bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic analysis of a family affected by congenital myasthenic syndrome due to a Novel mutation in the SLC5A7 gene
Authors: Tian Sheng , Sun Huan , Gao Fen-Fang , Zhang Kang , Nan Jing , Niu Mu , Jia Xiao , Xu Gang , Ge Wei
Published: June 2024

Background

Mutations in the SLC5A7 gene cause congenital myasthenia, a rare genetic disorder. Mutation points in the SLC5A7 gene differ among individuals and encompass various genetic variations; however, exon deletion variants have yet to be reported in related cases. This study aims to explore the clinical phenotype and genetic traits of a patient with congenital myasthenic syndrome due to SLC5A7 gene variation and those of their family members.

Case presentation

We describe a case of a Chinese male with congenital myasthenic syndrome presenting fluctuating limb weakness. Genetic testing revealed a heterozygous deletion mutation spanning exons 1–9 in the SLC5A7 gene. QPCR confirmed a deletion in exon 9 of the SLC5A7 gene in the patient’s mother and brother. Clinical symptoms of myasthenia improved following treatment with pyridostigmine.

Conclusion

Exons 1, 5, and 9 of the SLC5A7 gene encode the choline transporter’s transmembrane region. Mutations in these exons can impact the stability and plasma membrane levels of the choline transporter. Thus, a heterozygous deletion in exons 1–9 of the SLC5A7 gene could be the pathogenic cause for this patient. In patients exhibiting fluctuating weakness, positive RNS, and seronegativity for myasthenia gravis antibodies, a detailed family history should be considered, and enhanced genetic testing is recommended to determine the cause.
Identifying emerging hot spots of road traffic injury severity using spatiotemporal methods: longitudinal analyses on major roads in Ghana from 2005 to 2020
Authors: Mesic Aldina , Damsere-Derry James , Feldacker Caryl , Mooney Stephen J. , Gyedu Adam , Mock Charles , Kitali Angela , Wagenaar Bradley H. , Wuaku Daniel Hardy , Afram Martin Owusu , Larley Joshua , Opoku Irene , Ekuban Ernest , Osei-Ampofo Maxwell , Stewart Barclay
Published: June 2024

Background

Although road traffic injuries and deaths have decreased globally, there is substantial national and sub-national heterogeneity, particularly in low- and middle-income countries (LMICs). Ghana is one of few countries in Africa collecting comprehensive, spatially detailed data on motor vehicle collisions (MVCs). This data is a critical step towards improving roadway safety, as accurate and reliable information is essential for devising targeted countermeasures.

Methods

Here, we analyze 16 years of police-report data using emerging hot spot analysis in ArcGIS to identify hot spots with trends of increasing injury severity (a weighted composite measure of MVCs, minor injuries, severe injuries, and deaths), and counts of injuries, severe injuries, and deaths along major roads in urban and rural areas of Ghana.

Results

We find injury severity index sums and minor injury counts are significantly decreasing over time in Ghana while severe injury and death counts are not, indicating the latter should be the focus for road safety efforts. We identify new, consecutive, intensifying, and persistent hot spots on 2.65% of urban roads and 4.37% of rural roads. Hot spots are intensifying in terms of severity and frequency on major roads in rural areas.

Conclusions

A few key road sections, particularly in rural areas, show elevated levels of road traffic injury severity, warranting targeted interventions. Our method for evaluating spatiotemporal trends in MVC, road traffic injuries, and deaths in a LMIC includes sufficient detail for replication and adaptation in other countries, which is useful for targeting countermeasures and tracking progress.
New Orleans school meal programs during the COVID-19 pandemic: challenges and innovations identified through qualitative interviews
Authors: Knapp Megan B. , Creveling Kristine , Washington Domonique , Ennin Naana , Numa Tiffany
Published: June 2024

Background

School meal programs are critical to reducing childhood food insecurity. This study identified challenges and innovations in school meal service in a disaggregated charter school system during COVID-19 in New Orleans, Louisiana.

Methods

Semi-structured qualitative key informant interviews were conducted with school officials and school food providers. Interviews were recorded, transcribed, and coded. Using an immersion-crystallization approach, patterns were identified.

Results

Nine participants described challenges and solutions/innovations in food service focused around five themes: food service, procurement and costs, staffing, communication and outreach, and collaborations and partnerships. Participants faced challenges in meal service logistics, procuring food and supplies, staffing shortages, timely communication, lack of city-wide coordination, and the need to rapidly shift operations due to an evolving pandemic. While the disaggregated system created challenges in a city-wide response, the decentralized system along with policy changes offered opportunities for flexibility and innovation in meal programs through new partnership and coordination between schools and community, development of new processes for food service and procurement, and diverse modes of communication.

