bluuebunny/crossref_metadata_2025_split huggingface dataset:
A positive allosteric modulator for the muscarinic receptor (M1 mAChR) improves pathology and cognitive deficits in female APPswe/PSEN1ΔE9 mice
Authors: Abd‐Elrahman Khaled S. , Sarasija Shaarika , Colson Tash‐Lynn L. , Ferguson Stephen S. G. 
Published: November 2021

Background and PurposeAlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and women account for 60% of diagnosed cases. β‐Amyloid (Aβ) oligomers are considered the principal neurotoxic species in AD brains. The M1 muscarinic ACh receptor (M1 mAChR) plays a key role in memory and learning. M1 mAChR agonists show pro‐cognitive activity but cause many adverse off‐target effects. A new orally bioavailable M1 mAChR positive allosteric modulator (PAM), VU0486846, is devoid of direct agonist activity or adverse effects but was not tested for disease‐modifying efficacy in female AD mice.Experimental ApproachNine‐month‐old female APPswe/PSEN1ΔE9 (APPswe) and wildtype mice were treated with VU0486846 in drinking water (10 mg·kg−1·day−1) for 4 or 8 weeks. Cognitive function of mice was assessed after treatment, and brains were harvested for biochemical and immunohistochemical assessment.Key ResultsVU0486846 improved cognitive function of APPswe mice when tested in novel object recognition and Morris water maze. This was paralleled by a significant reduction in Aβ oligomers and plaques and neuronal loss in the hippocampus. VU0486846 reduced Aβ oligomer production in APPswe mice by increasing M1 mAChR expression and shifting the processing of amyloid precursor protein from amyloidogenic cleavage to non‐amyloidogenic cleavage. Specifically, VU0486846 reduced the expression of β‐secretase 1 (BACE1), whereas it enhanced the expression of the α‐secretase ADAM10 in APPswe hippocampus.Conclusion and ImplicationsUsing M1 mAChR PAMs can be a viable disease‐modifying approach that should be exploited clinically to slow AD in women.
Alzheimer's disease and cerebrovascular pathology alter inward rectifier potassium (KIR2.1) channels in endothelium of mouse cerebral arteries
Authors: Lacalle‐Aurioles María , Trigiani Lianne J. , Bourourou Miled , Lecrux Clotilde , Hamel Edith 
Published: November 2021

Background and PurposeInward rectifier potassium (KIR) channels are key effectors of vasodilatation in neurovascular coupling (NVC). KIRchannels expressed in cerebral endothelial cells (ECs) have been confirmed as essential modulators of NVC. Alzheimer's disease (AD) and cerebrovascular disease (CVD) impact on EC‐KIRchannel function, but whether oxidative stress or inflammation explains this impairment remains elusive.Experimental ApproachWe evaluated KIRchannel function in intact and EC‐denuded pial arteries of wild‐type (WT) and transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APP mice, recapitulating amyloid β‐induced oxidative stress seen in AD) or a constitutively active form of TGF‐β1 (TGF mice, recapitulating inflammation seen in cerebrovascular pathology). The benefits of antioxidant (catalase) or anti‐inflammatory (indomethacin) drugs also were investigated. Vascular and neuronal components of NVC were assessed in vivo.Key ResultsOur findings show that (i) KIRchannel‐mediated maximal vasodilatation in APP and TGF mice reaches only 37% and 10%, respectively, of the response seen in WT mice; (ii) KIRchannel dysfunction results from KIR2.1 subunit impairment; (iii) about 50% of K+‐induced artery dilatation is mediated by EC‐KIRchannels; (iv) oxidative stress and inflammation impair KIRchannel function, which can be restored by antioxidant and anti‐inflammatory drugs; and (v) inflammation induces KIR2.1 overexpression and impairs NVC in TGF mice.Conclusion and ImplicationsTherapies targeting both oxidative stress and inflammation are necessary for full recovery of KIR2.1 channel function in cerebrovascular pathology caused by AD and CVD.
Growth and linkage of normal faults experiencing multiple non‐coaxial extension: A case from the Qikou Sag, Bohai Bay Basin, East China
Authors: Wang Shunyu , Liu Keyu , Wang Haixue , Chen Meiyi 
Published: November 2021

