bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrapartum care measures and indicators for monitoring the implementation of WHO recommendations for a positive childbirth experience: a scoping review
Authors: Vallely Lauren Hannah , Shalit Anna , Nguyen Renae , Althabe Fernando , Pingray Verónica , Bonet Mercedes , Armari Elizabeth , Bohren Meghan , Homer Caroline , Vogel Joshua Peter
Published: November 2023

Objective

We aimed to identify all available studies describing measures or indicators used to monitor 41 intrapartum care practices described in the 2018 WHO intrapartum care recommendations, with a view to informing development of standardised measurement of implementing these recommendations.

Design

Systematic scoping review.

Methods

We conducted a scoping review to identify studies reporting measures of intrapartum care published between 1 January 2000 and 28 June 2021. Primary and secondary outcome measures included study characteristics (publication year, journal, country and World Bank classification) and intrapartum care measure characteristics (definition, numerator, denominator, measurement level and measurement approach). We searched MEDLINE, EMBASE, CINAHL, Cochrane Library, the Maternity and Infant Care Database, Global Index Medicus and grey literature using structured search terms related to included recommendations, focusing on respectful and supportive care, and clinical practices performed throughout labour and birth. The measures identified were classified by the WHO recommendation and their characteristics reported.

Results

We identified 150 studies which described 1331 intrapartum care measures. These measures corresponded to 35 of the 41 included WHO recommendations, and represented all domains of the WHO recommendations (care throughout labour and birth, first stage of labour, second stage of labour, third stage of labour). A total of 40.1% (534 of 1331 measures) of measures were related to respectful maternity care. Most studies used a questionnaire or survey measurement approach (522 of 1331 measures, 39.2%).

Conclusion

This scoping review presents a database of existing intrapartum care measures used to monitor the quality of intrapartum care globally. There is no clear consensus on a core set of measures for evaluating the practice of the WHO’s intrapartum care recommendations. This review provides a foundation to support the development of a core set of internationally standardised intrapartum care measures for the WHO intrapartum care recommendations, highlighting key areas requiring consensus and validation, and measure development.
Impact of SARS-CoV-2 infection on patients with systemic lupus erythematosus in England prior to vaccination: a retrospective observational cohort study
Authors: Rabe Adrian Paul J , Loke Wei Jie , Kalyani Rubana N , Tummala Raj , Stirnadel-Farrant Heide A , Were John , Winthrop Kevin L
Published: November 2023

Objectives

Determine the prevaccination healthcare impact of COVID-19 in patients with systemic lupus erythematosus (SLE) in England.

Design

Retrospective cohort study of adult patients with SLE from 1 May to 31 October 2020.

Setting

Clinical Practice Research Datalink (CPRD) Aurum and Hospital Episode Statistics (HES) databases from general practitioners across England combining primary care and other health-related data.

Participants

Overall, 6145 adults with confirmed SLE diagnosis ≥1 year prior to 1 May 2020 were included. Most patients were women (91.0%), white (67.1%), and diagnosed with SLE at age <50 (70.8%). Patients were excluded if they had a COVID-19 diagnosis before 1 May 2020.

Primary and secondary outcome measures

Demographics and clinical characteristics were compared. COVID-19 severity was determined by patient care required and procedure/diagnosis codes. COVID-19 cumulative incidence, hospitalisation rates, lengths of stay and mortality rates were determined and stratified by SLE and COVID-19 severity.

Results

Of 6145 patients, 3927 had mild, 1288 moderate and 930 severe SLE at baseline. The majority of patients with moderate to severe SLE were on oral corticosteroids and antimalarial treatments. Overall, 54/6145 (0.88%) patients with SLE acquired and were diagnosed with COVID-19, with 45 classified as mild, 6 moderate and 3 severe COVID-19. Cumulative incidence was higher in patients with severe SLE (1.4%) compared with patients classified as mild (0.8%) or moderate (0.8%). Ten COVID-19-specific hospital admissions occurred (n=6 moderate; n=4 severe). Regardless of COVID-19 status, hospital admission rates and length of stay increased with SLE severity. Of 54 patients with SLE diagnosed with COVID-19, 1 (1.9%) COVID-19-related death was recorded in a patient with both severe SLE and severe COVID-19.

Conclusions

SLE severity did not appear to impact COVID-19 outcomes in this study. The COVID-19 pandemic is evolving and follow-up studies are needed to understand the relationship between COVID-19 and SLE.
Why do some people who had a stroke not receive the recommended 45 min of occupational therapy and physiotherapy? A Delphi study
Authors: Clark Beth , Truman Juliette , Whitall Jill , Hughes Ann-Marie , Turk Ruth , Burridge Jane
Published: November 2023

Objectives

To gain a consensus among therapists for reasons why a person who had a stroke may not receive the Royal College of Physicians’ recommended minimum of 45 min of daily therapy.

Design

Three-round remote e-Delphi study.

Setting

National study, based in the UK.