Conclusion

These findings add to the understanding of challenges faced and innovations implemented to continue school meal programs in a disaggregated school system. Collaboration with community organizations, leveraging resources, coordinated communication, and policies allowing for flexibility were key to response and should be encouraged to build capacity and resiliency in emergencies. In future city-wide emergency preparedness planning efforts, school leaders and food providers should be included in the planning to ensure continued equitable food access for students.
Clinical significance of chronic bronchitis in different racial groups
Authors: Choi Joon Young , Yoo Kwang Ha , Jung Ki-Suck , Kim Victor , Rhee Chin Kook
Published: June 2024

Backgrounds

Limited data are available on racial differences in the clinical features of chronic bronchitis (CB) patients with chronic obstructive pulmonary disease (COPD). In this study, we aimed to compare clinical features among CB patients of different races. We also analyzed the clinical significance of CB, defined classically and based on the COPD Assessment Test (CAT), to validate the CAT-based definition.

Methods

We analyzed patient data extracted from the Korean COPD Subgroup Study (KOCOSS) cohort (2012–2021) and US Genetic Epidemiology of COPD (COPDGene) study (2008–2011). We compared clinical characteristics among CB and non-CB patients of three different races using two CB definitions.

Results

In this study, 3,462 patients were non-Hispanic white (NHW), 1,018 were African American (AA), and 1,793 were Asian. The proportions of NHW, AA, and Asian patients with CB according to the classic definition were 27.4%, 20.9%, and 10.7%, compared with 25.2%, 30.9%, and 23.0% according to the CAT-based definition, respectively. The risk of CB prevalence was highest in NHW and lowest in Asian COPD patients. Among all races, CB patients were more likely to be current smokers, have worse respiratory symptoms and poorer health-related quality of life (HrQoL), and to have decreased lung function and exercise capacity. Most of these characteristics showed similar associations with the outcomes between the two definitions of CB. A binominal regression model revealed that CB patients of all races had an increased risk of future exacerbations according to both CB definitions, except for Asian patients with classically defined CB.

Conclusions

The presence of CB was associated with worse respiratory symptoms, HrQoL, exercise capacity and lung function, and more exacerbations, regardless of race or CB definition. The CAT-based definition may be more useful for assessing the risk of future exacerbations in Asian COPD patients.
A balance focused biometric does not predict rehabilitation needs and outcomes following total knee arthroplasty
Authors: Lee Jonathan J. , Arora Prerna , Finlay Andrea K. , Amanatullah Derek F.
Published: June 2024

Background

Both length of hospital stay and discharge to a skilled nursing facility are key drivers of total knee arthroplasty (TKA)-associated spending. Identifying patients who require increased postoperative care may improve expectation setting, discharge planning, and cost reduction. Balance deficits affect patients undergoing TKA and are critical to recovery. We aimed to assess whether a device that measures preoperative balance predicts patients’ rehabilitation needs and outcomes after TKA.

Methods

40 patients indicated for primary TKA were prospectively enrolled and followed for 12 months. Demographics, KOOS-JR, and PROMIS data were collected at baseline, 3-months, and 12-months. Single-leg balance and sway velocity were assessed preoperatively with a force plate (Sparta Science, Menlo Park, CA). The primary outcome was patients’ discharge facility (home versus skilled nursing facility). Secondary outcomes included length of hospital stay, KOOS-JR scores, and PROMIS scores.

Results

The mean preoperative sway velocity for the operative leg was 5.7 ± 2.7 cm/s, which did not differ from that of the non-operative leg (5.7 ± 2.6 cm/s, p = 1.00). Five patients (13%) were discharged to a skilled nursing facility and the mean length of hospital stay was 2.8 ± 1.5 days. Sway velocity was not associated with discharge to a skilled nursing facility (odds ratio, OR = 0.82, 95% CI = 0.27–2.11, p = 0.690) or longer length of hospital stay (b = -0.03, SE = 0.10, p = 0.738). An increased sway velocity was associated with change in PROMIS items from baseline to 3 months for global07 (“How would you rate your pain on average?” b = 1.17, SE = 0.46, p = 0.015) and pain21 (“What is your level of pain right now?” b = 0.39, SE = 0.17, p = 0.025) at 3-months.

Conclusion

Preoperative balance deficits were associated with postoperative improvements in pain and function after TKA, but a balance focused biometric that measured single-leg sway preoperatively did not predict discharge to a skilled nursing facility or length of hospital stay after TKA making their routine measurement cost-ineffective.
Optimization of traction parameters for lumbar scoliosis
Authors: He Wei , Li Jia-Long , Wang Jia-Yu , He Da , Song Kai
Published: June 2024

Background

Scoliosis is a high incidence disease that endangers the physical and mental health of adolescents. Traction therapy, as a conservative treatment plan, is helpful to improve the recovery speed of patients by studying the influence of different traction factors on the therapeutic effect.

Methods

Based on the thin layer CT data of the lumbar spine of a 16-year-old patient with scoliosis, Mimics21.0 was used to extract the 3D digital model, and Geomagic Wrap2021 was used to perform the smooth surface. After that, SolidWorks was used to manually construct the structures, such as the intervertebral disc, and Ansys17.0 was used to add constraints, ligaments, and other features. Three-factor ANOVA was carried out after an orthogonal experiment that considered traction mode, traction angle, and traction force was finished.

