bluuebunny/crossref_metadata_2025 huggingface dataset:
Individually dosed omalizumab facilitates peanut oral immunotherapy in peanut allergic adolescents
Authors: Brandström Josef , Vetander Mirja , Sundqvist Ann‐Charlotte , Lilja Gunnar , Johansson S. G. O. , Melén Erik , Sverremark‐Ekström Eva , Nopp Anna , Nilsson Caroline
Published: July 2019

Background

Peanut oral immunotherapy (pOIT) has showed good short‐term outcomes, but allergic reactions may prevent effective up‐dosing and is a major cause of stopping OIT. In placebo‐controlled trials, omalizumab has been shown to facilitate allergen immunotherapy and increase tolerance to peanut.

Objective

We hypothesized that by combining omalizumab with pOIT, and monitor treatment effects with basophil allergen threshold sensitivity tests (CD‐sens), peanut allergic patients could safely initiate pOIT and thereafter slowly withdraw omalizumab.

Methods

This is the 2nd part of a one‐armed open phase‐2 study where peanut allergic adolescents (n = 23) started pOIT after an individualized omalizumab treatment. The pOIT dose was increased from 280 to 2800 mg peanut protein in 8 weeks followed by an individualized step‐wise withdrawal of omalizumab, based on clinical symptoms and CD‐sens levels. pOIT continued for 12 weeks followed by an open peanut challenge. Peanut CD‐sens and allergen‐binding activity (ABA) and IgE‐ab, IgG‐ab and IgG4‐ab to peanut and its components were measured during the study.

Results

All 23 patients successfully reached the 2800 mg maintenance dose. Moderate/systemic allergic reactions were rare while receiving full‐dose omalizumab. Eleven of 23 (48%) successfully continued with pOIT after omalizumab was stopped. Compared to treatment failures, median baseline IgE‐ab to peanut components Ara h 1‐3 and CD‐sens to peanut were significantly lower among successfully treated patients and IgG4‐ab to peanut, Ara h 2 and 6 increased significantly more during treatment.

Conclusions and clinical relevance

This study indicates that omalizumab is an effective adjunctive therapy for initiation and rapid up‐dosing of pOIT; however, adverse events from pOIT become more frequent as omalizumab doses are decreased.

Clinical trials registration: ClinicalTrials.gov; NCT02402231. EudraCT; 2012‐005625‐78.
Accounting for detectability and abundance in survey design for a declining species
Authors: Burns Phoebe A. , McCall Claire , Rowe Kevin C. , Parrott Marissa L. , Phillips Ben L.
Published: July 2019

Aim

As populations decline they become harder to detect simply because there are fewer animals to observe. In such cases, survey effort that was once reliable may become inadequate and the species incorrectly labelled locally extinct, causing management efforts to cease. For declining populations, then, we need to determine the survey effort necessary to detect the species, assuming only a single individual is present at a site. Detectability, however, often varies wildly with seasonal, behavioural and environmental variables. Thus, we need statistical analyses and survey design which can deal with highly variable detection rates and allow us to detect even very small populations. This is especially true in Australia, where many mammal species are experiencing serious decline. Here, we examine a threatened Australian rodent, the New Holland Mouse (Pseudomys novaehollandiae): we determine minimum survey requirements for reliable detection and show that historical survey effort is inadequate to assert local extinction.

Location

Victoria, Australia.

Methods

Using a 48‐year live‐trapping dataset, we estimated P. novaehollandiae abundance and detectability using N‐mixture modelling in a Bayesian framework, testing the effects of seasonal fluctuations and environmental variables to determine ideal conditions for occupancy surveys. We used these findings to assess the adequacy of historical resurvey efforts in confirming local extinctions.

Results

We found that detectability followed seasonal fluctuations distinct from changes in abundance, was strongly reduced by brighter moon phases, and slightly increased over the course of a survey and when raining. When abundance was low, standard historical survey efforts were inadequate to assert the species' absence with appropriate statistical confidence, indicating that further surveys would be required to test purported local extinctions.

Main conclusions

Our results highlight the potential for considerable intra‐species heterogeneity in detectability caused by shifting local abundances and survey conditions, as well as the importance of accounting for detectability when monitoring threatened and declining species.
Over‐the‐scope clip for acute esophageal variceal bleeding
Authors: Mangas‐Sanjuan Carolina , Martínez-Moreno Belén , Bozhychko Maryana , Compañy Luis , Martinez Juan , Ruiz Francisco , Casellas Juan Antonio , Aparicio José Ramón
Published: July 2019

Over‐the‐scope clip (OTSC) has been reported to control non‐variceal bleeding; however, the use of this device for acute variceal hemorrhage (AVH) is very limited. We report our experience regarding the use of OTSC in patients with AVH in terms of technical success and safety. A retrospective clinical experience case series study was conducted from October 2017 to June 2019 at two tertiary care centers. Adult patients with AVH as a result of small varices managed with OTSC after endoscopic band ligation (EBL) failure were enrolled. Standard gastroscope and OTSC ‘type a’ with a cap of 11 mm in diameter were used in all procedures. Total of five patients with chronic liver disease (Child‐Pugh score ≤8) and portal hypertension (hepatic venous pressure gradient, mean 14.4 ± 1.3 mmHg) were included. Four of them presented collapse of the bleeding varix, and one had wall disruption associated with fibrosis secondary to prior banding. We were able to stop AVH in all patients without clip‐related adverse events during a 30‐day follow‐up period. Two patients developed solid food dysphagia after 3 months of clip deployment that resolved after removal using a bipolar cutting device. Twin grasper or anchor were not used to aid or facilitate the approximation of opposite edges in any patient. No additional local therapies or new endoscopic session for variceal eradication were required. This case series shows preliminary success controlling AVH with OTSC after EBL failure in patients with small varices. Esophageal dysphagia may appear as a complication during follow up but it can be resolved by clip removal.
Prevalence of drooling, swallowing, and feeding problems in cerebral palsy across the lifespan: a systematic review and meta‐analyses
Authors: Speyer Renée , Cordier Reinie , Kim Jae‐Hyun , Cocks Naomi , Michou Emilia , Wilkes‐Gillan Sarah
Published: July 2019