Participants

Occupational therapists and physiotherapists with experience of delivering therapy after stroke and awareness of the 45 min guideline.

Results

Forty-five therapists consented to participate in the study. Thirty-five (78%) completed round one, 29 of 35 (83%) completed round 2 and 26 of 29 (90%) completed round three. A consensus (75%) was reached for 32 statements. Reasons why a person may not receive 45 min were related to the suitability of the guideline for the individual (based on factors like therapy tolerance or medical status) or the capability of the service to provide the intervention. In addition to the statements for which there was a consensus, 32 concepts did not reach a consensus. Specifically, there was a lack of consensus concerning the suitability of the guideline for people receiving Early Supported Discharge (ESD) services and a lack of agreement about whether people who need more than 45 min of therapy actually receive it.

Conclusion

Some people do not receive 45 min of therapy as they are considered unsuitable for it and some do not receive it due to services’ inability to provide it. It is unclear which reasons for guideline non-achievement are most common. Future research should focus on why the guideline is not achieved in ESD, and why people who require more than 45 min may not receive it. This could contribute to practical guidance for therapists to optimise therapy delivery for people after stroke.
Association between white blood cell count and adverse pregnancy outcomes: a retrospective cohort study from a tertiary hospital in China
Authors: Zhang Yu , Qian Yiling , Liu Chuanwei , Fan Xiaofang , Li Xuesong , Song Yuping , Fan Yujuan , Hu Zheng , Yang Jialin
Published: November 2023

Objectives

This study aimed to clarify the relationship between white blood cell (WBC) and adverse pregnancy outcomes.

Design

A total of 25 270 pregnant women underwent peripheral blood white blood cell count tests in the first, second and third trimesters. Adverse pregnancy outcomes were gestational hypertension, pre-eclampsia, gestational diabetes mellitus, preterm birth, low birth weight, caesarean delivery, macrosomia and fetal distress. Due to acute infectious disease or other diseases, 1127 were excluded.

Setting

Minhang Hospital, China.

Participants

A total of 24 143 pregnant women were included in this study.

Primary and secondary outcome measures

The primary outcome was the adverse pregnancy outcomes.

Results

For the 24 143 participants, we calculated adjusted ORs for adverse pregnancy outcomes associated with an increased WBC count. For gestational hypertension, the ORs were 1.18 (95% CI, 1.05 to 1.24) in the first trimester and 1.10 (1.06 to 1.13) in the second trimester; for pre-eclampsia, ORs were 1.14 (95% CI, 1.47 to 1.64) in the first trimester and 1.10 (1.05 to 1.16) in the second trimester; for gestational diabetes mellitus, ORs were 1.06 (95% CI, 1.00 to 1.13) in the first trimester and 1.10 (1.04 to 1.16) in the second trimester; for preterm birth, ORs were 1.12 (95% CI, 1.06 to 1.18) in the first trimester, 1.10 (1.06 to 1.13) in the second trimester and 1.12 (1.09 to 1.15) in the third trimester; for low birth weight, ORs were 1.09 (95% CI, 1.02 to 1.17) in the first trimester, 1.03 (0.99 to 1.08) in the second trimester and 1.12 (1.08 to 1.16) in the third trimester. Significant associations were not observed obviously for caesarean delivery, macrosomia and fetal distress.

Conclusions

Our results indicate strong, continuous associations of maternal WBC count with increased risks of adverse pregnancy outcomes.
Registry study of immune-related adverse events using electronic patient-reported outcome in patients with cancer receiving immune checkpoint inhibitors: protocol for a multicentre cohort study
Authors: Hirata Taiki , Kawaguchi Takashi , Azuma Kanako , Torii Ayako , Usui Hiroaki , Kim Soan , Hayama Tatsuya , Hirate Daisuke , Kawahara Yosuke , Kumihashi Yuki , Chisaka Tomomi , Wako Tetsuya , Yoshimura Akinobu , Miyaji Tempei , Yamaguchi Takuhiro
Published: November 2023

Introduction

The use of immune checkpoint inhibitors (ICIs) is rapidly expanding in cancer treatment. ICIs have a unique safety profile, characterised by immune-related adverse events (irAEs). The safety profile of ICIs lacks patient experience and perspectives. This study primarily aims to obtain a database for descriptive research on the status of irAEs using the Patient-Reported Outcomes version of the Common Terminology Criteria (PRO-CTCAE) in patients with gastrointestinal cancer, lung cancer and malignant pleural mesothelioma treated with regimens containing ICIs.

Methods and analysis

This is an ongoing, multicentre, observational study in Japan. Eligible patients must be at least 20 years old and have been diagnosed with lung cancer, malignant pleural mesothelioma or gastrointestinal cancer and plan to use ICIs. Participants will install the electronic PRO (ePRO) application and report adverse events via ePRO using PRO-CTCAE once weekly for up to 48 weeks. A registry will be established using background information obtained from medical records. The sample size is determined by 1 year projection without using statistical methods. Statistical analyses will include point estimates and 95% CIs for the incidence of each adverse event by cancer type and regimen at each time point.

