bluuebunny/crossref_metadata_2025 huggingface dataset:
Medicines and Healthcare products Regulatory Agency’s “Consultation on proposals for legislative changes for clinical trials”: a response from the Trials Methodology Research Partnership Adaptive Designs Working Group, with a focus on data sharing
Authors: Law Martin , Couturier Dominique-Laurent , Choodari-Oskooei Babak , Crout Phillip , Gamble Carrol , Jacko Peter , Pallmann Philip , Pilling Mark , Robertson David S. , Robling Michael , Sydes Matthew R. , Villar Sofía S. , Wason James , Wheeler Graham , Williamson S. Faye , Yap Christina , Jaki Thomas
Published: October 2023

In the UK, the Medicines and Healthcare products Regulatory Agency consulted on proposals “to improve and strengthen the UK clinical trials legislation to help us make the UK the best place to research and develop safe and innovative medicines”. The purpose of the consultation was to help finalise the proposals and contribute to the drafting of secondary legislation. We discussed these proposals as members of the Trials Methodology Research Partnership Adaptive Designs Working Group, which is jointly funded by the Medical Research Council and the National Institute for Health and Care Research. Two topics arose frequently in the discussion: the emphasis on legislation, and the absence of questions on data sharing. It is our opinion that the proposals rely heavily on legislation to change practice. However, clinical trials are heterogeneous, and as a result some trials will struggle to comply with all of the proposed legislation. Furthermore, adaptive design clinical trials are even more heterogeneous than their non-adaptive counterparts, and face more challenges. Consequently, it is possible that increased legislation could have a greater negative impact on adaptive designs than non-adaptive designs. Overall, we are sceptical that the introduction of legislation will achieve the desired outcomes, with some exceptions. Meanwhile the topic of data sharing — making anonymised individual-level clinical trial data available to other investigators for further use — is entirely absent from the proposals and the consultation in general. However, as an aspect of the wider concept of open science and reproducible research, data sharing is an increasingly important aspect of clinical trials. The benefits of data sharing include faster innovation, improved surveillance of drug safety and effectiveness and decreasing participant exposure to unnecessary risk. There are already a number of UK-focused documents that discuss and encourage data sharing, for example, the Concordat on Open Research Data and the Medical Research Council’s Data Sharing Policy. We strongly suggest that data sharing should be the norm rather than the exception, and hope that the forthcoming proposals on clinical trials invite discussion on this important topic.
Prednisolone Versus Colchicine for Acute Gout in Primary Care (COPAGO): protocol for a two-arm multicentre, pragmatic, prospective, randomized, double-blind, controlled clinical trial of prednisolone and colchicine for non-inferiority with a parallel group design
Authors: Truthmann Julia , Freyer Martins Pereira Julia , Richter Adrian , Schuster Franziska , Witte Amelie , Böhm Susanne , Greser Alexandra , Kamin Petra , Stracke Sylvia , Dörr Marcus , Bülow Robin , Engeli Stefan , Gágyor Ildikó , Hummers Eva , Chenot Jean-François
Published: October 2023

Background

Gout is the most common form of rheumatic disease in which monosodium urate crystals are deposited in the joints followed by acute inflammatory reactions. There are various approved drugs that can be prescribed for pain relief during an acute gout attack. However, to date, no direct comparison of efficacy of colchicine and prednisolone for the treatment of acute gout attacks has been investigated. Furthermore, the majority of previous research studies were not only conducted in tertiary centres but also excluded patients with common comorbidities due to contraindications to naproxen.

Methods

This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial investigates whether prednisolone (intervention) is non-inferior to treatment with colchicine (active control) in patients with acute gout. Adult patients presenting with acute gout to their general practitioners in 60 practices across 3 university sites (Greifswald, Göttingen, and Würzburg) are eligible to participate in the study. Participants in the intervention group receive 30 mg prednisolone for 5 days. Those in the control group receive low-dose colchicine (day 1: 1.5 mg; days 2–5: 1 mg). The primary outcome is the absolute level of the most severe pain on day 3 (in the last 24 h) measured with an 11-item numerical rating scale. Day 0 is the day patients take their study medication for the first time. They are then asked to fill out a study diary the same time each day for pain quantification. Pain scores are used for comparison between the two medications. Secondary outcomes are average response to treatment, swelling, tenderness and physical function of the joint, patients’ global assessment of treatment success, use of additional pain medication and non-pharmacological pain therapies. For safety reasons, potential side effects and course of systolic blood pressure are assessed.

Discussion

This trial will provide evidence on the effectiveness of pain reduction and side effects of colchicine and prednisolone in acute gout in primary care.

Trial registration

ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered). URL of trial registry record: https://clinicaltrials.gov/study/NCT05698680
Normalized economical speed is influenced by aging and not by exercise habituation
Authors: Horiuchi Masahiro , Saito Akira , Motoyama Kiyotaka , Tashiro Takehiro , Abe Daijiro
Published: October 2023

Objective

A U-shaped relationship between energy cost of walking (Cw) and walking speed indicates that there is a specific speed minimizing the Cw, called economical speed (ES). It is mostly slower in older adults than young adults; however, effects of leg length on the ES have been ignored. We investigated effects of aging and exercise habituation on the normalized ES by leg length (ESnormalized). We quantified time delay of stride length and step frequency in sedentary young (SY), active young (AY), and active elderly (AE) adults in response to sinusoidal gait speed change at 30-s and 180-s periods with an amplitude of ± 0.56 m･s− 1.

