bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preschool HABIT-ILE: study protocol for a randomised controlled trial to determine efficacy of intensive rehabilitation compared with usual care to improve motor skills of children, aged 2–5 years, with bilateral cerebral palsy
Authors: Sakzewski Leanne , Reedman Sarah , McLeod Kate , Thorley Megan , Burgess Andrea , Trost Stewart , Ahmadi Matthew , Rowell David , Chatfield Mark , Bleyenheuft Yannick , Boyd Roslyn N 
Published: March 2021

IntroductionYoung children with bilateral cerebral palsy (BCP) often experience difficulties with gross motor function, manual ability and posture, impacting developing independence in daily life activities, participation and quality of life. Hand Arm Bimanual Intensive Training Including Lower Extremity (HABIT-ILE) is a novel intensive motor intervention integrating upper and lower extremity training that has been developed and tested in older school-aged children with unilateral and BCP. This study aims to compare an adapted preschool version of HABIT-ILE to usual care in a randomised controlled trial.Methods and analysis60 children with BCP aged 2–5 years, Gross Motor Function Classification System (GMFCS) II–IV will be recruited. Children will be stratified by GMFCS and randomised using concealed allocation to either receive Preschool HABIT-ILE or usual care. Preschool HABIT-ILE will be delivered in groups of four to six children, for 3 hours/day for 10 days (total 30 hours). Children receiving Preschool HABIT-ILE be provided a written home programme with the aim of achieving an additional 10 hours of home practice (total dose 40 hours). Outcomes will be assessed at baseline, immediately following intervention and then retention of effects will be tested at 26 weeks. The primary outcome will be the Peabody Developmental Motors Scales–Second Edition to evaluate gross and fine motor skills. Secondary outcomes will be gross motor function (Gross Motor Function Measure-66), bimanual hand performance (Both Hands Assessment), self-care and mobility (Pediatric Evaluation of Disability Inventory-Computer Adapted Test), goal attainment (Canadian Occupational Performance Measure), global performance of daily activities (ACTIVLIM-CP), cognition and adaptive function (Behavior Rating Inventory of Executive Function—Preschool Version), habitual physical activity (ActiGraph GT3X+) and quality of life (Infant Toddler Quality of Life Questionnaire and Child Health Utility Index-9). Analyses will follow standard principles for RCTs using two-group comparisons on all participants on an intention-to-treat basis. Comparisons between groups for primary and secondary outcomes will be conducted using regression models.Ethics and disseminationEthics approval has been granted by the Medical Research Ethics Committee Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC/19/QCHQ/59444) and The University of Queensland (2020000336/HREC/19/QCHQ/59444).Trial registration numberACTRN126200000719.
Urban–rural differences in overweight and obesity among 25–64 years old Myanmar residents: a cross-sectional, nationwide survey
Authors: Thapa Rupa , Dahl Cecilie , Aung Wai Phyo , Bjertness Espen 
Published: March 2021

ObjectivesTo investigate whether urban–rural location and socioeconomic factors (income, education and employment) are associated with body mass index (BMI) and waist–hip ratio (W/H-ratio), and to further explore if the associations between urban–rural location and BMI or W/H-ratio could be mediated through variations in socioeconomic factors.DesignCross-sectional, WHO STEPS survey of non-communicable disease risk factors.SettingUrban and rural areas of Myanmar.ParticipantsA total of 8390 men and women aged 25 to 64 years included during the study period from September to December 2014. Institutionalised people (Buddhist monks and nuns, hospitalised patients) and temporary residents were excluded.ResultsThe prevalence of overweight and obesity was higher in the urban areas and increased with increasing socioeconomic status (SES) score. Mean BMI was higher among urban residents (ß=2.49 kg/m2; 95% CI 2.28 to 2.70; p<0.001), individuals living above poverty line, that is, ≥US$1.9/day (ß=0.74 kg/m2; 95% CI 0.43 to 1.05; p<0.001), and those with high education attainment (ß=1.48 kg/m2; 95% CI 1.13 to 1.82; p<0.001) when adjusting for potential confounders. Similarly, greater W/H-ratio was observed in participants living in an urban area, among those with earnings above poverty line, and among unemployed individuals. The association between urban–rural location and BMI was found to be partially mediated by a composite SES score (9%), income (17%), education (16%) and employment (16%), while the association between urban–rural location and W/H-ratio was found to be partially mediated by income (12%), education (6%) and employment (6%).ConclusionResidents living in urban locations had higher BMI and greater W/H-ratio, partially explained by differences in socioeconomic indicators, indicating that socioeconomic factors should be emphasised in the management of overweight and obesity in the Myanmar population. Furthermore, new national or subnational STEPS surveys should be conducted in Myanmar to observe the disparity in trends of the urban–rural differential.
Retrospective review of nicotine exposures in California from 2012 to 2018 and analysis of the impacts of e-cigarette regulations
Authors: Driller Gabrielle , Plasencia Emily , Apollonio Dorie E 
Published: March 2021

