bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated safety analysis of filgotinib for ulcerative colitis: Results from SELECTION and SELECTIONLTE
Authors: Schreiber Stefan , Rogler Gerhard , Watanabe Mamoru , Vermeire Séverine , Maaser Christian , Danese Silvio , Faes Margaux , Van Hoek Paul , Hsieh Jeremy , Moerch Ulrik , Zhou Yan , de Haas Angela , Rudolph Christine , Oortwijn Alessandra , Loftus Edward V.
Published: September 2023

Background

Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC).

Aim

To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long‐term extension study SELECTIONLTE (NCT02914535).

Methods

Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11‐week SELECTION induction study, the 47‐week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure‐adjusted incidence rates (EAIRs) per 100 censored patient‐years of exposure with 95% confidence intervals were reported for treatment‐emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status.

Results

This interim analysis included 1348 patients representing 3326.2 patient‐years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic‐experienced than biologic‐naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib.

Conclusion

FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age.

ClinicalTrials.gov Identifiers (NCT numbers)

NCT02914522, NCT02914535.
Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy‐confirmed nonalcoholic steatohepatitis
Authors: Alkhouri Naim , Lazas Donald , Loomba Rohit , Frias Juan P. , Feng Shibao , Tseng Leo , Balic Kemal , Agollah Germaine D. , Kwan Tinna , Iyer Janani S. , Morrow Linda , Mansbach Hank , Margalit Maya , Harrison Stephen A.
Published: September 2023

Background

An approved therapy for nonalcoholic steatohepatitis (NASH) and fibrosis remains a major unmet medical need.

Aim

To investigate the histological and metabolic benefits of pegozafermin, a glycoPEGylated FGF21 analogue, in subjects with biopsy‐confirmed NASH.

Methods

This proof‐of‐concept, open‐label, single‐cohort study, part 2 of a phase 1b/2a clinical trial, was conducted at 16 centres in the United States. Adults (age 21–75 years) with NASH (stage 2 or 3 fibrosis, NAS≥4) and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) ≥8% received subcutaneous pegozafermin 27 mg once weekly for 20 weeks. Primary outcomes were improvements in liver histology, and safety and tolerability.

Results

Of 20 enrolled subjects, 19 completed the study. Twelve subjects (63%) met the primary endpoint of ≥2‐point improvement in NAFLD activity score with ≥1‐point improvement in ballooning or lobular inflammation and no worsening of fibrosis. Improvement of fibrosis without worsening of NASH was observed in 26% of subjects, and NASH resolution without worsening of fibrosis in 32%. Least‐squares mean relative change from baseline in MRI‐PDFF was −64.7% (95% CI: −71.7, −57.7; p < 0.0001). Significant improvements from baseline were also seen in serum aminotransferases, noninvasive fibrosis tests, serum lipids, glycaemic control and body weight. Adverse events (AEs) were reported in 18 subjects (90%). The most frequently reported AEs were mild/moderate nausea and diarrhoea. There were no serious AEs, discontinuations due to AEs, or deaths.

Conclusions

Pegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH. ClinicalTrials.gov: NCT04048135.
Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease
Authors: Wu Tiffany , Hagiwara May , Gnass Esteban , Barman Hannah , Sasson David , Treem William , Ren Kaili , Marins Ed G. , Karki Chitra , Malhi Harmeet
Published: September 2023

Background

Alpha‐1 antitrypsin deficiency (AATD) is caused by mutations in SERPINA1, which encodes alpha‐1 antitrypsin, a protease inhibitor (Pi). Individuals with AATD and the homozygous Pi*ZZ genotype have variable risk of progressive liver disease but the influence of comorbid lung disease is poorly understood.

Aims

To characterise patients with AATD Pi*ZZ and liver disease (AATD‐LD‐Pi*ZZ) with or without lung disease and describe liver disease‐related clinical events longitudinally.

Methods

This was an observational cohort study of patients in the Mayo Clinic Healthcare System (January 2000–September 2021). Patients were identified using diagnosis codes and natural language processing. Fibrosis stage (F0–F4) was assessed using a hierarchical approach at baseline (90 days before or after the index date) and follow‐up. Clinical events associated with liver disease progression were assessed.

Results

AATD‐LD‐Pi*ZZ patients with lung disease had a longer median time from AATD diagnosis to liver disease diagnosis versus those without lung disease (2.2 vs. 0.2 years, respectively). Compared to those without lung disease, patients with lung disease had a longer time to liver disease‐related clinical events (8.5 years and not reached, respectively). AATD‐LD‐Pi*ZZ patients without lung disease were more likely to undergo liver transplantation compared with those with lung disease.

