bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Patients Decision Aids on Shared Decision‐Making and Patient Satisfaction Prior to Pelvic Floor Surgery
Authors: Athey Ruth , Bugeja Roberta , Jones Georgina , Jha Swati
Published: February 2025

Objective

Evaluate usability and utility of National Institute for Clinical Excellence (NICE) Patient Decision Aid's (PtDA's) for pelvic floor surgery. PtDA's reviewed were uterine prolapse, vault prolapse and stress urinary incontinence (SUI).

Design

Ten women given the PtDA's during routine clinical care were recruited from each cohort and underwent a semi‐structured interview with a clinical researcher.

Setting

Urogynaecology outpatients in an NHS tertiary teaching hospital.

Population or Sample

Women considering surgical management of uterine/vault prolapse or SUI. Exclusion criteria included those under 18, unable to communicate in English or not eligible for all surgical options discussed in the PtDA's.

Methods

A qualitative, semi‐structured interview evaluating women's opinions of the decision aid and the way in which they utilised the PtDA was conducted. The interviews were recorded and transcribed prior to undertaking thematic analysis utilising NVivo software.

Main Outcome Measure

The outcomes of interest were feedback for content, language, format and usage of the PtDA's and women's usage of PtDA's in decision‐making.

Results

Amendments suggested included removal of mesh from the SUI PtDA as this is not routinely available on the NHS and addition of a statement regarding the use of mesh in prolapse surgery. Additional anatomical diagrams were suggested. The need for a robust and regular update system was highlighted as was the provision of foreign language, audio and electronic versions.

Conclusions

PtDA's need updating to ensure relevant content. Clear, detailed and relevant information is required alongside active clinician engagement to reach a mutually agreeable treatment plan.
Description and provider perspectives on a school‐based speech/mental health co‐therapy model for students with intellectual/developmental disabilities
Authors: Müller Eve , Offutt Kelly , Kern Ann , Oginz Jessica , Stromberg Michael
Published: February 2025

The purpose of this article is to (a) provide a detailed description of how one school in the United States developed decision‐making guidelines for implementing a speech‐language/mental health (SLP/MHP) co‐therapy service delivery model, and (b) summarize study findings based on interviews conducted with school‐based speech‐language pathologists (SLPs), school‐based licensed mental health providers (MHPs), and administrators about their perceptions of using this co‐therapy model to provide services to students with intellectual/developmental disabilities (e.g., autism) and co‐occurring language and mental health support needs. We used qualitative analysis to identify key themes from the 19 interviews we conducted with school‐based staff, including SLPs, MHPs and administrators. Thematic analysis indicated that: (a) students demonstrated progress during co‐therapy and benefited from its more holistic approach to complex, interdisciplinary content and skills; (b) SLPs felt more confident handling their students' emotional regulation needs, challenging behaviours and/or other mental health support needs; and (c) MHPs felt more confident adapting language to make therapeutic content accessible to their students with language support needs. Interviewees also discussed logistical challenges and recommendations for further guidance/training. Findings from interviews indicate that SLP/MHP co‐therapy may offer a promising service delivery option for students with intellectual/developmental disabilities receiving both speech‐language and mental health services through their individualized education programs (IEPs).
The role of Hox genes in shaping embryonic external morphology of the primitive insect Thermobia domestica (Zygentoma)
Authors: Lu Hu‐Na , Zhang Peiyan , Wang Yifan , Luo Kai , Yan Ziyu , Zeng Mei , Lv Ya‐Nan , Bai Shali , Zeng Jiaming , Li Sheng , Bai Yu , Luan Yun‐Xia
Published: February 2025

Insects represent one of the most evolutionarily successful groups, with their diversity hypothesized to be related to the regulatory roles of Hox genes, a set of related genes encoding homeodomain transcription factors determining the identity of segments along the anterior‐posterior axis of the embryo. However, functional insights into the roles of Hox genes in primitive ametabolous insects, which represent the critical transition from aquatic crustaceans to winged insects, have been limited. In this study, we identified complete protein‐coding sequences of 10 Hox genes in the Zygentoma Thermobia domestica, and applied clustered regularly interspaced short palindromic repeats (CRISPR) / CRISPR‐associated nuclease 9 (Cas 9) mediated gene knockout (KO) to decipher their functions. We found that the roles of pb, Dfd, and Scr are vital in specifying the appendages of the head in T. domestica, and these roles are relatively conserved in crustaceans and winged insects. Antp is essential for the development of the prothorax segment and the first pair of legs in T. domestica. Ubx and abd‐A fully repress appendage development in the abdomen of T. domestica, which implies a functional switch from crustaceans to insects. Additionally, the role of ftz in segmenting the abdomen of T. domestica suggests it has acquired new functions in primitive insects, beyond its traditional Hox‐like roles. Although KOs of lab, Hox3, and Abd‐B did not result in obvious external phenotypic changes, they led to a significant decrease in hatching rates and substantial deviations in daily survival numbers compared to the negative control. These findings underscore the indispensable roles of all Hox genes during the embryonic development of T. domestica. Our study sheds new light on the functional evolution of Hox genes in ametabolous insects and enhances our understanding of the genetic underpinnings of insect development and diversification.
Ergonomics in Dermatological Surgery: An International Survey Among Dermatologists
Authors: Lim Puo Nen , Kelly Aine Sinead , Lawrence Marc , Hunt William Thomas Nicholas
Published: February 2025

