Multiple Centers Research Articles

AI-powered prediction of HCC recurrence after surgical resection: Personalised intervention opportunities using patient-specific risk factors.

Hepatocellular carcinoma (HCC) recurrence following surgical resection remains a significant clinical challenge, necessitating reliable predictive models to guide personalised interventions. In this study, we sought to harness the power of artificial intelligence (AI) to develop a robust predictive model for HCC recurrence using comprehensive clinical datasets. Leveraging data from 958 patients across multiple centres in Australia and Hong Kong, we employed a multilayer perceptron (MLP) as the optimal classifier for model generation. Through rigorous internal cross-validation, including a cohort from the Chinese University of Hong Kong (CUHK), our AI model successfully identified specific pre-surgical risk factors associated with HCC recurrence. These factors encompassed hepatic synthetic function, liver disease aetiology, ethnicity and modifiable metabolic risk factors, collectively contributing to the predictive synergy of our model. Notably, our model exhibited high accuracy during cross-validation (.857 ± .023) and testing on the CUHK cohort (.835), with a notable degree of confidence in predicting HCC recurrence within accurately classified patient cohorts. To facilitate clinical application, we developed an online AI digital tool capable of real-time prediction of HCC recurrence risk, demonstrating acceptable accuracy at the individual patient level. Our findings underscore the potential of AI-driven predictive models in facilitating personalised risk stratification and targeted interventions to mitigate HCC recurrence by identifying modifiable risk factors unique to each patient. This model aims to aid clinicians in devising strategies to disrupt the underlying carcinogenic network driving recurrence.

Impact of Positive Resection Margins on Recurrence and Survival Following Resection and Adjuvant Chemotherapy in Pancreatic Cancer: Results of the PRODIGE 24-CCTG PA-6 Randomized Controlled Trial.

This study investigated the correlation between positive resection margins and outcomes in patients with pancreatic ductal adenocarcinoma who underwent surgery and adjuvant chemotherapy according to the pivotal trial PRODIGE 24-CCTG PA-6. The primary focus is on elucidating the prognostic significance of specific resection margins, including those associated with the superior-mesenteric vein (SMV), medial, and posterior pancreas. The analysis involved 400 patients across multiple centers in France and Canada. Surgical resection and subsequent adjuvant chemotherapy were core interventions. This study assessed the prognostic impact of resection margins, highlighting the significance of standardized pathology assessments. Additionally, the influence of chemotherapy regimen choice, comparing gemcitabine to mFOLFIRINOX, on the implications of positive resection margins was examined. Only three margins, SMV (HR=1.48 95% CI [1.11;1.96], P<.001), medial (HR=1.92 95% CI [1.36;2.73], P<.001) and posterior (HR=1.65 95% CI [1.21;2.24], P=.002), had a significant prognostic impact on disease-free survival and were sufficient compared with the seven recommended margins (Kappa=0.90 95% CI [0.87; 0.94]). R1 status was significant independent prognostic factor for poorer survival in gemcitabine-treasted patients (HR=1.97 95% CI [1.23;3.16], P=.005) but lost its significance with mFOLFIRINOX (HR=1.46 95% CI [0.91;2.35], P=.114). All efforts should be made to evaluate the three margins of the highest prognostic value, with the others being secondary. A key finding of this study is the likely effect of mFOLFIRINOX on local invasion in operated patients, which seems to correct the impairment related to margin involvement, probably explaining the improvements in DFS and OS.

Correlation of Left Atrial Volume Index with Pro-BNP in Heart Failure with Preserved Ejection Fraction

Objective: To determine the correlation between left atrial (LA) volume index and Pro- BNP in heart failure patients with preserved ejection fraction. Methodology: This descriptive Cross-Sectional Study was conducted at Department of Cardiology, Liaquat University of Medical &amp; Health Sciences (LUMHS), Jamshoro, Pakistan, during Six months after the approval of synopsis from March 26, 2021 to September 25, 2021. All patients who fulfilled the inclusion criteria and visited to LUMHS, Jamshoro were included in the study. Informed consent was taken after explaining the procedure, risks and benefits of the study. Peripheral venous blood samples were obtained for assessment of pro- BNP level. A detailed comprehensive echocardiography was performed in all patients. All the collected data were entered into the proforma attached at the end and used electronically for research purpose. Results: The age of the patients ranged from 19 to 59 years with a median of 58 with interquartile range 12. In distribution of gender, 20 (60.5%) patients were male while 13 (39.4%) were female. Pearson’s correlation coefficient showed weak and non-significantly linear correlation between left atrial volume index and Pro-BNP levels i.e. (r= 0.134) in the region P &lt; 0.05. Conclusion: It is to be concluded that there was a weak correlation between left atrial volume index and Pro-BNP levels. More studies are necessary to evaluate the statistical association with a larger sample size and with more parameters in multiple study centers in Pakistan are needed to validate the findings of the present study.