Results

The ES was significantly slower in the following sequence: AE, SY, and AY, whereas ESnormalized was slower in the AE than in other young groups, with no difference between AY and SY. AE and SY showed greater step variabilities at the 180-s period, whereas AY showed relatively smaller step variabilities at both periods. Collectively, the ESnormalized slowed due to aging, not due to exercise habituation. When optimizing the appropriate SL-SF combination for sinusoidal speed changes, young and elderly adults may adopt different strategies. Exercise habituation may reduce step variabilities in young adults.
A transgenic mice model of retinopathy of cblG-type inherited disorder of one-carbon metabolism highlights epigenome-wide alterations related to cone photoreceptor cells development and retinal metabolism
Authors: Matmat Karim , Conart Jean-Baptiste , Graindorge Paul-Henri , El Kouche Sandra , Hassan Ziad , Siblini Youssef , Umoret Rémy , Safar Ramia , Baspinar Okan , Robert Aurélie , Alberto Jean-Marc , Oussalah Abderrahim , Coelho David , Guéant Jean-Louis , Guéant-Rodriguez Rosa-Maria
Published: October 2023

Background

MTRgene encodes the cytoplasmic enzyme methionine synthase, which plays a pivotal role in the methionine cycle of one-carbon metabolism. This cycle holds a significant importance in generating S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the respective universal methyl donor and end-product of epigenetic transmethylation reactions.cblGtype of inherited disorders of vitamin B12 metabolism due to mutations inMTRgene exhibits a wide spectrum of symptoms, including a retinopathy unresponsive to conventional therapies.

Methods

To unveil the underlying epigenetic pathological mechanisms, we conducted a comprehensive study of epigenomic-wide alterations of DNA methylation by NGS of bisulfited retinal DNA in an original murine model with conditionalMtrdeletion in retinal tissue. Our focus was on postnatal day 21, a critical developmental juncture for ocular structure refinement and functional maturation.

Results

We observed delayed eye opening and impaired visual acuity and alterations in the one-carbon metabolomic profile, with a notable dramatic decline in SAM/SAH ratio predicted to impair DNA methylation. This metabolic disruption led to epigenome-wide changes in genes involved in eye development, synaptic plasticity, and retinoid metabolism, including promoter hypermethylation ofRarα, a regulator ofLratexpression. Consistently, we observed a decline in cone photoreceptor cells and reduced expression ofLrat,Rpe65,andRdh5, three pivotal genes of eye retinoid metabolism.

Conclusion

We introduced an original in vivo model for studyingcblGretinopathy, which highlighted the pivotal role of altered DNA methylation in eye development, cone differentiation, and retinoid metabolism. This model can be used for preclinical studies of novel therapeutic targets.
A mutant methionyl-tRNA synthetase-based toolkit to assess induced-mesenchymal stromal cell secretome in mixed-culture disease models
Authors: Burgess Jeremy D. , Amerna Danilyn , Norton Emily S. , Parsons Tammee M. , Perkerson Ralph B. , Faroqi Ayman H. , Wszolek Zbigniew K. , Guerrero Cazares Hugo , Kanekiyo Takahisa , Delenclos Marion , McLean Pamela J.
Published: October 2023

Background

Mesenchymal stromal cells (MSCs) have a dynamic secretome that plays a critical role in tissue repair and regeneration. However, studying the MSC secretome in mixed-culture disease models remains challenging. This study aimed to develop a mutant methionyl-tRNA synthetase-based toolkit (MetRSL274G) to selectively profile secreted proteins from MSCs in mixed-culture systems and demonstrate its potential for investigating MSC responses to pathological stimulation.

Methods

We used CRISPR/Cas9 homology-directed repair to stably integrate MetRSL274G into cells, enabling the incorporation of the non-canonical amino acid, azidonorleucine (ANL), and facilitating selective protein isolation using click chemistry. MetRSL274G was integrated into both in H4 cells and induced pluripotent stem cells (iPSCs) for a series of proof-of-concept studies. Following iPSC differentiation into induced-MSCs, we validated their identity and co-cultured MetRSL274G-expressing iMSCs with naïve or lipopolysaccharide (LPS)-treated THP-1 cells. We then profiled the iMSC secretome using antibody arrays.

Results

Our results showed successful integration of MetRSL274G into targeted cells, allowing specific isolation of proteins from mixed-culture environments. We also demonstrated that the secretome of MetRSL274G-expressing iMSCs can be differentiated from that of THP-1 cells in co-culture and is altered when co-cultured with LPS-treated THP-1 cells compared to naïve THP-1 cells.

Conclusions

The MetRSL274G-based toolkit we have generated enables selective profiling of the MSC secretome in mixed-culture disease models. This approach has broad applications for examining not only MSC responses to models of pathological conditions, but any other cell type that can be differentiated from iPSCs. This can potentially reveal novel MSC-mediated repair mechanisms and advancing our understanding of tissue regeneration processes.
Stem cell therapy for inherited retinal diseases: a systematic review and meta-analysis
Authors: Chen Xiaodong , Xu Ningda , Li Jiarui , Zhao Mingwei , Huang Lvzhen
Published: October 2023

Purpose

Stem cell therapy is a promising therapeutic approach for inherited retinal diseases (IRDs). This study aims to quantitatively examine the effectiveness and safety of stem cell therapy for patients with IRDs, including retinitis pigmentosa and Stargardt disease (STGD).

