bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ensuring Valid Inference for Cox Hazard Ratios After Variable Selection
Authors: Van Lancker Kelly , Dukes Oliver , Vansteelandt Stijn 
Published: June 2023

AbstractThe problem of how to best select variables for confounding adjustment forms one of the key challenges in the evaluation of exposure effects in observational studies, and has been the subject of vigorous recent activity in causal inference. A major drawback of routine procedures is that there is no finite sample size at which they are guaranteed to deliver exposure effect estimators and associated confidence intervals with adequate performance. In this work, we will consider this problem when inferring conditional causal hazard ratios from observational studies under the assumption of no unmeasured confounding. The major complication that we face with survival data is that the key confounding variables may not be those that explain the censoring mechanism. In this paper, we overcome this problem using a novel and simple procedure that can be implemented using off-the-shelf software for penalized Cox regression. In particular, we will propose tests of the null hypothesis that the exposure has no effect on the considered survival endpoint, which are uniformly valid under standard sparsity conditions. Simulation results show that the proposed methods yield valid inferences even when covariates are high-dimensional.
Dirichlet Process Mixture Models for the Analysis of Repeated Attempt Designs
Authors: Daniels Michael J. , Lee Minji , Feng Wei 
Published: June 2023

AbstractIn longitudinal studies, it is not uncommon to make multiple attempts to collect a measurement after baseline. Recording whether these attempts are successful provides useful information for the purposes of assessing missing data assumptions. This is because measurements from subjects who provide the data after numerous failed attempts may differ from those who provide the measurement after fewer attempts. Previous models for these designs were parametric and/or did not allow sensitivity analysis. For the former, there are always concerns about model misspecification and for the latter, sensitivity analysis is essential when conducting inference in the presence of missing data. Here, we propose a new approach which minimizes issues with model misspecification by using Bayesian nonparametrics for the observed data distribution. We also introduce a novel approach for identification and sensitivity analysis. We re-analyze the repeated attempts data from a clinical trial involving patients with severe mental illness and conduct simulations to better understand the properties of our approach.
Response to mRNA SARS‐CoV‐2 vaccination evaluated by B‐cell receptor repertoire after tixagevimab/cilgavimab administration
Authors: Funakoshi Yohei , Yakushijin Kimikazu , Ohji Goh , Matsutani Takaji , Hojo Wataru , Sakai Hironori , Matsumoto Sakuya , Watanabe Marika , Kitao Akihito , Saito Yasuyuki , Kawamoto Shinichiro , Yamamoto Katsuya , Koyama Taiji , Nagatani Yoshiaki , Kimbara Shiro , Imamura Yoshinori , Kiyota Naomi , Ito Mitsuhiro , Minami Hironobu 
Published: June 2023

SummaryThe use of anti‐SARS‐CoV‐2 antibody products like tixagevimab/cilgavimab represents an important strategy to protect immunocompromised patients with haematological malignancies from COVID‐19. Although patients who receive these agents should still be vaccinated, the use of tixagevimab/cilgavimab can mask the production of anti‐spike antibody after vaccination, making it hard to assess vaccine response. We have newly established a quantification method to assess the response to SARS‐CoV‐2 vaccination at the mRNA level using B‐cell receptor (BCR) repertoire assay and the Coronavirus Antibody Database (CoV‐AbDab). Repeated blood samples before and after vaccination were analysed for the BCR repertoire, and BCR sequences were searched in the database. We analysed the number and percentage frequency of matched sequences. We found that the number of matched sequences increased 2 weeks after the first vaccination and quickly decreased. Meanwhile, the number of matched sequences more rapidly increased after the second vaccination. These results show that the postvaccine immune response can be assessed at the mRNA level by analysing the fluctuation in matching sequences. Finally, BCR repertoire analysis with CoV‐AbDab clearly demonstrated the response to mRNA SARS‐CoV‐2 vaccination even after tixagevimab/cilgavimab administration in haematological malignancy patients who underwent allogeneic haematopoietic stem cell transplantation.
Vaccination in sickle cell disease: Immunocompromised or immunocompetent?
Authors: Han Jin , Saraf Santosh L. , Gordeuk Victor R. 
Published: June 2023