Understanding the emission behaviour of 0D Cs4PbBr6 perovskite nanocrystals at room temperature

We report 0D Cs4PbBr6 perovskite nanocrystals emitting at room temperature, synthesized by hot injection technique. Effect of injection temperature (TR) on the emission of Cs4PbBr6 nanocrystals (NCs) has been studied. High-quality NCs are synthesized in the 100 °C–180 °C temperature range. Pure phase Cs4PbBr6 nanocrystals are formed at lower temperatures (TR = 100 °C), while at higher temperatures, CsPbBr3 impurity phase appears along with Cs4PbBr6. Cs4PbBr6 nanocrystals emit blue light with broad emission spectra in the 400–500 nm wavelength range, while a green emission from CsPbBr3 impurities at 520 nm wavelength is observed. The emission spectra from Cs4PbBr6 NCs shows multiple radiative centers in the 400–500 nm range, unaffected by the change in excitation wavelength. The emission of pure Cs4PbBr6 is attributed to charge transfer states of Pb2+ ions and surface states incorporated by presence of ligands on NC surface. Further, it is to be emphasized that the Cs4PbBr6 perovskite NCs are highly stable and maintain their emission even after two years of synthesis.

Learning generalizable AI models for multi-center histopathology image classification

Investigation of histopathology slides by pathologists is an indispensable component of the routine diagnosis of cancer. Artificial intelligence (AI) has the potential to enhance diagnostic accuracy, improve efficiency, and patient outcomes in clinical pathology. However, variations in tissue preparation, staining protocols, and histopathology slide digitization could result in over-fitting of deep learning models when trained on the data from only one center, thereby underscoring the necessity to generalize deep learning networks for multi-center use. Several techniques, including the use of grayscale images, color normalization techniques, and Adversarial Domain Adaptation (ADA) have been suggested to generalize deep learning algorithms, but there are limitations to their effectiveness and discriminability. Convolutional Neural Networks (CNNs) exhibit higher sensitivity to variations in the amplitude spectrum, whereas humans predominantly rely on phase-related components for object recognition. As such, we propose Adversarial fourIer-based Domain Adaptation (AIDA) which applies the advantages of a Fourier transform in adversarial domain adaptation. We conducted a comprehensive examination of subtype classification tasks in four cancers, incorporating cases from multiple medical centers. Specifically, the datasets included multi-center data for 1113 ovarian cancer cases, 247 pleural cancer cases, 422 bladder cancer cases, and 482 breast cancer cases. Our proposed approach significantly improved performance, achieving superior classification results in the target domain, surpassing the baseline, color augmentation and normalization techniques, and ADA. Furthermore, extensive pathologist reviews suggested that our proposed approach, AIDA, successfully identifies known histotype-specific features. This superior performance highlights AIDA’s potential in addressing generalization challenges in deep learning models for multi-center histopathology datasets.

Comparison of the Efficacy, Safety, and Quality of Life of Pegylated Liposomal Doxorubicin-Cyclophosphamide versus Epirubicin-Cyclophosphamide in Patients with Early-Stage HER2-Negative Breast Cancer: A Prospective, Randomized, Multicenter, Phase II Study

Plain Language SummaryThis study compared two chemotherapy treatments for human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer: one using a drug called pegylated liposomal doxorubicin (PLD) and the other using epirubicin. A total of 256 women with stage I or II breast cancer from multiple medical centers in Taiwan were included in this study. They were randomly assigned to receive either PLD or epirubicin along with another drug called cyclophosphamide. Traditional treatments like anthracyclines (including doxorubicin and epirubicin) have been widely used but can have serious side effects. PLD is a newer drug that seems to work as well as traditional anthracyclines but with fewer harmful effects. The study found that both treatments were equally effective in 5-year disease-free survival and overall survival. However, the PLD treatment caused fewer severe side effects, such as hair loss and blood-related problems. Also, patients who received PLD reported feeling better during and after treatment compared to those who received epirubicin. This study is one of the first to directly compare PLD and epirubicin in a randomized trial for HER2-negative early-stage breast cancer patients. The results suggest that PLD could be a treatment option for these patients, offering similar effectiveness with fewer side effects to epirubicin treatments.