ObjectivesTo review the association between US e-cigarette regulations and the number of reported nicotine exposures, and identify higher-risk productsDesignRetrospective review of de-identified medical records.SettingCaliforniaParticipantsCases reported to California Poison Control System in 2012–2018.Primary and secondary outcome measuresSuspected nicotine toxicity; route of exposure and product characteristics.ResultsWe examined 5277 exposures, of which 3033 involved combustible cigarettes, 1489 involved e-cigarettes and 818 involved other substances (ie, chewing tobacco, nicotine patches, nicotine lozenges, hookah, etc). Implementation of the Child Nicotine Poisoning Prevention Act of 2015 was not significantly associated with reduced exposures. Exposures for e-cigarettes increased significantly after the 2017 Food and Drug Administration Compliance Policy (p=0.003, coefficient (coeff)=0.61). Total exposures for all tobacco and nicotine products also increased significantly after the policy change (p=0.01, coeff=1.26). Nicotine exposure outcomes classified as being of minor and moderate severity increased significantly after implementation of the 2017 Compliance Policy (p=0.004, coeff=0.54 and p=0.002, coeff=0.56, respectively). Ingestion was the most common route of exposure (87.7%), followed by inhalation (8.1%), dermal (6.5%), ocular (2.1%) and other (intranasal, rectal, sublingual and unknown) routes (0.2%); some cases reported multiple routes of exposure. Exposure cases involving e-cigarettes fell into three problem categories: product design, labelling and the appeal of flavours.ConclusionsOur analysis found that despite previous studies suggesting that the Child Nicotine Poisoning Prevention Act appeared to have reduced exposures for e-cigarettes, there was no significant change in exposures after its implementation. In contrast, there was a 30% increase in California e-cigarette exposures following the 2017 Compliance Policy. We conclude that current regulations are insufficient to reduce nicotine toxicities due to e-cigarette use.
Point-of-care HbA1c testing in an urban primary care diabetes clinic in South Africa: a mixed methods feasibility study
Authors: Hirst Jennifer A , Bobrow Kirsten , Farmer Andrew , Morgan Jennie , Levitt Naomi 
Published: March 2021

IntroductionMonitoring and treatment of type 2 diabetes in South Africa usually takes place in primary care using random blood glucose testing to guide treatment decisions. This study explored the feasibility of using point-of-care haemoglobin A1c (HbA1c) testing in addition to glucose testing in a busy primary care clinic in Cape Town, South Africa.Subjects185 adults aged 19–88 years with type 2 diabetes.Materials and methodsParticipants recruited to this mixed methods cohort study received a point-of-care HbA1c test. Doctors were asked to use the point-of-care HbA1c result for clinical decision-making. Qualitative interviews were held with clinical staff.ResultsPoint-of-care HbA1c test results were obtained for 165 participants of whom 109 (65%) had poor glycaemic control (>8% HbA1c, 64 mmol/mol). Medical officers reported using a combination of HbA1c and blood glucose 77% of the time for clinical decision-making. Nurses found the analyser easy to use and doctors valued having the HbA1c result to help with decision-making.DiscussionOur results suggest that 30% of patients may have received inappropriate medication or not received necessary additional medication if random blood glucose alone had been used in routine appointments. Clinicians valued having access to the HbA1c test result to help them make treatment decisions.
How can we estimate QALYs based on PHQ-9 scores? Equipercentile linking analysis of PHQ-9 and EQ-5D
Authors: Furukawa Toshi A , Levine Stephen Z , Buntrock Claudia , Ebert David D , Gilbody Simon , Brabyn Sally , Kessler David , Björkelund Cecilia , Eriksson Maria , Kleiboer Annet , van Straten Annemieke , Riper Heleen , Montero-Marin Jesus , Garcia-Campayo Javier , Phillips Rachel , Schneider Justine , Cuijpers Pim , Karyotaki Eirini 
Published: March 2021