Sickle cell disease (SCD) is an immunocompromised condition and patients with SCD may have a reduced immune response to certain vaccinations. The report by Nakahara et al. demonstrated that SCD patients exhibited elevated and more sustained IgG production following COVID‐19 vaccination, when compared to healthy controls. This suggests that the immune response to vaccinations may vary among different types of vaccines in individuals with SCD.Commentary on: Nakahara et al. Enhanced IgG immune response to COVID‐19 vaccination in patients with sickle cell disease. Br J Haematol 2023;202:937–941.
The Index of Economic Disparity: Measuring trends in economic disparity across Canadian Census Subdivisions and rural and urban communities
Authors: Weaver David , Krawchenko Tamara , Markey Sean 
Published: June 2023

AbstractTerritorial inequalities have long been a subject of study and concern in Canada. In the face of large structural changes such as industrial shifts and the decarbonization of our economies, there is an urgency to understand such inequalities and design effective policy interventions for those places facing persistent economic decline. This paper shares a novel composite index that measures economic disparity across Canadian Census Subdivisions (CSDs) using Census data from 2001 through 2016 and the 2011 National Household Survey. Named the “Index of Economic Disparity,” it is comprised of an equally weighted average of four sub‐indices that assign percentile rankings for all CSDs based on whether they experience persistent and substantial decline in key economic areas: population, labour force outcomes, working‐age share of population, and industrial diversity. The variation of outcomes across geographies—urban and rural—highlights the importance of place‐based policies.
Is everyone really middle class? Social class position and identification in Alberta
Authors: Maroto Michelle , Brown Delphine , Durou Guillaume 
Published: June 2023

AbstractIn defining social class, researchers often rely on measures of objective class position, even though subjective perceptions of social class identity can better account for the creation of social class boundaries. We explore the relationship between measures of objective class position and subjective class identity using data from an online survey of 1155 residents in Alberta, Canada, a conservative province dependent on a fluctuating energy sector. We find that although most Albertans identified as middle class, the strength of class identity and views regarding linked social class fates varied across categories with poverty class and uppermiddleclass respondents standing out. In reporting class identity, respondents considered measures related to objective class position, especially their income and economic security levels, but gaps still remained. We then use the results of this exploratory study to advocate for more comprehensive measures of social class.
Exploring olfactory receptor family 7 subfamily C member 1 as a novel oral cancer stem cell target for immunotherapy
Authors: Miyamoto Sho , Hirohashi Yoshihiko , Morita Rena , Miyazaki Akihiro , Ogi Kazuhiro , Kanaseki Takayuki , Ide Kentaro , Shirakawa Jumpei , Tsukahara Tomohide , Murai Aiko , Sasaya Takashi , Koike Kazushige , Kina Shinichiro , Kawano Toshihiro , Goto Takahiro , Ntege Edward Hosea , Shimizu Yusuke , Torigoe Toshihiko 
Published: June 2023

AbstractThe mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that share characteristics associated with normal stem cells, including self‐renewal and multi‐differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen‐specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC‐2 and HSC‐3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G‐protein‐coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell‐targeted immunotherapy, in CSC‐targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen‐A24‐restricted OR7C1 oral CSC‐specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC‐targeted immunotherapy in oral cancer.
Performance of the ACMG‐AMP criteria in a large familial renal glucosuria cohort with identified SLC5A2 sequence variants
Authors: Barata Rui , Fila Marc , Dalla‐Vale Fabienne , Bogarin Roberto , Nunes Paula , Ramalho José , Rueff José , Calado Joaquim 
Published: June 2023