Aim

To determine the prevalence of drooling, swallowing, and feeding problems in persons with cerebral palsy (CP) across the lifespan.

Method

A systematic review was conducted using five different databases (AMED, CINAHL, Embase, MEDLINE, and PubMed). The selection process was completed by two independent researchers and the methodological quality of included studies was assessed using the STROBE and AXIS guidelines. Meta‐analyses were conducted to determine pooled prevalence estimates of drooling, swallowing, and feeding problems with stratified group analyses by type of assessment and Gross Motor Function Classification System level.

Results

A total of 42 studies were included. Substantial variations in selected outcome measures and variables were observed, and data on adults were limited. Pooled prevalence estimates determined by meta‐analyses were as high as 44.0% (95% confidence interval [CI] 35.6–52.7) for drooling, 50.4% (95% CI 36.0–64.8) for swallowing problems, and 53.5% (95% CI 40.7–65.9) for feeding problems. Group analyses for type of assessments were non‐significant; however, more severely impaired functioning in CP was associated with concomitant problems of increased drooling, swallowing, and feeding.

Interpretation

Drooling, swallowing, and feeding problems are very common in people with CP. Consequently, they experience increased risks of malnutrition and dehydration, aspiration pneumonia, and poor quality of life.

What this paper adds

Drooling, swallowing, and feeding problems are very common in persons with cerebral palsy (CP).

The prevalence of drooling, swallowing, and feeding problems is 44.0%, 50.4%, and 53.5% respectively.

There are limited data on the prevalence of drooling, swallowing, and feeding problems in adults.

Higher Gross Motor Function Classification System levels are associated with higher prevalence of drooling, swallowing, and feeding problems.

There is increased risk for malnutrition, dehydration, aspiration pneumonia, and poor quality of life in CP.
Political corruption and capture of the minority
Authors: Giannoccolo Pierpaolo , Lisciandra Maurizio
Published: July 2019

This article presents a model of political corruption in which a briber can choose either to bribe only the incumbent party or to capture also the opposition party to sterilize its monitoring role. The analysis also explores interparty collusion, media independence, and political contestability. The model suggests that policies aiming to strengthen the role of minorities can produce ambiguous effects as they may induce bribers' avoidance behavior. Reputational sanctions appear to be less effective than criminal ones, although political contestability increases their deterrence effect. Paradoxically, harsh criminal sanctions may induce tacit collusion because minorities highly regard their outcomes once in power.
Increased risk of epilepsy in patients registered in the Swedish Dementia Registry
Authors: Zelano J. , Brigo F. , Garcia‐Patek S.
Published: July 2019

Background and purpose

Data on epilepsy in dementia, particularly on its risk factors, are scarce. Confounding comorbidities and the rising incidence of epilepsy in older age have hampered studies in this field. The occurrence and risk factors for epilepsy in the Swedish Dementia Registry (SveDem), a large cohort of patients with dementia, have been examined.

Methods

Information on epilepsy and seizure‐related diagnoses, comorbidities and survival were extracted for all individuals in SveDem (n = 81 192) and three randomly selected age‐ and gender‐matched controls from the population register, excluding all with a dementia diagnosis (n = 223 933). The risk of epilepsy following dementia diagnosis was estimated with Kaplan–Meier curves, and Cox proportional hazard modelling was used to identify risk factors and adjust for comorbidities.

Results

A diagnosis of epilepsy was found more frequently amongst dementia patients [4.0%, 95% confidence interval (CI) 3.8–4.1] than controls (1.9%, 95% CI 1.9–2.0). The risk of incident epilepsy after dementia was 2.1% (95% CI 1.9–2.3) at 5 years and 4.0% (95%CI 3.4–4.6) at 10 years, compared to 0.8% (95% CI 0.8–0.8) and 1.6% (95% CI 1.4–1.8) respectively for controls. The risk was greatest for early‐onset Alzheimer's disease. In multivariate analysis, dementia was associated with a hazard ratio of 2.52 (95% CI 2.31–2.74) for epilepsy. Young age, male sex, stroke, brain trauma, brain tumour and low Mini‐Mental State Examination score significantly increased the risk.

Conclusions

Dementia, particularly young‐onset Alzheimer's disease, increases the risk of subsequent epilepsy. Further studies are needed to determine optimal management and the impact of epilepsy on prognosis.
Postoperative memory prognosis in temporal lobe epilepsy surgery: The contribution of postictal memory
Authors: Sveikata Lukas , Kavan Nicole , Pegna Alan J. , Seeck Margitta , Assal Frederic , Momjian Shahan , Schaller Karl , Vulliemoz Serge
Published: July 2019

Objective

The prediction of verbal memory decline after temporal lobe epilepsy (TLE) surgery remains difficult at an individual level. We evaluated the prognostic value of postictal memory testing in predicting the postoperative verbal memory function.