Results

① A three-dimensional biomechanical model of lumbar scoliosis was created. ② The model’s correctness was confirmed by comparing it to the corpse and other finite element models, as well as by verifying it under a range of working settings. ③ Traction force (P = 0.000), traction angle (P = 0.000), the interaction between traction force and traction angle (P = 0.000), and the interaction between traction mode and traction angle (P = 0.045) were all significant. ④ The interaction between traction force and traction angle has the most significant effect on Cobb, and traction with a certain angle is better than traditional axial traction. ⑤ Traction mode is not significant, but the interaction between traction mode and traction angle is significant.

Conclusions

A certain angle of traction can aid in improving outcomes and the traction force can be suitably decreased in the clinical formulation of the traction plan. The uniformity of correcting effect is more favorable when higher fixation techniques like positive suspension or traction bed traction are used, as opposed to overhanging traction.
Qualitative and quantitative assessment of non-clear cell renal cell carcinoma using contrast-enhanced ultrasound
Authors: Zhang WeiPing , Wang JingLing , Chen Li , Shi Jiayu
Published: June 2024

Background

Non-clear cell renal cell carcinoma (nccRCC) represents a rare form of renal cell carcinoma (RCC) in the clinic. It is now understood that contrast-enhanced ultrasound (CEUS) exhibits diverse manifestations and can be prone to misdiagnosis. Therefore, summarizing the distinctive features of contrast-enhanced ultrasonography is essential for differentiation from ccRCC.

Objective

This study aims to evaluate the diagnostic efficacy of qualitative and quantitative CEUS in diagnosing nccRCC to enhance our understanding of this condition.

Methods

We conducted a retrospective analysis of 21 patients with confirmed nccRCC following surgery and assessed the characteristic conventional ultrasound and CEUS imaging features. The paired Wilcoxon signed-rank sum test was employed to compare differences in CEUS time-intensity curve (TIC) parameters between the lesions and the normal renal cortex.

Results

Routine ultrasound revealed the following primary characteristics in the 21 nccRCC cases: hypoechoic appearance (10/21, 47.6%), absence of liquefaction (18/21, 66.7%), regular shape (19/21, 90.5%), clear boundaries (21/21, 100%), and absence of calcification (17/21, 81%). Color Doppler flow imaging (CDFI) indicated a low blood flow signal (only 1 case of grade III). Qualitative CEUS analysis demonstrated that nccRCC predominantly exhibited slow progression (76.1%), fast washout (57%), uniformity (61.9%), low enhancement (71.5%), and ring enhancement (61.9%). Quantitative CEUS analysis revealed that parameters such as PE, WiAUC, mTTI, WiR, WiPI, WoAUC, WiWoAUC, and WOR in the lesions were significantly lower than those in the normal renal cortex (Z=-3.980, -3.563, -2.427, -3.389, -3.980, -3.493, -3.528, -2.763, P < 0.001, < 0.001, = 0.015, = 0.001, < 0.001, < 0.001, < 0.001, = 0.006). However, there were no significant differences in RT, TTP, FT, or QOF (all P > 0.05).

Conclusion

nccRCC exhibits distinctive CEUS characteristics, including slow progression, fast washout, low homogeneity enhancement, and ring enhancement, which can aid in distinguishing nccRCC from ccRCC.
Developing mental health curricula and a service provision model for clinical associates in South Africa: a Delphi survey of family physicians and psychiatrists
Authors: Moodley Saiendhra Vasudevan , Wolvaardt Jacqueline , Grobler Christoffel
Published: June 2024

Background

Clinical associates are a health professional cadre that could be utilised in mental health task sharing in South Africa but this is training dependent. The objectives of the study were to identify the potential curricula content, training sites, and teaching modalities for undergraduate and potential postgraduate clinical associate mental health training and to identify the tasks that they should perform based on these curricula.

Methods

We utilised the Delphi method to reach consensus on items with the panel comprising psychiatrists and family physicians. The first round questionnaire of the Delphi survey was developed based on a literature review and the results from earlier phases of the overall study. The survey was administered electronically and consisted of three rounds. Following both the first and second rounds, an updated questionnaire was constructed omitting the items on which consensus was reached. The questionnaire consisted primarily of nine-point scales with consensus based on 70% of participants rating 1,2,3 or 7,8,9.

Results

There were 26 participants in the first round with this number falling to 23 in later rounds. There was strong consensus on a training attachment to a mental health clinic at a community health centre (CHC) at undergraduate (96.2%) and postgraduate level (100%). Consensus was reached on the importance of training on the management of six categories of disorders at the undergraduate level and nine categories of disorders at the postgraduate level. Clerking patients as a teaching modality reached 100% consensus at both undergraduate and postgraduate levels. PHC clinics, CHCs and district hospitals reached consensus as appropriate settings for clinical associates to provide mental health services. In addition, GP practices and secondary hospitals reached consensus for those with postgraduate training. Consensus was reached on ten of the 21 listed tasks that could be performed based on undergraduate training and 20 of the 21 tasks based on a postgraduate qualification in mental health.