AbstractFamilial Renal Glucosuria (FRG) is a co‐dominantly inherited trait characterized by orthoglycaemic glucosuria. From 2003 to 2015 we have reported several cohorts validating SLC5A2 (16p11.2), encoding SGLT2 (Na+/glucose cotransporter family member 2), as the gene responsible for FRG. The aim of this work was to validate the variants identified in our extended FRG cohort of published, as well more recent unreported cases, according to the ACMG‐AMP 2015 criteria. Forty‐six variants were evaluated, including 16 novel alleles first described in this study. All are rare, ultra‐rare or absent from population databases and most are missense changes. According to the ACMG‐AMP standards, only 74% of the variants were classified as P/LP. The lack of descriptions of unrelated patients with similar variants or failing to test additional affected family members, averted a conclusion for pathogenicity in the alleles that scored VUS, highlighting the importance of both family testing and variant reporting. Finally, the cryo‐EM structure of the hSGLT2–MAP17 complex in the empagliflozin‐bound state improved the ACMG‐AMP pathogenicity score by identifying critical/functional protein domains.
The effects of noninvasive brain stimulation on cognitive function in patients with mild cognitive impairment and Alzheimer's disease using resting‐state functional magnetic resonance imaging: A systematic review and meta‐analysis
Authors: Wang Tao , Yan Shaozhen , Lu Jie 
Published: June 2023

AbstractObjectiveThe aim of this systematic review and meta‐analysis was to evaluate the efficacy of noninvasive brain stimulation (NIBS) on cognition using functional magnetic resonance imaging (fMRI) in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), thus providing the neuroimaging mechanism of cognitive intervention.MethodsEnglish articles published up to April 30, 2023 were searched in the PubMed, Web of Science, Embase, and Cochrane Library databases. We included randomized controlled trials where resting‐state fMRI was used to observe the effect of NIBS in patients with MCI or AD. RevMan software was used to analyze the continuous variables, and SDM‐PSI software was used to perform an fMRI data analysis.ResultsA total of 17 studies comprising 258 patients in the treatment group and 256 in the control group were included. After NIBS, MCI patients in the treatment group showed hyperactivation in the right precuneus and decreased activity in the left cuneus and right supplementary motor area. In contrast, patients in the control group showed decreased activity in the right middle frontal gyrus and no hyperactivation. The clinical cognitive scores in MCI patients were significantly improved by NIBS, while not in AD. Some evidence regarding the modulation of NIBS in resting‐state brain activity and functional brain networks in patients with AD was found.ConclusionsNIBS could improve cognitive function in patients with MCI and AD. fMRI evaluations could be added to evaluate the contribution of specific NIBS treatment therapeutic effectiveness.
Using systematic conservation planning to inform restoration of freshwater habitat and connectivity for salmon
Authors: Finn Riley J. R. , Chalifour Lia , Gergel Sarah E. , Hinch Scott G. , Scott David C. , Martin Tara G. 
Published: June 2023

AbstractInstream barriers remain ubiquitous threats to freshwater species and their habitats. Decisions regarding barrier removal are often aimed at maximizing habitat area and connectivity for freshwater fish; yet can be challenging due to the sheer number of barriers, uncertainty in species presence, abundance, and habitat quality, as well as limited budgets alongside high costs of restoration. Here, we apply systematic conservation planning to prioritize in‐stream barrier removal aimed at restoring habitat connectivity for 14 populations of wild Pacific salmon in the lower Fraser River, Canada's most productive salmon‐bearing river. To understand how priorities change when stream quality is considered, we contrast scenarios that maximize habitat extent with scenarios that include four indicators of habitat quality. Region‐wide, approximately 64% of naturally accessible stream length is currently blocked by barriers. We estimate approximately 75% of this alienated habitat (over 1600 km of stream), could have full access restored with an investment of $200 million CAD, whereas 60% could be restored for half this amount. When stream quality was considered within the optimization, priorities for barriers removal shifted away from urbanized floodplain valleys towards less developed areas. The spatial shift in priorities meant that species like chum salmon (Oncorhynchus keta) would see less restored habitat. To inform barrier removal strategies using these model scenarios, an iterative and adaptive approach will be required that includes the values and priorities of rights and titleholders. Continuous improvement in data quality, accuracy, and feedback from monitoring as barriers are restored is also crucial.
Developmental trajectories of spoken language comprehension and functional communication in children with cerebral palsy: A prospective cohort study
Authors: Vaillant Emma , Oostrom Kim J. , Beckerman Heleen , Vermeulen R. Jeroen , Buizer Annemieke I. , Geytenbeek Johanna J. M. 
Published: June 2023

