bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and psychometric evaluation of the sexual satisfaction questionnaire for postmenopausal women (PWSSQ): an exploratory mixed method study protocol
Authors: Shahrahmani Nasim , Babazadeh Raheleh , Ebadi Abbas
Published: July 2024

Background

The concept of sexual satisfaction in menopausal women is very different from that in premenopausal women, and this difference is due to aging and physical, hormonal, cultural, and psychological changes. Therefore, the first step in discovering methods for assessing sexual satisfaction in postmenopausal women is to develop a measurement instrument. This study was conducted to develop and evaluate the psychometric properties of a sexual satisfaction instrument for postmenopausal women.

Methods

The current study is an exploratory-sequential mixed-methods research project that will be divided into two parts: qualitative and quantitative. Aligned with the primary objective of the research, which is to elucidate the concept of sexual satisfaction in postmenopausal women, the hybrid concept analysis model developed by Schwartz and Kim will be employed. This model comprises three key phases: the theoretical phase, the fieldwork phase, and the final analytical phase. Those who met the inclusion criteria and exhibited maximum variance in terms of age, educational level, employment status, and menopausal duration were recruited. The conventional content analysis will be carried out following the steps proposed by Graneheim and Lundman. Second, in the quantitative phase, the psychometric properties of the instrument were evaluated, including the content, face and construct validity and reliability via internal consistency and stability. The psychometric properties described in the COSMIN checklist will be utilized for designing the instrument.

Discussion

A valid and reliable scale for evaluating the sexual satisfaction of postmenopausal women should be developed, and educational content should be designed to improve the sexual satisfaction of this group of women.
Internet use and frailty in middle-aged and older adults: findings from developed and developing countries
Authors: Li Liang
Published: July 2024

Background

With increasing trend of internet use in all age groups, whether internet use can prevent frailty in middle-aged and older adults remains unclear.

Methods

Five cohorts, including Health and Retirement Study (HRS), China Health and Retirement Longitudinal Study (CHARLS), the Survey of Health, Ageing and Retirement in Europe (SHARE), English Longitudinal Study of Aging (ELSA), and Mexican Health and Aging Study (MHAS), were used in this study. Internet use, social isolation, and frailty status was assessed using similar questions. The Generalized estimating equations models, random effects meta-analysis, COX regression, and mediation analysis were utilized.

Results

In the multicohort study, a total of 155,695 participants were included in main analysis. The proportion of internet use was varied across countries, ranging from 5.56% in China (CHARLS) to 83.46% in Denmark (SHARE). According to the generalized estimating equations models and meta-analysis, internet use was inversely associated with frailty, with the pooled ORs (95%CIs) of 0.72 (0.67,0.79). The COX regression also showed that participants with internet use had a lower risk of frailty incidence. Additionally, the association was partially mediated by social isolation and slightly pronounced in participants aged 65 and over, male, not working for payment, not married or partnered, not smoking, drinking, and not co-residence with children.

Conclusions

Our findings highlight the important role of internet use in preventing frailty and recommend more engagements in social communication and activities to avoid social isolation among middle-aged and older adults.
Closing the gap: advancing implementation science through training and capacity building
Authors: Brownson Ross C. , Cabassa Leopoldo J. , Drake Bettina F. , Shelton Rachel C.
Published: July 2024

In their article on “Navigating the Field of Implementation Science Towards Maturity: Challenges and Opportunities,” Chambers and Emmons describe the rapid growth of implementation science along with remaining challenges. A significant gap remains in training and capacity building. Formats for capacity building include university degree programs, summer training institutes, workshops, and conferences. In this letter, we describe and amplify on five key areas, including the need to (1) identify advanced competencies, (2) increase the volume and reach of trainings, (3) sustain trainings, (4) build equity focused trainings, and (5) develop global capacity. We hope that the areas we highlight will aid in addressing several key challenges to prioritize in future efforts to build greater capacity in implementation science.
Co-administration of GnRH-agonist and hCG (double trigger) for final oocyte maturation increases the number of top-quality embryos in patients undergoing IVF/ICSI cycles
Authors: Tu Binbin , Zhang Hua , Chen Lixue , Yang Rui , Liu Ping , Li Rong , Qiao Jie
Published: July 2024

Background

The utilization of a double trigger, involving the co-administration of gonadotropin-releasing hormone agonist (GnRH-a) and human chorionic gonadotropin (hCG) for final oocyte maturation, is emerging as a novel approach in gonadotropin-releasing hormone antagonist (GnRH-ant) protocols during controlled ovarian hyperstimulation (COH). This protocol involves administering GnRH-a and hCG 40 and 34 h prior to ovum pick-up (OPU), respectively. This treatment modality has been implemented in patients with low/poor oocytes yield. This study aimed to determine whether the double trigger could improve the number of top-quality embryos (TQEs) in patients with fewer than three TQEs.

Methods

The stimulation characteristics of 35 in vitro fertilization (IVF) cycles were analyzed. These cycles were triggered by the combination of hCG and GnRHa (double trigger cycles) and compared to the same patients’ previous IVF attempt, which utilized the hCG trigger (hCG trigger control cycles). The analysis involved cases who were admitted to our reproductive center between January 2018 and December 2022. In the hCG trigger control cycles, all 35 patients had fewer than three TQEs.