Ethics and dissemination

This research will be conducted per the Declaration of Helsinki, the Ethical Guidelines for Life Science and Medical Research Involving Human Subjects issued by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare, and the revised Personal Information Protection Law. The study protocol was approved by the Ethics Committee (approval ID T2021-0180) of Tokyo Medical University Hospital on 15 October 2021.

Registration details

The study began enrolling patients in December 2021. The target enrolment is 260; as of October 2022, 141 have been enrolled, and the enrolment is scheduled to end on 30 June 2023.

Trial registration number

UMIN000046418
‘It’s the stuff they can do better than us’: case studies of general practice surgeries’ experiences of optimising the skill-mix contribution of practice-based pharmacists in Wales
Authors: Bartlett Sophie , Bullock Alison , Morris Felicity
Published: November 2023

Objective

Pharmacists are increasingly joining the general practice skill-mix. Research is still in relative infancy, but barriers and facilitators to their integration are emerging, as well as indications that pharmacists’ skillset remain underutilised. This study explores first-hand experiences and perspectives among general practice teams of the processes that underpin the effective integration and sustained contribution of pharmacists in general practice.

Design and setting

This research employed a qualitative case study approach involving general practice teams in Wales. Data were collected from eight general practices where each practice represented one case study. Data were collected via online interviews (one-to-one or group) and written feedback. Data were pattern coded and analysed thematically through a constant comparative approach. Data interpretations were confirmed with participants and wider general practice teams.

Participants

Eight general practice teams across Wales (comprising combinations of practice and business managers, general practitioners (GPs) and general practice pharmacists) represented eight case studies. Cases were required to have had experience of working with a general practice pharmacist.

Results

Data were yielded from five practice managers, two GPs, three general practice pharmacists and a business manager. A total of 3 hours and 2 min of interview data was recorded as well as 2038 words of written feedback. Three foundations to pharmacists’ effective contribution to general practice were identified: defining the role (through identifying the right pharmacist, mapping skillset to demand and utilising the increasing need for specialist skills), appropriate infrastructure and workforce review, and an appropriate employment model.

Conclusion

Pharmacists are becoming increasingly critical to the general practice skill-mix and utilisation of their specialist skillset is crucial. This paper identifies how to enable the effective integration and sustained contribution of pharmacists to general practice.
Evaluation of ALBA device for upper extremity motor function in adults with subacute and chronic acquired brain injury: a randomised controlled trial protocol in a tertiary clinic of the metropolitan region of Chile
Authors: Salazar-Cifuentes Pamela , Contreras Thomas , Hernández Emilio , Leiva-Abarca Evelyn , Castro-Flores Paola , San Juan Daniela , Araneda Rodrigo , Ebner-Karestinos Daniela
Published: November 2023

Introduction

Stroke is a significant worldwide cause of death and a prevalent contributor to long-term disability among adults. Survivors commonly encounter a wide array of motor, sensory and cognitive impairments. Rehabilitation interventions, mainly targeting the upper extremities, include a wide array of components, although the evidence indicates that the intensity of practice and task-specific training play crucial roles in facilitating effective results. Assisted therapy with electronic devices designed for the affected upper extremity could be employed to enable partial or total control of this limb, while simultaneously incorporating the aforementioned characteristics in the rehabilitation process.

Methods and analysis

32 adults who had a subacute or chronic stroke, aged over 18 years old, will be included for this randomised controlled trial aiming to determine the non-inferiority effect of the inclusion of a robotic device (ALBA) to regular treatment against only regular rehabilitation. Participants will be assessed before and after 4 weeks of intervention and at 3 months of follow-up. The primary outcome will be the Fugl-Meyer assessment for upper extremities; secondary outcomes will include the questionnaires Functional Independence Measure, Medical Outcomes Study 36-item Short-Form Health Survey as well as the System Usability Scale.

Ethics and dissemination

Full ethical approval was obtained for this study from the scientific and ethical review board Servicio de Salud Metropolitano Oriente of Santiago (approval number: SSMOriente030522), and the recommendations of the Chilean law no 20120 of 7 September 2006, concerning scientific research in the human being, its genome and human cloning, will be followed. Ahead of inclusion, potential participants will read and sign a written informed consent form. Future findings will be presented and published in conferences and peer-reviewed journals.