Methods

We searched PubMed, EMBASE, Web of Science, Cochrane Library databases, and the ClinicalTrials.gov website. The latest retrieval time was August 20, 2023. The primary outcomes were rates and mean difference (MD) of best-corrected visual acuity (BCVA) improvement. Subgroup analyses were conducted according to administration routes and stem cell types. This study was registered with PROSPERO (CRD42022349271).

Results

Twenty-one prospective studies, involving 496 eyes (404 RP and 92 STGD) of 382 patients (306 RP and 76 STGD), were included in this study. For RP, the rate of BCVA improvement was 49% and 30% at 6 months and 12 months, respectively, and the BCVA was significantly improved in the operative eyes at 6 months post-treatment (MD = − 0.12 logMAR, 95% CI .17 to − 0.06 logMAR; P < 0.001), while there was no significant difference at 12 months post-treatment (MD = -0.06 logMAR; 95% CI − 0.13 to 0.01 logMAR; P = 0.10). For STGD, the rate of BCVA improvement was 60% and 55% at 6 months and 12 months, respectively, and the BCVA was significantly improved in the operative eyes at 6 months (MD = − 0.14 logMAR, 95% CI − 0.22 to − 0.07 logMAR; P = 0.0002) and 12 months (MD = − 0.17 logMAR, 95% CI − 0.29 to − 0.04 logMAR; P = 0.01). Subgroup analyses showed suprachoroidal space injection of stem cells may be more efficient for RP. Eleven treated-related ocular adverse events from three studies and no related systemic adverse events were reported.

Conclusions

This study suggests stem cell therapy may be effective and safe for patients with RP or STGD. The long-term vision improvement may be limited for RP patients. Suprachoroidal space injection of stem cells may be a promising administration route for RP patients. Limited by the low grade of evidence, large sample size randomized clinical trials are required in the future.
Validity of the total SOFA score in patients ≥ 80 years old acutely admitted to intensive care units: a post-hoc analysis of the VIP2 prospective, international cohort study
Authors: Polok Kamil , Fronczek Jakub , Putowski Zbigniew , Czok Marcelina , Guidet Bertrand , Jung Christian , de Lange Dylan , Leaver Susannah , Moreno Rui , Flatten Hans , Szczeklik Wojciech
Published: October 2023

Background

Little is known about the performance of the Sequential Organ Failure Assessment (SOFA) score in older critically ill adults. We aimed to evaluate the prognostic impact of physiological disturbances in the six organ systems included in the SOFA score.

Methods

We analysed previously collected data from a prospective cohort study conducted between 2018 and 2019 in 22 countries. Consecutive patients ≥ 80 years old acutely admitted to intensive care units (ICUs) were eligible for inclusion. Patients were followed up for 30 days after admission to the ICU. We used logistic regression to study the association between increasing severity of organ dysfunction and mortality.

Results

The median SOFA score among 3882 analysed patients was equal to 6 (IQR: 4–9). Mortality was equal to 26.1% (95% CI 24.7–27.5%) in the ICU and 38.7% (95% CI 37.1–40.2%) at day 30. Organ failure defined as a SOFA score ≥ 3 was associated with variable adjusted odds ratios (aORs) for ICU mortality dependant on the organ system affected: respiratory, 1.53 (95% CI 1.29–1.81); cardiovascular 1.69 (95% CI 1.43–2.01); hepatic, 1.74 (95% CI 0.97–3.15); renal, 1.87 (95% CI 1.48–2.35); central nervous system, 2.79 (95% CI 2.34–3.33); coagulation, 2.72 (95% CI 1.66–4.48). Modelling consecutive levels of organ dysfunction resulted in aORs equal to 0.57 (95% CI 0.33–1.00) when patients scored 2 points in the cardiovascular system and 1.01 (0.79–1.30) when the cardiovascular SOFA equalled 3.

Conclusions

Different components of the SOFA score have different prognostic implications for older critically ill adults. The cardiovascular component of the SOFA score requires revision.
Comparative efficacy of nine exercise methods on the prognosis in chronic kidney disease patients with hemodialysis: a systematic review and network meta-analysis
Authors: Ren Ning , Yang Huiting , Cai Zelin , Wang Ruye , Wang Zeng , Zhao Ying , Miao Chenyun , Chen Yun , Zhang Yang , Zhu Xingyu , Chen Hongyu , Zhang Qin
Published: October 2023

Background

Several kinds of physical activities have been applied to improve the prognosis of patients with hemodialysis (HD). However, the comparative efficacy of physical activities on the outcomes in HD patients is still unknown. This study explored the effectiveness and safety of all exercise types in HD patients.

Methods

We searched randomized clinical trials from the PubMed, EMBASE, and Cochrane Library databases. Physical exercises interventions included resistance exercise (RE), aerobic exercise (AE), electrical muscle stimulation (EMS), range of motion (ROM), resistance exercise + aerobic exercise (RE + AE), stretching exercise (STE), respiratory muscle training (RMT), peripheral muscle training (PMT), walking exercise (WE), or usual care/sham exercise (UC/SE). Primary outcomes were six-minute walk test (6-mwt) and quality of life (QOL). Secondary outcomes were Kt/V, VO2max, hemoglobin (Hb), C-reactive protein (CRP), interleukin-6 (IL-6), and systolic and diastolic blood pressure (sbp and dbp). Frequentist network meta-analysis with multivariate random effects models provided mean with 95% confidence intervals (95%CI).