Conclusion

In patients with AATD and lung disease, there is a delay in the diagnosis of comorbid liver disease. Our findings suggest that liver disease may progress more rapidly in patients without comorbid lung disease.
Model‐informed precision dosing of vancomycin for rapid achievement of target area under the concentration‐time curve: A simulation study
Authors: Oda Kazutaka , Yamada Tomoyuki , Matsumoto Kazuaki , Hanai Yuki , Ueda Takashi , Samura Masaru , Shigemi Akari , Jono Hirofumi , Saito Hideyuki , Kimura Toshimi
Published: September 2023

In this study, we aimed to evaluate limited sampling strategies for achieving the therapeutic ranges of the area under the concentration‐time curve (AUC) of vancomycin on the first and second day (AUC0–24, AUC24–48, respectively) of therapy. A virtual population of 1000 individuals was created using a population pharmacokinetic (PopPK) model, which was validated and incorporated into our model‐informed precision dosing tool. The results were evaluated using six additional PopPK models selected based on a study design of prospective or retrospective data collection with sufficient concentrations. Bayesian forecasting was performed to evaluate the probability of achieving the therapeutic range of AUC, defined as a ratio of estimated/reference AUC within 0.8–1.2. The Bayesian posterior probability of achieving the AUC24–48 range increased from 51.3% (a priori probability) to 77.5% after using two‐point sampling at the trough and peak on the first day. Sampling on the first day also yielded a higher Bayesian posterior probability (86.1%) of achieving the AUC0–24 range compared to the a priori probability of 60.1%. The Bayesian posterior probability of achieving the AUC at steady‐state (AUCSS) range by sampling on the first or second day decreased with decreased kidney function. We demonstrated that second‐day trough and peak sampling provided accurate AUC24–48, and first‐day sampling may assist in rapidly achieving therapeutic AUC24–48, although the AUCSS should be re‐estimated in patients with reduced kidney function owing to its unreliable predictive performance.
Assessing pharmacogenomic literacy in China through validation of the Chinese version of the Minnesota Assessment of Pharmacogenomic Literacy
Authors: Zhang Lusi , Zhou Shuqin , Allen Josiah D. , Wang Fan , Pittenger Amy L. , Bishop Jeffrey R.
Published: September 2023

Pharmacogenomics (PGx) implementation into clinical care is rapidly increasing in China. However, the extent to which the public understands PGx testing and important knowledge domains requiring patient education or counseling remains unclear. To address this, we created and validated the Chinese version of the Minnesota Assessment of Pharmacogenomic Literacy (MAPL‐CTM). The MAPL‐C was developed by translating the English MAPL to Chinese following cross‐cultural translation guidelines. An online survey validated the MAPL‐C and assessed Chinese individuals' PGx literacy. Validation analyses were performed and associations of PGx literacy with participants' characteristics were quantified. Of 959 high‐quality responses, the majority of respondents were Han Chinese (96.3%), men (54.5%), aged 18–29 years (70.9%), residing in China (97.3%), and had received college or higher education (95.0%). Out of 15 starting items developed to query specific predefined knowledge domains, two uninformative items were excluded, resulting in a 13‐item MAPL‐C. Chinese participants' MAPL‐C performance was best explained by a three‐factor model, encompassing PGx concepts and function, testing limitations, and privacy. Higher MAPL‐C performance was associated with younger age, higher education, and previous genetic testing experience. Correct response rates for questions related to testing limitations were lower than those in other domains. The creation and validation of the MAPL‐C fills a gap in determining PGx knowledge among Chinese speakers, quantifying PGx literacy within a Chinese cohort, and identifying response patterns and knowledge gaps. The MAPL‐C can be useful in clinical practice to guide patient counseling, assess PGx education interventions, and quantify PGx knowledge in relation to outcomes in research studies involving Chinese participants.
Prevalence and prescribing patterns of oral corticosteroids in the United States, Taiwan, and Denmark, 2009–2018
Authors: Wallace Beth I. , Tsai Hui‐Ju , Lin Paul , Aasbjerg Kristian , Wu Ann Chen , Tsai Yi‐Fen , Torp‐Pedersen Christian , Waljee Akbar K. , Yao Tsung‐Chieh
Published: September 2023

Oral corticosteroids (OCS) are commonly prescribed for acute, self‐limited conditions, despite studies demonstrating toxicity. Studies evaluating longitudinal OCS prescribing in the general population are scarce and do not compare use across countries. This study investigated and compared OCS prescription patterns from 2009 to 2018 in the general populations of the United States, Taiwan, and Denmark. This international population‐based longitudinal cohort study used nationwide claims databases (United States: Optum Clinformatics Data Mart; de‐identified; Taiwan: National Health Insurance Research Database; and Denmark: National Prescription and Patient Registries/Danish National Patient Registry) to evaluate OCS prescribing. We classified annual OCS duration as short‐term (1–29 days), medium‐term (30–89 days), or long‐term (≥90 days). Longitudinal change in annual prevalence of OCS use and physician prescribing patterns were reported. Among 54,630,437 participants, average annual percentage of overall OCS use was 6.8% in the United States, 17.5% in Taiwan, and 2.2% in Denmark during 2009–2018. Prevalence of OCS prescribing increased at an average annual rate of 0.1%–0.17%, mainly driven by short‐term prescribing to healthy adults. One‐quarter to one‐fifth of OCS prescribing was associated with a diagnosis of respiratory infection. Family practice and internal medicine physicians were among the highest OCS prescribers across countries and durations. Age‐ and sex‐stratified trends mirrored unstratified trends. This study provides real‐world evidence of an ongoing steady increase in OCS use in the general populations of the United States, Taiwan, and Denmark. This increase is largely driven by short‐term OCS prescribing to healthy adults, a practice previously viewed as safe but recently shown to incur substantial population‐level risk.
State‐owned Enterprises in China as Macroeconomic Stabilizers: Their Special Function in Times of Economic Policy Uncertainty
Authors: Fang Mingyue , Ruan Rui
Published: September 2023