There is a high prevalence of musculoskeletal pain among dermatological surgeons, particularly in the neck, upper and lower back, and shoulders. We performed an international survey which revealed a lack of ergonomic education and use of ergonomic tools in dermatological surgery. Most respondents were aware of bad posture during surgery, but few regularly checked their posture. Behavioural interventions, such as alternating between standing and sitting, and taking frequent breaks, are recommended to reduce pain. Ergonomic workstation adaptations, including the use of surgical loupes, good lighting and adjustable stools, are crucial for reducing strain.
Less trash, more treasure. Waste production and reduction in Orthopaedic surgery
Authors: Drobetz Nikolas , Xu Joshua , Chang David , Hazan Daniel , Collins William , Drobetz Herwig
Published: February 2025

Background

The operating theatre generates substantial waste, raising environmental concerns. This study quantified the waste generated during four common orthopaedic procedures and identified recyclable materials. It also assessed the associated carbon footprint to highlight opportunities for sustainable waste management.

Methods

This prospective study was conducted at a single regional hospital in New South Wales, Australia, from July to September 2024. Sixty procedures were analysed: 15 total knee arthroplasties (TKA), 15 total hip arthroplasties (THA), 15 ankle fracture fixations, and 15 hand injury surgeries. Waste was categorized as landfill, recyclable, or biohazardous. Landfill waste was further analysed for potentially recyclable components, with data extrapolated to nationwide operation numbers. Carbon dioxide emissions were calculated using the formula tCO2‐e = Q × EF, where Q is waste weight, EF is the emission factor (0.879), and tCO2‐e is tonnes of carbon dioxide emissions.

Results

Across 60 procedures, 425.7 kg of waste was generated, averaging 8.2 kg per case. TKA produced the most waste (11.7 kg per case), while hand injury surgeries generated the least (3.9 kg per case). Potentially recyclable waste constituted 12% of landfill waste, with TKA having the highest recyclable proportion (13%). Recyclable materials comprised 44% of total waste. Proper segregation could reduce up to 75 t of CO2‐emissions annually from TKA alone in Australia.

Conclusions

A significant portion of orthopaedic theatre waste is recyclable, offering opportunities to reduce the carbon footprint of surgeries. Improved staff training and recycling facilities are crucial for optimizing waste management in healthcare.
Robot‐assisted resection of oesophageal leiomyoma: a single‐centre retrospective analysis of 57 cases
Authors: Wang Ruizhen , Guo Yuhang , Duan Xiaofeng , Jiang Hongjing
Published: February 2025

Backgrounds

Oesophageal leiomyoma is the most common benign tumour of the oesophagus, and complete tumour enucleation is the preferred treatment. The aim of this study is to evaluate the clinical application and technical advantages of Robotic‐assisted Thoracoscopic Surgery (RATS) during the resection of oesophageal leiomyoma.

Methods

A retrospective study was conducted on patients who underwent robotic surgery for oesophageal diseases at our hospital from September 2017 to December 2023. Demographic statistics and clinical pathological characteristics, intraoperative and postoperative outcomes, immune histopathological staining, tumour pathology diagnosis and follow‐up were analyzed.

Results

A total of 57 patients were enrolled in the study, including 42 males and 15 females with an average age of 49 years All patients received surgical treatment, with 54 patients undergoing robot‐assisted resection of oesophageal tumour, one patient undergoing conversion to thoracotomy, and two patients undergoing exploratory surgery. The mean surgical time was 130 minutes, and the mean blood loss was 50 mL. Of the 55 patients who underwent tumour resection, 54 were pathologically diagnosed as oesophageal leiomyoma and one as atypical leiomyoma. Only one patient developed pulmonary infection after surgery, and there was no perioperative mortality. The average postoperative hospital stay was 9 days. All patients were followed up for a median time of 16 months (range: 1 to 70 months), and there was no recurrence or long‐term complications after surgery.

Conclusion

Robot‐assisted resection of oesophageal leiomyoma is safe and feasible, and can provide ideal short‐and medium‐term results.
Reframing spontaneous preterm birth as a preventable adverse outcome—A clinical audit of a preventative toolbox
Authors: Ramachandran Aparna , Perez Darazel , Gordon Adrienne , Hyett Jon
Published: February 2025

Introduction

Spontaneous preterm birth is a major cause of perinatal morbidity and mortality and has traditionally been viewed as an inevitable event affecting a small proportion of pregnancies. Clinical practice guidelines recommend measures to predict pregnancies at risk of spontaneous preterm birth and prophylactic treatments. We performed this study to assess adherence to current guidelines for prediction and prevention of spontaneous preterm birth and to evaluate the effectiveness of current predictive tools.

Material and Methods

Retrospective audit of all spontaneous preterm birth in singleton pregnancies preceded by spontaneous labor or preterm prelabor rupture of membranes less than 37 weeks at an Australian metropolitan hospital from January 1, 2019, and December 31, 2020. Termination of pregnancy and fetal abnormalities were excluded. Electronic medical record data was collected for maternal demographic information, antenatal care and use of current predictive measures, use of prophylactic treatments, and pregnancy and newborn outcomes.