BackgroundQuality-adjusted life years (QALYs) are widely used to measure the impact of various diseases on both the quality and quantity of life and in their economic valuations. It will be clinically important and informative if we can estimate QALYs based on measurements of depression severity.ObjectiveTo construct a conversion table from the Patient Health Questionnaire-9 (PHQ-9), the most frequently used depression scale in recent years, to the Euro-Qol Five Dimensions Three Levels (EQ-5D-3L), one of the most commonly used instruments to assess QALYs.MethodsWe obtained individual participant data of randomised controlled trials of internet cognitive-behavioural therapy which had administered depression severity scales and the EQ-5D-3L at baseline and at end of treatment. Scores from depression scales were all converted into the PHQ-9 according to the validated algorithms. We used equipercentile linking to establish correspondences between the PHQ-9 and the EQ-5D-3L.FindingsIndividual-level data from five trials (total N=2457) were available. Subthreshold depression (PHQ-9 scores between 5 and 10) corresponded with EQ-5D-3L index values of 0.9–0.8, mild major depression (10–15) with 0.8–0.7, moderate depression (15–20) with 0.7–0.5 and severe depression (20 or higher) with 0.6–0.0. A five-point improvement in PHQ-9 corresponded approximately with an increase in EQ-5D-3L score by 0.03 and a ten-point improvement by approximately 0.25.Conclusions and Clinical ImplicationsThe conversion table between the PHQ-9 and the EQ-5D-3L scores will enable fine-grained assessment of burden of depression at its various levels of severity and of impacts of its various treatments.
LRP1Bmutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types
Authors: Brown Landon C , Tucker Matthew D , Sedhom Ramy , Schwartz Eric B , Zhu Jason , Kao Chester , Labriola Matthew K , Gupta Rajan T , Marin Daniele , Wu Yuan , Gupta Santosh , Zhang Tian , Harrison Michael R , George Daniel J , Alva Ajjai , Antonarakis Emmanuel S , Armstrong Andrew J 
Published: March 2021

BackgroundLow-density lipoprotein receptor-related protein 1b (encoded byLRP1B) is a putative tumor suppressor, and preliminary evidence suggestsLRP1B-mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).MethodsWe conducted a multicenter, retrospective pan-cancer analysis of patients withLRP1Balterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP)LRP1Balterations compared withLRP1Bvariants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) byLRP1Bstatus.ResultsWe identified 101 patients (44 Duke, 35 JHU, 22 UM) withLRP1Balterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients withLRP1BP/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LPLRP1Balterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).ConclusionsThis multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUSLRP1Balterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.
Research facilities and highlights at the Centro Nacional de Aceleradores (CNA)
Authors: Gómez-Camacho J. , García López J. , Guerrero C. , López Gutiérrez J. M. , García-Tenorio R. , Santos-Arévalo F. J. , Chamizo E. , Ferrer F. J. , Jiménez-Ramos M. C. , Balcerzyk M. , Fernández B. 
Published: March 2021

AbstractThe Centro Nacional de Aceleradores is a user-oriented accelerator facility in Seville, Spain. Its main facilities are a 3 MV tandem accelerator, an 18 MeV proton Cyclotron, a tandetron used for AMS, a compact accelerator used for radiocarbon measurements, a $$^{60}$$

60

Co irradiator and a PET/CT scanner. The technical specifications and research applications of these facilities are described. A neutron beam line associated to a charged pulsed beam in the tandem allows for time of flight measurements which determine the neutron energy. The use of an adequate stripper gas in the AMS tandetron permits to measure heavy radionuclides with very low detection levels, allowing to perform environmental studies using these radionuclides as tracers. The use of the microbeam in the tandem accelerator allows to apply the ion beam-induced current technique to investigate the spectroscopic properties and radiation hardness of different semiconductor detectors.
Refining the Molecular Framework for Pancreatic Cancer with Single-cell and Spatial Technologies
Authors: Guo Jimmy A. , Hoffman Hannah I. , Weekes Colin D. , Zheng Lei , Ting David T. , Hwang William L. 
Published: March 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy in urgent need of a molecular framework for guiding therapeutic strategies. Bulk transcriptomic efforts over the past decade have yielded two broad consensus subtypes: classical pancreatic/epithelial versus basal-like/squamous/quasi-mesenchymal. Although this binary classification enables prognostic stratification, it does not currently inform the administration of treatments uniquely sensitive to either subtype. Furthermore, bulk mRNA studies are challenged by distinguishing contributions from the neoplastic compartment versus other cell types in the microenvironment, which is accentuated in PDAC given that neoplastic cellularity can be low. The application of single-cell transcriptomics to pancreatic tumors has generally lagged behind other cancer types due in part to the difficulty of extracting high-quality RNA from enzymatically degradative tissue, but emerging studies have and will continue to shed light on intratumoral heterogeneity, malignant–stromal interactions, and subtle transcriptional programs previously obscured at the bulk level. In conjunction with insights provided by single-cell/nucleus dissociative techniques, spatially resolved technologies should also facilitate the contextualization of gene programs and inferred cell–cell interactions within the tumor architecture. Finally, given that patients often receive neoadjuvant chemotherapy and/or chemoradiotherapy even in resectable disease, deciphering the gene programs enriched in or induced by cytotoxic therapy will be crucial for developing insights into complementary treatments aimed at eradicating residual cancer cells. Taken together, single-cell and spatial technologies provide an unprecedented opportunity to refine the foundations laid by prior bulk molecular studies and significantly augment precision oncology efforts in pancreatic cancer.
Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness
Authors: Zhang Yijuan , Recouvreux M. Victoria , Jung Michael , Galenkamp Koen M.O. , Li Yunbo , Zagnitko Olga , Scott David A. , Lowy Andrew M. , Commisso Cosimo 
Published: March 2021

Abstract

Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is also operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer–associated fibroblasts (CAF). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca2+ and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has a dual function in CAFs—it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging.