Results

Patients who received the double trigger cycles yielded a significantly higher number of 2PN cleavage embryos (3.54 ± 3.37 vs. 2.11 ± 2.15, P = 0.025), TQEs ( 2.23 ± 2.05 vs. 0.89 ± 0.99, P < 0.001), and a simultaneously higher proportion of the number of cleavage stage embryos (53.87% ± 31.38% vs. 39.80% ± 29.60%, P = 0.043), 2PN cleavage stage embryos (43.89% ± 33.01% vs. 27.22% ± 27.13%, P = 0.014), and TQEs (27.05% ± 26.26% vs. 14.19% ± 19.76%, P = 0.019) to the number of oocytes retrieved compared with the hCG trigger control cycles, respectively. The double trigger cycles achieved higher rates of cumulative clinical pregnancy (20.00% vs. 2.86%, P = 0.031), cumulative persistent pregnancy (14.29% vs. 0%, P < 0.001), and cumulative live birth (14.29% vs. 0%, P < 0.001) per stimulation cycle compared with the hCG trigger control cycles.

Conclusion

Co-administration of GnRH-agonist and hCG for final oocyte maturation, 40 and 34 h prior to OPU, respectively (double trigger) may be suggested as a valuable new regimen for treating patients with low TQE yield in previous hCG trigger IVF/intracytoplasmic sperm injection (ICSI) cycles.
Functions of methyltransferase-like 3 in breast cancer: pathogenesis, drug resistance, and therapeutic target
Authors: Xiao Dongqiong , Zhang Mingfu , Qu Yi , Su Xiaojuan
Published: July 2024

Breast cancer (BC) is a highly prevalent malignancy worldwide, with complex pathogenesis and treatment challenges. Research reveals that methyltransferase-like 3 (METTL3) is widely involved in the pathogenesis of several tumors through methylation of its target RNAs, and its role and mechanisms in BC are also extensively studied. In this review, we aim to provide a comprehensive interpretation of available studies and elucidate the relationship between METTL3 and BC. This review suggests that high levels of METTL3 are associated with the pathogenesis, poor prognosis, and drug resistance of BC, suggesting METTL3 as a potential diagnostic or prognostic biomarker and therapeutic target. Collectively, this review provides a comprehensive understanding of how METTL3 functions through RNA methylation, which provides a valuable reference for future fundamental studies and clinical applications.
The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in immune-oncology era (SEVURO-CN): study protocol for a multi-center, prospective, randomized trial
Authors: Park Jee Soo , Kim Jongchan , Jeon Jinhyung , Lee Jongsoo , Jang Won Sik , Lee Seung Hwan , Han Woong Kyu , Choi Young Deuk , Koo Kyo Chul , Cho Kang Su , Chung Byung Ha , Ham Won Sik
Published: July 2024

Background

The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN.

Methods

This study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤ 3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy [ST] only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2022 and will enroll 55 patients.

Discussion

This study is one of the few prospective randomized trials to evaluate the benefit of CN in the treatment of synchronous mRCC in the IO era. The SEVURO-CN trial will help identify the role and timing of CN, thereby rediscovering the value of CN.

Trial registration

ClinicalTrials.gov, NCT05753839. Registered on 3 March 2023.
Designing a highly efficient type III polyketide whole-cell catalyst with minimized byproduct formation
Authors: Xiang La , Zhang Xuanxuan , Lei Yanyan , Wu Jieyuan , Yan Guangru , Chen Wei , Li Shizhong , Wang Wenzhao , Jin Jian-Ming , Liang Chaoning , Tang Shuang-Yan
Published: July 2024

Background

Polyketide synthases (PKSs) are classified into three types based on their enzyme structures. Among them, type III PKSs, catalyzing the iterative condensation of malonyl-coenzyme A (CoA) with a CoA-linked starter molecule, are important synthases of valuable natural products. However, low efficiency and byproducts formation often limit their applications in recombinant overproduction.

Results

Herein, a rapid growth selection system is designed based on the accumulation and derepression of toxic acyl-CoA starter molecule intermediate products, which could be potentially applicable to most type III polyketides biosynthesis. This approach is validated by engineering both chalcone synthases (CHS) and host cell genome, to improve naringenin productions in Escherichia coli. From directed evolution of key enzyme CHS, beneficial mutant with ~ threefold improvement in capability of naringenin biosynthesis was selected and characterized. From directed genome evolution, effect of thioesterases on CHS catalysis is first discovered, expanding our understanding of byproduct formation mechanism in type III PKSs. Taken together, a whole-cell catalyst producing 1082 mg L−1 naringenin in flask with E value (evaluating product specificity) improved from 50.1% to 96.7% is obtained.