Long-term outcomes in critically ill patients with acute respiratory failure.

This review aims to explore the latest evidence on long-term outcomes in patients admitted to the ICU because of acute respiratory failure (ARF). As the survival rate of critically ill patients with acute respiratory failure improves, long-term mortality and disability still influence the quality of life of survivors and their caregivers. Patients admitted to the ICU because of ARF are at risk of developing the postintensive care syndrome, which presents with physical, cognitive and mental symptoms, all of which may impair their quality of life. Caregivers seem to be affected as well, which may lead to intergenerational trauma. The need for more care, including prone positioning, invasive support (e.g. mechanical ventilation, ECMO) and deep sedation are probably adjunctive risk factors for poor long-term outcomes. There is not much data on the long-term outcomes of patients who have survived ARF. More follow-up studies should be conducted, especially in centers providing higher levels of costly care (e.g. ECMO). Randomized controlled trials on interventions for ARF should include patient-centered long-term outcomes in addition to mortality rates. The high mortality rates associated with ARF mandate collaboration among multiple centers to achieve an adequate sample size for studying the long-term outcomes of survivors.

A correlation of computed tomographic esophageal hiatal cross-sectional surface area between brachycephalic and nonbrachycephalic cats.

In humans and dogs, especially brachycephalics, enlargement of the esophageal hiatus and insufficiency have been correlated with decreased lower esophageal sphincter pressure and increased frequency of gastroesophageal reflux. In cats, it has been suggested that gastroesophageal reflux occurs frequently with upper airway obstruction, including brachycephalics. Therefore, the purpose of the study was to determine whether the esophageal hiatal cross-sectional surface area (EH-CSA) differs between brachycephalic and nonbrachycephalic cats. Clinical records and CT images of cats that underwent thoracic, abdominal, and entire skull CT at multiple centers between January 2015 and September 2022 were retrospectively reviewed. Esophageal hiatal parameters (EH-CSA, EH-long axis diameter, and EH-short axis diameter) and craniometric indices (cranial index, skull index, and facial index) were measured by using multiplanar reconstruction, and the correlation of craniometry with EH-CSA was investigated. Ninety-eight cats (group 1: 42 brachycephalic cats and group 2: 56 nonbrachycephalic cats) were included. Esophageal hiatal cross-sectional surface area in brachycephalic cats was significantly larger than that in nonbrachycephalic cats. The EH-CSA significantly increased with the craniometric indices tending to increase with brachycephalism. The present study contributes to the veterinary literature by providing the EH-CSA as anatomical evidence that could likely correlate to gastroesophageal reflux predisposition in brachycephalic cats.

Does adding coenzyme Q10 to dehydroepiandrosterone sulphate positively impact fertility outcomes in young, poor responder infertile women undergoing antagonist protocol for IVF/ICSI cycles?

Background. One of the biggest issues in reproductive medicine is treating women with low ovarian reserves or a poor ovarian response (POR) to stimulation. Oxidative stress was suggested as one of the major contributors to POR. However, the pathophysiology remains unknown. Focusing on certain subpopulations within the diverse group of poor responders may help determine the best therapy for these patients. Objective. To investigate the effect of adding coenzyme A Q10 to dehydroepiandrosterone (DHEA) in young, poor responder infertile females undergoing in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Methods. One hundred and sixty-eight females with poor ovarian response (Poseidon Group 3) from multiple centres were randomly divided into two groups. The first group received DHEA orally along with coenzyme 10, while the second group received only DHEA. Both groups underwent controlled ovarian stimulation. Results. There was a significant improvement in the quality of oocytes and the number and quality of embryos transferred in the coenzyme A Q10 group. However, no significant differences were observed in other parameters between the groups. Conclusion. In young, poor-responder women with decreased ovarian reserve, pretreatment with CoQ10 enhances oocyte and embryo quality and boosts ovarian response to stimulation. An improvement in clinical pregnancy and live birth rates may be possible.