Results

Two hundred sixty‐seven spontaneous preterm births were included, comprising 3.5% of all births over the study period. Seventy‐eight percent of these were in women defined as low‐risk for preterm birth. Screening for bacteriuria was performed in 59.1% and 65.9% of low‐ and high‐risk women, respectively. Cervical length measurement was performed in 65% and 72% of low‐ and high‐risk women; only 10.7% of low‐risk and 11.4% of high‐risk women with sPTB had a short cervix prior to 24+6 weeks gestation. The mean gestational age at birth was 34+0 and 35+0 weeks for low‐ and high‐risk women (p = 0.38); the rate of perinatal death was 9.6% in low‐risk pregnancies and 4.2% in high‐risk pregnancies (p = 0.39).

Conclusions

Adherence to clinical guideline recommendations for prediction and prevention of sPTB was suboptimal in this cohort. The majority of spontaneous preterm births occur in women without risk factors and most women with sPTB in this cohort were not identified as having a short cervix in the early second trimester; these preterm births are therefore not identified by current predictive tools. Preterm birth continues to be associated with an increased risk of perinatal death despite the use of current predictive and preventative measures.
Insect Meal (Tenebrio molitor) Has High Nutrient Digestibility for Newly Weaned Piglets
Authors: Pereira Juliana Carolina , da Silva Alan Roberto Alves , Rossiti Bernardetti Cajaíba Oliveira , da Silva Eduardo Rodrigues , da Silva Letícia Garbin Ribeiro , Evangelista Mariane Zabotto , dos Santos Ruiz Urbano , Tse Marcos Livio Panhoza
Published: February 2025

This study aimed to evaluate the inclusion of insect larvae meal (Tenebrio molitor) on the apparent total digestibility of dry matter (DM), gross energy (GE), ether extract (EE), crude protein (CP), neutral and acid detergent fiber (NDF and FDA), and the apparent and standardized ileal digestibility of amino acids (Exp.1) and to evaluate the inclusion of insect meal with iron and manganese supplementation on growth performance and serum hemoglobin concentration by collecting blood (day zero), on the 14th and 32nd days of the experiment (Exp.2). The standardized ileal digestibility values for amino acids and crude protein of insect meal were similar to those found for soybean meal, with high metabolizable energy values (Exp.1), and there was no difference in performance for any of the variables analyzed (p ≥ 0.05) in any of the periods (Exp.2). For serum hemoglobin values, there was no interaction (p ≥ 0.05) between the treatments used and the collection days; however, hemoglobin values increased (p < 0.05) at each collection time. It can therefore be concluded that insect meal for pigs can be considered an alternative ingredient to soybean meal as a source of protein in piglet nutrition due to high digestibility of amino acids without deleterious effect on productive performance.
Imagining Futures: Evaluation of a blended programme of dialectical behaviour therapy and the creative arts for young women with a history of self‐harm
Authors: Smith L. M. , Barrett B. , Barnes S. , Oltean B. , Ige L. , Day C. , Tranah T.
Published: February 2025

Objectives

To evaluate an arts‐enhanced dialectical behavioural therapy skills group for managing emotions and self‐harm, implemented via an innovative public sector/third sector partnership to increase access to care.

Design

This is a pilot mixed‐methods study.

Methods

To assess participant experience in the ‘Imagining Futures’ programme, we examined self‐report questionnaires and qualitative focus group interviews using framework analysis. We collected recruitment, session attendance and programme completion rates. To explore impact, we also report on quantitative psychological outcome measures, including self‐harm frequency and overall well‐being.

Results

We recruited 45 young women (mean age: 15.9, s.d. = 1.24, range 13.9–18.0 years) with a history of emotional dysregulation, self‐harm and other contextual risks who were not receiving support from statutory child and adolescent mental health services in the United Kingdom. Participants were 22% not in education, employment or training and 77% were from United Kingdom racially minoritized backgrounds. The overall completion rate was 62% (n = 28/45). Qualitative data analysed from respondents (n = 25/28 young people and n = 12 parents) suggested high levels of satisfaction with the project. Thirteen themes were identified which described service elements perceived to support engagement and observed impact. There was an important role for relationships and the creative components. Quantitative clinical data indicated reductions in the frequency of self‐harming, significant reductions in the perceived impact of difficulties and increased perceived social support.

Conclusions

This novel delivery of a DBT skills group, incorporating blended psychology arts activities, has the potential to support engagement with psychological supports that improve mental well‐being.
Novel drugs approved by the EMA, the FDA and the MHRA in 2024: A year in review
Authors: Topouzis Stavros , Papapetropoulos Andreas , Alexander Steve P. H. , Cortese‐Krott Miriam , Kendall Dave A. , Martemyanov Kirill , Mauro Claudio , Nagercoil Nithyanandan , Panettieri Reynold A. , Patel Hemal H. , Schulz Rainer , Stefanska Barbara , Stephens Gary J. , Teixeira Mauro M. , Vergnolle Nathalie , Wang Xin , Ferdinandy Péter
Published: February 2025