Conclusions

The Delphi panel’s recommendations provide a clear roadmap for enhancing mental health curricula for clinical associates, enabling their utilisation in mental health service provision. A future postgraduate mental health qualification for clinical associates would allow for expanded task sharing.
Human rights among Korean dental hygiene students in hospital clinical practice
Authors: Won Yoon-Ah , Noh Hie-Jin
Published: June 2024

Background

The human rights of dental hygiene students should be guaranteed during practice at medical institutions for their mental and physical health as well as professionalism, for patient safety. Safe and well guaranteed clinicians can perform their work in a more stable way. This study investigated the human rights circumstances of dental hygiene students during their hospital clinical practice at dental institutions.

Methods

This study used a cross-sectional survey design. Convenience sampling was conducted on 121 third- and fourth-year dental hygiene students from universities in Seoul, Gyeonggi, and Gangwon. The survey used the Human Rights Indicators for Dental Hygiene Students to investigate the rights to safety, equality, and personality to understand participants’ experiences of guaranteed fundamental rights. Data were collected from October 31 to November 8, 2019. A chi-square test was used to assess differences in experience according to general characteristics.

Results

During dental hygiene practice at dental institutions, less than 50% of students felt safe. When human rights violations occurred in dental institutions, only 42.4% of students received guidance on response measures from their universities. While 72.1% of students who practiced at dental university hospitals were given information on first aid supplies (facilities) within dental institutions, only approximately 45% of students who practiced at lower-scale dental institutions were given this information (p < 0.05). Regarding equality rights, only 52.5% of trainees reported that they had received equal treatment from healthcare workers during hospital clinical practice.

Conclusions

During dental practice at dental institutions, Korean dental hygiene students confirmed that human rights (including safety rights, equality rights, and personality rights) were guaranteed to varying degrees. Dental hygiene students’ rights during hospital clinical practice in dental institutions should be guaranteed across institutions regardless of their scale. This is necessary for dental hygiene students’ human rights and safe policies and guidelines in dental institution clinical practice and regular monitoring systems.
Psychometric evaluation of the Vietnamese version of nurses’ ethical behaviors for protecting patient rights scale (V-NEBPPRS): a methodological study
Authors: Do Thi Ninh , Lee Gunjeong , Susmarini Dian
Published: June 2024

Background

Recognizing patients’ rights as fundamental human rights, the global healthcare community, including the World Health Organization and various nursing organizations, has emphasized the critical role of nurses in upholding these rights through ethical practice and patient-centered care. However, in the complex landscape of healthcare, nurses in Vietnam face various ethical issues and challenges that may impede their ability to protect patient rights effectively, necessitating tools for better ethical decision-making and practice.

Purpose

This study aims to translate the Nurses’ Ethical Behaviours for Protecting Patient Rights Scale (NEBPPR) into Vietnamese and evaluate the validity and reliability of the V-NEBPPRS.

Methods

The original scale underwent a cross-cultural translation process to be adapted into Vietnamese. Construct validity was assessed using confirmatory factor analysis (CFA). The convergent validity, discriminant validity, and reliability of the V-NEBPPRS were evaluated.

Results

After removing four items with factor loading below 0.5, the V-NEBPPRS comprises 24 items divided into five factors. CFA demonstrated a good model fit (χ2/df = 2.86; GFI = 0.87; IFI = 0.85; CFI = 0.84; RMSEA = 0.07). Convergent and discriminant validity were confirmed with extracted mean variance ranging from 0.54 to 0.67, 0.54 to 0.67, and composite reliability from 0.73 to 0.81. Cronbach’s α coefficient was 0.85 for the total scale and ranged from 0.70 to 0.79 for five subscales.

Conclusion

The V-NEBPPRS is a reliable tool, providing nursing leaders and researchers with the means to utilize the V-NEBPPRS for assessing and promoting nurses’ awareness and behaviour in safeguarding patients’ rights, thereby contributing to improved overall health outcomes.
Healthcare professionals’ experiences of video consultations in palliative care in rural areas: an intervention study in community care
Authors: Brännström Margareta , Philipsson Johan , Andersson Sofia
Published: June 2024

Background

The population is aging, leading to an increased need for palliative care and end-of-life care. There is a lack of research on the use of video consultations for knowledge transfer between specialist and general palliative care. The aim of this study was to describe healthcare professionals’ experiences of video consultations in palliative care in community homecare and nursing homes in rural areas.

Methods

Individual interviews (n = 11) were conducted with five community nurses, one occupational therapist, two specialist palliative nurses, and three specialist palliative care physicians. The data were analysed using reflexive thematic analysis.

Results

The analysis identified three themes: feeling comfortable with increased availability of specialist expertise; seeing each other facilitates communication; and being supported by physically present care professionals is essential.