Results

A total of 58 eligible studies were included. AE, RMT, and RE + AE significantly improved 6-mwt compared with UC/SE. SE was the worst intervention and reduced QOL much more than the UC/SE and other exercise types. AE and RE + AE were associated with higher VO2max, while ROM and RE + AE induced higher Hb levels. All physical activities did not elevate blood pressure, CRP and IL-6. Only ROM decreased sbp/dbp. CRP is significantly lower in RE.

Conclusion

Physical activities play a crucial role in the different outcomes of HD patients. They can be applied to specific area for their specific efficacy.
An open-label pilot trial assessing tolerability and feasibility of LSD microdosing in patients with major depressive disorder (LSDDEP1)
Authors: Donegan Carina Joy , Daldegan-Bueno Dimitri , Sumner Rachael , Menkes David , Evans William , Hoeh Nicholas , Sundram Frederick , Reynolds Lisa , Ponton Rhys , Cavadino Alana , Smith Todd , Roop Partha , Allen Nathan , Abeysinghe Binu , Svirskis Darren , Forsyth Anna , Bansal Mahima , Muthukumaraswamy Suresh
Published: October 2023

Background

Globally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2).

Methods

Twenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5–15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen.

Discussion

The results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial.

Trial registration

ANZCTR, ACTRN12623000486628. Registered on 12 May 2023.
The Fifth Bioelectronic Medicine Summit: today’s tools, tomorrow’s therapies
Authors: Chang Eric H. , Gabalski Arielle H. , Huerta Tomas S. , Datta-Chaudhuri Timir , Zanos Theodoros P. , Zanos Stavros , Grill Warren M. , Tracey Kevin J. , Al-Abed Yousef
Published: October 2023

The emerging field of bioelectronic medicine (BEM) is poised to make a significant impact on the treatment of several neurological and inflammatory disorders. With several BEM therapies being recently approved for clinical use and others in late-phase clinical trials, the 2022 BEM summit was a timely scientific meeting convening a wide range of experts to discuss the latest developments in the field. The BEM Summit was held over two days in New York with more than thirty-five invited speakers and panelists comprised of researchers and experts from both academia and industry. The goal of the meeting was to bring international leaders together to discuss advances and cultivate collaborations in this emerging field that incorporates aspects of neuroscience, physiology, molecular medicine, engineering, and technology. This Meeting Report recaps the latest findings discussed at the Meeting and summarizes the main developments in this rapidly advancing interdisciplinary field. Our hope is that this Meeting Report will encourage researchers from academia and industry to push the field forward and generate new multidisciplinary collaborations that will form the basis of new discoveries that we can discuss at the next BEM Summit.
Higher incidence of co-expression of BCR-ABL fusion transcripts in an Eastern Indian population
Authors: Kumar Ajeet , Mishra Vatsal , Singh Chandra Bhan , Patel Rashmi , Samrat Siddharth , Rai Madhukar , Kumar Nilesh , Tilak Vijay , Gupta Vineeta , Ali Akhtar
Published: October 2023

Background

Chronic myeloid leukaemia (CML) is a haematopoietic stem cell disorder, caused by a balanced reciprocal translocation (t(9;22) (q34;q11)) that leads to the formation of BCR (Breakpoint Cluster Region)-ABL (Abelson) fusion transcripts known as Philadelphia (Ph) chromosome. The prevalence of BCR-ABL fusion transcripts in Indian CML population is poorly understood, and few studies have been reported from India. The aim of the present study was to determine the frequencies as well as prognostic effects of the three fusion transcripts, i.e. b2a2, b3a2 and e1a2 in an Indian population.

Methods

RNA was isolated from total 123 samples, 27 bone marrow (BM) samples and 96 peripheral blood (PB) samples, of CML patient followed by cDNA synthesis. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed using TaqMan® assay (ABI, CA, USA) to monitor BCR-ABL transcript.

Results

Ph' chromosome was observed in 103 patients whereas it was not detected in 20 cases. qRT-PCR revealed that the b3a2 fusion transcripts were the most common transcript in CML patients (63.41%) while b2a2 fusion transcript was present in 16.26% cases. Co-expression of b3a2 + b2a2 fusion transcript was observed in 0.81% cases whereas co-expression of b3a2 + e1a2 fusion transcript was found in 1.63% cases. There was no correlation observed between b3a2 fusion transcript and platelet count. The fusion transcript b2a2 was observed in relatively younger patients compared to b3a2 fusion transcript. Although this correlation was not statistically significant.

Conclusion

The co-expression of BCR-ABL fusion transcripts was higher (63.41% aggregate of b3a2) in the present population in contrast with other populations reported. This finding was consistent with the frequency data reported from Sudan.
Applying after-action reviews to child and family teams to improve mental health service linkage within child welfare services: a study protocol
Authors: Sklar Marisa , Kenneally Ryan , Aarons Gregory A. , Fettes Danielle L.
Published: October 2023

Background

Half of child-welfare-involved children and adolescents meet the criteria for at least one mental health diagnosis. This project proposes to improve successful mental health service linkage in child welfare services (CWS) by adapting and testing the after-action review (AAR) team effectiveness intervention to augment the child and family team (CFT) services’ intervention. Despite being both required and a collaborative approach to service planning, CFT meetings are implemented with questionable fidelity and consistency, rarely including the voice of children and families as intended.