In the past year, the European Medicines Agency (EMA), the Food and Drug Administration (FDA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) authorised 53 novel drugs. While the 2024 harvest is not as rich as in 2023, when 70 new chemical entities were approved, the number of ‘orphan’ drug authorisations in 2024 (21) is similar to that of 2023 (24), illustrating the dynamic development of therapeutics in areas of unmet need. The 2024 approvals of novel protein therapeutics (15) and advanced therapy medicinal products (ATMPs, 6) indicate a sustained trend also noticeable in the 2023 new drugs reviewed in this journal last year (16 and 11, respectively). Clearly, the most striking characteristic of the 2024 drug yield is the creative pharmacological design, which allows these medicines to employ a novel approach to target a disease. Some notable examples are the first drug successfully using a ‘dock‐and‐block’ mechanism of inhibition (zenocutuzumab), the first approved drug for schizophrenia designed as an agonist of M1/M4 muscarinic receptors (xanomeline), the first biparatopic antibody (zanidatamab), binding two distinct epitopes of the same molecule, the first haemophilia therapy that instead of relying on external supplementation of clotting factors, restores Factor Xa activity by inhibiting TFPI (marstacimab), or the first ever authorised direct telomerase inhibitor (imetelstat) that reprogrammes the oncogenic drive of tumour cells. In addition, an impressive percentage of novel drugs were first in class (28 out of 53 or 53% of the total) and a substantial number can be considered disease agnostic, indicating the possibility of future approved extensions of their use for additional indications. The 2024 harvest demonstrates the therapeutic potential of innovative pharmacological design, which allows the effective targeting of intractable disorders and addresses crucial, unmet therapeutic needs.
The Natural Course of Bosch‐Boonstra‐Schaaf Optic Atrophy Syndrome
Authors: Valentin Ilia , Caro Martin Maria del Pilar , Fischer Christine , Brennenstuhl Heiko , Schaaf Christian P.
Published: February 2025

(Likely) pathogenic variants in NR2F1 are associated with Bosch‐Boonstra‐Schaaf optic atrophy syndrome (BBSOAS, OMIM #615722), a rare neurodevelopmental disorder. Patients present with a variety of symptoms, including intellectual disability, developmental delay, visual impairment, muscular hypotonia, seizures, and/or autistic features. Since it was first described in 2014, the phenotype has steadily expanded. However, there is limited information regarding the natural course of the disorder. Here, we present data on genetic variants and phenotype development of 47 individuals who responded to our questionnaire. A questionnaire was developed to assess the phenotype more comprehensively and to better understand the course of symptoms. In addition, families sent medical documents and photographs. To investigate the genotype‐phenotype correlation in our cohort, we compared clinical features of two genotypically distinct groups (variants in the DNA‐binding domain (DBD, n = 17) versus variants elsewhere in the gene (n = 30)). We observed a range of common symptoms including developmental delay, muscular hypotonia, optic atrophy, nystagmus, strabismus, autistic features, and thin corpus callosum on brain MRI. Overall, more improvement than worsening was reported. Individuals with variants in the DBD showed a higher prevalence of severe clinical features, such as infantile spasms (46.7% vs. 3.8%, p = 0.002) or nonverbality (50% vs. 3.4%, p = 0.0004), age at diagnosis was statistically significantly different between the two genotypic groups (mean 4.7 years vs. 8.9 years, p = 0.048). Our study confirms characteristic clinical features of BBSOAS. Variants in the DBD are associated with a more severe clinical phenotype. We found no evidence that the disease progresses; rather, several symptoms are reported to improve over time. However, prospective longitudinal studies are needed to further investigate disease progression.
From Conflict to Counsel: The Interplay of Board‐TMT Cognitive Conflict, TMT Tenure, and Board Tenure on Board Advice Giving
Authors: Veltrop Dennis B. , Mostert Irene , Dirks Paula M. G. , de Haan Jakob
Published: February 2025

Research Question/Issue

We recognize the collaborative nature of board advice giving and investigate (1) how the level of cognitive conflict between boards and top management teams (TMTs) is associated with board advice giving and (2) how this relation is shaped by TMT tenure and board tenure.

Research Findings/Insights

Using insights from a unique multi‐source dataset from 285 board members of 102 Dutch financial firms, we find that TMT tenure and board tenure both moderate the relation between board‐TMT cognitive conflict and board advice giving. In addition, when considering the combined moderating effect of TMT tenure and board tenure, we find that board‐TMT cognitive conflict is most positively (negatively) associated with board advice giving when TMT tenure is low (high), while board tenure is high (low).

Theoretical/Academic Implications

Our work complements prior work by integrating insights from group research and resource dependence theory. It provides a nuanced view on the link between board‐TMT cognitive conflict and board advice giving. We highlight that the way cognitive conflict translates into board advice depends not only on the TMT's receptiveness to board challenge but also on the board's in‐depth understanding of organizational affairs.

Practitioner/Policy Implications

Our work points out that boards taking a critical stance may backfire if boards do not “measure up” to TMTs' organizational experience. We contest that longer‐tenured boards are ill‐equipped to provide critical advice and highlight the crucial role of TMT tenure therein. As such, policymakers and organizations should consider the combined impact of TMT tenure and board tenure when trying to stimulate that boards effectively challenge management.
Human Midbrain Organoids Enriched With Dopaminergic Neurons for Long‐Term Functional Evaluation
Authors: Wang Xinyue , Sun Gaoying , Tang Mingming , Li Da , Qi Jianhuan , Wang Chuanyue , Wang Yukai , Hu Baoyang
Published: February 2025