Conclusion

HCPs suggest that video consultations are an effective way to increase access to specialist palliative care and provide more equal care to patients with palliative care needs in rural community care.
Multi-omics profiling reveal cells with novel oncogenic cluster, TRAP1low/CAMSAP3low, emerge more aggressive behavior and poor-prognosis in early-stage endometrial cancer
Authors: Mao Xiaodan , Tang Xiaoyue , Ye Jingxuan , Xu Shuxia , Wang Yue , Liu Xianhua , Wu Qibin , Lin Xite , Zhang Maotong , Liu Jiangfeng , Yang Juntao , Sun Pengming
Published: June 2024

The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1low/CAMSAP3low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1low/CAMSAP3low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.
“In Sweden you are worthless. In Denmark you get an identity again” – on being perceived and received as a person who uses drugs in different drug policy settings
Authors: Holeksa Julie
Published: June 2024

Background

Policies to address substance use differ greatly between settings, where goals may range from zero-tolerance to harm reduction. Different approaches impact formats of care, policing, and even interpersonal interactions, and may play a role in the labelling and stigmatization of people who use drugs (PWUD). Where Sweden has a more restrictive policy, aiming to have a society free from drugs, Denmark has embraced harm reduction principles. The aim of this study was to explore PWUDs’ experiences of interpersonal interactions, policing, and service formats in the two countries.

Methods

The data consists of 17 qualitative semi-structured interviews with Swedish PWUD who have been in both Sweden and Denmark. Recruitment took place at harm reduction sites in both countries, and through snowball sampling.

Results

Participants reflected on how they were perceived by those in public spaces, and received by care systems and personnel. In public settings in Sweden, participants felt they were ignored, rendered invisible, and lost their humanity. In Denmark, they were perceived and acknowledged, valued as people. This was simultaneously linked to being embodied by the availability of differing service offerings and policing practices, which solidified their “right to be out” in public. Reflecting on their reception in the treatment system, strict formatting in Sweden caused participants to feel that an identity was projected upon them, limiting their opportunities or growth of new facets of identity. Care relations in Denmark fostered more opportunity for autonomy and trust.

Conclusion

A zero-tolerance policy and associated public discourses could solidify and universalize stigmatizing categorizations as a central feature of PWUD identity and reception from those around them, exacerbating social exclusion. Conversely, harm reduction-centered policies fostered positive interactions between individuals with care providers, public, and police, which may promote inclusion, empowerment, and wellbeing.
DNA methylation variations underlie lettuce domestication and divergence
Authors: Cao Shuai , Sawettalake Nunchanoke , Li Ping , Fan Sheng , Shen Lisha
Published: June 2024

Background

Lettuce (Lactuca sativa L.) is an economically important vegetable crop worldwide. Lettuce is believed to be domesticated from a single wild ancestorLactuca serriolaand subsequently diverged into two major morphologically distinct vegetable types: leafy lettuce and stem lettuce. However, the role of epigenetic variation in lettuce domestication and divergence remains largely unknown.

Results

To understand the genetic and epigenetic basis underlying lettuce domestication and divergence, we generate single-base resolution DNA methylomes from 52Lactucaaccessions, including major lettuce cultivars and wild relatives. We find a significant increase of DNA methylation during lettuce domestication and uncover abundant epigenetic variations associated with lettuce domestication and divergence. Interestingly, DNA methylation variations specifically associated with leafy and stem lettuce are related to regulation and metabolic processes, respectively, while those associated with both types are enriched in stress responses. Moreover, we reveal that domestication-induced DNA methylation changes could influence expression levels of nearby and distal genes possibly through affecting chromatin accessibility and chromatin loop.

Conclusion

Our study provides population epigenomic insights into crop domestication and divergence and valuable resources for further domestication for diversity and epigenetic breeding to boost crop improvement.
Defatting of donor transplant livers during normothermic perfusion—a randomised clinical trial: study protocol for the DeFat study
Authors: Abbas Syed Hussain , Ceresa Carlo D. L. , Hodson Leanne , Nasralla David , Watson Christopher J. E. , Mergental Hynek , Coussios Constantin , Kaloyirou Fotini , Brusby Kerrie , Mora Ana , Thomas Helen , Kounali Daphne , Keen Katie , Pollok Joerg-Matthias , Gaurav Rohit , Iype Satheesh , Jassem Wayel , Perera M. Thamara PR , Hakeem Abdul Rahman , Knight Simon , Friend Peter J.
Published: June 2024

Background

Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes.

Methods

In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months).

Discussion

This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths.