China has many state‐owned enterprises (SOEs) and they have accounted for a large proportion of China's GDP over the last four decades. China's rapid growth contradicts literature that focuses on the inefficiency of SOEs. This study shows that, in periods of economic policy uncertainty (EPU), SOEs have performed a special function as “macroeconomic stabilizers.” Using Chinese listed firm data from 2008 to 2019, we investigate five aspects of SOEs' unique functions as macroeconomic stabilizers: employment, investment, growth, financial operation, and expectations. When EPU increased, SOEs had more employment, higher investment expenditure, lower performance volatility, more robust financial structures, and more stable expectations than private firms. We employ the US–China trade war as an exogenous shock on EPU to conduct a difference‐in‐difference‐in‐differences approach to mitigate the problem of potentially omitted variables. The findings of this study provide a new perspective to better explain the functions of SOEs in the 21st century.
‘I don't chase drugs as much anymore, and I'm not dead’: Client reported outcomes associated with safer opioid supply programs in Ontario, Canada
Authors: Schmidt Rose A. , Kaminski Nat , Kryszajtys David T. , Rudzinski Katherine , Perri Melissa , Guta Adrian , Benoit Anita C. , Bayoumi Ahmed M. , Challacombe Laurel , Hales Jessica , Kenny Kathleen , Kolla Gillian , O'Reilly Emmet , Sereda Andrea , Rai Nanky , Strike Carol
Published: September 2023

Introduction

The ongoing opioid overdose crisis, which has killed over 30,000 people in Canada since 2016, is driven by the volatility of an unregulated opioid drug supply comprised primarily of fentanyl. The Canadian government has recently funded safer opioid supply (SOS) programs, which include off‐label prescriptions of pharmaceutical‐grade opioids to high risk individuals with the goal of reducing overdose deaths.

Methods

In 2021, we examined the implementation and adaption of four SOS programs in Ontario. These programs use a primary care model and serve communities experiencing marginalisation. We conducted semi‐structured interviews with program clients. We present the results of a thematic analysis with the aim of describing clients' self‐reported impact of these programs on their health and well‐being.

Results

We interviewed 52 clients between June and October 2021 (mean age 47 years, 56% men, 17% self‐identified Indigenous, 14% living with HIV). Our results indicate multifaceted pathways to improved self‐reported health and well‐being among clients including changes to drug use practices, fewer overdoses, reduced criminalised activity, improved trust and engagement in health care, and increased social stability (e.g., housing).

Discussion and Conclusion

Most clients reported that the intervention saved their life because of the reduced frequency of overdoses. Findings suggest that SOS programs improved clients' health outcomes and increase opportunities for engagement in health services. Our results provide insight into the mechanisms behind some of the emergent evidence on the impact of safer supply prescribing.
Accelerating local extinction associated with very recent climate change
Authors: Holzmann Kim L. , Walls Ramona L. , Wiens John J.
Published: September 2023

Climate change has already caused local extinction in many plants and animals, based on surveys spanning many decades. As climate change accelerates, the pace of these extinctions may also accelerate, potentially leading to large‐scale, species‐level extinctions. We tested this hypothesis in a montane lizard. We resurveyed 18 mountain ranges in 2021–2022 after only ~7 years. We found rates of local extinction among the fastest ever recorded, which have tripled in the past ~7 years relative to the preceding ~42 years. Further, climate change generated local extinction in ~7 years similar to that seen in other organisms over ~70 years. Yet, contrary to expectations, populations at two of the hottest sites survived. We found that genomic data helped predict which populations survived and which went extinct. Overall, we show the increasing risk to biodiversity posed by accelerating climate change and the opportunity to study its effects over surprisingly brief timescales.
Revisiting the impact of families on family firm performance
Authors: Jaskiewicz Peter , Combs James G. , Uhlenbruck Klaus , Datta Amlan
Published: September 2023

Family owners monitor managers, attenuating principal–agent conflicts and improving firm performance. However, family owners also appropriate resources, creating principal–principal conflicts that harm firm performance. Although these effects occur simultaneously, research does not explain when one outweighs the other. We theorize that agency costs are minimized when the family's involvement on the board of directors is proportional to its ownership; too little board involvement fuels principal–agent conflicts, and too much fuels principal–principal conflicts. Consistent with our theorizing, evidence from French panel data shows firm performance increases as family board involvement and family ownership jointly increase, and performance is maximized when family board involvement and family ownership are proportional.
Creativity governance: A conceptual framework for tailoring governance to the creativity and uncertainty in entrepreneurial projects
Authors: Araki Michael , Martins Henrique Castro
Published: September 2023