Conclusions

The growth selection system has greatly contributed to both enhanced activity and discovery of byproduct formation mechanism in CHS. This research provides new insights in the catalytic mechanisms of CHS and sheds light on engineering highly efficient heterologous bio-factories to produce naringenin, and potentially more high-value type III polyketides, with minimized byproducts formation.
Experimental investigation for nonalcoholic fatty pancreas management using probiotics
Authors: Matboli Marwa , Al-Amodi Hiba S. , Hamady Shaimaa , Ali Marwa , Roushdy Marian MS , Hasanin Amany Helmy , Aboul-Ela Yasmin M. , Albadawy Reda , Gomaa Eman , Kamel Hala F. M. , ELsawi Hind A , Farid Laila M. , Abouelkhair Mariam B. , Elmakromy Gena M , Fawzy Nesma Mohamed
Published: July 2024

Background

Nonalcoholic fatty pancreatitis (NAFP) presents a pressing challenge within the domain of metabolic disorders, necessitating further exploration to unveil its molecular intricacies and discover effective treatments. Our focus was to delve into the potential therapeutic impact of ZBiotic, a specially engineered strain of probiotic B. subtilis, in managing NAFP by targeting specific genes linked with necroptosis and the TNF signaling pathway, including TNF, ZBP1, HSPA1B, and MAPK3, along with their upstream epigenetic regulator, miR-5192, identified through bioinformatics.

Methods

Rats were subjected to either a standard or high-fat, high-sucrose diet (HFHS) for eight weeks. Subsequently, they were divided into groups: NAFP model, and two additional groups receiving daily doses of ZBiotic (0.5 ml and 1 ml/kg), and the original B. subtilis strain group (1 ml/kg) for four weeks, alongside the HFHS diet.

Results

ZBiotic exhibited remarkable efficacy in modulating gene expression, leading to the downregulation of miR-5192 and its target mRNAs (p < 0.001). Treatment resulted in the reversal of fibrosis, inflammation, and insulin resistance, evidenced by reductions in body weight, serum amylase, and lipase levels (p < 0.001), and decreased percentages of Caspase and Nuclear Factor Kappa-positive cells in pancreatic sections (p < 0.01). Notably, high-dose ZBiotic displayed superior efficacy compared to the original B. subtilis strain, highlighting its potential in mitigating NAFP progression by regulating pivotal pancreatic genes.

Conclusion

ZBiotic holds promise in curbing NAFP advancement, curbing fibrosis and inflammation while alleviating metabolic and pathological irregularities observed in the NAFP animal model. This impact was intricately linked to the modulation of necroptosis/TNF-mediated pathway-related signatures.
Identifying longitudinal cognitive resilience from cross-sectional amyloid, tau, and neurodegeneration
Authors: Boyle Rory , Townsend Diana L. , Klinger Hannah M. , Scanlon Catherine E. , Yuan Ziwen , Coughlan Gillian T. , Seto Mabel , Shirzadi Zahra , Yau Wai-Ying Wendy , Jutten Roos J. , Schneider Christoph , Farrell Michelle E. , Hanseeuw Bernard J. , Mormino Elizabeth C. , Yang Hyun-Sik , Papp Kathryn V. , Amariglio Rebecca E. , Jacobs Heidi I. L. , Price Julie C. , Chhatwal Jasmeer P. , Schultz Aaron P. , Properzi Michael J. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Hohman Timothy J. , Donohue Michael C. , Buckley Rachel F. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2024

Background

Leveraging Alzheimer’s disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR.

Methods

We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women).

Results

The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline.

Conclusion

These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.
Nutrition guidance within a multimodal intervention improves diet quality in prodromal Alzheimer’s disease: Multimodal Preventive Trial for Alzheimer’s Disease (MIND-ADmini)
Authors: Levak Nicholas , Lehtisalo Jenni , Thunborg Charlotta , Westman Eric , Andersen Pia , Andrieu Sandrine , Broersen Laus M. , Coley Nicola , Hartmann Tobias , Irving Gerd Faxén , Mangialasche Francesca , Ngandu Tiia , Pantel Johannes , Rosenberg Anna , Sindi Shireen , Soininen Hilkka , Solomon Alina , Wang Rui , Kivipelto Miia
Published: July 2024

Background

Multimodal lifestyle interventions can benefit overall health, including cognition, in populations at-risk for dementia. However, little is known about the effect of lifestyle interventions in patients with prodromal Alzheimer’s disease (AD). Even less is known about dietary intake and adherence to dietary recommendations within this population making it difficult to design tailored interventions for them.

Method

A 6-month MIND-ADmini pilot randomized controlled trial (RCT) was conducted among 93 participants with prodromal AD in Sweden, Finland, Germany, and France. Three arms were included in the RCT: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management, and social stimulation); 2) multimodal lifestyle intervention + medical food product; and 3) regular health advice (control group). Adherence to dietary advice was assessed with a brief food intake questionnaire by using the Healthy Diet Index (HDI) and Mediterranean Diet Adherence Screener (MEDAS). The intake of macro- and micronutrients were analyzed on a subsample using 3-day food records.

Results

The dietary quality in the intervention groups, pooled together, improved compared to that of the control group at the end of the study, as measured with by HDI (p = 0.026) and MEDAS (p = 0.008). The lifestyle-only group improved significantly more in MEDAS (p = 0.046) and almost significantly in HDI (p = 0.052) compared to the control group, while the lifestyle + medical food group improved in both HDI (p = 0.042) and MEDAS (p = 0.007) during the study. There were no changes in macro- or micronutrient intake for the intervention groups at follow-up; however, the intakes in the control group declined in several vitamins and minerals when adjusted for energy intake.