Constructing Pd and Cu Crowding Single Atoms by Protein Confinement to Promote Sonogashira Reaction.

For multicenter-catalyzed reactions, it is important to accurately construct heterogeneous catalysts containing multiple active centers with high activity and low cost, whichis more challenging compared to homogeneous catalysts because of the low activity and spatial confinement of active centers in the loaded state. Herein, a convenient protein confinement strategy is reported to locate Pd and Cu single atoms in crowding state on carbon coated alumina for promoting Sonogashira reaction, the most powerful method for constructing the acetylenic moiety in molecules. The single-atomic Pd and Cu centers take advantage in not only the maximized atomic utilization for low cost, but also the much-enhanced performance by facilitating the activation of aryl halides and alkynes. Their locally crowded dispersion brings them closer to each other, which facilitates the transmetallation process of acetylide intermediates between them. Thus, the Sonogashira reaction is drove smoothly by the obtained catalyst with a turnover frequency value of 313 h-1, much more efficiently than that by commercial Pd/C and CuI catalyst, conventional Pd and Cu nanocatalysts, and mixed Pd and Cu single-atom catalyst. The obtained catalyst also exhibits the outstanding durability in the recycling test.

Genetic polymorphisms and their correlation with dyslipidemia in Chinese patients diagnosed with diabetes mellitus.

Dyslipidemia is a common complication in patients with diabetes mellitus (DM) that increases the risk of cardiovascular disease. Genetic polymorphisms have been implicated in the development of dyslipidemia. To investigate the association between polymorphisms of candidate genes involved in lipid metabolism and dyslipidemia in Chinese patients with DM. A cross-sectional study was conducted on 1098 Chinese patients with DM recruited from multiple healthcare centers. Demographic and clinical data were collected, and dyslipidemia was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Genomic DNA was extracted from blood samples and genotyping for selected polymorphisms of candidate genes (APOE, LPL, CETP, and others) was performed using PCR and DNA sequencing techniques. Statistical analyses were performed using logistic regression models adjusted for potential confounding factors. The study population consisted of 578 males (52.6%) and 520 females (47.4%), with a mean age of 58.4 ± 12.2 years. The prevalence of dyslipidemia was 64.8%. Significant associations were found between dyslipidemia and the APOE rs7412 T/T, APOE rs429358 C/C, LPL rs328 G/G, and CETP rs708272 G/G genotypes after adjusting for covariates. Subgroup analyses showed generally consistent associations across subgroups, although some variations in effect sizes were observed. This study identified significant associations between genetic polymorphisms of APOE, LPL, and CETP genes and dyslipidemia in Chinese patients with DM.

Tunable cold/warm white light emitting devices based on carbon dots with multiple emissive centers

The correlated color temperature (CCT) of lighting is closely related to human emotions. However, there is still a relative lack of white light emitting devices (W-LEDs) with tunable CCT to meet application demands in different scenarios. Here, we develop a W-LED with tunable CCT based on multiple emissive centers of carbon dots (CDots) synthesized through controlled thermal carbonization of citric acid and urea. The reaction at 160 °C for 4 h results in amorphous CDots, which exhibit excitation wavelength dependent photoluminescence (PL) containing two peaks at 446 and 520 nm. However, by increasing the reaction temperature and duration, crystalline CDots are obtained, which show broad PL peaking at 650 nm. Based on their complementary spectral ranges, a W-LED with an extremely high color rendering index of 96 is demonstrated. Moreover, a W-LED with both 365 and 405 nm electroluminescent chips is designed. The W-LED shifts from cold to warm white, when the excitation chips switch from 365 to 405 nm. This adjustable CCT can create a harmonious, enjoyable, and safe lighting environment to meet the demands of different scenes.

Regulating Planarized Intramolecular Charge Transfer for Efficient Single-Phase White-Light Emission in Undoped Metal-Organic Framework Nanocrystals.