AbstractAimTo investigate spoken language comprehension (SLC), single‐word comprehension (SWC), functional communication development, and their determinants, in children with cerebral palsy.MethodThis was a prospective cohort study in the Netherlands spanning 2 years 6 months. The main outcomes were SLC and SWC, assessed by the Computer‐Based instrument for Low motor Language Testing (C‐BiLLT) and the Peabody Picture Vocabulary Test‐III‐NL (PPVT‐III‐NL) respectively; and functional communication, measured by a subscale of the Focus on the Outcomes of Communication Under Six‐34 (FOCUS‐34). Linear mixed models were used to determine developmental trajectories, which were compared with norm and reference data. Potential determinants, for example intellectual functions, speech production, functional communication level (classified with the Communication Function Classification System, CFCS), and functional mobility, were added to assess their effects.ResultsChildren with cerebral palsy (n = 188; mean age 59 months, range 17–110) were monitored for 2 years 6 months. Developmental trajectories for SLC (C‐BiLLT) and SWC (PPVT‐III‐NL) were nonlinear; those for functional communication (FOCUS‐34) were linear. Compared with norm and reference groups, significantly delayed SLC, SWC, and functional communication development were found. Determinants for SLC and SWC were intellectual functions and functional communication level (CFCS); and for functional communication development (FOCUS‐34), speech production and arm–hand functioning.InterpretationChildren with cerebral palsy showed delayed SLC, SWC, and functional communication development compared with norm and reference groups. Remarkably, functional mobility was not associated with the development of SLC, SWC, or functional communication.What this paper adds

Children with cerebral palsy have delayed spoken language comprehension (SLC), single‐word comprehension (SWC), and functional communication development, compared to norm and reference data.
Determinants for SLC and SWC development are intellectual functions and functional communication level.
Determinants for functional communication development are speech production and arm–hand functioning.
Functional mobility is not associated with SLC, SWC, or functional communication.
High diabetes‐specific distress among adults with type 1 diabetes and impaired awareness of hypoglycaemia despite widespread use of sensor technology
Authors: Ali Namam , El Hamdaoui Soumia , Nefs Giesje , Walburgh Schmidt Jesper W. J. , Tack Cees J. , de Galan Bastiaan E. 
Published: June 2023