Conclusion

These results suggest that dietary intervention as part of multimodal lifestyle interventions is feasible and results in improved dietary quality in a population with prodromal AD. Nutrient intakes remained unchanged in the intervention groups while the control group showed a decreasing nutrient density.

Trial registration

ClinicalTrials.gov NCT03249688, 2017–07-08.
Association between tobacco smoke exposure and depression: the NHANES 2005–2018 and Mendelian randomization study
Authors: Guo Yikun , Yan Jun
Published: July 2024

Objective

The relationship between tobacco smoke exposure (TSE) and depression is controversial. This study combined observational research and Mendelian randomization (MR) to explore the relationship of depression with both smoking status and cotinine levels.

Method

We collected relevant data from the National Health and Nutrition Examination Survey (NHANES) database from 2005 to 2018, and used weighted multifactorial logistic regression modelling to assess the correlation between TSE and depression, and assessed the causal relationship of depression with both smoking status and cotinine levels by MR.

Result

Current smokers had the highest risk of depression (OR 1.94; P < 0.01); there was a positive trend for correlation between daily smoking and depression (OR 1.66; P for trend < 0.01). Serum ketamine levels above 3.00 ng/ml had a higher risk of depression (OR 2.13; P < 0.001). MR results showed that current smoking (OR = 4.66; P < 0.001) and previous smoking (OR 2.09; P < 0.01) were risk factors for the onset of depression, and that there was no causal association between cotinine levels and depression.

Conclusion

Smoking is significantly associated with depression and plays a potential causal role in the development of depression. Cotinine was significantly associated with depression, however MR results showed no causal relationship between cotinine and depression.
Predictive modeling of perioperative patient deterioration: combining unanticipated ICU admissions and mortality for improved risk prediction
Authors: Bakkes Tom H.G.F. , Mestrom Eveline H.J. , Ourahou Nassim , Kaymak Uzay , de Andrade Serra Paulo J. , Mischi Massimo , Bouwman Arthur R. , Turco Simona
Published: July 2024

Objective

This paper presents a comprehensive analysis of perioperative patient deterioration by developing predictive models that evaluate unanticipated ICU admissions and in-hospital mortality both as distinct and combined outcomes.

Materials and Methods

With less than 1% of cases resulting in at least one of these outcomes, we investigated 98 features to identify their role in predicting patient deterioration, using univariate analyses. Additionally, multivariate analyses were performed by employing logistic regression (LR) with LASSO regularization. We also assessed classification models, including non-linear classifiers like Support Vector Machines, Random Forest, and XGBoost.

Results

During evaluation, careful attention was paid to the data imbalance therefore multiple evaluation metrics were used, which are less sensitive to imbalance. These metrics included the area under the receiver operating characteristics, precision-recall and kappa curves, and the precision, sensitivity, kappa, and F1-score. Combining unanticipated ICU admissions and mortality into a single outcome improved predictive performance overall. However, this led to reduced accuracy in predicting individual forms of deterioration, with LR showing the best performance for the combined prediction.

Discussion

The study underscores the significance of specific perioperative features in predicting patient deterioration, especially revealed by univariate analysis. Importantly, interpretable models like logistic regression outperformed complex classifiers, suggesting their practicality. Especially, when combined in an ensemble model for predicting multiple forms of deterioration. These findings were mostly limited by the large imbalance in data as post-operative deterioration is a rare occurrence. Future research should therefore focus on capturing more deterioration events and possibly extending validation to multi-center studies.

Conclusions

This work demonstrates the potential for accurate prediction of perioperative patient deterioration, highlighting the importance of several perioperative features and the practicality of interpretable models like logistic regression, and ensemble models for the prediction of several outcome types. In future clinical practice these data-driven prediction models might form the basis for post-operative risk stratification by providing an evidence-based assessment of risk.
Genomic characterization of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) strains circulating in three university hospitals in Northern Italy over three years
Authors: Fox Valeria , Mangioni Davide , Renica Silvia , Comelli Agnese , Teri Antonio , Zatelli Michela , Orena Beatrice Silvia , Scuderi Cristina , Cavallero Annalisa , Rossi Marianna , Casana Maddalena , Mela Ludovica , Bielli Alessandra , Scutari Rossana , Morelli Paola , Cariani Lisa , Casari Erminia , Vismara Chiara Silvia , Matinato Caterina , Callegaro Annapaola , Bottazzi Barbara , Cassani Barbara , Perno Carlo Federico , Gori Andrea , Muscatello Antonio , Bandera Alessandra , Alteri Claudia
Published: July 2024

Objectives

Genomic surveillance of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is crucial for virulence, drug-resistance monitoring, and outbreak containment.

Methods

Genomic analysis on 87 KPC-Kp strains isolated from 3 Northern Italy hospitals in 2019-2021 was performed by whole genome sequencing (WGS), to characterize resistome, virulome, and mobilome, and to assess potential associations with phenotype resistance and clinical presentation. Maximum Likelihood and Minimum Spanning Trees were used to determine strain correlations and identify potential transmission clusters.

