Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Changes in nutritional status and the development of obesity and metabolic syndrome following pediatric heart transplantation.

BACKGROUND: Nutritional status in pediatric patients undergoing heart transplantation (HT) is frequently a focus of clinical management and requires high resource utilization. Pre-operative nutrition status has been shown to affect post-operative mortality but no studies have been performed to assess how nutritional status may change and the risk of developing nutritional comorbidities long-term in the post-transplant period. METHODS: A single-center retrospective chart review of patients ≥2 years of age who underwent heart transplantation between 1/1/2005 and 4/30/2020 was performed. Patient data were collected at listing, time of transplant, 1-year, and 3-year follow-up post-transplant. Nutrition status was classified based on body mass index (BMI) percentile in the primary analysis. Alternative nutritional indices, namely the nutrition risk index (NRI), prognostic nutrition index (PNI), and BMI z-score, were utilized in secondary analyses. RESULTS: Of the 63 patients included, the proportion of patients with overweight/obese status increased from 21% at listing to 41% at 3-year follow-up. No underweight patients at listing became overweight/obese at follow-up. Of patients who were overweight/obese at listing, 88% maintained that status at 3-year follow-up. Overweight/obese status at listing, 1-year, and 3-year post-transplantation were significantly associated with developing metabolic syndrome. In comparison to the alternative nutritional indices, BMI percentile best predicted post-transplant metabolic syndrome. CONCLUSIONS: The results suggest that pediatric patients who undergo heart transplantation are at risk of developing overweight/obesity and related nutritional sequelae (ie, metabolic syndrome). Improved surveillance and interventions targeted toward overweight/obese HT patients should be investigated to reduce the burden of associated comorbidities.

Attitudes and behaviors regarding sun exposure in Japan compared to Europe and North America.

The objective of our study was to assess the attitudes and behaviors in Japan regarding sun exposure and compare them to those in Europe and North America. The study population was a representative sample of individuals aged >18 years from Ipsos panels in Japan (N = 1000), North America (N = 1000), and Europe (N = 6000) using the quota method. Questionnaires covered habits, practices, and perceptions regarding sun exposure. Results revealed that the majority of people (80.1%) believed that the sun gives them energy, and 61.1% considered that being tanned made them look healthier. However, there was a significant difference between men and women regarding the appeal of tanned skin, with 54.95% of men versus 34.67% (p < 0.001) of women seeing a tan as an aesthetic asset. People aged <40 years were less likely to find a tan attractive (30.3%) compared to those aged ≥40 years (48.9%) (p < 0.001). Of those questioned, 45.70% of used sunscreen with a much higher use among women (70.10%) than men (18.74%) (p < 0.001). Almost 54% of people said they stayed in the shade to protect themselves from the sun with this behavior being more prevalent among women (67.05%) and fair-skinned individuals (56.13%). Fear of the risks of sun exposure was more common among women, with 84.8% fearing premature skin aging, compared to 71.8% of men (p < 0.001). In Japan, 44.30% of those questioned said tanned skin was attractive (p < 0.001); for Europeans and North Americans the proportions were 81.1% and 77.6%, respectively. Only a quarter (25.80%) thought it essential to return from vacation with a tan. On the other hand, Europeans showed a strong recognition of the energy the sun brings (83.18%), and widely believed that tanned skin is attractive (82.32%) and healthy (73.15%). In North America, attitudes were similar to those in Europe regarding the attractiveness of tanned skin (77.65%) and the importance of returning tanned from vacation (48.15%). Compared to Europeans and North Americans, the Japanese seemed to be more cautious about sun-induced hazards and considered lighter skin to be more attractive.

Visual supplementation is an effective tool in cataract surgery counselling by eye-care practitioners.

BACKGROUND: Informed consent constitutes an important aspect of eye care. However, patients often experience difficulties understanding and retaining information presented to them during consultations. This study investigates the efficacy of pictorial aids in supplementing preoperative counselling of patients undergoing cataract surgery. METHODS: Patients attending routine pre-cataract surgery counselling were randomized to receive either a standard verbal consultation (control) or a verbal consultation with a digitalized pictorial aid illustrating key surgical steps (intervention). Patients were assessed after the consultation on their knowledge, satisfaction, anxiety and preparedness using an anonymous questionnaire. RESULTS: Seventy-six patients were recruited and randomized into the control and intervention groups. The intervention group attained better Knowledge Scores (control: 5 [2-6] vs. intervention: 6 [6]), and more patients "strongly agreed" that they were more prepared (control: 78.9% vs. intervention: 97.4%, P=0.028). A higher proportion of patients in the control group either "disagreed" or "neither disagree nor agreed (neutral)" that they were less worried (control: 15.8% vs. intervention: 0.0%, Fisher's Exact Test P=0.025). Although the consultation duration was shorter in the intervention group (21±4mins vs. 27±6mins, P<0.001), the use of digital pictorial aids during consultation resulted in more effective counselling with increased patient knowledge, easier decision-making process and reduced patient anxiety. CONCLUSION: Pictorial aids add to the repository of tools available to eye-care practitioners and are low-cost, easy to implement, and can effectively augment existing preoperative counselling processes to ensure accurate and effective preoperative counselling of patients.