Human midbrain organoids with functional dopaminergic (DA) neurons are invaluable for the therapeutic development of Parkinson's disease (PD). However, current methods face significant limitations, including challenges in generating pint‐sized organoids enriched with DA neurons and the lack of robust functional assays for efficiently evaluating neural networks over extended periods. Here we present an innovative approach that combines developmental patterning with mechanical cutting to produce small midbrain organoids, with diameters less than 300 μm, suitable for long‐term evaluation, along with a comprehensive functional assay system consisting of calcium transient assay, neurite extension assay, and multielectrode array (MEA) assay. Radial cutting of organoids into four to eight portions according to their sizes at the appropriate developmental stage significantly increases the yield of viable organoids while reducing necrotic cell regions. Using the functional assay system, we demonstrate that DA neurons within the organoids extend long projections, respond to dopamine stimulation, and form neural networks characterised by giant depolarising potential‐like events. Our approach supports the generation of midbrain organoids and PD models that can be used for long‐term functional testing.
The Risk Factors and Predictors of Chronic Obstructive Pulmonary Disease in Patients With Obstructive Sleep Apnea–Hypopnea Syndrome at Plateau
Authors: Geng Yumei , Hu Yu , Li Bin , Dawa Zhuoma , Zhang Fang
Published: February 2025

Background

OSAHS patients with COPD (i.e., overlap syndrome) have a significantly worse prognosis than those with OSAHS alone, and the role of plateau hypoxia in the occurrence of the disease is still unclear. This underscores the urgent need to explore the risk factors for the incidence of COPD in patients with OSAHS and to identify predictors for the occurrence of overlap syndrome at plateau.

Methods

Fifty patients with OSAHS and 34 patients with overlap syndrome were enrolled in this study. Demographic, auxiliary examination, and laboratory data were collected.

Results

All patients enrolled were obstructive sleep apnea–hypopnea syndrome. The apnea–hypopnea index (AHI), the number of hypopnea, and the oxygen desaturation index were higher in the group of patients with overlap syndrome than in the group of patients with OSAHS. The mean pulse oxygen saturation was lower than that in the group of patients with OSAHS (p < 0.05). The right heart structure and function indexes (PASP, right atrial transverse diameter, RVTD, BNP, TNI) in patients with overlap syndrome were worse than those in patients with OSAHS (p < 0.05), and this worse cardiovascular status was positively correlated with inflammatory factors such as high‐sensitivity C‐reactive protein, IL‐6, and PCT (p < 0.05). Binary logistic regression analysis indicated that PASP, smoking index, and AHI were independent risk factors for OSAHS developing into overlap syndrome. ROC curve showed that the area under the curve of the combination of the three markers for predicting overlap syndrome was 0.908 (95% CI 0.843–0.974, p = 0.000), with a sensitivity of 0.882 and a specificity of 0.820. The optimal cutoff values for PASP were 42.5 mmHg, 15 for the smoking index, and 25.65 for the AHI based on the Youden index.

Conclusions

Our study reveals that overlap syndrome has more frequent nighttime hypopnea and hypoxia than OSAHS alone. The cardiovascular complications of overlapping syndromes at plateau are more pronounced, possibly due to the exacerbation of the systemic inflammatory response. The combination of PASP, smoking index, and AHI can be a powerful tool for predicting and assessing the occurrence of COPD in OSAHS patients from plateau populations in China. These findings have the potential to significantly improve the management and prognosis of patients with overlap syndrome.
Decentralized Clinical Trials in the Era of Real‐World Evidence: A Statistical Perspective
Authors: Chen Jie , Di Junrui , Daizadeh Nadia , Lu Ying , Wang Hongwei , Shen Yuan‐Li , Kirk Jennifer , Rockhold Frank W. , Pang Herbert , Zhao Jing , He Weili , Potter Andrew , Lee Hana
Published: February 2025

There has been a growing trend that activities relating to clinical trials take place at locations other than traditional trial sites (hence decentralized clinical trials or DCTs), some of which are at settings of real‐world clinical practice. Although there are numerous benefits of DCTs, this also brings some implications on a number of issues relating to the design, conduct, and analysis of DCTs. The Real‐World Evidence Scientific Working Group of the American Statistical Association Biopharmaceutical Section has been reviewing the field of DCTs and provides in this paper considerations for decentralized trials from a statistical perspective. This paper first discusses selected critical decentralized elements that may have statistical implications on the trial and then summarizes regulatory guidance, framework, and initiatives on DCTs. More discussions are presented by focusing on the design (including construction of estimand), implementation, statistical analysis plan (including missing data handling), and reporting of safety events. Some additional considerations (e.g., ethical considerations, technology infrastructure, study oversight, data security and privacy, and regulatory compliance) are also briefly discussed. This paper is intended to provide statistical considerations for decentralized trials of medical products to support regulatory decision‐making.
Effect of a Supratherapeutic Dose of Omaveloxolone on the Corrected QT Interval in Healthy Participants: A Randomized, Double‐Blind, Placebo‐ and Active‐Controlled, Three‐Way Crossover Study
Authors: Zahir Hamim , Murai Masako , Wu Lucy , Valentine Michelle , Hynes Scott M.
Published: February 2025