Methods

Sixty‐three consecutive patients were included in the analysis who underwent TLE surgery at our center with preoperative interictal/postictal and postoperative memory testing. Verbal memory was evaluated using the Rey Auditory Verbal Learning Test (RAVLT). We used reliable change indices with 90% confidence interval (90% RCIs) to evaluate a significant postoperative memory decline. The sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC), and accuracy (ACC) were calculated. The analysis was performed for all TLE patients and for the subgroup with hippocampal sclerosis (HS).

Results

Left‐TLE patients (n = 31) had lower verbal memory scores on RAVLT than right‐TLE at 3 months (57% vs 78%) and 12 months (53% vs 78%) after surgery. The 90% RCI was estimated to be a loss of 4 out of 15 items. The predictive value was Sn = 42%, Sp = 84%, PPV = 39%, NPV = 86%, AUC = 0.630, and ACC = 76% to predict a verbal memory decline in the whole group (n = 63). In HS patients (n = 41), the postictal verbal memory test had Sn = 50%, Sp = 88%, PPV = 50%, NPV = 88%, AUC = 0.689, and ACC = 81% to predict a significant postoperative decline.

Significance

Postictal memory is a noninvasive bedside memory test that can help predict the postoperative verbal memory decline in patients with HS with an overall accuracy of 81%.
Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes
Authors: Huang Wei , Cheng Chao , Shan Wen‐Shan , Ding Zhen‐Fei , Liu Fu‐En , Lu Wei , He Wei , Xu Jie‐Gou , Yin Zong‐Sheng
Published: July 2019

Osteoarthritis (OA) is a common joint disease characterized by the progressive degeneration of articular cartilage with no effective treatment methods available. Cartilage degeneration is closely related to an anabolic and catabolic imbalance in chondrocytes, and accumulating evidence has revealed that autophagy is a crucial protective mechanism that maintains the balance of anabolic and catabolic activities. Therefore, studies aiming to identify additional genes that regulate autophagy as a promising therapeutic strategy for OA are needed. In this study, we analyzed the GSE113825 datasets from Gene Expression Omnibus and validated that serum‐ and glucocorticoid‐regulated kinase 1 (SGK1) was upregulated in OA cartilage. Based on the results from loss‐of‐function studies, SGK1 silencing promoted the deposition of glycosaminoglycans in interleukin 1 beta (IL‐1β)‐treated chondrocytes, and significantly alleviated IL‐1β‐induced downregulation of Collagen II and Aggrecan, as well as the upregulation of a disintegrin and metalloproteinase with thrombospondin motifs 5 and matrix metalloproteinase‐13. Furthermore, SGK1 knockdown reversed the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating autophagy. Moreover, SGK1 directly bound to forkhead box protein O1 (FoxO1) and increased its phosphorylation, which in turn resulted in its translocation from the nucleus. The decreased FoxO1 levels led to a decrease in LC3‐I/LC3‐II conversion and Beclin‐1 levels, subsequently inhibiting autophagosome formation and increasing P62 levels, thus indicating a downregulation of autophagy. Taken together, we identified a critical role of SGK1 in the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance, which may represent a potential novel therapeutic target for OA.
Complex genetic interactions between DNA polymerase β and the NHEJ ligase
Authors: Kurosawa Aya , Kuboshima Hiroyuki , Adachi Noritaka
Published: July 2019

Mammalian cells possess multiple pathways for repairing various types of DNA damage. Although the molecular mechanisms of each DNA repair pathway have been analyzed by biochemical analysis and cell biological analysis, interplay between different pathways has not been fully elucidated. In this study, using human Nalm‐6–mutant cell lines, we analyzed the relationship between the base excision repair factor DNA polymerase β (POLβ) and DNA ligase IV (LIG4), which is essential for DNA double‐strand break (DSB) repair by non‐homologous end‐joining (NHEJ). We found that cells lacking both POLβ and LIG4 grew significantly more slowly than either single mutant, indicating cooperative functions of the two proteins in normal cell growth. To further investigate the genetic interaction between POLβ and LIG4, we examined DNA damage sensitivity of the mutant cell lines. Our results suggested that NHEJ acts as a backup pathway for repairing alkylation damage (when converted into DSBs) in the absence of POLβ. Surprisingly, despite the critical role of POLβ in alkylation damage repair, cells lacking POLβ exhibited increased resistance to camptothecin (a topoisomerase I inhibitor that induces DNA single‐strand breaks), irrespective of the presence or absence of LIG4. A LIG4‐independent increased resistance associated with POLβ loss was also observed with ionizing radiation; however, cells lacking both POLβ and LIG4 were more radiosensitive than either single mutant. Taken together, our findings provide novel insight into the complex interplay between different DNA repair pathways.
The national blueprint for 21st century data and specimen collection and observational cohort studies: NHLBI State of the Science Workshop on factor VIII inhibitors
Authors: Konkle Barbara A. , Recht Michael ,   on behalf of the members of Working Group 2, the NHLBI State of the Science Workshop on factor VIII inhibitors: Generating a national blueprint for future research
Published: July 2019

Introduction

A devastating complication of hemophilia A, the congenital deficiency of coagulation factor VIII (FVIII), therapy is the development of inhibitory antibodies (inhibitors) to infused FVIII concentrate affecting up to 30% of people with the most severe form of the disease. Although the number of patients affected by hemophilia A with inhibitors is small, the physical, emotional, financial, and public health impact is overwhelming to the patient, family, and medical system. To best serve this patient population, as well as enhance knowledge around this complication, a robust data and specimen collection strategy must be designed.