Given the influence of agency theory, corporate governance is tightly associated with the idea of monitoring. But what happens when the decision‐maker must act in an uncertain, open‐ended world? In this article, we propose a typology of firms' projects drawing on two parameters stemming from recent advancements in creativity theory: opacity and unlikelihood. This results in a matrix with four types of projects that display different qualities of entrepreneurialness: replicative projects, incubation projects, insightful projects, and innovative projects. We draw on the knowledge governance literature to suggest mechanisms and strategies of governance based on the prevailing type of project that the organization pursues. Our framework contributes to the theoretical understanding of the interplay between governance, creativity, and entrepreneurship literature while offering practical insights for designing better‐tailored governance mechanisms that align with a firm's prevailing project type.
Treatment‐related outcome from patient report outcome (PRO) of children with severe and moderate hemophilia A in China: An analysis report of registration data from patient organization “hemophilia home care center”
Authors: Guan Tao , Ai Di , Zhao Nan , Liu Guoqing , Yao Wanru , Chen Zhenping , Li Zhenping , Zhou Yaohan , Wu Runhui
Published: September 2023

Objectives

To assess current treatment‐related outcomes for children with severe and moderate haemophilia A (cHA) in China.

Methods

This cross‐section Patient Report Outcome (PRO) report collected PRO data of severe and moderate cHAs registered in the 'Hemophilia Home Care Center' database (http://web.bjxueyou.cn) between January 2021 and November 2022. Data included records of bleeding, activities, and concentrates consumption. All patients had a confirmed diagnosis of moderate or severe haemophilia A (FVIII: C ≤ 5%) and were < 18 years old.

Results

Among 1038 analysable cases, 9.6% of children with inhibitors had a higher rate of intracranial haemorrhage, dropout school rate, and higher FVIII consumption than children without inhibitors. Among 100 children with inhibitors, 36 patients were treated without immune tolerance induction (ITI), 14 patients with irregular treatment and 50 patients received ITI. Children with ITI had a lower ABR (2.4 (0,6.6) vs. 13.4 (9.5, 26.6), p<.001) and AJBR (0 (0, 3.1) vs. 8.9 (1.6, 19.3), p < .001) compared to those without ITI. Among 938 children without inhibitors, 28.5% received on‐demand treatment and 71.5% received prophylaxis. Of 528 children with 1343.8 (1050.4, 2922.9)IU/kg/year median FVIII consumption, 43.0% received low‐dose, 43.2% received intermediate‐dose, and 13.8% received high‐dose regimen; these children with prophylaxis had a lower ABR (3.1 (0, 10.7) vs. 12.8 (2.4, 45.5), p < .001), AJBR (0.5 (0, 3.9) vs. 3.0 (0, 12.0), p < .001) and disability rate (9.0% vs.18.5%, p = .032) compared to children who received on‐demand treatment.

Conclusion

The high rate of drop‐out of school and disability still present a huge gap to meet the needs in China. It is necessary to improve the level of medical accessibility and medicine affordability and strengthen the patient/parent's education in China.
In‐vitro comparison of two different toothbrush bristles about peri‐implant sulcus penetration
Authors: Montevecchi Marco , Valeriani Leoluca , Bellanova Leonardo , Stefanini Martina , Zucchelli Giovanni
Published: September 2023

Objective

The aim of this preclinical study was to compare the ability of tapered and cylindrical bristles to penetrate the peri‐implant sulcus.

Methods

A full mandibular dental arch was reproduced in plaster cast. In site #3.6 a hollow glass cylinder was positioned simulating a 4 mm diameter implant and the gingival component was recreated by using dedicated silicone. A Bass brushing technique was performed from the vestibular side in humid environment. During it, the penetration of the bristles between the gum and the implant was recorded by mean of an optic fibre fixed inside the cylinder. The protocol included 5 toothbrushes per group and 10 tests per toothbrush, for a total of 50 assessments for each of the two groups.

A scale of 5 grades for bristle penetration was defined: grade 0 (× < 2 mm), grade 1 (2 ≤ × < 3 mm), grade 2 (3 ≤ × < 4 mm), grade 3 (4 ≤ × < 5 mm) and grade 4 (5 ≤ × < 8 mm). From the video recordings the highest value of penetration was identified for each test.

Results

The tapered bristles showed an 8 times greater penetration capacity (p = 0.001) in respect to the cylindrical bristles (multilevel analysis). The percentage of tests reaching depths ≥3 mm was 86% for tapered group and 28% for the cylindrical group.