AbstractOblique‐slip faults, which are essentially reactivated pre‐existing fault caused by non‐coaxial stress, are common in rift basins. Large faults with lengths exceeding thousands of kilometres are mostly rooted faults and would have experienced numerous reactivations. Using 3D seismic and drilling data, we investigated the geometry, kinematic features, growth and linkage, and three‐dimensional evolution of the Nandagang fault system (NDGFS) on the Qinan Slope in the Qikou Sag, Bohai Bay Basin. A hybrid fault model incorporating a lengthening stage and a displacement accrual stage was used to analyse the growth and linkage of NDGFS. By using the throw/displacement backstripping approach, ratios of maximum displacement to fault length (Dmax/L) of the evolving NDGFS were also obtained to delineate faulting stages of the hybrid fault model. From the pre‐Cenozoic basement to the Quaternary strata, NDGFS comprises three fault systems separated vertically by two unconformities, namely the lower, the middle and the upper systems. On planar view, NDGFS encompasses three structural trending zones with variable vertical growth styles. The E–W and NEE–SWW trending zones are mainly dominated by growth faults, while the NE–SW zones are characterised by dip‐linkage faults. For NDGFS, both the middle and deeper fault segments experienced a two‐stage hybrid faulting and reached their final lengths in ca. 20%–30% less time than the usual faulting lifetime proposed by previous researchers. In contrast, the upper faults, especially the segments within the Neogene Guantao (Ng) and Minghuazhen (Nm) formations, only experienced a lengthening stage. The slip rates and the pre‐existing faults have strong influences on the duration that faults accomplished their lengthening stages. A Dmax/L ratio of 0.015 obtained from the evolving NDGFS is determined to be effective in delineating between the lengthening stage and the displacement accrual stage, which may have a broad application for normal faults in similar geological settings.
Relationship between ideal cardiovascular health metrics and hearing loss: A 10‐year retrospective cohort study
Authors: Tseng Tzu‐Hsiang , Yeo Li‐Xian , Chen Wei‐Liang , Kao Tung‐Wei , Wu Li‐Wei , Yang Hui‐Fang , Peng Tao‐Chun 
Published: November 2021

AbstractObjectiveThe role of ideal cardiovascular health (CVH) metrics in developing hearing loss remains uncertain. Thus, our objective was to analyse the connection between hearing loss and ideal CVH metrics in a 10‐year retrospective cohort.Study DesignRetrospective cohort study.SettingA health management centre in Taiwan.ParticipantsParticipants who underwent the first annual health check‐up between 2000 and 2006 and with a follow‐up check‐up more than ten years later.Main outcome measuresHearing thresholds were measured at 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz. Individuals with a best ear pure‐tone audiometry four‐frequency average of >25 dB HL were defined as having hearing loss. The ideal CVH metrics were classified into 7 categories based on the American Heart Association's definition. The associations of hearing loss with the sum of the ideal CVH metrics and each ideal CVH metric were examined by multiple logistic regression analysis.ResultsThe present study consisted of 6974 participants. The 10‐year follow‐up showed that the odds ratio (OR) of hearing loss was .74 for participants with 5–7 ideal CVH metrics (95% CI, .59–.93, p = .01) compared with those with 0–2 ideal CVH metrics. Among the CVH metrics, participants with an ideal smoking status might have reduced odds of developing hearing loss; the OR was .72 (95% CI, .58–.89, p = .003).ConclusionsParticipants with an increased number of ideal CVH metrics and better performance on the smoking metric had a significantly protective effect regarding hearing loss development.
Impact of adding an IgG4 conjugate to routine direct immunofluorescence testing for subepithelial and intraepithelial autoimmune blistering disorders
Authors: Lehman Julia S. , Johnson Emma F. , Camilleri Michael J. , Gibson Lawrence E. , Comfere Nneka I. , Kalaaji Amer N. , Peters Margot S. , Cervenka Derek J. , Doppler Joseph M. , Lange Colleen R. , Miller Cameron J. , Wieland Carilyn N. 
Published: November 2021