Trial registration number

International ClinicalTrials.gov Registry (NCT05824416;https://clinicaltrials.gov/ct2/show/NCT05824416?term=uMOV&draw=2&rank=1).
Stratification of risk for emergent intracranial abnormalities in children with headaches: a Pediatric Emergency Care Applied Research Network (PECARN) study protocol
Authors: Tsze Daniel S , Kuppermann Nathan , Casper T Charles , Barney Bradley J , Richer Lawrence P , Liberman Danica B , Okada Pamela J , Morris Claudia R , Myers Sage R , Soung Jane K , Mistry Rakesh D , Babcock Lynn , Spencer Sandra P , Johnson Michael D , Klein Eileen J , Quayle Kimberly S , Steele Dale W , Cruz Andrea T , Rogers Alexander J , Thomas Danny G , Grupp-Phelan Jacqueline M , Johnson Tiffani J , Dayan Peter S
Published: November 2023

Introduction

Headache is a common chief complaint of children presenting to emergency departments (EDs). Approximately 0.5%–1% will have emergent intracranial abnormalities (EIAs) such as brain tumours or strokes. However, more than one-third undergo emergent neuroimaging in the ED, resulting in a large number of children unnecessarily exposed to radiation. The overuse of neuroimaging in children with headaches in the ED is driven by clinician concern for life-threatening EIAs and lack of clarity regarding which clinical characteristics accurately identify children with EIAs. The study objective is to derive and internally validate a stratification model that accurately identifies the risk of EIA in children with headaches based on clinically sensible and reliable variables.

Methods and analysis

Prospective cohort study of 28 000 children with headaches presenting to any of 18 EDs in the Pediatric Emergency Care Applied Research Network (PECARN). We include children aged 2–17 years with a chief complaint of headache. We exclude children with a clear non-intracranial alternative diagnosis, fever, neuroimaging within previous year, neurological or developmental condition such that patient history or physical examination may be unreliable, Glasgow Coma Scale score<14, intoxication, known pregnancy, history of intracranial surgery, known structural abnormality of the brain, pre-existing condition predisposing to an intracranial abnormality or intracranial hypertension, head injury within 14 days or not speaking English or Spanish. Clinicians complete a standardised history and physical examination of all eligible patients. Primary outcome is the presence of an EIA as determined by neuroimaging or clinical follow-up. We will use binary recursive partitioning and multiple regression analyses to create and internally validate the risk stratification model.

Ethics and dissemination

Ethics approval was obtained for all participating sites from the University of Utah single Institutional Review Board. A waiver of informed consent was granted for collection of ED data. Verbal consent is obtained for follow-up contact. Results will be disseminated through international conferences, peer-reviewed publications, and open-access materials.
Anomaly Detection in Cloud Using Hexabullus Optimisation-Enabled Fuzzy Classifier with Smart Contract-Enabled Secure Communication
Authors: Sammy F. , Vigila S. Maria Celestin
Published: November 2023

Cloud computing forms a mainstream in the emerging field of Internet of Things (IoT) networks, which provides high storage and access to data whenever needed. The cloud architecture is highly vulnerable to various anomalies due to the centralised process that has the capability of ruining the reputation or causing the loss of trust in an organisation. Preventing anomalies in cloud architecture extends the lifetime of the system and increases privacy preservation. In this research, blockchain technology is adopted for facilitating secure communication in the network, and anomaly detection is performed using the proposed Hexabullus optimisation-based Fuzzy classifier based on the entropy-based rules. The importance of this research relies on the calculation of entropy and anomaly detection using optimal rules generated using the proposed hexabullus optimisation. The experimental results show that the proposed blockchain-enabled cloud architecture prevents the occurrence of attacks more efficiently. The proposed hexabullus optimisation-based anomaly detection is evaluated with existing methods that attained an improved accuracy of 88%, precision of 88%, and recall of 90%, which is highly efficient in rendering the secure communication of the data in the cloud.
About this title - Characterization, Prediction and Modelling of Crustal Present-Day
In-Situ
Stresses
Authors: Goteti R. , Finkbeiner T. , Ziegler M. O. , Massiot C.
Published: November 2023

Geomechanics has a marked impact on safe and sustainable use of the subsurface. This Special Publication contains contributions detailing the latest efforts in present-day
in-situ
stress characterization, prediction and modelling on a borehole to plate-tectonic scale. A particular emphasis is on the uncertainties that are often associated with geomechanics.
OptiClass
: An Optimized Classifier for Application Layer Protocols Using Bit Level Signatures
Authors: Swarnkar Mayank , Sharma Neha
Published: November 2023

Network traffic classification has many applications, such as security monitoring, quality of service, traffic engineering, and so on. For the aforementioned applications, Deep Packet Inspection (DPI) is a popularly used technique for traffic classification because it scrutinizes the payload and provides comprehensive information for accurate analysis of network traffic. However, DPI-based methods reduce network performance because they are computationally expensive and hinder end-user privacy as they analyze the payload. To overcome these challenges, bit-level signatures are significantly used to perform network traffic classification. However, most of these methods still need to improve performance as they perform one-by-one signature matching of unknown payloads with application signatures for classification. Moreover, these methods become stagnant with the increase in application signatures. Therefore, to fill this gap, we propose
OptiClass
, an optimized classifier for application protocols using bit-level signatures.
OptiClass
performs parallel application signature matching with unknown flows, which results in faster, more accurate, and more efficient network traffic classification.
OptiClass
achieves twofold performance gains compared to the state-of-the-art methods. First,
OptiClass
generates bit-level signatures of just 32 bits for all the applications. This keeps
OptiClass
swift and privacy-preserving. Second,
OptiClass
uses a novel data structure called
BiTSPLITTER
for signature matching for fast and accurate classification. We evaluated the performance of
OptiClass
on three datasets consisting of twenty application protocols. Experimental results report that
OptiClass
has an average recall, precision, and F1-score of 97.36%, 97.38%, and 97.37%, respectively, and an average classification speed of 9.08 times faster than five closely related state-of-the-art methods.
Extending the Technology Acceptance Model: A New Perspective on the Adoption of Blockchain Technology
Authors: Chen Chih-Hung
Published: November 2023