Conclusion

This preclinical study shows a clear and superior penetration capacity of the tapered bristles in respect to traditional cylindrical ones. For tapered bristles, a potentially greater hygienic efficacy around dental implants is suggested.
Effectiveness of online faculty calibration: A randomized crossover study
Authors: Biorn Camille M. , Rogo Ellen J. , Williams Rachelle
Published: September 2023

Purpose

Dental hygiene faculty members must be able to provide evidence of skill calibration for clinical evaluation of students. The purpose of this study was to evaluate the effectiveness of online instructional videos as compared to in‐person sessions for faculty calibration.

Methods

A randomised crossover pretest/posttest research design was used to evaluate online and in‐person faculty calibration activities. Fifteen faculty members from a baccalaureate dental hygiene programme were randomly assigned to an AB or BA sequence for calibration sessions on two different instruments. Following a 2‐week washout period, the groups switched activity modalities. A pretest, posttest and retention test, administered 10 weeks following the activity, were administered to determine learning levels and the new and retained knowledge. A 7‐point Likert scale questionnaire evaluated the reaction to and impact of the calibration activities. Descriptive statistics analysed demographic and Likert scale data. Paired samples t‐tests were used to analyse the research questions (p ≤ 0.05).

Results

Online calibration activities yielded higher posttest scores than in‐person activities (p = 0.01). Findings related to feelings of confidence revealed that a greater percentage of participants agreed that online calibration activities increased their ability to evaluate student performance. Findings related to feelings of preparedness supported equal percentages of participants who agreed the online and in‐person activities increased their ability to teach dental hygiene instrumentation. There was no significant difference between in‐person and online retention test scores (p = 0.235).

Conclusion

Faculty members agreed that both online and in‐person calibration activities were an effective use of their time and contributed to greater feelings of confidence and preparedness. However, the online calibration activities seemed to be more effective at increasing calibration on instrumentation. More research is needed to determine additional effective strategies for the online calibration of clinical faculty.
Quality outcomes for end‐of‐life care among people with haematological malignancies at a New Zealand cancer centre
Authors: Kim Ann , O'Callaghan Anne , Hemmaway Claire , Johney Leslie , Ho Jess
Published: September 2023

Background

Little is known about the end‐of‐life (EOL) experience and specialist palliative care use patterns of patients with haematological malignancies (HMs) in New Zealand.

Aims

This retrospective analysis sought to examine the quality of EOL care received by people with HMs under the care of Auckland District Health Board Cancer Centre's haematology service and compare it to international data where available.

Methods

One hundred consecutive adult patients with HMs who died on or before 31 December 2019 were identified. We collected information on EOL care quality indicators, including anticancer treatment use and acute healthcare utilisation in the last 30 days of life, place of death and rate and timing of specialist palliative care input.

Results

During the final 14 and 30 days of life, 15% and 27% of the patients received anticancer therapy respectively. Within 30 days of death, 22% had multiple hospitalisations and 25% had an intensive care unit admission. Death occurred in an acute setting for 42% of the patients. Prior contact with hospital and/or community (hospice) specialist palliative care service was noted in 80% of the patients, and 67% had a history of hospice enrolment. Among them, 15% and 28% started their enrolment in their last 3 and 7 days of life respectively.

Conclusions

The findings highlight the intensity of acute healthcare utilisation at the EOL and high rates of death in the acute setting in this population. The rate of specialist palliative care access was relatively high when compared with international experiences, with relatively fewer late referrals.
Social network analysis of EU flood risk management plans: Case Finland
Authors: Banafa Thomas , Eräranta Susa , Peltonen Lasse , Keskinen Marko
Published: September 2023

Flood risks are increasing in Europe, and the EU Floods Directive is one of the main efforts to implement and harmonize effective flood risk governance and management among member states. At the same time, the ongoing shift from mere flood protection to multi‐functional flood risk governance calls for increased collaboration among a diversity of actors, typically with varying interests and responsibilities. In this study, we analyze the actor networks unfolding from flood risk management plans to visualize the diversity of roles and connections between actors participating in flood risk management measures. We introduce a new framework for analyzing flood risk management plans and related actor networks using Social Network Analysis and test it in the context of Finland. The framework helps to visualize the diversity of networks for different flood risk management strategies. The analysis also reveals the central roles that different types of actors—including those outside the public sector—occupy in the network. The findings suggest that Social Network Analysis can be used in the context of EU flood risk governance and that flood risk management plans offer an excellent opportunity for comparative governance studies in the EU.
The virtual brain endocast of Trogosus (Mammalia, Tillodontia) and its relevance in understanding the extinction of archaic placental mammals
Authors: Bertrand Ornella C. , Jiménez Lao Marina , Shelley Sarah L. , Wible John R. , Williamson Thomas E. , Meng Jin , Brusatte Stephen L.
Published: September 2023