Results

Overall, 15 different STs were found; the predominant ones included ST307 (35, 40.2%), ST512/1519 (15, 17.2%), ST20 (12, 13.8%), and ST101 (7, 8.1%). 33 (37.9%) KPC-Kp strains were noticed to be in five transmission clusters (median number of isolates in each cluster: 5 [3-10]), four of them characterized by intra-hospital transmission. All 87 strains harbored Tn4401a transposon, carrying blaKPC-3 (48, 55.2%), blaKPC-2 (38, 43.7%), and in one case (1.2%) blaKPC-33, the latter gene conferred resistance to ceftazidime/avibactam (CZA). Thirty strains (34.5%) harbored porin mutations; of them, 7 (8.1%) carried multiple Tn4401a copies. These strains were characterized by significantly higher CZA minimum inhibitory concentration compared with strains with no porin mutations or single Tn4401a copy, respectively, even if they did not overcome the resistance breakpoint of 8 ug/mL. Median 2 (IQR:1-2) virulence factors per strain were detected. The lowest number was observed in ST20 compared to the other STs (p<0.001). While ST307 was associated with infection events, a trend associated with colonization events could be observed for ST20.

Conclusions

Integration of genomic, resistance score, and clinical data allowed us to define a relative diversification of KPC-Kp in Northern Italy between 2019 and 2021, characterized by few large transmission chains and rare inter-hospital transmission. Our results also provided initial evidence of correlation between KPC-Kp genomic signatures and higher MIC levels to some antimicrobial agents or colonization/infection status, once again underlining WGS's importance in bacterial surveillance.
Differences in the pupillary responses to evening light between children and adolescents
Authors: Hartstein Lauren E. , LeBourgeois Monique K. , Durniak Mark T. , Najjar Raymond P.
Published: July 2024

Background

In the mammalian retina, intrinsically-photosensitive retinal ganglion cells (ipRGC) detect light and integrate signals from rods and cones to drive multiple non-visual functions including circadian entrainment and the pupillary light response (PLR). Non-visual photoreception and consequently non-visual sensitivity to light may change across child development. The PLR represents a quick and reliable method for examining non-visual responses to light in children. The purpose of this study was to assess differences in the PLRs to blue and red stimuli, measured one hour prior to bedtime, between children and adolescents.

Methods

Forty healthy participants (8–9 years, n = 21; 15–16 years, n = 19) completed a PLR assessment 1 h before their habitual bedtime. After a 1 h dim-light adaptation period (< 1 lx), baseline pupil diameter was measured in darkness for 30 s, followed by a 10 s exposure to 3.0 × 1013 photons/cm2/s of either red (627 nm) or blue (459 nm) light, and a 40 s recovery in darkness to assess pupillary re-dilation. Subsequently, participants underwent 7 min of dim-light re-adaptation followed by an exposure to the other light condition. Lights were counterbalanced across participants.

Results

Across both age groups, maximum pupil constriction was significantly greater (p < 0.001, ηp2 = 0.48) and more sustained (p < 0.001, ηp2 = 0.41) during exposure to blue compared to red light. For adolescents, the post-illumination pupillary response (PIPR), a hallmark of melanopsin function, was larger after blue compared with red light (p = 0.02, d = 0.60). This difference was not observed in children. Across light exposures, children had larger phasic (p < 0.01, ηp2 = 0.20) and maximal (p < 0.01, ηp2 = 0.22) pupil constrictions compared to adolescents.

Conclusions

Blue light elicited a greater and more sustained pupillary response than red light in children and adolescents. However, the overall amplitude of the rod/cone-driven phasic response was greater in children than in adolescents. Our findings using the PLR highlight a higher sensitivity to evening light in children compared to adolescents, and continued maturation of the human non-visual photoreception/system throughout development.
Collapse of Cancer Care Under the Current Conflict in Sudan
Authors: Ahmed Iman , Elhassan Moawia M.A. , Elnour Khatir , Sullivan Richard , Hammad Nazik
Published: July 2024

Sudan has been under an armed conflict between the Sudanese Armed Forces and the Rapid Support Forces (RSF) militia since April 15, 2023. The conflict has turned the country into the largest internal displacement humanitarian crisis with 9.05 million internally displaced persons including 2.2 million children younger than 5 years and caused 1.47 million Sudanese to flee the country as refugees. The conflict has had a major destructive impact on the health system, which has incurred targeting with air raids, ground invasion, vandalization, looting of assets and supplies, and killing of doctors, nurses, and other health personnel. Khartoum Oncology Hospital, Sudan's main cancer hub for treatment, diagnostics, and research has become nonfunctional as a result of the conflict. The National Cancer Institute in Wad Medani, the second largest hub, faced a similar fate as the conflict spread to Al-Gezira State. Patients with cancer have been displaced multiple times in Sudan with grave consequences on the continuity of care, worsening of their disease outcomes and palpable negative impacts on children. The oncology workforce in Sudan have themselves been displaced yet are working hard to provide services and care for patients under impossible circumstances. Sudan's doctors in diaspora have rallied to provide support but they face multiple obstacles. As the conflict continues to spread, we call upon the WHO, the United Nations Children's Fund, St Jude Hospital, and all relevant partners to implement an immediate evacuation operation with urgent air lifts of the affected children to continue their cancer care in neighboring countries as was done in Ukraine and Gaza.
A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of fadraciclib, an oral CDK2/9 inhibitor, in patients with advanced solid tumors and lymphoma.
Authors: Villalona-Calero Miguel Angel , Oh Do-Youn , Garralda Elena , Vieito Maria , Huang Julius , Piha-Paul Sarina A.
Published: July 2024