While previous studies have investigated the factors influencing Internet adoption, the findings may not be transferable to explain blockchain technology (BCT) adoption, despite its similarities to the Internet. This study addresses this gap by developing an extended technology acceptance model (TAM) to investigate the factors influencing BCT adoption. The model consists of four key factors, including strategic management and social influence at the firm level, and individual innovation and self-efficacy at the individual level. Data were collected from 384 employees at Taiwan Stock Exchange companies, and structural equation modeling was utilized to test the hypotheses. Results reveal that strategic management and social influence at the firm level have a direct impact on BCT adoption, which is indirectly influenced by perceived usefulness. Subsequently, training and support provided by the firm can enhance individual innovation and self-efficacy, which has direct effects on BCT adoption at the individual level and is partially mediated by perceived ease of use.
Feeding Difficulties and Feeding Behaviors of Thai Children with Cow’s Milk Protein Allergy
Authors: Charoensriwattanakul Kununya , Wannaphahoon Kamolmart , Chomtho Sirinuch , Chatchatee Pantipa , Suratannon Narissara , Kittipongpattana Pannipa , Suteerojntrakool Orapa
Published: November 2023

Background. Cow’s milk protein allergy (CMPA) is a common food allergy in infants and young children and may be a risk factor for feeding difficulties. Studies exploring feeding difficulties and feeding behaviors in Thai children with CMPA are scarce. Objectives. To determine the prevalence of feeding difficulties and feeding behaviors in Thai children with CMPA compared to healthy controls. Methods. A cross-sectional study was performed comparing children aged 1-6 years old diagnosed with CMPA and had eliminated cow’s milk for at least 4 months with age-matched healthy children. Feeding difficulties were evaluated using the Montreal Children’s Hospital Feeding Scale questionnaire, and feeding behaviors were measured using the Child Eating Behavior Questionnaire (CEBQ). Results. One hundred and twenty-two participants were recruited (30 children with CMPA and 92 controls). The median age of the CMPA and control groups was 31.0 (14.0, 43.3) and 40.0 (28.0, 53.8) months, respectively (

p

value = 0.01). The CMPA group had lower calcium, phosphorus, and zinc intake than the healthy controls. The prevalence of feeding difficulties between the two groups did not show a significant difference (36.7 vs. 43.5%,

p

value = 0.70). The slowness in the eating subscale of feeding behaviors exhibited a lower score in the CMPA group than in the healthy group. Feeding difficulties was positively correlated with the desire to drink (β 3.079,

p

value = 0.011) but negatively correlated with the enjoyment of food subscale of CEBQ among the CMPA children (β -10.684,

p

value < 0.001). Conclusion. Despite a similar prevalence of feeding difficulties between CMPA and healthy children, the CMPA group demonstrated some differences in feeding behaviors. The lower score of enjoyment of food and a higher score of desire to drink correlated with a higher degree of feeding difficulties in the CMPA children. The provision of appropriate nutrition for this group of children should be prioritized.
Influence of Intraoral Scanners, Operators, and Data Processing on Dimensional Accuracy of Dental Casts for Unsupervised Clinical Machine Learning: An In Vitro Comparative Study
Authors: Farook Taseef Hasan , Ahmed Saif , Giri Jamal , Rashid Farah , Hughes Toby , Dudley James
Published: November 2023