Omaveloxolone is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥ 16 years at a dose of 150 mg once daily. This double‐blind, randomized, placebo‐ and active‐controlled, three‐way crossover, thorough corrected QT interval (QTc) study (NCT05927649) evaluated the effect of supratherapeutic omaveloxolone exposure on QTc to exclude a clinically significant prolongation (defined as > 10 ms). Healthy adults were randomized to one of six sequences of three single oral doses (omaveloxolone 450 mg, placebo, or moxifloxacin 400 mg [open‐label positive control]) administered with an FDA high‐fat meal. Serial pharmacokinetic blood sampling and time‐matched electrocardiogram assessments were performed. The primary endpoint was placebo‐corrected change from baseline in QTcF (ΔΔQTcF) following omaveloxolone administration. Secondary endpoints included pharmacokinetic parameters of omaveloxolone and its major plasma metabolites (M17 and M22) and safety. All 30 enrolled participants completed the study. The mean omaveloxolone Cmax was 319 ng/mL in this study (4.5‐fold the mean steady‐state Cmax [71.5 ng/mL] with the approved dose). The mean QTcF intervals were < 450 ms, and mean changes from baseline were < 10 ms at all timepoints following all doses. The upper limit of the 90% CIs of ΔΔQTcF following omaveloxolone administration was < 10 ms at all timepoints. At the Cmax of omaveloxolone, M17, and M22, alone or combined, the upper limits of the 90% CIs of the model‐predicted ΔΔQTcF were all < 10 ms. No safety concerns were identified. Supratherapeutic omaveloxolone exposure that covers the worst‐case clinical exposure did not cause a clinically significant QTc prolongation and was generally well tolerated.
National Prescribing Practices for Pediatric Dystonia Among Providers in the United States
Authors: Davis Sarah Paige W. , Kane Natalie , Botteron Haley E. , Gelineau‐Morel Rose
Published: February 2025

While multiple oral medications are used to treat dystonia, limited information exists on current prescribing practices. This study analyzes real‐world prescribing practices for pediatric dystonia in the United States, evaluating prescription frequency, dosing, and the impact of comorbidities. Oracle electronic health record real‐world data were queried from 2014 to 2019 for encounters of patients under age 18 with a dystonia diagnosis and available medication records. Information was extracted on prescriptions for dystonia medications (baclofen, clonidine, carbidopa‐levodopa, gabapentin, tetrabenazine, trihexyphenidyl, and select benzodiazepines), dosing, and comorbid diagnoses of cerebral palsy (CP), epilepsy, or spasticity. A total of 4010 pediatric patients with dystonia were included. Benzodiazepines were most commonly prescribed (midazolam in 53.5% of patients, diazepam 46.7%, lorazepam 41.9%, clonazepam 28.3%). This was followed by baclofen (33.4%), clonidine (26.3%), and gabapentin (19.7%). Dystonia patients with epilepsy were more commonly prescribed benzodiazepines than patients without epilepsy (diazepam 79.1% vs. 29%; clonazepam 50.9% vs. 16%) and baclofen was more often prescribed in patients with CP (59.4%) or spasticity (63.8%) than those without (17%). All medications showed decreased milligram per kilogram dosage as patient weight increased. Benzodiazepines, baclofen, and clonidine were the most common medications prescribed to pediatric patients with dystonia in the United States, although medical comorbidities impact prescribing practices. There was significant variability in weight‐based dosing of all medications. There remains a need to determine which dystonia medications are most effective for each patient and the necessary drug exposure to maximize therapeutic efficacy and minimize adverse effects.
Widespread and Diverging Patterns of Change in Local Phylogenetic Diversity
Authors: Fernandez‐Fournier Philippe , Carroll Tadhg , Dornelas Maria , Mooers Arne Ø.
Published: February 2025

Aim

Ecosystems are witnessing drastic changes in biodiversity worldwide. However, it is still unclear whether changes in phylogenetic diversity—a measure of the evolutionary relationships among species—reflect observed changes in species richness. Specifically, we ask whether changes in local phylogenetic diversity correlate with changes in species richness and examine if major taxonomic groups show diverging trends.

Location

Global.

Methods

We estimate how local phylogenetic diversity has changed compared to species richness and whether there were diverging patterns across taxonomic groups. We use a database of compiled assemblage time series from around the world, BioTIME. We use assemblage total evolutionary history (Faith's phylogenetic diversity; PD) as well as average relatedness (mean pairwise distance and mean nearest taxon distance; MPD and MNTD, respectively) as measures of phylogenetic diversity and report taxon‐level and assemblage‐level posterior slope estimates from a Bayesian hierarchical model. We report trends in four major taxonomic groups: fish, birds, terrestrial mammals and terrestrial plants.

Results

We found strong evidence of widespread increases in MPD across fish and bird assemblages, reflecting decreases in average relatedness and strong evidence of a decrease of MPD in mammals, indicating the opposite. Conversely, we did not find consistent directional change in MNTD, though null average trends included notable positive and negative trends across studies and regions. We also found moderate evidence that SR and PD were increasing in fish assemblages, while they were decreasing in mammals.

Main Conclusions

Our findings suggest that changes in species composition are significantly altering the evolutionary makeup of assemblages at the local scale and that overall patterns diverge within and across taxonomic groups. We suggest potential drivers of these changes but highlight that our results are more generalisable for fish and birds than for mammals and plants, given the variation in geographical coverage and sample size.
Analysis of patient characteristics and safety of insulin glargine U300 use in 21 359 patients with type‐2 diabetes and chronic kidney disease: DPV registry study
Authors: Vijayan Anjaly , Lanzinger Stefanie , Forestier Nicole , Hess Gregor , Rottmann Marcus , Wosch Frank J. , Seufert Jochen , Holl Reinhard W. , Bramlage Peter ,   for the DPV
Published: February 2025

Aims

Managing type‐2 diabetes (T2D) in chronic kidney disease (CKD) patients requires consideration of kidney function, and many drugs have not been investigated thoroughly. Clinical studies have demonstrated Glargine U300 (Gla‐300) supports achievement of adequate glycemic control at low hypoglycemia risk.