The technology of combining multiple emission centers to exploit white-light-emitting (WLE) materials by taking advantage of porous metal-organic frameworks (MOFs) is mature, but preparing undoped WLE MOFs remains a challenge. Herein, a pressure-treated strategy is reported to achieve efficient white photoluminescence (PL) in undoped [Zn(Tdc)(py)]n nanocrystals (NCs) at ambient conditions, where the Commission International del'Eclairage coordinates and color temperature reach (0.31, 0.37) and 6560 K, respectively. The initial [Zn(Tdc)(py)]n NCs exhibit weak-blue PL consisting of localized excited (LE) and planarized intramolecular charge transfer (PLICT) states. After pressure treatment, the emission contributions of LE and PLICT states are balanced by increasing the planarization of subunits, thereby producing white PL. Meanwhile, the reduction of nonradiative decay triggered by the planarized structure results in 5-fold PL enhancement. Phosphor-converted light-emitting diodes based on pressure-treated samples show favorable white-light characteristics. The finding provides a new platform for the development of undoped WLE MOFs.

Rh(II)-Catalyzed Enantioselective S-Alkylation of Sulfenamides with Acceptor-Acceptor Diazo Compounds Enables the Synthesis of Sulfoximines Displaying Diverse Functionality.

The Rh(II)-catalyzed enantioselective S-alkylation of sulfenamides with α-amide diazoacetates at 1 mol % catalyst loading to obtain sulfilimines in high yields and enantiomeric ratios of up to 99:1 is reported. The enantioenriched sulfilimine products incorporate versatile amide functionality poised for further elaboration to diverse sulfoximines with multiple stereogenic centers, including by highly diastereoselective sulfilimine and sulfoximine α-alkylation with alkylating agents and epoxides and by interconversion of the amide to N-tert-butanesulfinyl aldimines, followed by diastereoselective additions.

Zero-Bias Anti-Ohmic Behaviour in Diradicaloid Molecular Wires.

Open-shell materials bearing multiple spin centres provide a key route to efficient charge transport in single-molecule electronic devices. They have narrow energy gaps, and their molecular orbitals align closely to the Fermi level of the metallic electrodes, thus allowing efficient electronic transport and higher conductance. Maintaining and stabilising multiple open-shell states-especially in contact with metallic electrodes-is however very challenging, generally requiring a continuous chemical or electrochemical potential to avoid self-immolation of the open-shell character. To overcome this issue, we designed, synthesised, and measured the conductance of a series of bis(indeno) fused acenes, where stability is imparted by a close-shell quinoidal conformation in resonance with the diradical electronic configuration. We show here that these compounds have anti-ohmic behaviour, with conductance increasing with increasing molecular length, at an unprecedented rate and across the entire bias window ( ). Density Functional Theory (DFT) calculations support our findings, showing the rapidly narrowing HOMO-LUMO gap, unique to these diradicaloid structures, is responsible for the observed behaviour. Our results provide a framework for achieving efficient transport in neutral compounds and demonstrate the promise that diradicaloid materials have in single-molecule electronics, owing to their great stability and unique electronic structure.

The volcanic architecture and tectono-magmatic framework of the Mount Grace carbonatites, southeastern Canadian Cordillera

The Mount Grace metamorphosed carbonatites (Late Devonian) outcrop as thin (0.5–4 m), laterally discontinuous, strata-bound mappable lenses within the Monashee complex of the southeastern Canadian Cordillera. The host stratigraphic sequence (Monashee cover gneiss) was metamorphosed and deformed in the Late Cretaceous to early Eocene followed immediately by exhumation of the Frenchman Cap and Thor Odin domes. We present seven stratigraphic logs for Mount Grace carbonatites including new and previously described outcroppings spanning ∼30 km. The Mount Grace carbonatite units were deposited regionally within or near the top of a shallow marine sedimentary sequence within miogeoclinal strata of the western margin of paleo-North America (Laurentia). The distribution of the Mount Grace carbonatite lithofacies and the preserved depositional structures and textures suggest that these are pyroclastic deposits resulting from phreatomagmatic eruptions. Our new data enhance the volcanological story with an eruption scenario involving phreatomagmatic reactions and deposition from pyroclastic density currents, sourced from multiple centers within a field of monogenetic maar volcanoes. The distribution of the Mount Grace carbonatites parallel to the western margin of the paleo-North American continent correlates well with regional Late Devonian alkaline magmatism associated with development of an extensional back-arc basin.