3125

Background: Fadraciclib (formerly CYC065)is a highly selective inhibitor of CDK2 (IC50= 5 nM) and CDK9 (IC50=26 nM) causing mitotic catastrophe and apoptotic death of cancer cells at sub-micromolar concentrations. In a previous Phase 1 study of intravenous fadraciclib monotherapy, a heavily pretreated endometrial cancer patient with CDNK2A, CDKN2B and PRMT5 loss achieved confirmed CR. This is the first study to evaluate oral fadraciclib monotherapy. Methods: A global Phase 1/2, open-label, dose-escalation study in subjects with advanced solid tumors or lymphoma (NCT04983810). The Phase 1 portion is exploring both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify MTD and/or RP2D using a standard 3+3 design. Results: As of January 31, 2024, 45 subjects have received fadraciclib at 8 dose levels (DL1-6a: 50-150 mg, bid given 3-5 days per week for 3-4 out of 4 weeks or DL6b: 125 mg, daily for 4/4 weeks). Heavily pretreated patients with breast, colorectal, gynecological cancers, and T cell lymphoma with ECOG PS 0:1 (9:36) were enrolled. Fadraciclib was well tolerated at dose levels 1 to 5 (up to 100 mg bid). Adverse events reported were nausea (n=31), vomiting (n=23), thrombocytopenia (n=6). Grade 3 DLT of hyperglycemia (1/2 DL6 and 2/6 DL6a) and nausea (1/2 DL6) was observed at doses above 125mg bid M-F, 4/4 weeks. Hyperglycemia was controlled after dose interruption and blood glucose levels returned to normal range after treatment. Preliminary PK analysis suggests dose dependent exposure. At DL5 and above, plasma concentration was above target concentration from CDK2 and CDK9 target engagement studies. Preliminary PD analysis of treated patient samples showed suppression of expression in multiple target genes, including MYC, MCL1, CCNE/cyclin E, CDKN2A, CDKN2B, and PRMT5. Preliminary efficacy data are available for 31 evaluable patients. Two PRs after the first cycle were observed in one patient with CTCL and one with angioimmunoblastic T-Cell Lymphoma (AITL). Twenty patients showed SD. Tumor size reduction was observed in 10 patients. A squamous NSCLC patient harboring a CDK2NB loss of function mutation and prior chemo- and immunotherapy achieved reduction of 22% in the sum of all target lesions after 1 cycle of treatment. Conclusions: Based on data from the CYC065-101 study, fadraciclib appears well tolerated from DL1 to 5. The MTD for the bid dosing schedule is 100mg bid, M-F, 4/4 weeks. The trial is ongoing with evaluation of a daily dosing schedule. Clinical trial information: NCT04983810 .
A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.
Authors: Gouda Mohamed Alaa , Shunyakova Jenny , Naing Aung , Dumbrava Ecaterina Elena , Hong David S. , Yuan Ying , Yang Peiying , Myers Alan , Liang Yulong , Ping Jing , Karp Daniel D. , Tsimberidou Apostolia Maria , Rodon Ahnert Jordi , Yap Timothy A. , Piha-Paul Sarina A. , Meric-Bernstam Funda , Fu Siqing
Published: July 2024

3152

Background: Paclitaxel resistance in patients is a clinical challenge that limits the durability of clinical benefit in patients with taxane-responsive advanced solid tumors. One proposed mechanism for this resistance is overexpression of spleen tyrosine kinase (SYK); which can be inhibited with new molecules including TAK-659. In this phase I study, we have investigated the combination of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors; hypothesizing that use of TAK-659 would help to overcome resistance to prior taxane-based therapy. Methods: We included patients with advanced solid tumors who received and progressed on prior taxane-based therapy. Patients received treatment with intravenous paclitaxel on day 1,8, and 15 in addition of daily TAK-659 in 28-day cycles. Six cohorts were treated during dose escalation at different dose levels followed by a dose expansion phase in patients with advanced ovarian cancer. We used the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for evaluation of toxicity and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for assessment of preliminary efficacy. Results: We included 49 patients with advanced solid tumors. The maximum tolerated dose was not reached in this study; and no patients experienced treatment-related deaths. Most adverse events were either grade 1 or 2. Grade 3 or more adverse events were reported in 47% of patients (n=23). The most common grade ≥3 adverse events were decreased neutrophil count (n=7; 14%), elevated lipase (n=6; 12%), anemia (n=5; 10%), increased amylase (n=4; 8%), and decreased white blood cell counts (n=4; 8%). In 44 patients with taxane-refractory tumors who were evaluable for efficacy, 9% (n=4) had RECIST partial response and 27% (n=12) had RECIST stable disease, including 3 patients with prolonged stable disease for at least 6 months. Conclusions: The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors. Clinical trial information: NCT03756818 .
Phase II study of the combination of lenvatinib (L) and eribulin (E) in advanced solid tumors.
Authors: Banwait Ranjit Singh , Ko Heidi Chwan , Michalek Joel , Lathrop Kate Ida , Bowhay-Carnes Elizabeth Ann , Fotopoulos Georgios , Elledge Richard M. , Karnad Anand B. , Kaklamani Virginia G.
Published: July 2024