Significance:
Glutamine deprivation drives stromal macropinocytosis to support CAF cell fitness and provide amino acids that sustain PDAC cell survival. Selective disruption of macropinocytosis in CAFs suppresses PDAC tumor growth.
This article is highlighted in the In This Issue feature, p. 1601
Targeted Therapy Given after Anti–PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity
Authors: Phadke Manali S. , Chen Zhihua , Li Jiannong , Mohamed Eslam , Davies Michael A. , Smalley Inna , Duckett Derek R. , Palve Vinayak , Czerniecki Brian J. , Forsyth Peter A. , Noyes David , Adeegbe Dennis O. , Eroglu Zeynep , Nguyen Kimberly T. , Tsai Kenneth Y. , Rix Uwe , Burd Christin E. , Chen Yian A. , Rodriguez Paulo C. , Smalley Keiran S.M. 
Published: March 2021

AbstractImmunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti–PD-1)→ TT (ceritinib–trametinib or dabrafenib–trametinib) was associated with improved antitumor responses in mouse models of BRAF- and NRAS-mutant melanoma. Mice with NRAS-mutant (SW1) or BRAF-mutant (SM1) mouse melanomas were treated with either IT, TT, or the sequence of IT→TT. Tumor volumes were measured, and samples from the NRAS-mutant melanomas were collected for immune-cell analysis, single-cell RNA sequencing (scRNA-seq), and reverse phase protein analysis (RPPA). scRNA-seq demonstrated that the IT→TT sequence modulated the immune environment, leading to increased infiltration of T cells, monocytes, dendritic cells and natural killer cells, and decreased numbers of tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Durable responses to the IT→TT sequence were dependent on T-cell activity, with depletion of CD8+, but not CD4+, T cells abrogating the therapeutic response. An analysis of transcriptional heterogeneity in the melanoma compartment showed the sequence of IT→TT enriched for a population of melanoma cells with increased expression of MHC class I and melanoma antigens. RPPA analysis demonstrated that the sustained immune response induced by IT→TT suppressed tumor-intrinsic signaling pathways required for therapeutic escape. These studies establish that upfront IT improves the responses to TT in BRAF- and NRAS-mutant melanoma models.
The Framework Convention for the Protection of National Minorities and Internalization: Lessons from the Western Balkans
Authors: Craig Elizabeth 
Published: March 2021

Abstract
The precise form of internalization of the provisions of the Council of Europe’s Framework Convention for the Protection of National Minorities in domestic law is crucial in ensuring its long-term effectiveness. Experiences in the Western Balkans raise important questions about the role of minority (or community) rights legislation in deeply divided societies. This article uses the case-studies of Bosnia and Herzegovina, Kosovo and the Republic of North Macedonia to highlight key themes and limitations that have emerged. Comparative analysis reveals a surprising divergence of approaches to internalization in the region. The article further demonstrates that the ‘nation-cum-state paradigm’ remains prevalent, despite the premise of universality. It argues that such legislation can play an important symbolic and practical role, but that legal internalization needs to be seen as an ongoing process. It concludes that attention needs to be given to ensuring the continued particularization and adaptation of such legislation in light of both the limitations and changing circumstances, providing a key lesson also for other divided societies.
New Christians, Converted Hindus, Jesuits, and the Inquisition
Authors: Franco José Eduardo , Tavares Célia 
Published: March 2021

Abstract
This paper analyses the complex relationship between Jesuits, New Christians, converted Hindus, and the Inquisition. The collaboration of Jesuits with the Holy Office did not prevent voices from being raised within the Society of Jesus against the tribunal’s practices, which were observed with caution by the first Jesuit leaders. For their part, conversos were initially welcomed into the Society and even assumed high positions in the Society, such as the second superior general. Despite the difficult history of intolerance and inquisitorial persecution against New Christians, in the seventeenth century, Jesuits in Portugal became prominent advocates of their cause. In turn, Hindu conversion strategies fueled disputes and tensions between the Society of Jesus and the Inquisition of Goa. Their strained relations make these disputes an important historiographical subject for understanding many of the plots and dramas of Portuguese society under the Old Regime.