AbstractBackgroundCertain autoimmune bullous dermatoses are mediated by autoantibodies of the IgG4 subclass. We determined the diagnostic impact of adding IgG4 to our conventional direct immunofluorescence (DIF) panel.MethodsFor all cases submitted to our referral laboratory for DIF over 1 month (n = 630), we performed IgG4 testing and collected consecutive biopsy specimens showing definite or indeterminate linear or cell‐surface deposition of IgG, IgG4, and/or C3. On retrospective blinded review, we classified the pattern and whether the findings were definite, indeterminate, or negative. When present, substantial background staining was recorded.ResultsSeventy DIF specimens met the inclusion criteria. Of 22 (31.4%) specimens equivocal for linear or cell‐surface deposition, 9 (40.9%) had definitive IgG4 findings, either linear (3 of 14 equivocal linear cases; 21.4%) or cell‐surface (6 of 8 equivocal cell‐surface cases; 75.0%). Background deposition was substantial in 14 cases (20.0%) for IgG but in none for C3 or IgG4.ConclusionIgG4 allowed the classification of over 40% of DIF cases that were otherwise equivocal by IgG and C3. IgG4 staining showed lower levels of non‐specific background staining than IgG or C3. IgG4 appears to contribute most value in cases with cell‐surface deposition or with equivocal linear IgG deposition and negative C3 results.
Developing a novel intervention for type 1 diabetes and disordered eating using a participatory action design process: Safe management of people with Type 1 diabetes and EAting Disorders studY (STEADY)
Authors: Zaremba Natalie , Robert Glenn , Allan Jacqueline , Harrison Amy , Brown Jennie , Konstantara Emmanouela , Rosenthal Miranda , Pillay Divina , Beckwith Anita , Treasure Janet , Hopkins David , Ismail Khalida , Stadler Marietta 
Published: November 2021

AbstractAimsTo develop a cognitive behavioural therapy‐based intervention for people with type 1 diabetes and disordered eating using Experience‐Based Co‐Design as part of the Safe management of people with Type 1 diabetes and EAting Disorders studY (STEADY).MethodsFifteen people with type 1 diabetes and experience of disordered eating (33 ± 11 years old, 22 ± 12 years diabetes duration) and 25 healthcare professionals working in type 1 diabetes or eating disorders (44 ± 9 years old; 14 ± 10 years of professional experience) attended six Experience‐Based Co‐Design workshops from July 2019 to March 2020 to collaboratively develop intervention content.ResultsWe developed a cognitive behaviour therapy intervention ‘toolkit’ that can be tailored for individual patient needs. Participants designed and revised toolkit materials to ensure acceptability and relevance for people with diabetes and disordered eating by engaging in guided discussion, brainstorming, and rapid testing to review toolkit prototypes in an iterative process. Workshop themes were ‘Insulin titration’; ‘Hypoglycaemia’; ‘Coming to terms with diabetes’; ‘Fear of weight gain’; ‘Toolkit revision’; and ‘Practical elements of STEADY therapy’. The intervention is focussed on improving diabetes self‐care and embedded in a multidisciplinary healthcare approach. The intervention will be delivered in 12 sessions by a diabetes specialist nurse trained in cognitive behavioural therapy.ConclusionsThrough an iterative co‐design process, people with type 1 diabetes and healthcare professionals collaboratively developed a novel intervention toolkit that can be used with a wide range of disordered eating presentations. The intervention will be tested in the STEADY feasibility randomised controlled trial.
Why has there been a fall in child labour and an increase in school attendance in Mexico?
Authors: Valero‐Gil Jorge , Valero Magali 
Published: November 2021

SummaryMotivationIt is imperative to understand the factors affecting child labour and school attendance in order to develop policies aimed at improving children's lives. The need for such policies is because poor households may underinvest in human capital. Individual factors have been shown to affect child labour and school attendance, but we examine which factors cause the strongest effects by considering them simultaneously.PurposeWe evaluate the factors that have led to the changes in child labour and school attendance of children aged 12–14 in Mexico during the 2000–2020 period. We consider income, the education of the household head, government cash transfers, access to public health institutions, remittances, and demographic characteristics as possible sources of the changes.Methods and approachWe use a variant of the Oaxaca–Blinder decomposition, which allows decomposition when the variables to be explained are dichotomous. The change in child labour and school attendance over time can then be decomposed into explained and unexplained portions, with each factor contributing a specific amount to the explained portion of the change.FindingsThe most important factor influencing improvements in child labour and school attendance was the improvement in the parents' human capital, measured as years of education. The result is not due to a high correlation between income and education, as significant explanatory power is lost as we exclude education from the analysis. The result is also robust to separating Mexican states into those with high and those with low incidence of poverty. The increase in government assistance and greater access to social health insurance also play an important role.Policy implicationsPublic policies aimed at increasing school attendance and those aimed at reducing child labour should consider improved education as a major goal. In addition, important consideration should be given to the possible impact on children of poverty‐fighting policy changes. Our findings suggest that government policies aimed at reducing poverty in Mexico are important in influencing both child labour and school attendance, and policy changes have had undesirable effects on both.
Pediatric ranges of normality for 2D speckle‐tracking echocardiography atrial strain: differences between p‐ and r‐gating and among new (Atrial Designed) and conventional (Ventricular Specific) software's
Authors: Marchese Pietro , Scalese Marco , Giordano Raffaele , Assanta Nadia , Franchi Eliana , Koestenberger Martin , Ravaglioli Antonio , Kutty Shelby , Cantinotti Massimiliano 
Published: November 2021