Methods

Using a parallel group trial design, with non-equivalent comparison groups, and qualitative and quantitative methodology, this study will tailor and assess the impact of the AAR on enhancing CFT outcomes. The authors will conduct a qualitative needs assessment targeting the ongoing implementation of the CFT services intervention in a large, publicly funded, CWS system. A qualitative inquiry consisting of interviews and focus groups with key stakeholders will result in the preparation of an action plan to address identified gaps between the current and desired CFT services intervention outcomes. The AAR implementation strategy will be adapted and tailored to address the CFT services’ intervention needs. To test the effectiveness of the AAR on improving outcomes associated with the CFT services intervention, we will utilize blocked randomization of four CWS caseworkers from two CWS system regions to either the intervention condition (CFT + AAR) or standard implementation (CFT as usual). The authors will collect data from the CWS caseworkers and additional CFT members via web-based surveys. Mechanisms of the AAR team effectiveness intervention for CFT implementation will be assessed.

Discussion

By inclusion of child and family voice, the AAR-enhanced CFT should lead to increased fidelity to the CFT intervention and greater levels of parental satisfaction with the service and shared decision-making, thus resulting in enhanced follow-through with service plans and linkage to mental health treatment services for children. The knowledge gained by this randomized clinical trial has the potential to benefit service delivery and integration for CWS leaders, caseworkers, formal and informal CFT member support persons, parents/caregivers, and children with open cases. Improving intervention effectiveness, both at the system and family levels, is crucial for practice efficiencies and improved child and family outcomes.

Trial registration

NCT05629013. Approval date: November 28, 2022 (version 1).

Trial sponsor

University of California, San Diego.

Responsible party

Danielle Fettes.
Nonlinear plasmonics: second-harmonic generation and multiphoton photoluminescence
Authors: Wang Jiyong , Zhang Lei , Qiu Min
Published: October 2023

The study on the nonlinear optical responses arising from plasmonic nanoantennas, known as nonlinear plasmonics, has been massively investigated in recent years. Among the most basic nonlinear optical responses, second-harmonic generation (SHG) and multiphoton photoluminescence (MPL), two-photon photoluminescence in particular, has aroused extensive interests, due to their distinct properties of being ultrasensitive to the spatial symmetry and ultrafast response time of hot electrons. In this review, we give insights into fundamental roles dominating the radiations of such nonlinear optical processes and their recent research advances. Different from other reviews on nonlinear plasmonics, which mainly focused on parametric processes, this review pays equal attentions to the incoherent process of MPL. An in-depth description on the excitation and emission processes of MPL in accordance with recent studies is fully presented. By using the high ‘symmetry rule’ of SHG and ultrafast response time of MPL, advanced applications in surface enhanced spectroscopy, ultra-sensitive photodetector, biosensor and ultrafast laser pulses are highlighted in the end.
Using an Adapted Tumor Board Evaluation Tool for Quality Assessment of a Thoracic Multidisciplinary Cancer Conference: A Pilot Study
Authors: Marrara Bianca , Ibekwe Opuruiche , Masika Martin , Attwood Kristopher , Gaudioso Carmelo , Nwogu Chukwumere
Published: October 2023

PURPOSE

Multidisciplinary cancer conferences (MCCs) are crucial for the management of complex oncology patients. Tools to evaluate MCC performance are needed. The aim of this pilot study was to assess the applicability of an existing validated performance assessment tool to evaluate the quality of thoracic MCCs (T-MCCs).

METHODS

Data were collected from weekly T-MCCs over a 5-week period using the MCC Performance Assessment Tool and a self-assessment survey. Audio recordings were used to supplement observation notes. Case presentation, discussion duration, decision making contribution, recommendations, and consensus were captured. Quality of information and contribution were rated on a 1-5 scale. The data were analyzed using descriptive statistics to calculate means and composite scores representing overall MCC performance.

RESULTS

A total of 44 cases were observed at the T-MCC with the mean presentation and discussion time of 6 minutes and 22 seconds. Quality of case history, radiologic and pathological information, and reason for case discussion were rated above average (>3), whereas inclusion of comorbidities and patient views were rated below average. Surgical oncologists had a higher discussion contribution compared with medical and radiation oncologists (3.6 v 2.9 and 2.4, respectively). The overall mean composite score was 55.9 (deemed average) with no cases categorized as poor or excellent. Radiologists and pathologists had mean preparation times of 81.7 and 144.0 minutes, respectively.

CONCLUSION

This study demonstrated the applicability of a previously validated tool to assess the quality of a T-MCC at an academic comprehensive cancer center. The tool was found to be useful in identifying elements of the T-MCC process that needed improvement.
Noninvasive Indices of MASLD Are Associated With Hypogonadism in Male Patients With Type 2 Diabetes Mellitus
Authors: Caretta Nicola , Scafa Raffaele , Graziani Andrea , Crepaldi Maria Cristina , Vedovato Monica , Avogaro Angelo , Ferlin Alberto
Published: October 2023

Context

Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease, affecting one-fourth of the adult population worldwide. Recent data found an association between MASLD and hypogonadism, but this relation in patients with type 2 diabetes mellitus (T2DM) is still unclear.