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Background: Tumor angiogenesis remains a focal point in cancer therapeutics, necessitating innovative strategies to counter resistance mechanisms. Lenvatinib, a multitargeted tyrosine kinase inhibitor, and eribulin, a microtubule inhibitor, exhibit promise in disrupting tumor vasculature. Understanding their efficacy and safety in combination therapy is crucial, especially in heavily pretreated patients with advanced solid tumors. Methods: A single-center phase II study (NCT02640508) enrolled patients with stage IV breast carcinoma, lung carcinoma, and sarcoma, evaluating the safety and efficacy of lenvatinib and eribulin combination therapy. Eribulin was given on day 1 and day 8 at 1.4 mg/m2 and lenvatinib at a dose of 20 mg starting on day 2 of a 21-day cycle. Immunohistochemistry assessed biomarkers CD31, e-cadherin, CA-9, and vimentin. Statistical analyses included multivariate modeling and Kaplan-Meier curves. The primary endpoint of the study was the overall response rate (ORR), defined per RECIST 1.1 as assessed by investigator imaging review. Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). Results: Among 29 patients enrolled, median age was 58 years, majority were female and had at least ≥3 prior lines of chemotherapy. Treatment with lenvatinib and eribulin resulted in an ORR of 24%, as seen in the table. Median PFS was 7.4 months and OS was 8.2 months. Toxicities were manageable with grade ≥3 neutropenia seen in 34.5%, febrile neutropenia in 17.2%, and hypertension in 13.8% of patients. Treatment-related adverse events leading to study-drug discontinuation occurred in 6.8% of patients. Vimentin-negative patients exhibited significantly increased OS (fold change 4.374, p<0.001) and PFS (fold change 3.395, p<0.001) after adjusting for age, CD31, and CA9. Conclusions: Lenvatinib combined with eribulin showcased promising anti-tumor activity in heavily pretreated patients with metastatic breast carcinoma, lung carcinoma, and sarcoma. Although manageable, neutropenia emerged as a notable adverse effect. These findings underscore the potential of this combination as a therapeutic strategy for advanced solid tumors, warranting further clinical investigation. The observed significant survival benefits in Vimentin-negative patients align with the biological role of Vimentin in tumor invasiveness and metastatic potential, supporting the plausibility of these results biologically. Acknowledgement: This clinical trial was supported by Eisai. Clinical trial information: NCT02640508 . [Table: see text]
Treatment outcomes of brain metastasis from primary renal cell carcinoma in United States: A National Cancer Database analysis.
Authors: Podder Vivek , Ganiyani Mohammad Arfat , Ahmad Shahzaib , Bellur Shreyas S , Khokhar Muhammad Abbas , Ayoobkhan Fathima Shehnaz , Pustake Manas , Jayram Diya K , Ozair Ahmad , Ranjan Tulika , Garje Rohan , Ahluwalia Manmeet Singh
Published: July 2024

4561

Background: The advent of stereotactic radiosurgery (SRS) in treatment of brain metastasis (BM) has improved both clinical outcomes and survival in patients with BM. Recent studies suggest that immunotherapy presents a promising potential in the treatment of patients with BM. However, data regarding the effectiveness of combining SRS with immunotherapy for BM in metastatic renal cell carcinoma (RCC) remain largely unknown. We aim to delineate the impact of various treatment therapies including combination therapy for treatment of RCCBM. Methods: We queried the National Cancer Database (NCDB) to include patients with BM from mRCC from 2004 to 2020. We divided the patients into groups based on the treatment they received. Resultantly, 5 different treatment groups i.e., WRBT± immunotherapy, SRS± immunotherapy and immunotherapy alone were identified. We excluded patients with unknown treatment status. We analyzed survival outcomes using the Kaplan-Meier analysis and compared the effect of treatment modalities on survival with the log-rank test. Results: The NCDB yielded 6,446 patients diagnosed with BM from mRCC. In eligible cases, the median age was 63 years (range: 19-90+ years), 69.2% were male, 86.8% were White, 7.9% were Black, 41.9% had Medicare as primary payor, 27.7% had annual income >$74,063, 79.3% belonged from metropolitan areas, 39.6% were treated at academic/research program, 68.3% had Charlson-Deyo score of 0, 44.6% had an unknown grade of the primary RCC. 1,705 (43.44%) patients who were given WBRT had a median overall survival (OS) of 5.65 months, 427 (10.88%) patients were treated with SRT + immunotherapy had an OS of 19.0 months, 987 (25.15%) patients who underwent SRT only had an OS of 9.7 months, 431 (10.98%) patients who received immunotherapy only showed an OS of 12.9 months, and 375 (9.55%) patients who underwent WBRT + immunotherapy had an OS of 12.78 months (log-rank p <0.001). Conclusions: This national database analysis reveals that the combination of SRS with immunotherapy significantly increases the OS in RCCBM compared to immunotherapy, WBRT, or combination of WRBT and immunotherapy. Further prospective studies are warranted to confirm these findings. [Table: see text]
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): Long-term outcomes from the JAVELIN Bladder 100 trial in patients (pts) with histological subtypes.
Authors: Loriot Yohann , Gupta Shilpa , Powles Thomas , Grivas Petros , Petrylak Daniel P. , Tyroller Karin , Jacob Natalia , Hoffman Jason , Bellmunt Joaquim
Published: July 2024