Simultaneous Electrochemical Detection of Dopamine and Uric Acid via Au@Cu-Metal Organic Framework.

The incorporation of noble metals with metal-organic frameworks (MOFs) are conducive to the simultaneous electrochemical detection of analytes owing to multiple accessible reaction sites. Herein, Au@Cu-metal organic framework (Au@Cu-MOF) is successfully synthesized and modified as a screen-printed carbon electrode (SPCE), which serves as an excellent electrocatalyst for the oxidation of dopamine (DA) and uric acid (UA). The sensor shows a linear range from 10 µM to 1000 µM, with sensitivity and detection limit of 0.231 µA µM-1 cm-2 and 3.40 µM for DA, and 0.275 µA µM-1 cm-2 and 10.36 µM for UA. Au@Cu-MOF could realize the individual and simultaneous electrochemical sensing of DA and UA, with distinguishable oxidation peak potentials. Moreover, it exhibits reproducibility, repeatability, and stability. Ultimately, the sensor provides an avenue for an ultrasensitive label-free electrochemical detection of DA and UA.

Value of ultrasound in assessing response to neoadjuvant chemotherapy in breast cancer.

AIM: To analyse the utility of ultrasound in assessing response to neoadjuvant chemotherapy (NAC) and predicting residual cancer burden (RCB) index and pathological complete response (pCR) MATERIALS AND METHODS: This was a retrospective study with 417 patients over 7 years. The difference in longest diameter (LD) of the index lesion from baseline to end, baseline to mid, and mid to end was evaluated with respect to RCB class using logistic regression and ordered logistic regression. RESULTS: Change in LD measurements from baseline to end, baseline to mid, and mid to end of chemotherapy as a predictor of RCB class show a negative relationship with a statistically significant association. This would suggest that a smaller change in LD measurements would be associated with an eventual higher RCB class. Change in LD measurements from baseline to end and baseline to mid chemotherapy as a predictor of pCR class show a negative relationship with a statistically significant association (p<0.05). This similarly indicates an inversely proportional relationship between changes in LD measurements and RCB class 0 for baseline to end and baseline to mid. CONCLUSION: This study has shown significance in reducing LD measurements on ultrasound as a predictor of PCR and RCB class. This adds weight to the current practice of using ultrasound at the start, mid and end of chemotherapy cycles to monitor NACT responses.

A review of zeolitic imidazolate frameworks (ZIFs) as electrochemical sensors for important small biomolecules in human body fluids.

Small biomolecules play a critical role in the fundamental processes that sustain life and are essential for the proper functioning of the human body. The detection of small biomolecules has garnered significant interest in various fields, including disease diagnosis and medicine. Electrochemical techniques are commonly employed in the detection of critical biomolecules through the principle of redox reactions. It is also a very convenient, cheap, simple, fast, and accurate measurement method in analytical chemistry. Zeolitic imidazolate frameworks (ZIFs) are a unique type of metal-organic framework (MOF) composed of porous crystals with extended three-dimensional structures. These frameworks are made up of metal ions and imidazolate linkers, which form a highly porous and stable structure. In addition to their many advantages in other applications, ZIFs have emerged as promising candidates for electrochemical sensors. Their large surface area, pore diameter, and stability make them ideal for use in sensing applications, particularly in the detection of small molecules and ions. This review summarizes the critical role of small biomolecules in the human body, the standard features of electrochemical analysis, and the utilization of various types of ZIF materials (including carbon composites, metal-based composites, ZIF polymer materials, and ZIF-derived materials) for the detection of important small biomolecules in human body fluids. Lastly, we provide an overview of the current status, challenges, and future outlook for research on ZIF materials.

Corrigendum: Introducing a healthcare-assistive robot in primary care: a preliminary questionnaire survey.

[This corrects the article DOI: 10.3389/frobt.2023.1123153.].

Introducing a healthcare-assistive robot in primary care: a preliminary questionnaire survey.