AbstractAimsImpaired awareness of hypoglycaemia (IAH) has been associated with increased diabetes distress and use of sensor technology can reduce diabetes distress. The aim of this study was to examine diabetes‐specific distress (emotions, cognitions, behaviours) in relation to IAH status and use of glucose sensors in people with type 1 diabetes.MethodsIndividuals with type 1 diabetes from an academic diabetes outpatient clinic completed the Clarke questionnaire (to assess hypoglycaemic awareness), Problem Areas in Diabetes (PAID‐5), Hypoglycaemia Fear Survey‐II (HFS‐II), Attitudes to Awareness of Hypoglycaemia Survey (A2A), Nijmegen Clinical Screening Instrument Survey (NCSI) and Hyperglycaemia Avoidance Scale (HAS).ResultsOf the 422 participants (51.9% male, diabetes duration 30 [16–40] years, HbA1c 60 ± 11 mmol/mol [7.6 ± 1.0%], 351 [88.2%] used a glucose sensor; 82 [19.4%]) had IAH. Compared to individuals with normal awareness, those with IAH more often had PAID‐5 scores ≥8 (35.4% vs. 21.5%, p = 0.008) and higher scores on all HFS‐II subscores (total [40.2 ± 21.5 vs. 27.9 ± 17.2, p < 0.001]), HFS‐II behaviour (18.5 ± 10.0 vs. 15.1 ± 8.0, p = 0.005), HFS‐II worry (21.8 ± 13.5 vs. 12.7 ± 10.9, p < 0.001), HAS worries (17.5 ± 7.3 vs. 14.3 ± 7.0, p < 0.001) and NCSI hypoglycaemia items. HAS behaviour, A2A and NCSI hyperglycaemia scores did not differ between individuals with or without IAH. Restricting the analyses to individuals using a glucose sensor did not materially change the results.ConclusionsDiabetes‐specific distress remains a major problem among individuals with type 1 diabetes, particularly those with IAH, despite the widespread use of (intermittently scanned) sensor technology. Further studies are needed to examine strategies to lower diabetes‐specific distress in individuals with IAH.
Orforglipron (LY3502970), a novel, oral non‐peptide glucagon‐like peptide‐1 receptor agonist: A Phase 1a, blinded, placebo‐controlled, randomized, single‐ and multiple‐ascending‐dose study in healthy participants
Authors: Pratt Edward , Ma Xiaosu , Liu Rong , Robins Deborah , Haupt Axel , Coskun Tamer , Sloop Kyle W. , Benson Charles 
Published: June 2023

AbstractAimTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in healthy participants.Materials and MethodsThis was a double‐blind, placebo‐controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single‐dose orforglipron, with four cohorts receiving escalating doses (0.3‐6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2‐24 mg).ResultsNinety‐two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract‐related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3‐6 mg). On Day 28, the mean t1/2 was 48.1 to 67.5 hours across the dose range (2‐24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron‐treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28.ConclusionsOrforglipron's long half‐life (25‐68 hours) allows once‐daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP‐1RAs, which supports continued clinical development.
Compensating patients in trials: Perspectives from an ethical committee versus sponsor
Authors: Peyro‐Saint‐Paul Laure , Gaillard Cathy , Paris Adeline , Gourio Charlotte , Zerger Céleste , Ficheux Maxence , Grandazzi Guillaume , Parienti Jean‐Jacques , Morello Rémy 
Published: June 2023

AbstractBackgroundAccording to European clinical research legislation, no undue influence, including financial incentives, should be used to encourage participation in clinical trials. Financial compensation should be based on the inconvenience experienced by patients and is determined by the sponsor.ObjectivesThe objective of this study was to assess the adequacy of patients' financial compensation by obtaining an external ethical opinion compared to the actual compensation provided.MethodsWe randomly selected and reviewed 50 clinical drug trials, including 25 academic and 25 industry‐sponsored studies. An external ethics group consisting of three members from French ethics committees, blinded to the actual compensation and the sponsor, retrospectively reviewed the study characteristics and assessed whether financial compensation was appropriate. Cohen's Kappa test measured agreement between actual compensation and the ethics group's opinion, and the McNemar test measured discrepancies.ResultsThere was no agreement between the actual financial compensation and the ethics group's opinion (K = −.07; 95% CI = [−.16–.02]). More discrepancies were found in favour of financial compensation according to the ethics group than provided by sponsors (12 vs. 2, p = .016). The ethics group recommended financial compensation in 12 out of 50 studies (24%), which were studies with a higher number of additional visits (p = .004) and were more frequently sponsored by industry (p = .008). Sponsors only provided financial compensation in 2 out of 50 studies (4%).ConclusionPatients are rarely compensated despite the perceived inconvenience. Both sponsors and ethics members struggle to determine the need for financial compensation, indicating a need for more precise recommendations for both parties.