4567

Background: Results from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) led international treatment guidelines to recommend avelumab 1L maintenance as a standard-of-care treatment for pts with aUC without progression after 1L platinum-based chemotherapy (PBC). Around 20% of UCs are mixed with other histological subtypes/variants; these tumors do not have specific treatment guidelines and represent an unmet treatment need. In the large real-world AVENANCE study (NCT04822350; N=594) of avelumab 1L maintenance in pts with aUC in France, outcomes in pts with histological subtypes were consistent with those in the overall population. Here, we report a post hoc analysis of long-term outcomes from JAVELIN Bladder 100 in pts with predominantly UC mixed with <50% histological subtype component. Methods: Eligible pts had unresectable locally advanced or metastatic UC without progression after 1L PBC and were randomized 1:1 to receive avelumab + best supportive care (BSC) or BSC alone. The primary endpoint was overall survival (OS) measured from randomization; secondary endpoints included progression-free survival (PFS) and safety. This post hoc analysis was conducted in all pts with histological subtypes. Results: In the avelumab + BSC and BSC alone arms, respectively, 44/350 and 57/350 pts had histological subtypes. At efficacy data cutoff (June 4, 2021), median follow-up in both arms was ≥38.0 mo. In pts with histological subtypes, OS and PFS measured from randomization were prolonged with avelumab + BSC vs BSC alone (Table). Long-term safety (cutoff, April 6, 2023) in treated pts with histological subtypes was generally consistent with the overall safety population. Treatment-related adverse events (TRAEs) of any grade occurred in 36 pts (83.7%) in the avelumab + BSC arm vs 1 pt (1.8%) in the BSC alone arm; grade ≥3 TRAEs occurred in 9 pts (20.9%) and 0 pts, respectively. Conclusions: This exploratory analysis shows the long-term efficacy and safety of avelumab 1L maintenance in pts with histological subtypes in JAVELIN Bladder 100. No new safety concerns were identified. These results were consistent with those in the overall population and support the use of avelumab 1L maintenance in pts with aUC without progression following 1L PBC, including pts with predominantly UC mixed with <50% histological subtype component. Clinical trial information: NCT02603432 . [Table: see text]
Preliminary efficacy and safety results from RC48-C017: A phase II study of neoadjuvant treatment with disitamab vedotin plus toripalimab in patients with muscle invasive bladder cancer (MIBC) with HER2 expression.
Authors: Sheng Xinan , Yang Kaiwei , Ji Yongpeng , Zhou Li , Zou Benkui , Huang Hang , Wang Yonghua , Bai Xue , Feng Dan , Yang Yong , Bian Jiasheng , Yu Zhixian , Niu Haitao , Du Peng , Fang Jianmin , He Zhisong , Guo Jun
Published: July 2024

4568

Background: Disitamab vedotin (DV) is a novel humanized anti-HER2 antibody-drug conjugate. DV plus toripalimab (a recombinant humanized anti-PD-1 monoclonal antibody) showed promising antitumor activity in metastatic urothelial carcinoma (ASCO 2023). This study aimed to evaluate the safety and efficacy of DV plus toripalimab as neoadjuvant therapy in MIBC patients with HER2 expression. Methods: This is a prospective multicenter phase 2 trial which planned to enroll 40 pts. Primary endpoint is pathological CR (pCR) rate; secondary endpoints include pathologic response rate, safety and tolerability. Study enrolled pts who are previously untreated MIBC (cT2-T4aN0-1M0), medically fit for and agree to undergo curative intent RC+PLND. HER2 expression was required to be immunochemistry (IHC) ≥ 1+ tested locally. Pts received DV 2 mg/kg plus toripalimab 3 mg/kg every two weeks for 6 cycles, followed by RC+ PLND within 4 weeks. Here we present preliminary efficacy and safety results. Results: 44 pts were enrolled and clinical stage at diagnosis was: cT2N0 (38.6%), cT3N0 (29.5%), cT4aN0 (13.6%), cT2-4aN1 (18.2%). HER2 expression of IHC 1+, 2+ or 3+ was 11.4%, 56.8%, and 31.8%, respectively. By the data cut-off date (Feb-2024), 29 pts (65.9%) completed RC + PLND. The pCR rate was 62.1% (18/29). The pathologic response rate was 75.9% (22/29). Common treatment-related adverse events (TRAEs) were mostly Grade 1 or 2, including alopecia (36.4%), alanine aminotransferase increased (31.8%), aspartate aminotransferase increased (25.0%), rash (22.7%), gamma-glutamyl transferase increased (22.7%), peripheral sensory neuropathy (22.7%), and asthenia (20.5%). Grade 3-4 TRAEs were reported in 15.9% of pts. No deaths occurred. No surgery was cancelled due to TRAEs. Survival data are not yet mature. Conclusions: Neoadjuvant treatment with DV plus toripalimab showed promising efficacy results and was well tolerated in operable MIBC pts with HER2 expression. These results will support further investigation for DV plus toripalimab in this population. Clinical trial information: NCT05297552 .