After successfully diversifying during the Paleocene, the descendants of the first wave of mammals that survived the end‐Cretaceous mass extinction waned throughout the Eocene. Competition with modern crown clades and intense climate fluctuations may have been part of the factors leading to the extinction of these archaic groups. Why these taxa went extinct has rarely been studied from the perspective of the nervous system. Here, we describe the first virtual endocasts for the archaic order Tillodontia. Three species from the middle Eocene of North America were analyzed: Trogosus hillsii, Trogosus grangeri, and Trogosus castoridens. We made morphological comparisons with the plaster endocast of another tillodont, Tillodon fodiens, as well as groups potentially related to Tillodontia: Pantodonta, Arctocyonidae, and Cimolesta. Trogosus shows very little inter‐specific variation with the only potential difference being related to the fusion of the optic canal and sphenorbital fissure. Many ancestral features are displayed by Trogosus, including an exposed midbrain, small neocortex, orbitotemporal canal ventral to rhinal fissure, and a broad circular fissure. Potential characteristics that could unite Tillodontia with Pantodonta, and Arctocyonidae are the posterior position of cranial nerve V3 exit in relation to the cerebrum and the low degree of development of the subarcuate fossa. The presence of large olfactory bulbs and a relatively small neocortex are consistent with a terrestrial lifestyle. A relatively small neocortex may have put Trogosus at risk when competing with artiodactyls for potentially similar resources and avoiding predation from archaic carnivorans, both of which are known to have had larger relative brain and neocortex sizes in the Eocene. These factors may have possibly exacerbated the extinction of Tillodontia, which showed highly specialized morphologies despite the increase in climate fluctuations throughout the Eocene, before disappearing during the middle Eocene.
The outer membrane protein Tp92 of Treponema pallidum delays human neutrophil apoptosis via the ERK, PI3K/Akt, and NF‐κB pathways
Authors: Li Weiwei , Li Sijia , Wang Jianye , Yu Maoying , Yang Hongyu , He Zhangping , Tang Yuanyuan , Liu Jie , Guo Ningyuan , Xie Dongde , Liu Zhaoping , Zheng Kang , Xu Man , Wu Yimou
Published: September 2023

Syphilis is a persistent sexually transmitted disease caused by infiltration of the elusive pathogen Treponema pallidum. Despite the prevalence of human polymorphonuclear neutrophils (hPMNs) within cutaneous lesions, which are characteristic of incipient syphilis, their role in T. pallidum infection remains unclear. Tp92 is the only T. pallidum helical outer membrane protein that exhibits structural features similar to those of outer membrane proteins in other gram‐negative bacteria. However, the functional mechanism of this protein in immune cells remains unclear. Neutrophils are short‐lived cells that undergo innate apoptosis in response to external stimuli that typically influence this process. In this study, we determined that Tp92 impedes the activation of procaspase‐3 via the ERK MAPK, PI3K/Akt, and NF‐κB signaling pathways, consequently suppressing caspase‐3 activity within hPMNs, and thereby preventing hPMNs apoptosis. Furthermore, Tp92 could also modulate hPMNs apoptosis by enhancing the expression of the anti‐apoptotic protein Mcl‐1, stimulating IL‐8 secretion, and preserving the mitochondrial membrane potential. These findings provide valuable insights into the molecular mechanisms underlying T. pallidum infection and suggest potential therapeutic targets for syphilis treatment.
Toward an ontology of the mutant in the health sciences: Re/defining the person from Cronenberg's perspective
Authors: Holmes Dave , Turcotte Pier‐Luc , Adam Simon , Johansson Jim , Orser Lauren
Published: September 2023

Traditional health sciences (including nursing) paradigms, conceptual models, and theories have relied heavily upon notions of the ‘person’ or ‘patient’ that are deeply rooted in humanistic principles. Our intention here, as a collective academic assemblage, is to question taken‐for‐granted definitions and assumptions of the ‘person’ from a critical posthumanist perspective. To do so, the cinematic works of filmmaker David Cronenberg offer a radical perspective to revisit our understanding of the ‘person’ in nursing and beyond. Cronenberg's work explores bodily transformation and mutation, with the body as a fragile and malleable vessel. Cronenberg's work allows us to interrogate the body in all its complexity, contingency, and hybridity and provides avenues of rupture within current understandings of ‘the person’. Reinventing the definition of what it means to be human, critical posthumanism offers opportunities to both critique humanist theories and build affirmative futurities. Also drawing on the work of Deleuze and Guattari, specifically, their concept of becoming, we propose a critical posthumanist alternative to the conceptualization of the person in the health sciences, that of the becoming‐mutant, so frequently explored in Cronenberg's films. Such a conceptualization permits the inclusion of various technological interventions of the contemporary subject: The postperson. This position offers the health science disciplines a radical reconceptualization of the conceptual and theoretical approaches, extending beyond those trapped within the quagmire of humanistic principles.
The role of thwarted belongingness and perceived burdensomeness in passive suicide ideation among Latinx and Black youth
Authors: Vélez‐Grau Carolina , McTernan Melissa , Mufson Laura , Lindsey Michael A.
Published: September 2023

Introduction

The interpersonal theory of suicide (IPTS) is used to evaluate suicide risk. Yet, it has not been sufficiently tested with ethnoracially minoritized youth. This study aimed to test whether thwarted belongingness (TB) and perceived burdensomeness (PB) were associated with passive suicide ideation (SI) among Latinx and Black youth.