Purpose. This study assessed the impact of intraoral scanner type, operator, and data augmentation on the dimensional accuracy of in vitro dental cast digital scans. It also evaluated the validation accuracy of an unsupervised machine-learning model trained with these scans. Methods. Twenty-two dental casts were scanned using two handheld intraoral scanners and one laboratory scanner, resulting in 110 3D cast scans across five independent groups. The scans underwent uniform augmentation and were validated using Hausdorff’s distance (HD) and root mean squared error (RMSE), with the laboratory scanner as reference. A 3-factor analysis of variance examined interactions between scanners, operators, and augmentation methods. Scans were divided into training and validation sets and processed through a pretrained 3D visual transformer, and validation accuracy was assessed for each of the five groups. Results. No significant differences in HD and RMSE were found across handheld scanners and operators. However, significant changes in RMSE were observed between native and augmented scans with no specific interaction between scanner or operator. The 3D visual transformer achieved 96.2% validation accuracy for differentiating upper and lower scans in the augmented dataset. Native scans lacked volumetric depth, preventing their use for deep learning. Conclusion. Scanner, operator, and processing method did not significantly affect the dimensional accuracy of 3D scans for unsupervised deep learning. However, data augmentation was crucial for processing intraoral scans in deep learning algorithms, introducing structural differences in the 3D scans. Clinical Significance. The specific type of intraoral scanner or the operator has no substantial influence on the quality of the generated 3D scans, but controlled data augmentation of the native scans is necessary to obtain reliable results with unsupervised deep learning.
A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor–positive/HER2-negative Advanced or Metastatic Breast Cancer
Authors: Cescon David W. , Hilton John , Morales Murilo Serafin , Layman Rachel M. , Pluard Timothy , Yeo Belinda , Park In Hae , Provencher Louise , Kim Sung-Bae , Im Young-Hyuck , Wyce Anastasia , Krishnatry Anu Shilpa , Hicks Kirsty , Zhang Qu , Barbash Olena , Khaled Ahmed , Horner Thierry , Dhar Arindam , Oliveira Mafalda , Sparano Joseph A.
Published: November 2023

Purpose:

Endocrine-based therapy is the initial primary treatment option for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2− mBC.

Patients and Methods:

In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2− breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor.

Results:

The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8–20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73–4.83; P < 0.0001).

Conclusions:

Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.
Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable
Authors: Codilupi Tamara , Szybinski Jakub , Arunasalam Stefanie , Jungius Sarah , Dunbar Andrew C. , Stivala Simona , Brkic Sime , Albrecht Camille , Vokalova Lenka , Yang Julie L. , Buczak Katarzyna , Ghosh Nilabh , Passweg Jakob R. , Rovo Alicia , Angelillo-Scherrer Anne , Pankov Dmitry , Dirnhofer Stefan , Levine Ross L. , Koche Richard , Meyer Sara C.
Published: November 2023

Purpose:

Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition.

Experimental Design:

MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC/RNA sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice.

Results:

MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2,500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NOD/SCID gamma mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Because inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL/MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line–derived mouse model, marrow infiltration was decreased supporting dependency on AXL/MAPK.

Conclusions:

We report on a novel mechanism of AXL/MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN.
Platinum-Based Chemotherapy Attenuates the Effector Response of CD8 T Cells to Concomitant PD-1 Blockade
Authors: Mariniello Annapaola , Nasti Tahseen H. , Chang Daniel Y. , Hashimoto Masao , Malik Sakshi , McManus Daniel T. , Lee Judong , McGuire Donald J. , Cardenas Maria A. , Umana Pablo , Nicolini Valeria , Antia Rustom , Saha Ananya , Buchwald Zachary , Kissick Hayden , Ghorani Ehsan , Novello Silvia , Sangiolo Dario , Scagliotti Giorgio V. , Ramalingam Suresh S. , Ahmed Rafi
Published: November 2023

Purpose:

Combination of chemotherapy with programmed cell death 1 (PD-1) blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how chemotherapy affects the response of exhausted CD8 T cells to PD-1 blockade.

Experimental Design:

We used the well-established mouse model of T-cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of chemotherapy (cisplatin+pemetrexed) on T-cell response to PD-1 blockade, in the absence of the impact of chemotherapy on antigen release and presentation observed in tumor models.

Results:

When concomitantly administered with PD-1 blockade, chemotherapy affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of IFNγ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared with PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed chemotherapy, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by chemotherapy partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant chemotherapy, ultimately resulting in impaired overall CD8 T-cell effector functions.

Conclusions:

In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T-cell functions.

See related commentary by Vignali and Luke, p. 1705
Diabetes Mellitus and Acute Facial Palsy: A Nationwide Population-Based Study
Authors: Seo Hee Won , Ryu Soorack , Lee Seung Hwan , Chung Jae Ho
Published: November 2023