Trial registration

ISRCTN ISRCTN14957538. Registered in October 2022.
CTR > 0.7 predicts the subgroup of lung adenocarcinomas ≤ 2 cm at risk of poor outcome treated by sublobar resection compared to lobar resection
Authors: Jing Weiwei , Li Qi , Liu Mengxi , Zhang Yi , Chen Sifan , Zhang Ke , Li Dan , Zhao Min , Zheng Yineng , Li Wangjia , Wu Yangying , Xu Hongbo , Zhao Ziya , Kang Shaolei , Lv Fajin
Published: June 2024

Background

A standard surgical procedure for patients with small early-stage lung adenocarcinomas remains unknown. Hence, we aim in this study to assess the clinical utility of the consolidation-to-tumor ratio (CTR) when treating patients with small (2 cm) early stage lung cancers.

Methods

A retrospective cohort of 298 sublobar resection and 266 lobar resection recipients for early stage lung adenocarcinoma ≤ 2 cm was assembled from the First Affiliated Hospital of Chongqing Medical University between 2016 and 2019. To compare survival rates among the different groups, Kaplan-Meier curves were calculated, and the log-rank test was used. A multivariate Cox proportional hazard model was constructed utilizing variables that were significant in univariate analysis of survival.

Results

In the study, 564 patients were included, with 298 patients (52.8%) undergoing sublobar resection and 266 patients (47.2%) undergoing lobar resection. Regarding survival results, there was no significant difference in the 5-year overall survival (OS, P = 0.674) and 5-year recurrence-free survival (RFS, P = 0.253) between the two groups. Cox regression analyses showed that CTR ≥ 0.75(P < 0.001), age > 56 years (P = 0.007), and sublobar resection(P = 0.001) could predict worse survival. After examining survival results based on CTR categorization, we segmented the individuals into three categories: CTR<0.7, 0.7 ≤ CTR<1, and CTR = 1.The lobar resection groups had more favorable clinical outcomes than the sublobar resection groups in both the 0.7 ≤ CTR < 1(RFS: P < 0.001, OS: P = 0.001) and CTR = 1(RFS: P = 0.001, OS: P = 0.125). However, for patients with 0 ≤ CTR < 0.7, no difference in either RFS or OS was found between the lobar resection and sublobar resection groups, all of which had no positive events. Patients with a CTR between 0.7 and 1 who underwent lobar resection had similar 5-year RFS and OS rates compared to those with a CTR between 0 and 0.7 who underwent sublobar resection (100% vs. 100%). Nevertheless, a CTR of 1 following lobar resection resulted in notably reduced RFS and OS when compared to a CTR between 0.7 and 1 following lobar resection (P = 0.005 and P = 0.016, respectively).

Conclusion

Lobar resection is associated with better long-term survival outcomes than sublobar resection for small lung adenocarcinomas ≤ 2 cm and CTR ≥ 0.7.
Residual deficits of knee and hip joint coordination and clinical performance after return to sports in athletes with anterior cruciate ligament reconstruction
Authors: Sinsurin Komsak , Kiratisin Pongthanayos , Irawan Dimas Sondang , Vachalathiti Roongtiwa , Richards Jim
Published: June 2024

Background

Biomechanical changes and neuromuscular adaptations have been suggested as risk factors of secondary injury in individuals after anterior cruciate ligament reconstruction (ACLr). To achieve a better understanding of preventive mechanisms, movement quality is an important factor of consideration. Few studies have explored time-series analysis during landing alongside clinical performance in injured and non-injured individuals. The purpose of the study was to investigate the biomechanical risks of recurrent injury by comparing clinical and jump-landing performance assessments between athletes with ACLr and healthy controls.

Method

This study was observational study. Sixteen athletes with and without ACLr voluntarily participated in clinical and laboratory measurements. Single-leg hop distance, isokinetic tests, landing error score, and limb symmetry index (LSI) were included in clinical report. Lower limb movements were recorded to measure joint biomechanics during multi-directional landings in motion analysis laboratory. Hip-knee angle and angular velocity were explored using discrete time-point analysis, and a two-way mixed analysis of variance (2 × 4, group × jump-landing direction) was used for statistical analysis. Time series and hip-knee coordination analyses were performed using statistical parametric mapping and descriptive techniques.

Results

Significantly lower single-leg hop distance was noted in ACLr group (158.10 cm) compared to control group (178.38 cm). Although the hip and knee moments showed significant differences between four directions (p < 0.01), no group effect was observed (p > 0.05). Statistical parametric mapping showed significant differences (p ≤ 0.05) between groups for hip abduction and coordinate plot of hip and knee joints. Athletes with ACLr demonstrated a higher velocity of hip adduction. Time-series analysis revealed differences in coordination between groups for frontal hip and knee motion.