A Healthcare-assistive Infection-control RObot (HIRO) is a healthcare-assistive robot that is deployed in an outpatient primary care clinic to sanitise the premises, monitor people in its proximity for their temperature and donning of masks, and usher them to service points. This study aimed to determine the acceptability, perceptions of safety, and concerns among the patients, visitors, and polyclinic healthcare workers (HCWs) regarding the HIRO. A cross-sectional questionnaire survey was conducted from March to April 2022 when the HIRO was at Tampines Polyclinic in eastern Singapore. A total of 170 multidisciplinary HCWs serve approximately 1,000 patients and visitors daily at this polyclinic. The sample size of 385 was computed using a proportion of 0.5, 5% precision, and 95% confidence interval. Research assistants administered an e-survey to gather demographic data and feedback from 300 patients/visitors and 85 HCWs on their perceptions of the HIRO using Likert scales. The participants watched a video on the HIRO's functionalities and were given the opportunity to directly interact with it. Descriptive statistics was performed and figures were presented in frequencies and percentages. The majority of the participants viewed the HIRO's functionalities favourably: sanitising (96.7%/91.2%); checking proper mask donning (97%/89.4%); temperature monitoring (97%/91.7%); ushering (91.7%/81.1%); perceived user friendliness (93%/88.3%), and improvement in the clinic experience (96%/94.2%). A minority of the participants perceived harm from the HIRO's liquid disinfectant (29.6%/31.5%) and that its voice-annotated instructions may be upsetting (14%/24.8%). Most of the participants accepted the HIRO's deployment at the polyclinic and perceived it to be safe. The HIRO used ultraviolet irradiation for sanitisation during after-clinic hours instead of disinfectants due to the perceived harm.

Corrigendum to 'Single domain antibodies derived from ancient animals as broadly neutralizing agents for SARS-CoV-2 and other coronaviruses': Biomedical Engineering Advances 4 (2022) 100054.

[This corrects the article DOI: 10.1016/j.bea.2022.100054.].

Immune Activation following Irbesartan Treatment in a Colorectal Cancer Patient: A Case Study.

Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.

Consumer Experience of Mistreatment and Fraud in Financial Services: Implications from an Integrative Consumer Vulnerability Framework.

This study utilizes the National Financial Well-Being Survey (NFWS) from the Consumer Financial Protection Bureau (CFPB) to investigate the profiles of American consumers who experience mistreatment or a type of fraud in financial services (compromised accounts). An integrative consumer vulnerability framework was used as the theoretical framework to examine how disadvantaged consumer characteristics and vulnerable consumer characteristics are associated with mistreatment and compromised accounts. Consumers in vulnerable states, due to low financial capability, cognitive decline, material hardships, financial shocks, and more exposure to various financial services, were more likely to report experiencing mistreatment and having their financial accounts compromised. Consumers from higher socio-economic status were more likely to have been victims of mistreatment and compromised accounts in financial services. These findings offer implications for consumer financial education and protection.

Targeting the FGF/FGFR axis and its co-alteration allies.

BACKGROUND: We analyzed the FGF/FGFR and co-alteration cancer landscape, hypothesizing that combination therapy might be useful in the presence of co-drivers. MATERIALS AND METHODS: We describe FGF/FGFR-altered pathways, prognosis, and co-alterations [cBioPortal (N = 7574)] and therapeutic outcomes [University of California San Diego Molecular Tumor Board (MTB) (N = 16)]. RESULTS: Patients whose cancers harbored FGF/FGFR alterations (N = 1074) versus those without them (N = 6500) had shorter overall survival (OS) (median: 23.1 versus 26.4 months, P = 0.038) (cBioPortal). Only 6.1% (65/1074 patients) had no pathogenic co-alterations accompanying FGF/FGFR axis abnormalities. The most frequently co-altered pathways/genes involved: TP53 (70%); cell cycle (58%); PI3K (55%); and receptor tyrosine kinases and mitogen-activated protein kinase (MAPK) (65%). Harboring alterations in both FGF/FGFR and in the TP53 pathway or in the cell cycle pathway correlated with shorter OS (versus FGF/FGFR-altered without those co-altered signals) (P = 0.0001 and 0.0065). Four of 16 fibroblast growth factor receptor (FGFR) inhibitor-treated patients presented at MTB attained durable partial responses (PRs) (9, 12, 22+, and 52+ months); an additional two, stable disease (SD) of ≥6 months (13+ and 15 months) [clinical benefit rate (SD ≥ 6 months/PR) = 38%]. Importantly, six patients with cyclin pathway co-alterations received the CDK4/6 inhibitor palbociclib (75 mg p.o. 3 weeks on, 1 week off) and the multikinase FGFR inhibitor lenvatinib (10 mg p.o. daily); three (50%) achieved a PR [9 (ovarian), 12 (biliary), and 52+ months (osteosarcoma)]. Palbociclib and lenvatinib were tolerated well. CONCLUSIONS: FGF/FGFR alterations portend a poor prognosis and are frequently accompanied by pathogenic co-aberrations. Malignancies harboring co-alterations that activate both cyclin and FGFR pathways can be co-targeted by CDK4/6 and FGFR inhibitors.