AbstractBackground2D speckle tracking echocardiography (STE) atrial strain (ε) analysis in children is gaining interest; however, pediatric nomograms remain limited. Comparison among conventional software's (designed for left ventricle and adapted to atria and using R‐gating analysis) and new software's (designed for atria and allowing for both R‐ and P‐gating) are lacking. The present study aims to establish pediatric nomograms for atrial ε using an atrial dedicated software and to compare values obtained by (a) R‐ and P‐gating and, (b) R‐gating with new and conventional software.MethodsEchocardiographic measurements included STE left (LA) and right (RA) atrial longitudinal reservoir, conduit and contractile ε. Age/weigh/height/heart rate, and body surface area (BSA) were used as independent variables in the statistical analysis.ResultsIn all, 580 healthy subjects (age range, 31 days‐18 years; mean age 7.5 years; median age 7.1 years; inter‐quartile range, 4.3–10.7 months; 45.5% female) were included. Feasibility of atrial ε measurements was high (98.9–96.8%). At lower age, atrial conduit ε was lower (p<0.001) while contractile ε was higher (p<0.001). All atrial ε values calculated with P‐gating method were lower—than R‐gating values (p<0.001). R‐gated LA ε reservoir values generated with the new software were lower, and R‐gated RA contractile ε higher than with the conventional software (p<0.011).ConclusionWe report pediatric atrial ε values from a dedicated atrial software. Maturational changes in STE atrial ε values were demonstrated. Significant differences were observed among ε values obtained with P‐ and R‐gating and with different software's.
A multifaceted approach in promoting positive mental health culture in Hong Kong secondary schools: The Mindshift educational networking programme
Authors: Suen Yi Nam , Lam Oi Bun Christina , Chan Kai Tai , Wong Tak Hing Michael , Lui Sai Yu Simon , Chan Yuk Yu Vinci , Lam Hoi Ying , Wong Ming Yin Stephanie , Hui Lai Ming Christy , Lee Ho Ming Edwin , Chang Wing Chung , Chan Kit Wa Sherry , Chen Yu Hai Eric 
Published: November 2021

AbstractAimMany young people with mental health problems refuse to seek help because of stigma and leave the problem untreated. Previous research suggests that contact interventions with education could improve the stigma of mental illness in young people, thereby encouraging help‐seeking in distress. The current study examined the effectiveness of a multifaceted programme, the Mindshift educational networking programme (MENP), in promoting a positive mental health culture in Hong Kong secondary schools.MethodsThe MENP provided activities at school, teacher and student levels to 14 Hong Kong secondary schools. School activities included visits, mental health talks and support for capstone projects. While teachers participated in workshops and regional seminars, students received ambassador training workshops, contact opportunities with people with psychosis and attachment programmes. The impact of MENP was evaluated by changes in students' knowledge, attitudes and behaviours toward people with psychosis and mental illness before and after the programme, as well as by teachers' feedback on the programme.ResultsThis study analysed data from 55 students and 20 teachers. It was found that the MENP improved students' knowledge of mood symptoms (p = .03), acceptance of people with psychosis (p = .04) and intended behaviour toward people with mental illness (p = .02). The feedback of the teachers on the programme was positive.ConclusionsThe results support the application of the multifaceted approach to promote a positive mental health culture in schools. The findings call on the government to implement the programme in schools in Hong Kong by providing financial support to relevant organizations.
Primary synovial sarcoma of bone: a retrospective analysis of 25 patients
Authors: Righi Alberto , Gambarotti Marco , Benini Stefania , Gibertoni Dino , Asioli Sofia , Magagnoli Giovanna , Gamberi Gabriella , Sbaraglia Marta , Cocchi Stefania , Staals Eric , Palmerini Emanuela , Dei Tos Angelo Paolo 
Published: November 2021