Introduction: Acute facial palsy, characterized by sudden hemifacial weakness, significantly impacts an individual’s quality of life. Despite several predisposing factors identified for acute facial palsy, the specific relationship between diabetes mellitus (DM) and acute facial palsy has not been comprehensively explored in recent studies. The aim of the study was to assess the risk of acute facial palsy in patients with DM using a nationwide population sample cohort. Methods: DM cohort and non-DM cohort were built using the Korean National Health Insurance Service-Sample Cohort which represents the entire population of the Republic of Korea from January 2002 to December 2019. The DM cohort comprised 92,872 patients with a record of medication and a diagnosis of DM. Individuals who had facial palsy before the diagnosis of DM were excluded. A comparison cohort comprised 1,012,021 individuals without DM matched sociodemographically in a 1:4 ratio. The incidence of Bell’s palsy (BP) and Ramsay Hunt syndrome (RHS) were evaluated in both cohorts. The risk factors for acute facial palsy were also assessed. Results: Among the 92,868 patients in the DM cohort, the incidence rate (IR) of BP and RHS were 31.42 (confidence interval [CI], 30.24–32.63) and 4.58 per 10,000 person-years (CI, 4.14–5.05), respectively. Among the 371,392 individuals in the non-DM cohort, the IR of BP was 22.11 per 10,000 person-years (CI, 21.62–22.59) and the IR of RHS was 2.85 per 10,000 person-years (CI, 2.68–3.02). IR ratios for BP and RHS were 1.42 (CI, 1.36–1.48) and 1.61 (CI, 1.43–1.80). In multivariate analysis, DM (hazard ratio [HR] 1.428), age (HR 1.008), and high comorbidity score (HR 1.051) were associated with increased risk of BP, and male (HR 0.803) and living in metropolis (HR 0.966) decreased the risk of BP. And DM (HR 1.615), high comorbidity score (HR 1.078), and living in metropolis (HR 1.201) were associated with increased risk for RHS. Conclusion: This study suggests that patients with DM had an increased risk of acute facial palsy including BP and RHS.
Sampling from Extracorporeal Circuit: A Step Forward for Dose Monitoring in Continuous Renal Replacement Therapy
Authors: Ruffa Maria Cristina , Bocciero Vittorio , Fabbri Sergio , Nencini Francesca , Fanelli Alessandra , Romagnoli Stefano , Ricci Zaccaria , Cauda Valentina , Villa Gianluca
Published: November 2023

Introduction: Continuous renal replacement therapies (CRRTs) require constant monitoring and periodic treatment readjustments, being applied to highly complex patients, with rapidly changing clinical needs. To promote precision medicine in the field of renal replacement therapy and encourage dynamic prescription, the Acute Dialysis Quality Initiative (ADQI) recommends periodically measuring the solutes extracorporeal clearance with the aim of assessing the current treatment delivery and the gap from the therapeutic prescription (often intended as effluent dose). To perform this procedure, it is therefore necessary to obtain blood and effluent samples from the extracorporeal circuit to measure the concentrations of a target solute (usually represented by urea) in prefilter, postfilter, and effluent lines. However, samples must be collected simultaneously from the extracorporeal circuit ports, with the same suction flow at an unknown rate. Methods: The proposed study takes the first step toward identifying the technical factors that should be considered in determining the optimal suction rate to collect samples from the extracorporeal circuit to measure the extracorporeal clearance for a specific solute. Results: The results obtained identify the low suction rate (i.e., 1 mL/min) as an ideal parameter for an adequate sampling method. Low velocities do not perturb the external circulation system and ensure stability prevailing pressures in the circuit. Higher velocities can be performed only with blood flows above 120 mL/min preferably in conditions of appropriate filtration fraction. Discussion/Conclusions: The specific value of aspiration flow rate must be proportioned to the prescription of CRRT treatments set by the clinician.
Characteristics of Patients with Classic Congenital Adrenal Hyperplasia Missed on the Newborn Screen
Authors: Saroufim Rita , Nebesio Todd D. , Eugster Erica A.
Published: November 2023

Introduction: Newborn screening for congenital adrenal hyperplasia (CAH) has been in place in the USA for over 20 years. However, not all patients with classic CAH are diagnosed as neonates. Our aim was to characterize patients with classic CAH who were missed on the newborn screen (NBS) in Indiana and determine if discriminating features were present that might have led to earlier detection. Methods: Medical records of children diagnosed with classic CAH due to 21-hydroxylase deficiency seen at Riley Hospital for Children in Indiana between January 2005 and December 2020 were reviewed. Patient characteristics, visit information, and laboratory results were collected. Statistical analysis was performed using SPSS version 28. Results: A total of 64 patients were identified of whom 12 (19%) were missed on the NBS. Mean age at diagnosis was 21.7 months (range: 2–74 months), 67% were girls and 66% had salt-wasting CAH. Eight (67%) presented with clinical evidence of hyperandrogenism, including clitoromegaly (n = 7), posterior labial fusion (n = 5), and pubic hair (n = 2). Screening was pursued due to a family history of CAH in the remaining 4. Genetic confirmation was present in 50%. There was no history of antenatal steroid exposure in any of the missed patients. No differences were seen with regard to sex, ethnicity, gestational age, birth weight, type of CAH, or serum 17-hydroxyprogesterone (17OHP) level at diagnosis in patients who were missed compared with those diagnosed on the NBS (14,948 ng/dL vs. 16,701 ng/dL, p = 0.74). However, the mean testosterone level at diagnosis was lower in patients who were missed compared with those who were diagnosed earlier (68 ± 60.28 ng/dL vs. 196.2 ± 206.0 ng/dL, p = 0.02). A positive family history of CAH was present in 42% of the missed patients. The timing of the NBS collection was not different between the two groups, p = 0.36. Conclusion: Nearly one-fifth of our patients with classic CAH were missed on the NBS. No specific features were identified that distinguished these children from those who were detected at birth. It is critical to maintain a high index of suspicion for CAH in order to recognize these patients as early as possible so as to avoid adverse effects and potential life-threatening adrenal crises.
Padrões de distribuição de elementos terras-raras nas suítes plutônicas Ediacaranas a Cambrianas no extremo nordeste da Província Borborema, Brasil
Authors: Pinheiro Dalton da Silva , Lucas Dinarte , Nascimento Marcos Antonio Leite do , Vilalva Frederico Castro Jobim
Published: November 2023