Objective

To evaluate in men with T2DM the association between total testosterone (TT) and noninvasive indices of hepatic steatosis (Fatty Liver Index [FLI], Hepatic Steatosis Index [HSI], Dallas Steatosis Index [DSI]) and fibrosis (AST to Platelet Ratio Index [APRI], Fibrosis-4 Index [FIB-4]), and their predictive cutoff values in identifying hypogonadism.

Methods

Cross-sectional study on 189 men with T2DM, without history of liver diseases and alcoholism, recruited on an outpatient basis. Interventions were andrological evaluation, metabolic parameters, TT, and liver indices. The main outcome measures were comparison of steatosis and fibrosis indices with testosterone levels and presence of hypogonadism. Receiver operating characteristic curves were used to identify cutoff values of liver indices in predicting low testosterone (<12 nmol/L).

Results

FLI, HSI, and DSI were negatively related with TT and were higher in the low-testosterone group than in the normal-testosterone group (FLI: 74.1 [61.4-93.5] vs 56.5 [32.1-78.2], P < .001; HSI: 41.5 [39.2-45.9] vs 40.1 [36.6-43.2], P = .005; DSI: 0.45 [−0.08-+1.04] vs −0.07 [−1.02-+0.58], P < .001). FLI and DSI also correlated with clinical symptoms of hypogonadism. No differences between groups were observed for APRI and FIB-4. FLI ≥63 was the best parameter as predictive index of low TT (sensitivity 73%, specificity 64%).

Conclusion

We found an association between noninvasive indices of steatosis and hypogonadism in patients with T2DM. These indices could be used to direct the patients to andrological evaluation.
FRI012 Exploring The Role Of FFA2 In Western Diet-induced Obesity And Metabolic Changes
Authors: Nnyamah Christine , Wicksteed Barton , Layden Brian T
Published: October 2023

Disclosure: C. Nnyamah: None. B. Wicksteed: None. B.T. Layden: None.

The obesity pandemic is a major health concern driving Type 2 Diabetes (T2D) and cardiovascular disease (CVD). One novel pathogenetic factor of obesity is the gut microbiome (GM), that is the microbes that reside in the digestive tract. Changes in the GM have profound effects on obesity. These symbiotic microbes break down dietary fiber that are otherwise indigestible, releasing nutrients (in particular, short chain fatty acids, SCFAs). Free Fatty Acid Receptor 2 (FFA2) is a G-protein coupled receptor (GPCR) that senses SCFAs and has been shown to influence the function of various organs responsible for nutrient-sensing and energy balance. Among other roles, FFA2 has been suggested to modulate the secretion of the appetite-regulating proteins GLP-1 and PYY from intestinal enteroendocrine cells and secretion of insulin (the master fuel-supply hormone) from the pancreatic beta cells. However, its role in adipose tissue is less clear. While highly expressed in adipose tissue, research using global knockouts (KOs) of FFA2 in mouse models has observed conflicting phenotypic results. Here, we use novel adipose-specific FFA2 KO (AdFFA2-KO) mice to explore adipose-determined outcomes when mice are fed obesogenic challenge diets with or without fiber-induced production of SCFAs for receptor activation. After confirming that Adiponectin-Cre x FFA2 fl/fl mice have no congenital defects and are metabolically similar to FFA2 fl/fl control mice on a normal chow diet, mice were placed on either a high fat, high sugar Western Diet (WD) or on WD supplemented with 10% fructooligosaccharides – a fermentable dietary fiber. On WD, AdFFA2-KO mice had significantly decreased glucose tolerance compared to floxed controls with no other clearly observable effects on basic metabolic parameters. Interestingly, upon receptor activation with a fiber-supplemented diet, AdFFA2-KO mice were moderately protected from WD-induced weight gain. Our ongoing research aims to detangle the observed phenotypic differences and demystify the FFA2-adipose signaling cascade using a multifaceted approach including in vivo assessment of food intake and energy expenditure, ex vivo evaluation of lipolysis and fatty-acid uptake with FFA2 agonists and antagonists, as well as RTqPCR probing of adipose-derived cytokines (adipokines) with known roles in the weight gain-weight loss cycle.

Presentation: Friday, June 16, 2023
FRI020 Adipocyte Subpopulations Regulate Growth Hormone-induced Lipolysis And Insulin Resistance
Authors: Siyar Sohana , Huang Jun , Sharma Rita , Kopchick John Joseph , Puri Vishwajeet , Lee Kevin Y
Published: October 2023

Disclosure: S. Siyar: None. J. Huang: None. R. Sharma: None. J.J. Kopchick: None. V. Puri: None. K.Y. Lee: None.

Growth Hormone (GH) administration has long been known to increase lipolysis in adipose tissue leading to increased circulating free fatty acid levels and insulin resistance. Previous studies from our lab have found that this effect is mediated, at least in part, through transcriptional repression of the lipid droplet associated protein Fat specific protein (FSP27 also known as CIDEC). Furthermore, recent studies suggest that within a single adipose tissue depot there are different subpopulations of adipocytes. We have identified three distinct subpopulations of adipocytes with unique gene expression profiles and metabolic activities. We have found that one of these subpopulations of adipocytes, termed Type 2 adipocytes, are highly responsive to GH stimulation. In order to assess the physiological role of GH-mediated lipolysis mediated by this subpopulation, we specifically expressed human FSP27 (hFSP27) in Type 2 adipocytes (Type2Ad-hFSP27tg mice). Type2AdhFSP27tg mice had reduced systemic plasma glycerol release after acute GH treatment, and improvement in acute, but not chronic, GH-induced glucose intolerance. These mice exhibited an 45% increase in fat mass and significant increase in adipocyte cell size further indicating a decreased lipolytic response to GH. This decreased lipolytic response was associated with improved hepatic insulin signaling and insulin-induced gene expression in Type2Ad-hFSP27tg mice. Taken together, these results indicate that specifically targeting a subpopulation of adipocytes is sufficient to reduce GH-induced lipolysis and insulin resistance and may provide a platform for improved medical therapies for growth and endocrine disorders.