Materials and Method

This cross‐sectional study analysed routine data of 21 359 T2D patients with CKD (1786 using Gla‐300; 19 568 without any insulin) from the prospective Diabetes‐Patienten‐Verlaufsdokumentation (DPV) registry to evaluate patient characteristics and safety of Gla‐300 use across different CKD stages.

Results

Patients on Gla‐300 had T2D onset at an earlier age (median age 55.1 vs. 62.3 years), longer diabetes duration (17.3 vs. 11.3 years), higher body weight (91.3 vs. 83.9 kg) and HbA1c levels (7.3% vs. 6.7%) than non‐insulin patients (all p < 0.001). Gla‐300 usage increased from CKD stage 1–4 (median dose 44 vs. 55 units) with higher baseline HbA1c levels (7.2% vs. 7.4%). Although severe hypoglycemia rates were low, a slight increase (0.01%/PY vs. 0.04%/PY) was observed with decreasing estimated glomerular filtration rate levels. Compared to others, stage 5 CKD patients had a distinct profile with lower HbA1c levels (6.9%), body weight (90 kg) and higher Gla‐300 usage (50 units). Metformin, SGLT‐2 inhibitors and GLP‐1 RA were common concomitant drugs with diminished usage in advanced CKD stages, while Gla‐300 was common at all stages.

Conclusion

Despite variations in patient profiles, Gla‐300 is widely used across all CKD stages, particularly in advanced stages with a low rate of severe hypoglycemia, suggesting its safe administration in CKD patients.
Efficacy and safety of a bio‐absorbable antibiotic delivery in calcium sulphate granules for the treatment of osteomyelitis in patients with diabetic foot: A randomized, double blinded, controlled clinical study The BIG D‐FOOT study
Authors: Monami Matteo , Bordoni Laura , Ragghianti Benedetta , Silverii Giovanni Antonio , Mannucci Edoardo
Published: February 2025

Background

Diabetic foot osteomyelitis (DFO) is associated with a considerably high risk of incident major amputations, disability and mortality. To assess the effects of a local antibiotic delivery system on the incidence of post‐surgical infective complications in patients with DFO.

Methods

This is a double‐blind, placebo‐controlled, parallel series, randomized controlled trial (RCT) aimed at verifying the efficacy and safety of a local calcium‐sulphate bio‐absorbable antibiotic delivery (either with tobramycin or vancomycin) in patients with DFO treated with surgical procedures. The trial enrolled adult patients with diabetes and Texas 3 grade ulcers complicated by osteomyelitis and accompanied by deep tissues infection. The primary end‐point was the percentage of infective complications (composite end‐point of dehiscence, infection, DFO recurrence and new DFO in adjacent sites) at 12 weeks.

Results

The study was prematurely terminated after the completion of the first 20 cases, because of the significant superiority of the active treatment arm. After 12 weeks of treatment, five of 20 wounds (25%) achieved the primary composite end‐point. All post‐surgical infective complications occurred in the placebo group, with a significant between‐group difference (unadjusted p = 0.010). No between‐group differences in overall costs were observed.

Conclusions

This is the first RCT in patients with DFO showing that the use of antibiotic‐impregnated calcium‐sulphate granules is economically sustainable and has the potential of improving the prognosis of DFO.
A Mechanistic Approach to Animal Dispersal—Quantifying Energetics and Maximum Distances
Authors: Wilkinson Caitlin , Brose Ulrich , Dyer Alexander , Hirt Myriam R. , Ryser Remo
Published: February 2025

Dispersal is a fundamental process driving many ecological patterns. During transfer, species often make large‐scale displacements resulting in significant energy losses with implications for fitness and survival, however generalising these losses across different taxonomic groups is challenging. We developed a bioenergetic dispersal model based on fundamental processes derived from species traits. By balancing energy storage and energy loss during active dispersal, our mechanistic model can quantify energy expenditures depending on landscape configuration and the species in focus. Moreover, it can be used to predict the maximum dispersal capacity of animals, which we compare with recorded maximum dispersal distances (n = 1571). Due to its foundation in bioenergetics it can easily be integrated into various ecological models, such as food‐web and meta‐community models. Furthermore, as dispersal is integral to ecological research, the quantification of dispersal capacities provides valuable insight into landscape connectivity, species persistence, and distribution patterns with implications for conservation research.
Cytomegalic parvalbumin neurons in fetal cases of hemimegalencephaly
Authors: Gelot Antoinette‐Bernabe , Draia‐Nicolau Tangra Ondina , Mathieu Rémi , Silvagnoli Lucas , Watrin Françoise , Cardoso Carlos , Manent Jean‐Bernard , de Chevigny Antoine , Represa Alfonso
Published: February 2025

Objective

Mutations in genes of the mTOR pathway have been identified as a major cause of hemimegalencephaly (HMG), focal cortical dysplasia type II, and tuberous sclerosis, cortical malformations associated with epilepsy. These conditions are characterized at the cellular level by increased size of pyramidal neurons that grow with dysmorphic features and in some cases by the presence of giant balloon cells. Our previous research in tuberous sclerosis has shown that parvalbumin (Pvalb) and calbindin immunoreactive cells in cortical and subcortical tuberal lesions show cytomegalic features, suggesting the involvement of GABAergic cells in mTOR‐related pathologies. In the present report, we propose to deepen our understanding of the role of interneurons in mTOR‐related cortical malformations by analyzing the maturation of Pvalb neurons in fetal samples of HMG.