Methods

Data were obtained from a cross‐sectional study. Some youth participants were recruited from an ongoing NIMH study of depressed Black youth in schools (N = 20). The rest were participants in a supplemental study of non‐depressed Latinx and Black youth in community agencies (N = 61). Multivariate logistic regression analyses were conducted to examine the relationships between passive SI and the IPTS constructs.

Results

Most participants identified as male (63.5%) and Latinx (59.5%), mean age 15.23 (SD = 1.4). Only TB remained significant when adjusting for age and gender, even after adding a measure of depression symptoms as a covariate. Notably, the interaction term (TBXPB) was not significantly associated with increased odds of passive SI in this sample.

Conclusion

These findings confirm the importance of examining the IPTS constructs and their relationship to passive SI in diverse populations. The relationship between TB and SI in Latinx and Black youth suggests it may be an important target for suicide prevention.
Was ist das? Martin Luther's catechism and pedagogical methods in the contemporary theological classroom
Authors: Westengard Brandon L.
Published: September 2023

Martin Luther is primarily known as a pastor and theologian of the 16th century Reformation. However, he was also a pedagogue passionate about educational reforms that united the spiritual life with the daily lived life. Believing that education served the purpose of equipping students for a life in service of one's neighbor, Luther took a practical and spiritual approach to critically engage content and even left space for teachers to differentiate based on their students' needs. This article provides a close look at the pedagogy and curriculum Luther outlines in the introduction to his Small Catechism and seeks to provide a creative adaptation to the contemporary theological/religious classroom. In the hopes that Luther's method can be of help in a variety of settings and spiritual traditions, the primary teaching method is driven by inquiry and the catechetical question “what is this?”
A retrospective evaluation of phenobarbital‐induced hematologic changes in 69 cats
Authors: Dohány Anna , Guija‐de‐Arespacochaga Abigail , Fux Daniela , Silberbauer Christina , Pákozdy Ákos
Published: September 2023

Background

Phenobarbital (PB) is used as a first‐line treatment for recurrent epileptic seizures in cats. While hematologic abnormalities are well‐known side effects of antiepileptic therapy with PB in humans and dogs, little is known about such alterations in cats.

Objectives

The aim of this retrospective study was to investigate the prevalence and clinical relevance of cytopenia during PB treatment in cats.

Methods

In this single‐center, retrospective clinical study, 69 cats—with suspected idiopathic epilepsy admitted to the Small Animal Clinic of the University of Veterinary Medicine in Vienna (VMU)—were included. A complete blood count for each patient was performed, and changes in hematocrit, leukocytes, neutrophils, and thrombocytes were documented and graded.

Results

Fifty‐three out of 69 cats (76.8%) showed cytopenias with a reduction of at least one cell fraction during PB treatment. The most frequent change was neutropenia (60%), followed by leukopenia (49.3%), thrombocytopenia (24.1%), and anemia (20.3%). Most of the changes were mild or moderate; only one patient (1.5%) showed severe leukopenia and neutropenia, and one was a life‐threatening neutropenia (1.5%) with a serum PB concentration within or even below the therapeutic range. These patients did not present with clinical symptoms other than those related to epileptic episodes. Cats who received combination therapy showed lower hematocrits than those who received monotherapy. A tendency for leukocytes and neutrophils to decrease during PB treatment was also seen.

Conclusions

Blood cytopenias may frequently occur in cats on chronic PB therapy, even when serum drug levels are within the therapeutic range. However, clinical signs are typically mild to moderate and rarely severe.
Hamiltonian knottedness and lifting paths from the shape invariant
Authors: Hind Richard , Zhang Jun
Published: September 2023

The Hamiltonian shape invariant of a domain $X \subset \mathbb {R}^4$, as a subset of $\mathbb {R}^2$, describes the product Lagrangian tori which may be embedded in $X$. We provide necessary and sufficient conditions to determine whether or not a path in the shape invariant can lift, that is, be realized as a smooth family of embedded Lagrangian tori, when $X$ is a basic $4$-dimensional toric domain such as a ball $B^4(R)$, an ellipsoid $E(a,b)$ with ${b}/{a} \in \mathbb {N}_{\geq ~2}$, or a polydisk $P(c,d)$. As applications, via the path lifting, we can detect knotted embeddings of product Lagrangian tori in many toric $X$. We also obtain novel obstructions to symplectic embeddings between domains that are more general than toric concave or toric convex.
The mega‐evolution of life with its three memory systems depends on sender–receiver communication and problem‐solving. A narrative review
Authors: De Loof Arnold
Published: September 2023