Presentation: Friday, June 16, 2023
FRI023 Increased Fibrosis In White Adipose Tissue Of Male And Female bGH Transgenic Mice Appears Independent Of TGF-β Action
Authors: Lach Grace , Bell Stephen , Young Jonathan A , List Edward O , Basu Reetobrata , Geitgey Delaney , Lee Kevin Y , Swegan Deborah , Caggiano Lydia J , Okada Shigeru , Kopchick John J , Berryman Darlene E
Published: October 2023

Disclosure: G. Lach: None. S. Bell: None. J.A. Young: None. E.O. List: None. R. Basu: None. D. Geitgey: None. K.Y. Lee: None. D. Swegan: None. L.J. Caggiano: None. S. Okada: None. J.J. Kopchick: None. D.E. Berryman: None.

Fibrosis is a pathological state caused by excess deposition of extracellular matrix proteins, which can disrupt tissue structure and function. Previous work has shown that male bovine growth hormone (bGH) transgenic mice have high levels of circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1), marked decrease in lifespan, and increased fibrosis in several tissues including white adipose tissue (WAT), which is more pronounced in the subcutaneous (Sc) depot. The current study expanded on these findings, evaluating: 1) WAT fibrosis in female bGH mice, 2) levels of circulating factors implicated in fibrosis, and 3) the role of TGF-β, a central mediator of fibrogenesis, in the development of bGH WAT fibrosis. Our findings confirmed that female bGH mice exhibit increased WAT fibrosis, most prominent in the Sc depot, like male bGH mice, but also significantly increased in the perigonadal depot, unlike male bGH mice. bGH mice of both sexes have elevated circulating levels of several markers of collagen turnover (plasma P1NP, P3NP and ICTP) and FGF21 relative to controls but no genotype-dependent alteration in fibroblast activation protein (FAP). TGF-β and TGF-β signaling in serum or WAT was either unchanged or reduced in male and female bGH mice at both young and mature ages. The treatment of bGH mice with a TGF-β antagonist, pirfenidone, did not attenuate bGH WAT fibrosis. Contrary to the effects of the chronic exposure to excess GH, acute GH treatments in vivo or in vitro did elicit a modest increase in TGF-β signaling. Finally, single nucleus RNA sequencing confirmed no perturbation in TGF-β or its receptor gene expression in any WAT cell population within subcutaneous bGH WAT; however, a striking increase in B lymphocyte infiltration in Sc bGH WAT was observed. Overall, these data suggest that bGH WAT fibrosis is independent of the action of TGF-β and reveals an intriguing shift in immune cells, particularly B cells, in bGH WAT that should be further explored considering the increasing importance of B cell-mediated WAT fibrosis and aging. Acknowledgements:This work was sponsored, in part, by ASPIRE grant funding from Pfizer. This work was also supported by the State of Ohio’s Eminent Scholar Program to J. J. K. that includes a gift from Milton and Lawrence Goll and by the startup funds from the Heritage College of Osteopathic Medicine at Ohio University, Athens, OH.

Presentation: Friday, June 16, 2023
FRI070 The Urinary Extracellular Vesicles Small RNA Profile Of Obesity Displays Distinct Patterns By RNA Subclass
Authors: Choi Dughyun , Kim Sewon , Kwon Soon Hyo
Published: October 2023

Disclosure: D. Choi: None. S. Kim: None. S. Kwon: None.

Introduction: Urinary extracellular vesicles (EVs) small RNAs are thought to function as potential biomarkers for various physiological states and various diseases. Since urine contains a relatively small amount of microRNA compared to other biofluids, analyzing the distinct pattern of each subclass of small RNAs may provide additional information about gene expression. We attempted to analyze urinary EVs small RNAs by subclass in obesity before and after weight loss. Methods: Urinary extracellular vesicles small RNA sequencing was performed on 6 obese patients before and after their weight loss, which was achieved through bariatric surgery, and the results were compared with those of 6 healthy volunteers. Each distinct subclass of urinary small EVs RNAs was analyzed using a multi-dimensional scaling (MDS) plot. Results: RNA sequencing revealed total number of 5205 urinary EVs small RNAs. In the MDS plot comparing distinct subclass of urinary EVs small RNAs, there were different patterns observed between obesity and healthy volunteers, however, no significant patterns were found between obesity before and after weight loss. More distinct difference patterns between obesity and healthy volunteers were observed in miRNA, tRNA, snoRNA, and snRNA subclasses of urinary EVs small RNAs, whereas piRNA and YRNA subclasses showed indistinct difference patterns (Figure).