Methods

We performed immunohistochemical staining of cortical samples from individuals with HMG from 21 gestational weeks to 10 postnatal months. The study focused on Pvalb cells, and pS6 counterstaining was performed to assess the activation of the mTOR pathway. To investigate the pathomechanisms behind the cytomegalic features, we examined mTOR pathway gene expression in Pvalb interneurons and cortical projection neurons using a single‐cell transcriptomic atlas of the human neocortex.

Results

Our results revealed cytomegalic features in Pvalb interneurons, indicating abnormal development in HMG patients compared to controls. This phenotype progressively worsened over time, suggesting ongoing developmental abnormalities associated with mTOR dysregulation, which may underlie the pathology of cortical malformations in HMG. Our transcriptomic data revealed similar expression patterns of mTOR and its upstream regulators in both Pvalb and glutamatergic neurons during development, suggesting that mTOR pathway disorders may induce similar phenotypes in both cell types.

Significance

The present data suggest that Pvalb interneurons are involved in the development of mTOR‐related cortical dysplasia and that they may be a contributor to the clinical phenotype of these patients.
Metabolomic and proteomic stratification of equine osteoarthritis
Authors: Anderson James R. , Phelan Marie M. , Caamaño‐Gutiérrez Eva , Clegg Peter D. , Rubio‐Martinez Luis M. , Peffers Mandy J.
Published: February 2025

Background

Equine osteoarthritis (OA) is predominantly diagnosed through clinical examination and radiography, leading to detection only after significant joint pathology. The pathogenesis of OA remains unclear and while many medications modify the disease's inflammatory components, no curative or reversal treatments exist. Identifying differentially abundant metabolites and proteins correlated with osteoarthritis severity could improve early diagnosis, track disease progression, and evaluate responses to interventions.

Objectives

To identify molecular markers of osteoarthritis severity based on histological and macroscopic grading.

Study design

Cross‐sectional study.

Methods

Post‐mortem synovial fluid was collected from 58 Thoroughbred racehorse joints and 83 joints from mixed breeds. Joints were histologically and macroscopically scored and categorised by OA and synovitis grade. Synovial fluid nuclear magnetic resonance metabolomic and mass spectrometry proteomic analyses were performed, individually and combined.

Results

In Thoroughbreds, synovial fluid concentrations of metabolites 2‐aminobutyrate, alanine and creatine were elevated for higher OA grades, while glutamate was reduced for both Thoroughbreds and mixed breeds. In mixed breeds, concentrations of three uncharacterised proteins, lipopolysaccharide binding protein and immunoglobulin kappa constant were lower for higher OA grades; concentrations of an uncharacterised protein were higher for OA grade 1 only, and apolipoprotein A1 concentrations were higher for OA grades 1 and 2 compared with lower grades. For Thoroughbreds, gelsolin concentrations were lower for higher OA grades, and afamin was lower at a higher synovitis grade. Correlation analyses of combined metabolomics and proteomics datasets revealed 58 and 32 significant variables for Thoroughbreds and mixed breeds, respectively, with correlations from −0.48 to 0.42 and −0.44 to 0.49.

Main Limitations

The study's reliance on post‐mortem assessments limits correlation with clinical osteoarthritis severity.

Conclusions

Following stratification of equine OA severity through histological and macroscopic grading, synovial fluid metabolomic and proteomic profiling identified markers that may support earlier diagnosis and progression tracking. Further research is needed to correlate these markers with clinical osteoarthritis severity.
Activated Protein C Resistance Testing: An Update From Australasia/Asia‐Pacific
Authors: Favaloro Emmanuel J. , Arunachalam Sandya , Dean Elysse , Salwa Mahzuza , Ahuja Monica , Connelly Lynne , Chapman Kent , Vong Ronny , Pasalic Leonardo
Published: February 2025

Introduction

Activated protein C resistance (APCR) represents a risk factor for thrombosis and is usually due to factor V Leiden (FVL). Clinicians may order either test (i.e., APCR or FVL) to help assess ‘thrombophilia’ in patients who present with thrombosis. APCR testing is usually achieved using clot‐based assays, whereas FVL is assessed by genetic testing. There are advantages and disadvantages to either approach.

Methods

We report updated findings for APCR testing in our geographic region, in part using recent data from the RCPAQAP, an international external quality assessment (EQA) program, with some 50–60 participants for APCR testing over the past decade. Data have been updated to cover the past 13 years (2010–2023 inclusive), with four samples assessed each year, but with a primary focus on new data from 2020 to 2023 inclusive. In addition, data for APCR testing over several years from four large tertiary‐level hospital laboratories have been assessed following a recent change in instrumentation and haemostasis methods.

Results

EQA data continue to show variable performance in both numerical values and their interpretation for APCR testing, with certain methods providing more consistently correct findings than others. In addition, participant interpretation of their own numerical values and transcription errors seem problematic. Finally, the change in recent laboratory testing has also evidenced local improvements.

Conclusion

APCR assays and testing laboratories continue to show variability in performance, with two methods (Pefakit and Staclot) showing the best performance overall. Targeted education may be of benefit, as most of the errors appear to originate from a small proportion of laboratories.