Conclusions

Athletes with ACLr landed with poor hip adduction control and stiffer knee on the involved side. Multi-directions landing should be considered over the entire time series, which may facilitate improved movement quality and return to sports in athletes with ACLr.
The anti-tumor immune response of radiotherapy combined with anti-CD200R1 in hepatocellular carcinoma.
Authors: Li Siqi , Li Kun , Jiang Peng , Li Hua , Yang Yang , Ye Linsen
Published: June 2024

2525

Background: Various clinical trials demonstrate the efficacy of regional radiotherapy or chemotherapy in augmenting the therapeutic response to PD1/L1 antibody in hepatocellular carcinoma (HCC). However, a significant proportion of HCC patients still exhibit suboptimal responses to these combination therapies. The immune-suppressive tumor microenvironment (TME) poses a formidable barrier to effective immunotherapy. Recent evidences underscore the pivotal role played by myeloid cells in modulating the immunosuppressive TME following regional treatments. Therefore, targeting the myeloid immunosuppressive checkpoint represents a promising strategy for enhancing the efficacy of current local-immune combination therapy. Methods: Initially, single cell RNA sequencing (scRNA-seq) was conducted on tumor infilitrating immune cells (TIICs) of mouse HCC tissues three days post-radiotherapy. Subsequently, the phenotype of tumor-infiltrating CD200+ macrophages was characterized in mouse HCC tissues using flow cytometry. Next, the specific mechanism underlying CD200 up-regulation in tumor-infiltrating macrophages was investigated using wild-type mice and STING KO mice. Furthermore, the chemotactic and interactive mechanisms between CD200+ macrophages and CD200R+ myeloid-derived suppressor cells (MDSCs) were investigated through in vitro and in vivo experiments. Finally, the systemic antitumor effect of combined radiotherapy and anti-CD200R treatment was observed in multiple non-immunogenic HCC mouse models. Results: The infiltration level of CD200+ macrophages in HCC tissues significantly increase following local radiotherapy. The accumulation of CD200+ macrophage subset relies on potent STING activation subsequent to radiotherapy. In vitro and in vivo experiments demonstrate the robust capacity of CD200+ macrophages in enhancing myeloid immunosuppression. Mechanistically, CD200+ macrophages recruit CXCR2+ CD200R+ MDSC through secretion of CXCL1/3, thereby amplifying the proliferation and immunosuppressive capacity of this specific MDSC subset via interaction between CD200 and CD200R. Targeted blockade of CD200R improve the inhibitory immune microenvironment by suppressing the immunosuppressive capacity of myeloid suppressor cells. Lastly, combined anti-CD200R1 with radiotherapy sensitized the therapeutic effect of PD-1/L1 antibody in multiple non-immunogenic HCC mouse models. Conclusions: Our studies identify CD200+ macrophages as a crucial immune suppressor that is essential for tumor immune resistance following radiotherapy. These findings unveil a novel mechanism of immune evasion mediated by STING activation, thereby offering a potential target for further optimization of local-immune combination therapy in HCC.
A first-in-human trial of selective CDK7 inhibitor Q901, in patients with advanced solid tumors: Interim results of a phase I study (QRNT-009).
Authors: Xie Hao , El-Khoueiry Anthony B. , Alistar Angela Tatiana , Babiker Hani M. , Mahalingam Devalingam , Barve Minal A. , Sohn Joohyuk , Borad Mitesh J. , Lee Jae Cheol , Ahn Jiye , Lee Dayoung , Choi Jinho , Kim Jeongjun , Yu Dong-Hoon , Lee Seung-Joo , Jeon Borami , Proniuk Stefan , Kim Jaeseung , Nam Kiyean
Published: June 2024

3078

Background: Q901 is a potent, covalently binding CDK7 inhibitor with excellent specificity for CDK7 against other protein kinases. Transcriptional regulation by CDK7 inhibition in cancer cells leads to DNA damage repair response inhibition and increased genomic instability. Q901 also regulates cell cycle checkpoints by inhibiting T-loop phosphorylation and transcriptionally downregulating CDK1, 2 and 4. In preclinical in vivo models, intravenous (iv) administration of Q901 once a week and once every three-week dosing regimen was well tolerated and showed significant antitumor activity. The safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy data for 18, 36 and 60 mg/m2 are presented. Methods: QRNT-009 (NCT05394103) is an ongoing Phase 1/2 multicenter, open-label, dose escalation and expansion study. Q901 is administered iv once weekly for four weeks, then once every two weeks thereafter in patients with advanced or metastatic ovarian cancer, castration-resistant prostate cancer (CRPC), breast cancer, endometrial cancer, colorectal cancer, small cell lung cancer (SCLC), or pancreatic cancers. Results: As of data cutoff (12Jan2024), 17 patients received Q901 across 3 dose levels: 5 patients at 18 mg/m2, 4 patients at 36 mg/m2, and 8 patients at 60 mg/m2. The median prior lines of systemic therapy were 4 (range 2 - 17). Of 17 patients who received Q901 across all doses, there were no treatment related SAEs, treatment discontinuations, or dose reductions. Most common TRAEs ≥ 15% were nausea (29.4%), anemia (23.6%) and fatigue (23.5%). As of data cutoff, no DLTs were observed. All plasma PK analyses across dose levels showed dose dependent increase of AUC0-last and Cmax. No major metabolite was observed. POLR2A, which is a CDK7 target engagement marker showed biologically effective change starting from 18 mg/m2. 1 patient with pancreatic cancer who received 18 mg/m2 had a partial response with CA19-9 reduction from 4,632 to 219. 2 patients at 18 mg/m2 and 2 patients at 36 mg/m2 had stable disease. Additional safety and efficacy data will be presented. Conclusions: Preliminary data from QRNT-009 study showed that selective CDK7 inhibitor Q901 is well tolerated. Preliminary antitumor activity and pharmacodynamic observations are encouraging. Dose escalation is ongoing to identify MTD or recommended dose for further studies. Clinical trial information: NCT05394103 .
Nivolumab plus ipilimumab (N+I) in patients (pts) with solid tumors with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: Chan John K , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Cannon Timothy Lewis , Ahn Eugene R. , Swiecicki Paul , Hobbs Evthokia , Nazemzadeh Reza , Bell Maria C , Hosein Peter Joel , Meric-Bernstam Funda , Hinshaw Dominique C. , Gregory Abby , Grantham Gina N. , Halabi Susan , Schilsky Richard L.
Published: June 2024