Aim

Working Group 2 (WG2) of the National Heart, Lung, and Blood Institute (NHLBI)‐ sponsored State of the Science (SOS) workshop on factor VIII inhibitors in 2018 was tasked with developing recommendations around the conduct of research, modeling efficient data and specimen collection, developing infrastructure support, establishing partnerships with all stakeholders, including international collaborators, addressing ethical issues, maximizing patient/family engagement and promoting training opportunities.

Methods

A group with diverse expertise was assembled who reviewed the current state of data and specimen collection in patients with hemophilia and developed recommendations for the future.

Results

Our results were presented at the SOS Workshop where additional feedback was gained.

Conclusion

Our charge and recommendations are summarized in this manuscript.
Elimination of intravenous alendronate by hemodialysis: A kinetic study
Authors: Iseri Ken , Watanabe Makoto , Lee Xiao‐Pen , Yamada Miho , Ryu Kakei , Iyoda Masayuki , Uchida Naoki , Sato Keizo , Shibata Takanori
Published: July 2019

Introduction

The potential utility of intravenous alendronate for the treatment of osteoporosis in hemodialysis patients was recently reported. However, the pharmacokinetics of intravenous alendronate in patients on hemodialysis is not clear.

Methods

Six hemodialysis patients (mean age, 80.5 years) with osteoporosis who had received intravenous alendronate prior to the study were enrolled. The participants received a 30‐min infusion of 900‐μg alendronate intravenously at the beginning of the dialysis session. The blood flow rate (Qb) and dialysate flow rate (Qd) were set at 200 mL/min and 500 mL/min, respectively. All patients used the same dialyzer (1.5‐m2 polysulfone membrane). At the completion of administration, plasma and dialysate samples were collected, and alendronate concentrations were determined using metal‐free high‐performance liquid chromatography (HPLC)‐tandem mass spectrometry (MS/MS).

Results

The plasma arterial alendronate concentration was 150.9 ± 46.09 ng/mL. It decreased through the dialyzer to 76.1 ± 34.1 ng/mL (venous alendronate concentration). Mean alendronate clearance was 113.9 ± 25.6 mL/min. Mean alendronate removal by hemodialysis, measured by the difference in arterial–venous concentrations, was 51.8%.

Conclusions

Fifty percent of intravenous alendronate was removed by hemodialysis, which is nearly equal to elimination of alendronate in patients with normal renal function. The elimination by hemodialysis would decrease the risk of excessive accumulation in bone. UMIN 000027182.
A nonsurgical and nonpharmacological care bundle for preventing upper urinary tract damage in patients with spinal cord injury and neurogenic bladder
Authors: Fang Hengying , Lin Jinxiang , Liang Limin , Long Xiaofang , Zhu Xiaojia , Cai Wenzhi
Published: July 2019

Aim

To establish a care bundle in spinal cord injury patients with neurogenic bladder to avoid upper urinary tract damage and to provide guidance for health care staff in use of nonsurgical and nonpharmacological adjunctive strategies to improve patients' clinical outcomes.

Background

Prevention of upper urinary tract damage is critical in the management of spinal cord injury patients with a neurogenic bladder, but there are no authoritative guidelines or high‐quality randomized controlled trials.

Design

The study was conducted on the basis of Fulbrook and Mooney's seven‐step method for care bundle development.

Data Sources

The databases PubMed, Embase, Science Citation Index, the Cumulative Index to Nursing and Allied Health Literature, the National Guideline Clearinghouse, the Cochrane Library, China Biology Medicine, China National Knowledge Infrastructure, and China Dissertation Database were searched from the date of each database's inception to April 2017.

Review methods

We evaluated the literature according to the Joanna Briggs Institute evidence pre‐ranking and grade recommendation system (2014 version). The results were examined using a self‐designed data extraction.

Results

A three‐element cluster including clean intermittent catheterization, bladder function training, and transcutaneous low‐frequency pulsed electrical stimulation was formed.

Conclusion

The development of this bundle can provide a scientific basis for effective prevention of neurogenic upper urinary tract damage in clinical practice.
Transmission of dental fear from parent to adolescent in an Appalachian sample in the USA
Authors: McNeil Daniel W. , Randall Cameron L. , Cohen Lindsey L. , Crout Richard J. , Weyant Robert J. , Neiswanger Katherine , Marazita Mary L.
Published: July 2019

Background

Dental fear/anxiety is associated with numerous negative outcomes. State dental fear is known to be transmitted from parents to their children in the dental setting, but it is not known how trait fear/anxiety might be shared between parents and offspring long term, and especially for adolescents.

Aim

This study aimed to: (a) compare dental fear levels of adolescents and their parents; (b) predict adolescent dental fear based on demographic variables, fear of pain, and parental dental fear; and, (c) determine relative contributions of mothers' and fathers' dental fear to adolescent fear.

Design

In this cross‐sectional study, the Dental Fear Survey and Fear of Pain Questionnaire‐9 were administered to 350 adolescents (age range 11‐17) and 515 of their parents, withttest and ANOVA used to calculate between‐group differences; multiple linear regression was used to predict adolescent fear from parent fear.