Production scheduling decision-making technology for multiple CNC machining centers with constraints on serviceable time

Production scheduling decision-making technology for multiple CNC machining centers with constraints on serviceable time

Size‐Dependent Optical Properties and Exciton Self‐Trapping Emission in Carbon Quantum Dots

AbstractCarbon quantum dots (CQDs), synthesized through controlled microplasma treatment of orange juice, exhibit unique luminescent characteristics. The impact of synthesis time on particle size was investigated. Deconvoluted emission spectra displayed broad bands, peaking at an excitation wavelength of 350 nm for CQD sizes of 2.06, 2.4, and 3.09 nm, indicating multiple fluorescence peaks. This suggests a mixture of CQDs with different excitation energies on their surfaces. Luminescence kinetics unveiled three exponential decay components with time constants of 2.73, 4.61, and 3.27 ns, indicating multiple luminescent centers. Emission behavior affected by excitation wavelengths ranging from 350 to 490 nm suggests that quantum transition probabilities are influenced by impurities or defects. These findings emphasize the size‐dependent optical properties and exciton self‐trapping (EST) emission of CQDs. The calculation of the Huang‐Rhys factor S values underscores the profound influence of carrier‐phonon coupling and the Huang‐Rhys factor on the emergence of ESTs within CQDs. Understanding these interactions is crucial for fully utilizing the capabilities of CQDs in applications spanning optoelectronics, sensors, bioimaging, and various technological fields.

Validation of the German version of the Asthma Impairment and Risk Questionnaire (AIRQ).

The Asthma Impairment and Risk Questionnaire (AIRQ), a 10-item, equally weighted, yes/no tool assessing symptom impairment and risk of exacerbations in patients with asthma aged ≥12 years, was developed and validated in a US patient population to evaluate varying levels of asthma control. This study aimed to validate the German language version of the AIRQ in patients aged ≥12 years with different levels of asthma control. A cross-sectional, observational, multi-centre study comprising a single visit was conducted in multiple specialised asthma centres and general practices in Germany. A total of 300 patients completed the following measures: 1) Patient Sociodemographic and Clinical Questionnaire, 2) AIRQ, 3) Asthma Control Test (ACT), and 4) Asthma Control Questionnaire (ACQ-6). Logistic regression analyses were conducted to assess the AIRQ score cut points with the greatest predictive validity in discriminating between different control levels relative to a standard of ACT plus prior-year exacerbations or ACQ-6 plus prior-year exacerbations. The German version of the AIRQ demonstrated a robust capability to correctly identify well-controlled versus not well- or very poorly controlled (AUC values of 0.90 or higher) and well- or not well-controlled versus very poorly controlled asthma (AUC values of 0.89 or higher). The German version of the AIRQ is a suitable tool to identify adults with varying levels of asthma control, which in turn can help to accurately identify patients with uncontrolled asthma in clinical practice.

Unsymmetric Co-Facial "Salixpyrrole" Hydrogen Evolution Catalysts: Two Metals are Better than One.

Designing ligand architectures that can mimic enzyme active sites is a promising approach for developing efficient small molecule activation catalysts for sustainable energy applications. Some key design features include chemically distinct binding pockets for multiple metal centers and a three-dimensional structure that controls the positioning of catalytic sites. With these principles in mind, mono- and bimetallic unsymmetric cofacial palladium complexes, 2 and 3, respectively, bearing ligands with calixpyrrole and salen coordination sites, or "salixpyrrole" ligands, are reported. These species were accessed in a straightforward Schiff-base reaction with appreciable yields. In addition, both 2 and 3 were found to be active hydrogen evolution electrocatalysts using para-toluenesulfonic acid monohydrate as the proton source. The two salixpyrrole species displayed different mechanisms of action, with 2 showing a second-order dependence on acid concentration, whereas 3 exhibited a first-order dependence. Moreover, the bimetallic catalyst was significantly more efficient, with higher turnover frequencies, 4640 s-1 vs 1680 s-1 for 2, and lower overpotentials, 0.39 V vs 0.69 V for 2. The results reported herein provide proof-of-concept that bimetallic catalysts with chemically distinct binding sites demonstrate enhanced catalytic properties in comparison to monometallic or symmetric analogues.