3130

Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with HTMB treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. HTMB was defined a priorias ≥9 mutations/megabase (Muts/Mb) via a qualifying test for TAPUR or approved by the Molecular Tumor Board. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Low accruing histology-specific cohorts with HTMB were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 86% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 26 pts with 13 tumor types with HTMB were enrolled. Table shows demographics and outcomes. Tissue tumor mutational burden (TMB) ranged from 8 to 374 Muts/Mb (median= 16). 1 CR (small intestine; TMB= 48 Muts/Mb; DOR= 36 wks), 7 PR (biliary tract, site unspecified [3], soft tissue sarcoma, uterus, vagina; median TMB= 17 Muts/Mb; median DOR= 20 wks [range, 5-231]) and 1 SD16+ (pancreas; TMB= 26 Muts/Mb; duration of SD= 26 wks) were observed for a DC rate of 35% (1-sided 90% CI: 22 to 100) and OR rate of 31% (95% CI: 14 to 52). The null hypothesis was rejected (p=0.011). Notably, 1 pt (uterus, 374 Muts/Mb) is still on tx with an ongoing 66-wk PR as of Jan 2024. Most pts, including 8/9 with DC, were microsatellite stable. 10 pts had ≥1 grade 3 tx-related adverse event (AE) or serious AE. Conclusions: N+I showed antitumor activity in pts with advanced solid tumors with HTMB. Additional study is warranted to confirm the efficacy of N+I in pts with HTMB. Clinical trial information: NCT02693535 . [Table: see text]
Cold-inducible RNA-binding protein as a context-specific functional mediator of breast cancer metastasis.
Authors: Dankner Matthew , Ouellet Veronique , Lafon Jakob , Ezzeddine Rima , Annis Matthew G , Siegel Peter M ,   QBCF-TMA
Published: June 2024

3136

Background: Cold-inducible RNA-binding protein (CIRBP) is a stress-induced mRNA-binding protein associated with clinical outcomes in a variety of human disease states. CIRBP’s role as a prognostic biomarker in breast cancer (BC) has yet to be established. Methods: We describe a clinically annotated tissue micro-array cohort of 1406 hormone receptor positive (HR+) and 281 triple negative primary breast cancers (TNBC) stained by immunohistochemistry (IHC) for CIRBP. Statistical analyses were performed with the Kaplan-Meier estimator, as well as univariate and multivariate Cox proportional-hazards models. Multivariate models incorporated tumor size, lymph node status, grade and CIRBP expression levels. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS). MDA-MB-231 TNBC cells and MDA-MB-361 HR+ cells were used for CIRBP knockout (KO) by CRISPR/Cas9, and subsequent mammary fat pad injections were performed in immunocompromised mice. Results: In N=281 primary TNBCs, high levels of CIRBP expression by IHC was associated with poor prognosis in multivariate analysis (OS: adjusted hazard ratio (aHR) 2.05, 95% confidence interval (CI) 1.24-3.41, P=0.005. PFS: aHR 2.46, 95% CI 1.33-4.57, P=0.004). However, in N=1406 HR+ primary BC, CIRBP expression was correlated with favorable prognosis (OS: aHR 0.927, 95% CI 0.88-0.98, P=0.05. PFS: aHR 0.904, 95% CI 0.85-0.96, P=0.002). CIRBP KO had minimal impact on mammary fat pad primary tumor growth in both MDA-MB-231 and MDA-MB-361 cell models. However, CIRBP KO resulted in the inhibition of efficient spontaneous metastasis to the liver and lungs in TNBC MDA-MB-231 cells but not HR+ MDA-MB-361 cells. Conclusions: CIRBP expression is associated with poor prognosis in TNBC but not HR+ BC patients, a finding validated with CRISPR/Cas9 KO in representative model systems. This finding highlights the prognostic significance of CIRBP in TNBC and suggests differential underlying mRNA targets bound and modulated by CIRBP in TNBC and HR+ BC, respectively.