AimsTo evaluate the diagnostic accuracy of SSX and SSX::SS18 antibodies in decalcified surgical specimens and outcome of synovial sarcomas (SS) of bone.Methods and resultsTwenty‐five cases were classified as bone SS (prevalence 0.32% among malignant primary bone sarcoma). Median age was 34 years (range = 9–79). Twenty‐four of 25 patients presented with non‐metastatic tumours, one with lung metastases. The majority of tumours involved the long bones of extremities with metaphyseal origin. Mean size of the tumour was 7.1 cm. Twenty cases (80%) were monophasic and five (20%) were biphasic. SS18::SSX fusion‐specific antibody had 92% sensitivity and 99% specificity for primary bone SS, whereas SSX C‐terminus antibody had 100% sensitivity and 94% specificity. Fluorescence in‐situ hybridisation (FISH) analysis was feasible in nine (36%) cases and detected SS18 rearrangement in all nine cases. All patients underwent surgical removal of their primary tumour, with adequate margins in 18 (72%) patients. Chemotherapy with metothrexate, cisplatin, doxorubicin and ifosfamide was used in the seven patients. Two patients with inadequate surgical margins received radiotherapy. With a median follow‐up of 80 months (range = 6–428), 5‐ and 10‐year overall survival (OS) was 66.6% and 47.9%, respectively, and 5 and 10 years’ disease‐free survival (DFS) was 36.8% [95% confidence interval (CI) = 18.0–55.7%] and 32.2% (95% CI = 14.6–51.2%), respectively. A significant improvement in 10 years’ DFS in patients undergoing chemotherapy compared with patients who did not was observed (P = 0.039).ConclusionsOur series highlights the utility of SS18::SSX fusion‐specific and SSX C‐terminus antibodies to support the diagnosis of SS. Adjustment chemotherapy was associated with improved prognosis in this series.
Chemically characterizing the cortical cell nano‐structure of human hair using atomic force microscopy integrated with infrared spectroscopy (AFM‐IR)
Authors: Fellows A. P. , Casford M. T. L. , Davies P. B. 
Published: November 2021

AbstractObjectiveThe use of conventional microscopy and vibrational spectroscopy in the optical region to investigate the chemical nature of hair fibres on a nanometre scale is frustrated by the diffraction limit of light, prohibiting the spectral elucidation of nanoscale sub‐structures that contribute to the bulk properties of hair. The aim of this work was to overcome this limitation and gain unprecedented chemical resolution of cortical cell nano‐structure of hair.MethodsThe hybrid technique of AFM‐IR, combining atomic force microscopy with an IR laser, circumvents the diffraction limit of light and achieves nanoscale chemical resolution down to the AFM tip radius. In this work, AFM‐IR was employed on ultra‐thin microtomed cross‐sections of human hair fibres to spectrally distinguish and characterize the specific protein structures and environments within the nanoscale components of cortical cells.ResultsAt first, a topographical and chemical distinction between the macrofibrils and the surrounding intermacrofibillar matrix was achieved based on 2.5 × 2.5 μm maps of cortical cell cross‐sections. It was found that the intermacrofibrillar matrix has a large protein content and specific cysteine‐related residues, whereas the macrofibrils showed bigger contributions from aliphatic amino acid residues and acidic‐/ester‐containing species (e.g. lipids). Localized spectra recorded at a spatial resolution of the order of the AFM tip radius enabled the chemical composition of each region to be determined following deconvolution of the Amide‐I and Amide‐II bands. This provided specific evidence for a greater proportion of α‐helices in the macrofibrils and correspondingly larger contributions of β‐sheet secondary structures in the intermacrofibrillar matrix, as inferred in earlier studies. Analysis of the parallel and antiparallel β‐sheet structures, and of selected dominant amino acid residues, yielded further novel composition and conformation results for both regions.ConclusionIn this work, we overcome the diffraction limit of light using atomic force microscopy integrated with IR laser spectroscopy (AFM‐IR) to characterize sub‐micron features of the hair cortex at ultra‐high spatial resolution. The resulting spectral analysis shows clear distinctions in the Amide bands in the macrofibrils and surrounding intermacrofibrillar matrix, yielding novel insight into the molecular structure and intermolecular stabilization interactions of the constituent proteins within each cortical component.