Presentation: Friday, June 16, 2023
FRI071 Changes In Branched-chain Amino Acids One-year After Sleeve Gastrectomy In Youth With Obesity And Its Association With Changes In Insulin Resistance
Authors: Becetti Imen , Lauze Meghan , Lee Hang , Bredella Miriam , Misra Madhusmita , Singhal Vibha
Published: October 2023

Disclosure: I. Becetti: None. M. Lauze: None. H. Lee: None. M. Bredella: None. M. Misra: None. V. Singhal: None.

Introduction: Branched-chain amino acids (BCAAs), isoleucine, leucine and valine, have been linked to obesity, insulin resistance (IR) and risk for type 2 diabetes. Adults with obesity have a reduction in BCAA levels following metabolic and bariatric surgery (MBS), which may contribute to the modulation of metabolic advantages of MBS. We examine for the first time this relationship in youth with moderate-to-severe obesity who underwent sleeve gastrectomy (SG). Objective: To examine changes in dietary intake and serum BCAAs in youth with obesity one-year after SG, and their associations with changes in markers of IR. Methods: 53 youth 13-25 years old with severe obesity (41 females) were followed for a year; 25 had SG and 28 were non-surgical controls (NS). Subjects had fasting glucose and insulin levels and a 24-hour food recall. We assessed baseline and 12-month change within (Wilcoxon signed-rank test) and between (Student’s t-test/Wilcoxon Rank Sum test) groups, and associations between BCAAs and markers of IR (Spearman’s correlation). Results: SG and NS groups were similar for age, sex and race. SG had higher median body mass index (BMI) vs. NS at baseline [45.3 (42.1, 53.7) vs. 41.9 (38.4, 47.1) kg/m2; p=0.02]. At baseline, SG and NS did not differ for intake or serum levels of isoleucine, leucine, valine or total BCAAs. SG and NS groups also did not differ at baseline for glycated hemoglobin (HbA1C) or Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, marker of IR). Over a year, SG vs. NS had greater reductions in BMI, serum isoleucine, leucine, valine and BCAAs (p≤0.02), and SG had significant within group reductions in intake of isoleucine, leucine, valine and BCAAs (p≤0.048). Further, SG vs. NS groups had greater reductions in HbA1c and HOMA-IR (p≤0.007). Serum BCAA levels were not associated with their dietary intake. Baseline HOMA-IR was positively associated with baseline serum levels of leucine (ρ=0.56, p=0.01). Over one year, decreases in HOMA-IR and HbA1c were positively associated with decreases in serum valine (ρ=0.60 and ρ=0.63, p=0.01 and p=0.007, respectively). Associations between changes in HOMA-IR and serum valine held after controlling for BMI (baseline and change) and dietary intake of valine. Conclusion: We demonstrate decreases in BCAA intake and serum levels one-year post-SG in youth with obesity. Associations between BCAAs and IR markers, even after controlling for BMI, suggest a potential role of BCAA in regulating metabolic health. Reducing serum levels of BCAAs may reduce IR.

Presentation: Friday, June 16, 2023
FRI105 Getting Fam-iliar With Familial Chylomicronemia Syndrome: A Case Report
Authors: Jimenez Aaron-Ross , Azul Jamesson
Published: October 2023

Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive lipid disorder of chylomicron metabolism causing severe hypertriglyceridemia that affects ∼1/1,000,000 individuals. Case Presentation: A 36-year-old male with a history of severely elevated triglyceride levels, recurrent pancreatitis, and biopsy-proven focal segmental glomerulosclerosis presented with severely elevated triglycerides. His initial acute pancreatitis episode was at 30 years old and attributed to alcohol intake. Triglyceride levels were not obtained at the time. He abstained from alcohol; however, his follow up triglyceride level was elevated (5,005 mg/dL, n=35-160 mg/dL) which normalized on an insulin infusion. He started fenofibrate and fish oil. After several additional hospital admissions for either pancreatitis or asymptomatic hypertriglyceridemia with a peak triglyceride level of 14,385 mg/dL, he committed to a low fat and vegan diet. Generic fish oil was transitioned to icosapent ethyl, and he was additionally started on niacin and atorvastatin. Even after following a strict diet and medication adherence, he continued having multiple admissions for acute pancreatitis, most recently complicated by dialysis dependent acute kidney injury in the setting of necrotizing pancreatitis. He has no known history of hypertriglyceridemia in his family. Due to persistent and severe hypertriglyceridemia despite conventional treatment, we suspected an underlying genetic cause, such as FCS. FCS should be suspected in those with recurrent pancreatitis, lipemia retinalis, and/or milky colored blood specimens. Eruptive xanthomas may also be present. Our patient did not have evidence of eruptive xanthomas on physical examination, but ophthalmology evaluation did show lipemia retinalis. The most common genetic pathologic variant in FCS is in the lipoprotein lipase-1 gene (LPL) that codes for an enzyme which assists in the lipolysis of plasma triglycerides (TG) in chylomicrons. Other common genes associated with severe hypertriglyceridemia are APOC2, APOAV, LMF-1, and GPIHBP-1. The mainstay of treatment for FCS are medications to reduce triglyceride levels and a significantly low-fat diet below 25 grams daily. Medium chain triglycerides can be utilized as they do not require enzymes to break down. Otherwise, there are currently no FDA-available therapies specifically targeted for use in those with FCS. Conclusions: This case demonstrates the unfortunate outcome of familial chylomicronemia syndrome despite concerted efforts to reduce triglyceride levels and eliminate additional risk factors.

Presentation: Friday, June 16, 2023