarivores exhibit the highest rates of evolution in the face and cranial vault, whereas terrestrial carnivores evolve the slowest. The basisphenoid, occipital, and jaw joint regions have less extreme differences among dietary groups. These patterns demonstrate that dietary niche shapes the tempo and mode of phenotypic evolution in deep time, despite a weaker than expected form-function relationship across large clades.

Felice|Ryan N|RN|
Tobias|Joseph A|JA|
Pigot|Alex L|AL|
Goswami|Anjali|A|

niche
cranial morphology
diet
macroevolution