Results

Adolescents' dental fear was predicted by their own fear of pain and their parents' dental fear, but not their parents' fear of pain nor their own age or gender. When considered together, fathers' but not mothers' dental fear predicted adolescents' dental fear.

Conclusions

Parents' fears/anxieties about dentistry are associated with adolescents' dental fear in a manner suggestive of intergenerational transmission.
Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers
Authors: Ahonen Jouni , Olkkola Klaus T. , Neuvonen Pertti J.
Published: July 2019

Twelve healthy volunteers were given orally placebo, itraconazole 100 mg or terbinafine 250 mg for 4 days. Midazolam 7.5 mg was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests carried out for 17 h. Itraconazole increased the area under the midazolam concentration‐time curve six‐fold (P < 0.001), the peak concentration 2.5‐fold (P < 0.001) and the elimination half‐life two‐fold (P < 0.001) compared with placebo and terbinafine pretreatments. The pharmacokinetic parameters did not differ between placebo and terbinafine phases. The higher concentrations of midazolam during the itraconazole phase were associated with increased effects. In contrast to itraconazole, terbinafine had no effect on midazolam pharmacokinetics and psychomotor performance tests were unchanged from placebo.
Increased risk of head injury in pediatric patients with attention deficit hyperactivity disorder
Authors: Grigorian Areg , Nahmias Jeffry , Dolich Matthew , Barrios Cristobal , Schubl Sebastian D. , Sheehan Brian , Lekawa Michael
Published: July 2019

Objective

The prevalence of attention deficit hyperactivity disorder (ADHD) in the general pediatric population is 7%, whereas the prevalence in trauma is unknown. We hypothesized pediatric patients with ADHD would have a higher risk of involvement in a mechanism of injury (MOI) requiring constant attention to surroundings, such as a bicycle collision.

Methods

The Pediatric Trauma Quality Improvement Program (2014–2016) was queried for patients with ADHD. Patients, less than 16 years of age, with ADHD were compared to those without ADHD.

Results

The prevalence of ADHD was 2.5% (2,866). ADHD patients had higher risk for bicycle collision (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.59–2.15; p < .001). ADHD bicyclists were less likely to wear a helmet (9.4% vs. 18.2%, p = .003) and had a higher rate of traumatic brain injury (TBI; 55.6% vs. 39.7%, p < .001), compared to non‐ADHD bicyclists.

Conclusions

Pediatric ADHD patients have a 60% higher risk of being involved in a bicycle collision. ADHD patients that are involved in a bicycle collision are less likely to wear a helmet with a higher rate of TBI. Increased public awareness, education, and supervision may help reduce risk of bicycle collisions and TBI in this population.
Angiotensin II receptor blocker attenuates stress pressor response in young adult African Americans
Authors: Jeong Jin Hee , Hanevold Coral , Harris Ryan A. , Kapuku Gaston , Pollock Jennifer , Pollock David , Harshfield Gregory
Published: July 2019

African Americans (AAs) are susceptible to hypertension (HTN) and its associated organ damage leading to adverse cardiovascular (CV) outcomes. Psychological stress is proposed to contribute to the development of HTN; however, the potential role of the renin‐angiotensin system (RAS) in stress‐related HTN in AAs is largely unknown. In this study, we tested the hypothesis that activation of RAS is a potential contributing factor for altered CV responses to stress, and suppression of angiotensin II (Ang II) activity will improve hemodynamic responses to a prolonged mental stressor in healthy young AAs. Utilizing a double‐blind, randomized, crossover study design, 132 normotensive AAs (25 ± 7 years) were treated with either a placebo (PLC) or 150 mg/d irbesartan (an Ang II type 1 receptor blocker; ARB) for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before, during and after a 45 minute‐mental stress. The magnitude of stress‐induced increase in blood pressure with ARB was blunted and delayed compared to PLC. Systolic blood pressure at the end of recovery on ARB was significantly lower compared to either PLC (110 ± 13 vs 117 ± 12 mm Hg respectively; P < 0.001) or the prestress level on ARB (P = 0.02). ARB treatment reduced overall vasoconstriction and improved poststress UNaV. ARB attenuated blood pressure responses to mental stress and improved the poststress BP recovery process which were partly linked to reduced overall vasoconstriction and improved stress‐induced UNaV in young adult AAs prior to the development of disease conditions. These results suggest that treatment approaches that inhibit RAS action could have significant relevance to potentially lower susceptibility to stress responses and eventually the premature development of HTN in AAs.
Different signalling in infarcted and non‐infarcted areas of rat failing hearts: A role of necroptosis and inflammation
Authors: Lichý Martin , Szobi Adrián , Hrdlička Jaroslav , Horváth Csaba , Kormanová Veronika , Rajtík Tomáš , Neckář Jan , Kolář František , Adameová Adriana
Published: July 2019

Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non‐infarcted areas separately and its mechanistic link with main features of HF. Post‐infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42‐day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post‐infarction failing hearts, TNF and pSer229‐RIP3 levels were comparably increased in both infarcted and non‐infarcted areas. Its cytotoxic downstream molecule p‐MLKL, indicating necroptosis execution, was detected in infarcted area. In non‐infarcted area, despite increased pSer229‐RIP3, p‐MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro‐necroptotic environment in non‐infarcted area. Collagen deposition and the inflammatory csp‐1‐IL‐1β axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non‐infarcted tissue, apoptosis was found to play an insignificant role. p‐MLKL‐driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non‐infarcted areas of failing hearts, respectively. Upregulation of pSer229‐RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression.
LncRNA MEG3 inhibits cell proliferation and induces apoptosis in laryngeal cancer via miR‐23a/APAF‐1 axis
Authors: Zhang Xiaowen , Wu Nan , Wang Jin , Li Zhijie
Published: July 2019

Long non‐coding RNA (LncRNA) MEG3 serves a regulatory role in the progression of several types of cancer, but the role of MEG3 in laryngeal cancer is still unknown. The aim of this study was to explore the regulatory role and mechanism of MEG3 in laryngeal cancer. MEG3 expression in 50 laryngeal cancer tissue samples was detected by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR). The effects of MEG3 overexpression on laryngeal cancer cells were investigated in vitro and in vivo. The mechanism of competitive endogenous RNA (ceRNA) was validated through luciferase reporter assay, RT‐qPCR and Western blotting. MEG3 was down‐regulated in laryngeal cancer tissues, and the low MEG3 expression was associated with advanced clinical stage. Additionally, MEG3 overexpression inhibited the proliferation and induced the apoptosis of laryngeal cancer cells in vitro and in vivo. Particularly, MEG3 bound to miR‐23a specifically and a reciprocal negative regulation existed between miR‐23a and MEG3. Moreover, MEG3 up‐regulated apoptotic protease activating factor‐1 (APAF‐1), a known miR‐23a's target, thereby leading to the activation of caspase‐9 and caspase‐3. Meanwhile, these activated effects were rescued by miR‐23a overexpression. In conclusion, the present study demonstrated that MEG3 functions as a novel tumour suppressive LncRNA in laryngeal cancer for the first time. Furthermore, MEG3 may act as a ceRNA to regulate APAF‐1 expression by competitive binding to miR‐23a, thereby regulating the progression of laryngeal cancer.
Stachydrine prevents LPS‐induced bone loss by inhibiting osteoclastogenesis via NF‐κB and Akt signalling
Authors: Meng Jiahong , Zhou Chenhe , Zhang Wenkan , Wang Wei , He Bin , Hu Bin , Jiang Guangyao , Wang Yangxin , Hong Jianqiao , Li Sihao , He Jiamin , Yan Shigui , Yan Weiqi
Published: July 2019

Osteoclast overactivation‐induced imbalance in bone remodelling leads to pathological bone destruction, which is a characteristic of many osteolytic diseases such as rheumatoid arthritis, osteoporosis, periprosthetic osteolysis and periodontitis. Natural compounds that suppress osteoclast formation and function have therapeutic potential for treating these diseases. Stachydrine (STA) is a bioactive alkaloid isolated from Leonurus heterophyllus Sweet and possesses antioxidant, anti‐inflammatory, anticancer and cardioprotective properties. However, its effects on osteoclast formation and function have been rarely described. In the present study, we found that STA suppressed receptor activator of nuclear factor‐κB (NF‐κB) ligand (RANKL)‐induced osteoclast formation and bone resorption, and reduced osteoclast‐related gene expression in vitro. Mechanistically, STA inhibited RANKL‐induced activation of NF‐κB and Akt signalling, thus suppressing nuclear factor of activated T cells c1 induction and nuclear translocation. In addition, STA alleviated bone loss and reduced osteoclast number in a murine model of LPS‐induced inflammatory bone loss. STA also inhibited the activities of NF‐κB and NFATc1 in vivo. Together, these results suggest that STA effectively inhibits osteoclastogenesis both in vitro and in vivo and therefore is a potential option for treating osteoclast‐related diseases.
Glucocorticoid receptor inhibits Müller glial galectin‐1 expression via DUSP1‐dependent and ‐independent deactivation of AP‐1 signalling
Authors: Hirose Ikuyo , Kanda Atsuhiro , Noda Kousuke , Ishida Susumu
Published: July 2019

Galectin‐1/LGALS1 is a hypoxia‐induced angiogenic factor associated with diabetic retinopathy (DR). Recently, we elucidated a hypoxia‐independent pathway to produce galectin‐1 in Müller glial cells stimulated by interleukin (IL)‐1β. Here we revealed glucocorticoid receptor (GR)‐mediated inhibitory mechanisms for Müller glial galectin‐1/LGALS1 expression. Activator protein (AP)‐1 site in the LGALS1 enhancer region, to which activating transcription factor2, c‐Fos and c‐Jun bind, was shown to be essential for IL‐1β‐induced galectin‐1/LGALS1 expression in Müller cells. Ligand (dexamethasone or triamcinolone acetonide)‐activated GR induced dual specificity phosphatase (DUSP)1 expression via the glucocorticoid response element and attenuated IL‐1β‐induced galectin‐1/LGALS1 expression by reducing phosphorylation of these AP‐1 subunits following AKT and extracellular signal‐regulated kinase (ERK)1/2 deactivation. Moreover, activated GR also caused DUSP1‐independent down‐regulation of IL‐1β‐induced LGALS1 expression via its binding to AP‐1. Administration of glucocorticoids to mice attenuated diabetes‐induced retinal galectin‐1/Lgals1 expression together with AKT/AP‐1 and ERK/AP‐1 pathways. Supporting these in vitro and in vivo findings, immunofluorescence analyses showed co‐localization of galectin‐1 with GR and phosphorylated AP‐1 in DUSP1‐positive glial cells in fibrovascular tissues from patients with DR. Our present data demonstrated the inhibitory effects of glucocorticoids on glial galectin‐1 expression via DUSP1‐dependent and ‐independent deactivation of AP‐1 signalling (transactivation and transrepression), highlighting therapeutic implications for DR.
Against Associate EU Citizenship
Authors: van den Brink Martijn , Kochenov Dimitry
Published: July 2019