O magmatismo Ediacarano a Cambriano no extremo NE da Província Borborema é representado por seis suítes plutônicas definidas com base em critérios químicos, petrográficos e texturais, sendo estas as suítes Shoshonítica, Calcioalcalina de alto K Porfirítica, Calcioalcalina de alto K Equigranular, Calcioalcalina, Alcalina e Alcalina Charnockítica. Este trabalho apresenta e discute os padrões de variação de elementos terras-raras (ETR) para essas suítes, utilizando a abordagem do método de lambda (λ) para obtenção dos coeficientes de forma (i.e. λ0, λ1, λ2, λ3) para os padrões de ETR. Os valores médios obtidos para tais coeficientes (notação λ0/λ1/λ2/λ3) são: suítes Shoshonítica (5,36/8,68/108,65/-1.438,32), Calcioalcalina de alto K Porfirítica (5,34/11,83/141,35/-1.464,81), Calcioalcalina de alto K Equigranular (5,43/9,29/152,15/-1.486,88), Calcioalcalina (4,77/5,44/149,65/-1.383,71), Alcalina (3,85/3,49/174,37/-1.282,47), AlcalinaFlores (5,63/4,12/152,31/-1.166,31) e Alcalina Charnockítica (5,60/9,98/128,10/-1.638,25). Os resultados apontam para forte influência no fracionamento de feldspatos nos padrões ETR observados, principalmente no que diz respeito às anomalias de Eu observadas utilizando λ0 como um marcador de fracionamento. Outros minerais como granada, clino e ortopiroxênio podem apresentar localmente influência sobre os baixos valores de λ1 e altos valores de λ3, enquanto os minerais que particionam álcalis influenciam valores altos de λ2.
The sense of ksénos in Ancient Greek
Authors: Ioannou Georgios
Published: November 2023

The present work looks at the term ksénos as an access point to the enacted model of hospitality—ksenía—in ancient Greece. It deduces the onomasiological and semasiological spread of the term across the model’s participants, namely GUEST, STRANGER but also HOST, into a schematic prototypical core within a complex and dynamic conceptual integration model. Along the spatial continuum of DISTANCE-APPROACHING-PROXIMITY, the analysis looks into APPROACHING as an emergent space, where GIFT-EXCHANGE is interpreted as a process of mental-space shift on the part of a stable SELF confronting the incoming OTHER. POSSESSIONS EXCHANGE conceptualised as non-commodifiable and non-alienable to the giver activates the metaphorical relation HAVE as BE. Thus, the abrupt confrontation is accommodated as an ad hoc partial substitutability of each participant’s identity by the identity of the other. Some Proto-Indo-European etymologies proposed in literature for the term are reviewed, and their compatibility with the present analysis is evaluated.
Synthetic-analytic variation in the formation of Greek comparatives and relative superlatives
Authors: Karkaletsou Foteini , Alexiadou Artemis
Published: November 2023

Many adjectives in Modern Greek form both synthetic and analytic comparatives and relative superlatives. To our knowledge, this is the first work to examine the triggers of the Synthetic-Analytic (S-A) variation in this language by means of a corpus study. To date, numerous studies have shown that a series of predictors (phonological, lexical, syntactic) appear to influence the S-A variation in English. The present paper focuses on some factors mentioned in the existing literature (e.g., frequency, number of syllables, syntactic position etc.) alongside Text Type, which is explicitly used as a predictor for the first time. Overall, our results suggest that 1) the S-A variation seems to be influenced by similar predictors cross-linguistically and 2) comparatives and relative superlatives show a partially different picture in Modern Greek, as is also the case in English (Cheung & Zhang 2016).
Work-related Alcohol Use
Authors: Halkjelsvik Torleif , Moan Inger Synnøve
Published: November 2023

Drinking alcohol with co-workers is a common practice in many countries. However, because consumption of alcohol is socially unaccepted in several religious groups, the use of alcohol in an occupational context may be discriminatory and have negative side-effects. In annual surveys of part- and fulltime employees in Norway conducted between 2015 and 2022, we found that employees affiliated with religious minorities more often experienced social exclusion due to work-related alcohol use than non-religious employees and the religious majority. Experiencing alcohol-related social exclusion was related to more negative perceptions of the social work environment and more absence from work. Restrictive alcohol practices and policies at the workplace were associated with less social exclusion and appeared to be protective for religious minorities, without impairing the social work environment of other employees. Social exclusion of religious minorities can be reduced if employers limit or avoid serving alcohol to employees.