Single domain antibodies derived from ancient animals as broadly neutralizing agents for SARS-CoV-2 and other coronaviruses.

With severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an emergent human virus since December 2019, the world population is susceptible to coronavirus disease 2019 (COVID-19). SARS-CoV-2 has higher transmissibility than the previous coronaviruses, associated by the ribonucleic acid (RNA) virus nature with high mutation rate, caused SARS-CoV-2 variants to arise while circulating worldwide. Neutralizing antibodies are identified as immediate and direct-acting therapeutic against COVID-19. Single-domain antibodies (sdAbs), as small biomolecules with non-complex structure and intrinsic stability, can acquire antigen-binding capabilities comparable to conventional antibodies, which serve as an attractive neutralizing solution. SARS-CoV-2 spike protein attaches to human angiotensin-converting enzyme 2 (ACE2) receptor on lung epithelial cells to initiate viral infection, serves as potential therapeutic target. sdAbs have shown broad neutralization towards SARS-CoV-2 with various mutations, effectively stop and prevent infection while efficiently block mutational escape. In addition, sdAbs can be developed into multivalent antibodies or inhaled biotherapeutics against COVID-19.

A copper-based metal-organic framework decorated with electrodeposited Fe2O3 nanoparticles for electrochemical nitrite sensing.

An amperometric nitrite sensor is reported based on a screen-printed carbon electrode (SPCE) modified with copper(II)-benzene-1,4-dicarboxylate (Cu-BDC) frameworks and iron(III) oxide nanoparticles (Fe2O3 NPs). First, copper(I) oxide (Cu2O) nanocubes were synthesized, followed by a solvothermal reaction between Cu2O and H2BDC to form square plate-like Cu-BDC frameworks. Then, Fe2O3 NPs were electrodeposited on Cu-BDC frameworks using a potentiostatic method. The Fe2O3@Cu-BDC nanocomposite benefits from high conductivity and large active surface area, offering excellent electrocatalytic activity for nitrite oxidation. Under optimal amperometric conditions (0.55 V vs. Ag/AgCl), the sensor has a linear range of 1 to 2000 µM with a detection limit of 0.074 µM (S/N = 3) and sensitivity of 220.59 µA mM-1 cm-2. The sensor also provides good selectivity and reproducibility (RSD = 1.91%, n = 5). Furthermore, the sensor exhibits long-term stability, retaining 91.4% of its original current after 4 weeks of storage at room temperature. Finally, assessing nitrite in tap and mineral water samples revealed that the Fe2O3@Cu-BDC/SPCE has a promising prospect in amperometric nitrite detection.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Pollutant dispersion by tall buildings: laboratory experiments and Large-Eddy Simulation.

Abstract: Pollutant dispersion by a tall-building cluster within a low-rise neighbourhood of Beijing is investigated using both full-scale Large-Eddy Simulation and water flume experiments at 1:2400 model-to-full scale with Particle Image Velocimetry and Planar Laser-Induced Fluorescence. The Large-Eddy Simulation and flume results of this realistic test case agree remarkably well despite differences in the inflow conditions and scale. Tall buildings have strong influence on the local flow and the development of the rooftop shear layer which dominates vertical momentum and scalar fluxes. Additional measurements using tall-buildings-only models at both 1:2400 and 1:4800 scales indicates the rooftop shear layer is insensitive to the scale. The relatively thicker incoming boundary layer affects the Reynolds stresses, the relative size of the pollutant source affects the concentration statistics and the relative laser-sheet thickness affects the spatially averaged results of the measured flow field. Low-rise buildings around the tall building cluster cause minor but non-negligible offsets in the peak magnitude and vertical location, and have a similar influence on the velocity and concentration statistics as the scale choice. These observations are generally applicable to pollutant dispersion of realistic tall building clusters in cities. The consistency between simulations and water tunnel experiments indicates the suitability of both methodologies.