UK nationals will lose their EU citizenship status as a result of the Brexit referendum. To prevent this, several commentators, including the European Parliament Brexit negotiator Guy Verhofstadt, proposed to grant associate EU citizenship to UK nationals to safeguard their rights as EU citizens after Brexit. We make the case against associate EU citizenship, dismissing it on three grounds. First, it violates the letter and the spirit of EU law. Second, it violates core EU values, including the EU's promise to respect the constitutional traditions of member states and the values of democracy and the rule of law. Third, it is against EU's interests, as associate EU citizenship fails to respect reciprocity in EU relations with third countries and undermines the coherence of the edifice of EU constitutionalism.
Family‐focused cognitive behavioral treatment for depressed adolescents in suicidal crisis with co‐occurring risk factors: a randomized trial
Authors: Esposito‐Smythers Christianne , Wolff Jennifer C. , Liu Richard T. , Hunt Jeffrey I. , Adams Leah , Kim Kerri , Frazier Elisabeth A. , Yen Shirley , Dickstein Daniel P. , Spirito Anthony
Published: July 2019

Background

Suicide is the second leading cause of death among adolescents. The purpose of this study was to test a family‐focused outpatient cognitive behavioral treatment (F‐CBT) protocol for depressed adolescents following psychiatric hospitalization for a suicide attempt or suicidal ideation, and who had a co‐occurring risk factor (suicidal behavior prior to the index admission, nonsuicidal self‐injury, and/or a substance use disorder), in a randomized Phase 2 efficacy trial.

Method

One hundred forty‐seven adolescents (mean age = 14.91 years; 76.2% female, 85.5% White) and their families, recruited primarily from an inpatient psychiatric hospitalization program, were randomly assigned to F‐CBT or enhanced treatment‐as‐usual (E‐TAU). A suicide attempt was the primary outcome variable. Depression, suicidal ideation, and nonsuicidal self‐injury are also reported here. Assessments were completed at pretreatment as well as 6, 12, and 18‐months postrandomization (Trial Registration ClinicalTrials.gov Identifier: NCT01732601).

Results

In the sample as a whole, rates of attempts decreased from 20% at 6 months to 9% at 12 months to 7% at 18 months. There was no evidence of a significant difference between treatment arms in rates of suicide attempts, major depressive disorder, suicidal ideation, or nonsuicidal self‐injury at any of the postrandomization assessment points.

Conclusions

Though F‐CBT was associated with reductions in suicidality, depression, and nonsuicidal self‐injury, E‐TAU showed an equally strong effect. Greater frequency of F‐CBT treatment sessions, particularly at the start of care, and alternative approaches to transitioning to care at 12 months, may be necessary when using F‐CBT with this population.
Effects of intracoelomic transmitter implantation on metabolic rate, swimming performance, growth and survival in juveniles of two salmonids
Authors: Darcy Andrew P. , Raby Graham D. , Johnson Timothy B. , Pitcher Trevor E. , Fisk Aaron T.
Published: July 2019

In this study, we investigated the effects of acoustic tag implantation on standard and routine metabolic rate (SMR and RMR, estimated via oxygen consumption), critical swimming speed (Ucrit), survival and growth in juveniles of rainbow trout Oncorhynchus mykiss and lake trout Salvelinus namaycush. Tag burdens ranged from 1.8% to 7.5% across the two species. Growth rates in acoustic‐tagged fish were equal to or higher than those in other treatments. Acoustic‐tagged S. namaycush had a marginally lower Ucrit than controls but that effect was not replicated in the O. mykiss experiment. Tagging did not have clear effects on metabolic rate but there was an interaction whereby SMR and RMR tended to increase with time since surgery in tagged O. mykiss but not in other treatments (the same trend did not occur in S. namaycush). Survival was high across treatments (mean 98% survival among O. mykiss, 97.5% among S. namaycush). There were no statistically significant effects of tag burden (percentage of body mass) except for a weak negative relationship with growth rate (across species) and a weak positive relationship with Ucrit but only in the O. mykiss. Collectively, our findings suggest there were minor, context‐dependent effects of acoustic tagging in juvenile S. namaycush and O. mykiss during an eight‐week laboratory experiment. Further research will be required to assess whether tagging can cause meaningful behavioural effects in these species in captivity or in the wild and whether there is a tag burden threshold above which deleterious effects consistently occur.
Stereological estimation of particle shape from vertical sections
Authors: Y. LARSEN NICK , ZIEGEL JOHANNA F. , NYENGAARD JENS R. , JENSEN EVA B. VEDEL
Published: July 2019

In the present paper, we describe a new simple stereological method of estimating volume tensors in 3D from vertical sections. The volume tensors provide information about particle shape in 3D. In a model‐based setting, the method requires that the particle distribution is invariant under rotations around the vertical axis. In a design‐based approach, where the vertical section is uniformly rotated around the vertical axis, the method provides information about an index of elongation of the particles in the direction of the vertical axis. The method has been implemented on human brain tissue for the analysis of neurons in layer III of the medial frontal gyrus of Brodmann Area 46. In the actual implementation, the new estimator shows similar precision as an earlier estimator, based on an optical rotator design, but it is a factor 3 faster to collect the measurements for the new estimator. Furthermore, the calculations needed for determining the new estimator are much simpler.

Lay Description

A new method is described for estimating volume tensors in 3 dimensions based on the stereological method: planar rotator. In general, volume tensors may provide information about particle volume, shape and direction. The new estimator was implemented on human brain tissue for the analysis of neurons in layer III of the medial frontal gyrus on Brodmann Area 46 and compared to a previous published method, based on an optical rotator design. The new estimator shows similar precision as the earlier estimator, but it is a factor 3 faster to collect the measurements. Besides, the calculations behind the new estimator are simpler and easier to implement to a software program.
Appropriate Nursing Home Nurse Hours per Resident Day in Korea: A Secondary Analysis of Longitudinal Data
Authors: Shin Juh Hyun
Published: July 2019

Purpose

To encourage the enactment of laws about mandatory nurse staffing in nursing homes, researchers should provide evidence of concrete nurse hours per resident day (HPRD). This article estimates optimal nurse staffing HPRD to achieve increased quality‐of‐care outcomes for nursing home residents.

Design

Secondary analysis of longitudinal data.

Methods

This study used secondary analysis of longitudinal nursing home survey data. Nurse staffing HPRD and quality‐of‐care survey data accrued from nursing homes operating under long‐term‐care insurance in Korea. The collected data include a total of six quarterly base measurements on nurse staffing HPRD and 15 quality indicators from 2014 to 2017. The proposed optimization model emerged to most appropriately combine nurse staffing HPRD to increase quality‐of‐care outcomes for nursing home residents by 3% to 8%. Optimal outcome measures were fixed as best outcomes and compiled from 15 nursing‐sensitive quality indicators.

Findings

Constrained nonlinear optimization was used for analysis. A 12% increase in registered nurse (RN) HPRD (from 0.168 HPRD [10 min 5 s] to 0.177 [10 min 38 s]) aligned with a 3% improvement in quality‐of‐care outcomes. A 20% RN HPRD increase aligned with a commensurate 5% to 8% increase in compiled quality‐of‐care outcomes (from 0.168 HPRD [10 min 5 s] to 0.202 HPRD [12 min 6 s]) without increasing certified nurse aide HPRD. About a 30% RN HPRD increase aligned with a commensurate 5% to 8% increase in compiled quality‐of‐care outcomes (from 0.168 HPRD [10 min 5 s] to 0.218 HPRD [13 min 6 s]) without increasing certified nurse aide HPRD.

Conclusions

It is urgent to institute mandatory nurse HPRD for nursing homes in Korea by law. This research provides evidence that increasing nursing HPRD improved residents’ outcomes in nursing homes.

Clinical Relevance

Findings from the optimization model implied that stable care by RNs in nursing homes is a key factor in achieving acceptable quality of care for residents.
The Relationship Between Depression and Frailty in Community‐Dwelling Older People: A Systematic Review and Meta‐Analysis of 84,351 Older Adults
Authors: Chu Wen , Chang Shu‐Fang , Ho Hsu‐Yu , Lin Hsiang‐Chun
Published: July 2019

Objectives

In this study we investigated the correlation between depression and frailty in older adults. Additionally, correlations among study designs (prospective vs. cross‐sectional), regions, depression indices, frailty indices, covariance corrections, and sexes were explored to support the analysis.

Methods

A systematic literature review and meta‐analysis were conducted. A total of 84,351 older adults, all 65 years of age or older, were analyzed. Both authors independently extracted and examined retrieved articles. Searched keywords included “depression” or “depressive”; “frailty” or “frail”; and “older people,” “elderly,” “geriatric,” or “senior.” Articles published between January 2000 and December 2016 were searched. A literature quality assessment was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic

Reviews and Meta‐Analyses

Systematic literature searches were conducted on the Embase, PubMed, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library databases, and collected studies were analyzed using a random effects model.

Results

Fourteen studies on people 65 years of age or older were collected, and a correlation analysis was conducted for depression and frailty. According to the meta‐analysis, the risk for frailty due to depression was nonsignificant among the subgroups for study design (p for heterogeneity = .149), region (p = .429), depression criteria (p = .934), covariate adjustment (p = .702), and frailty criteria (p = .661). Notably, the risk for frailty due to depression was significantly higher in men than in women (pooled odds ratios for men and women: 4.76 and 2.25, respectively; Qbetween χ2 = 9.93, p = .002).

Conclusion

Older adults with depression are more prone to frailty than are those without depression. Regardless of study design, region, depression index, frailty index, and covariance corrections, no significant differences were observed in the results of studies on depression and frailty in older adults. The only factor that had a significant influence was sex; older men with depression were at a higher risk for frailty than were older women with depression.

Clinical Relevance

Depression and frailty are pertinent health concerns related to geriatric syndromes. Because older adults with depression have a high risk for frailty, nursing personnel should use a depression index as early as possible to screen for depression and further reduce the occurrence of frailty in older adults. Furthermore, based on the aforementioned differences between the sexes, special attention should be paid to older men with depression to reduce their risk for frailty.