It should be the ultimate goal of any theory of evolution to delineate the contours of an integrative system to answer the question: How does life (in all its complexity) evolve (which can be called mega‐evolution)? But how to plausibly define ‘life’? My answer (1994–2023) is: ‘life’ sounds like a noun, but denotes an activity, and thus is a verb. Life (L) denotes nothing else than the total sum (∑) of all acts of communication (transfer of information) (C) executed by any type of senders–receivers at all their levels (up to at least 15) of compartmental organization: L = ∑C. The ‘communicating compartment’ is better suited to serve as the universal unit of structure, function and evolution than the cell, the smallest such unit. By paying as much importance to communication activity as to the Central Dogma of molecular biology, a wealth of new insights unfold. The major ones are as follows. (1) Living compartments have not only a genetic memory (DNA), but also a still enigmatic cognitive and an electrical memory system (and thus a triple memory system). (2) Complex compartments can have up to three types of progeny: genetic descendants/children, pupils/learners and electricians. (3) Of particular importance to adaptation, any act of communication is a problem‐solving act because all messages need to be decoded. Hence through problem‐solving that precedes selection, life itself is the driving force of its own evolution (a very clever but counterintuitive and unexpected logical deduction). Perhaps, this is the ‘vital force’ philosopher and Nobel laureate (in 1927) Henri Bergson searched for but did not find.

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Paleogeographical reconstruction of the South China Block during Gondwana assembly using detrital apatite: Pan-African source affinity concealed by detrital zircon
Authors: Xue Er-Kun , Chew David , Drakou Foteini , Wang Wei
Published: September 2023

Detrital zircon provenance analysis plays a key role in reconstructions of past tectonic and sedimentary environments. However, non-unique (or even erroneous) interpretations can be introduced due to the inherent limitations of both zircon provenance analysis (fertility bias, recycling) and those of single-proxy provenance systems in general. Apatite crystallizes in a wider range of lithologies than zircon, and can thus facilitate more detailed source reconstructions. In this study, detrital apatite analysis of Cryogenian to Ordovician sandstones in the Cathaysia Block was carried out in comparison with detrital zircon data for a better understanding of the source-sink process on the northern margin of Gondwana. In contrast to the abundant Grenvillian (1300−900 Ma) detrital zircons of igneous origin, detrital apatites show major Pan-African (650−500 Ma) age peaks that are mostly derived from metamorphic rocks (52%−72%). The apatite data show that the Cathaysia Block mainly received detritus from western Australia and India during the late Neoproterozoic to early Paleozoic, with much lower affinities to East Antarctica and the terranes of Iran-Turkey. Provenance variations include a shift with time in the major age populations from ca. 900 Ma to 600 Ma with a decrease in metamorphic apatite (from 72% to 52% of all grains) in the late Cryogenian, an increase in high-grade metamorphic apatite (from 27% to 56%) in the late Ediacaran−Cambrian, and an increase in igneous apatite (from 33% to 45% of all grains) in the Early Ordovician. In contrast, detrital zircon data could only reveal the source change in the late Ediacaran. These provenance switches were likely caused by the unroofing of Pan-African orogens (640−490 Ma) and subsequent erosion of their exposed cores, due to the rapid uplift of source rocks formed in the Pan-African orogens during the Gondwana assembly.
Detection of Two New RRATs at 111 MHz
Authors: Samodurov V. A. , Tyul’bashev S. A. , Toropov M. O. , Dolgushev A. V. , Oreshko V. V. , Logvinenko S. V.
Published: September 2023

At the LPA LPI radio telescope, a search was conducted for pulse signals in a specific area with declinations $$ + 52^\circ < \delta < + 55^\circ $$. The processing involved ten months of observations recorded in six frequency channels, each with a channel width of 415 kHz and a total bandwidth of 2.5 MHz. The analysis of the data revealed 22 000 events, exhibiting a pronounced dispersion delay of signals over the frequency channels, which are indicative of pulsar pulses. These pulses were found to belong to four known pulsars and two new rotating radio transients (RRAT). Additional pulse search was carried out in 32-channel data with a channel width of 78 kHz. This led to the discovery of 8 pulses for the transient J0249+52 and 7 pulses for the transient J0744+55. No periodic emission of transients was detected. The analysis of the observations indicates a high probability that the identified RRATs are pulsars with nullings, where the fraction of nullings is greater than 99.9%.
Erratum to: Features of the Interaction of Scheelite with HCl Solutions at 400 and 500°C, 100 MPa, and Various f(O2) (According to Experimental and Calculated Data)
Authors: Redkin A. F. , Kotova N. P.
Published: September 2023

An Erratum to this paper has been published: https://doi.org/10.1134/S1075701523360011
Aetiology, ejection fraction and mortality in chronic heart failure: a mediation analysis
Authors: Fritz Josef , Belovari Katrin , Ulmer Hanno , Zaruba Marc-Michael , Messner Moritz , Ungericht Maria , Siebert Uwe , Ruschitzka Frank , Bauer Axel , Poelzl Gerhard
Published: September 2023

Objective

Clinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality.

Methods

Using data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects.

Results

For the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR5%-points lower LVEF=1.07, 95% CI 1.04 to 1.10; pinteraction=0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HRindirect effectof 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF.

Conclusions

The direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF.