Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking.

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

Novel Providencia xianensis sp. nov.: A multidrug-resistant species identified in clinical infections.

Providencia genus is known to harbor certain opportunistic pathogens capable of causing human infections. Here, we report two strains of multidrug-resistant bacteria initially identified as Providencia rettgeri by mass spectrometry, but genome analysis revealed their ANI (79.84-84.20%) and dDDH (21.1-25.6%) values to fall below the accepted species threshold for known Providencia species. We therefore propose that these isolates be recognized as a novel species, Providencia xianensis sp. nov. Alarmingly, both strains, isolated from locations far apart, exhibited resistance to last-resort antibiotics, indicating their possible wide distribution, underscoring the urgency for immediate attention and enhanced surveillance for this emerging multidrug-resistant pathogen.

Design, synthesis, in vitro and in vivo evaluation and molecular docking study of novel pleuromutilin derivatives as antibacterial agents.

14 novel pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). The modification was focused on the C22 position of pleuromutilin. We conducted the characterization, in vitro and in vivo biological assessment of the compounds. Compound 18 exhibited the best antibacterial effect against MRSA (MIC = 0.015 µg/mL, MBC = 0.125 µg/mL). Compound 18 was further studied by time-kill kinetic and post-antibiotic effect (PAE) approaches. Besides, most compounds exhibited low cytotoxicity to RAW 264.7 cells. Compound 18 displayed decent bactericidal activity in vivo (-0.51 log10 CFU/mL). Molecular docking study indicated that compound 18 could be located stably at the ribosome (ΔGb = -7.30 kcal/mol). The results revealed that compound 18 might be further developed into a novel antibiotic.

Reviving Bistable Perception in Patients With Depression by Decreasing the Overestimation of Prior Precision.

Slower perceptual alternations, a notable perceptual effect observed in psychiatric disorders, can be alleviated by antidepressant therapies that affect serotonin levels in the brain. While these phenomena have been well documented, the underlying neurocognitive mechanisms remain to be elucidated. Our study bridges this gap by employing a computational cognitive approach within a Bayesian predictive coding framework to explore these mechanisms in depression. We fitted a prediction error (PE) model to behavioral data from a binocular rivalry task, uncovering that significantly higher initial prior precision and lower PE led to a slower switch rate in patients with depression. Furthermore, serotonin-targeting antidepressant treatments significantly decreased the prior precision and increased PE, both of which were predictive of improvements in the perceptual alternation rate of depression patients. These findings indicated that the substantially slower perception switch rate in patients with depression was caused by the greater reliance on top-down priors and that serotonin treatment's efficacy was in its recalibration of these priors and enhancement of PE. Our study not only elucidates the cognitive underpinnings of depression, but also suggests computational modeling as a potent tool for integrating cognitive science with clinical psychology, advancing our understanding and treatment of cognitive impairments in depression.

Composite antiferromagnetic and orbital order with altermagnetic properties at a cuprate/manganite interface.

Heterostructures from complex oxides allow one to combine various electronic and magnetic orders as to induce new quantum states. A prominent example is the coupling between superconducting and magnetic orders in multilayers from high-Tc cuprates and manganites. A key role is played here by the interfacial CuO2 layer whose distinct properties remain to be fully understood. Here, we study with resonant inelastic X-ray scattering the magnon excitations of this interfacial CuO2 layer. In particular, we show that the underlying antiferromagnetic exchange interaction at the interface is strongly suppressed to J≈70 meV, when compared with J≈130 meV for the CuO2 layers away from the interface. Moreover, we observe an anomalous momentum dependence of the intensity of the interfacial magnon mode and show that it suggests that the antiferromagnetic order is accompanied by a particular kind of orbital order that yields a so-called altermagnetic state. Such a 2D altermagnet has recently been predicted to enable new spintronic applications and superconducting proximity effects.

Effects of Huangqi Gancao Decoction on intestinal immunity and microbiota in immunocompromised mice models.

Background: The classical medicinal formula Huangqi Gancao Decoction (HQGCD), originating from the medical book" Yi Lin Gai Cuo". Up to now, the studies focusing on the immunoenhancement effects of HQGCD are few, and the actionpathway is not yet clear. Method: In this study, SPF male KM mice were utilized as a model for immunosuppression. Comprehensive observations were made regarding the general behavior and condition of the mice, in addition to monitoring fluctuations in body weight and food intake. The blood routine index was measured, and morphological changes in the ileum and colon tissues were examined. The level of secretory immunoglobulin A (sIgA), superoxide dismutase (SOD), and malondialdehyde (MDA) in ileum and colon tissues were quantified. Additionally, the bone marrow total DNA index was assessed. Flow cytometry analyzed the proportions of CD3⁺, CD4⁺, CD8⁺, and CD4+CD8+ double-positive (DP) T lymphocytes in small intestinal intraepithelial lymphocytes (IELs). Lastly, the composition and diversity of the cecal microbiota were evaluated using 16S rDNA sequencing technology. Results: After HQGCD intervention, there were no significant changes in the mice's feed intake and body weight. However, the tissue structures of the ileum and colon showed recovery. In the blood routine index, there was an increase in the total white blood cell count, lymphocyte count, red blood cell count, hematocrit, and hemoglobin content. Additionally, the bone marrow total DNA index was elevated. Level of SOD and sIgA in ileum and colon tissues increased, while the level of MDA decreased. The proportions of CD3⁺ and CD4⁺ T lymphocytes within IELs increased, along with an increase in DP T lymphocytes in IELs (DP IELs), whereas the proportion of CD8⁺ T lymphocytes decreased. The cecal microbiota underwent changes, with an increase in the variety and number of beneficial microbiota. Conclusion: HQGCD could restore the intestinal immune function of immunocompromised mice, and had a certain positive effect on cecal microbiota.

Scalable Dual In Situ Synthesis of Polyester Nanocomposites for High-Energy Storage.

Incorporating ultralow loading of nanoparticles into polymers has realized increases in dielectric constant and breakdown strength for excellent energy storage. However, there are still a series of tough issues to be dealt with, such as organic solvent uses, which face enormous challenges in scalable preparation. Here, a new strategy of dual in situ synthesis is proposed, namely polymerization of polyethylene terephthalate (PET) synchronizes with growth of calcium borate nanoparticles, making polyester nanocomposites from monomers directly. Importantly, this route is free of organic solvents and surface modification of nanoparticles, which is readily accessible to scalable synthesis of polyester nanocomposites. Meanwhile, uniform dispersion of as ultralow as 0.1 wt% nanoparticles and intense bonding at interfaces have been observed. Furthermore, the PET-based nanocomposite displays obvious increases in both dielectric constant and breakdown strength as compared to the neat PET. Its maximum discharged energy density reaches 15 J cm-3 at 690 MV m-1 and power density attains 218 MW cm-3 under 150 Ω resistance at 300 MV m-1, which is far superior to the current dielectric polymers that can be produced at large scales. This work presents a scalable, safe, low-cost, and environment-friendly route toward polymer nanocomposites with superior capacitive performance.

Identifying potential drug targets for idiopathic pulmonary fibrosis: a mendelian randomization study based on the druggable genes.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic interstitial lung disease characterized by progressive dyspnea and decreased lung function, yet its exact etiology remains unclear. It is of great significance to discover new drug targets for IPF. METHODS: We obtained the cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium as exposure and the genome wide association study (GWAS) of IPF from the International IPF Genetics Consortium as outcomes to simulate the effects of drugs on IPF by employing mendelian randomization analysis. Then colocalization analysis was performed to calculate the probability of both cis-eQTL of druggable genes and IPF sharing a causal variant. For further validation, we conducted protein quantitative trait locus (pQTL) analysis to reaffirm our findings. RESULTS: The expression of 45 druggable genes was significantly associated with IPF susceptibility at FDR < 0.05. The expression of 23 and 15 druggable genes was significantly associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLco) in IPF patients, respectively. IPF susceptibility and two significant genes (IL-7 and ABCB2) were likely to share a causal variant. The results of the pQTL analysis demonstrated that high levels of IL-7 in plasma are associated with a reduced risk of IPF (OR = 0.67, 95%CI: 0.47-0.97). CONCLUSION: IL-7 stands out as the most promising potential drug target to mitigate the risk of IPF. Our study not only sheds light on potential drug targets but also provides a direction for future drug development in IPF.

Exosomes regulate doxorubicin resistance in breast cancer via miR-34a-5p/NOTCH1.

Breast cancer (BRCA) is the most common cancer among women. Adriamycin (ADR), also known as doxorubicin (Dox), is a commonly used chemotherapeutic agent for BRCA patients, however, the susceptibility of tumor cells to develop resistance to Dox has severely limited its clinical use. One new promising therapeutic target for breast cancer patients is exosomes. The objective of this study was to investigate the role of exosomes in regulating Dox resistance in BRCA. In this study, the exosomes from both types of cells were extracted by differential centrifugation. The effect of exosomes on drug resistance was assessed by laser confocal microscopy, MTT assay, and qRT-PCR. The miRNA was transfected into cells using Lipofectamine 2000, which was then evaluated for downstream genes and changes in drug resistance. Exosomes from MCF-7 cells (MCF-7/exo) and MCF-7/ADR cells (ADR/exo) were effectively extracted in this study. The ADR/exo was able to endocytose MCF-7 cells and make them considerably more resistant to Dox. Moreover, we observed a significant difference in miR-34a-5p expression in MCF-7/ADR and ADR/exo compared to MCF-7 and MCF-7/exo. Among the miR-34a-5p target genes, NOTCH1 displayed a clear change with a negative correlation. In addition, when miR-34a-5p expression was elevated in MCF-7/ADR cells, the expression of miR-34a-5p in ADR/exo was also enhanced alongside NOTCH1, implying that exosomes may carry miRNA into and out of cells and perform their function. In conclusion, exosomes can influence Dox resistance in breast cancer cells by regulating miR-34a-5p/NOTCH1. These findings provide novel insights for research into the causes of tumor resistance and the enhancement of chemotherapy efficacy in breast cancer.

Imaging characteristics and treatment strategies for carotid artery occlusion caused by skull base fracture: Three case reports.

BACKGROUND: Traumatic internal carotid artery (ICA) occlusion is a rare complication of skull base fractures, characterized by high mortality and disability rates, and poor prognosis. Therefore, timely discovery and correct management are crucial for saving the lives of such patients and improving their prognosis. This article retrospectively analyzed the imaging and clinical data of three patients, to explore the imaging characteristics and treatment strategies for carotid artery occlusion, combined with severe skull base fractures. CASE SUMMARY: This case included three patients, all male, aged 21, 63, and 16 years. They underwent plain film skull computed tomography (CT) examination at the onset of their illnesses, which revealed fractures at the bases of their skulls. Ultimately, these cases were definitively diagnosed through CT angiography (CTA) examinations. The first patient did not receive surgical treatment, only anticoagulation therapy, and recovered smoothly with no residual limb dysfunction (Case 1). The other two patients both developed intracranial hypertension and underwent decompressive craniectomy. One of these patients had high intracranial pressure and significant brain swelling postoperatively, leading the family to choose to take him home (Case 2). The other patient also underwent decompressive craniectomy and recovered well postoperatively with only mild limb motor dysfunction (Case 3). We retrieved literature from PubMed on skull base fractures causing ICA occlusion to determine the imaging characteristics and treatment strategies for this type of disease. CONCLUSION: For patients with cranial trauma combined with skull base fractures, it is essential to complete a CTA examination as soon as possible, to screen for blunt cerebrovascular injury.

DASUNet: a deeply supervised change detection network integrating full-scale features.

The change detection (CD) technology has greatly improved the ability to interpret land surface changes. Deep learning (DL) methods have been widely used in the field of CD due to its high detection accuracy and application range. DL-based CD methods usually cannot fuse the extracted feature information at full scale, leaving out effective information, and commonly use transfer learning methods, which rely on the original dataset and training weights. To address the above issues, we propose a deeply supervised (DS) change detection network (DASUNet) that fuses full-scale features, which adopts a Siamese architecture, fuses full-scale feature information, and realizes end-to-end training. In order to obtain higher feature information, the network uses atrous spatial pyramid pooling (ASPP) module in the coding stage. In addition, the DS module is used in the decoding stage to exploit feature information at each scale in the final prediction. The experimental comparison shows that the proposed network has the current state-of-the-art performance on the CDD and the WHU-CD, reaching 94.32% and 90.37% on F1, respectively.

Did the COVID-19 pandemic delay treatment for localized breast cancer patients? A multicenter study.

BACKGROUND: Longer times between diagnosis and treatments of cancer patients have been estimated as effects of the COVID-19 pandemic. However, relatively few studies attempted to estimate actual delay to treatment at the patient level. OBJECTIVE: To assess changes in delays to first treatment and surgery among newly diagnosed patients with localized breast cancer (BC) during the COVID-19 pandemic. METHODS: We used data from the PAPESCO-19 multicenter cohort study, which included patients from 4 French comprehensive cancer centers. We measured the delay to first treatment as the number of days between diagnosis and the first treatment regardless of whether this was neoadjuvant chemotherapy or surgery. COVID-19 pandemic exposure was estimated with a composite index that considered both the severity of the pandemic and the level of lockdown restrictions. We ran generalized linear models with a log link function and a gamma distribution to model the association between delay and the pandemic. RESULTS: Of the 187 patients included in the analysis, the median delay to first treatment was 42 (IQR:32-54) days for patients diagnosed before and after the start of the 1st lockdown (N = 99 and 88, respectively). After adjusting for age and centers of inclusion, a higher composite pandemic index (> = 50 V.S. <50) had only a small, non-significant effect on times to treatment. Longer delays were associated with factors other than the COVID-19 pandemic. CONCLUSION: We found evidence of no direct impact of the pandemic on the actual delay to treatment among patients with localized BC.

Orienting role of the putative human posterior infero-temporal area in visual attention.

The dorsal attention network (DAN) is a network of brain regions essential for attentional orienting, which includes the lateral intraparietal area (LIP) and frontal eye field (FEF). Recently, the putative human dorsal posterior infero-temporal area (phPITd) has been identified as a new node of the DAN. However, its functional relationship with other areas of the DAN and its specific role in visual attention remained unclear. In this study, we analyzed a large publicly available neuroimaging dataset to investigate the intrinsic functional connectivities (FCs) of the phPITd with other brain areas. The results showed that the intrinsic FCs of the phPITd with the areas of the visual network and the DAN were significantly stronger than those with the ventral attention network (VAN) areas and areas of other networks. We further conducted individual difference analyses with a sample size of 295 participants and a series of attentional tasks to investigate which attentional components each phPITd-based DAN edge predicts. Our findings revealed that the intrinsic FC of the left phPITd with the LIPv could predict individual ability in attentional orienting, but not in alerting, executive control, and distractor suppression. Our results not only provide direct evidence of the phPITd's functional relationship with the LIPv, but also offer a comprehensive understanding of its specific role in visual attention.

Directly Converting Bulk Wood into Branch Micro-Nano Fibers to Synergistically Enhance the Strength and Toughness via Interface Engineering.

Hierarchical biobased micro/nanomaterials offer great potential as the next-generation building blocks for robust films or macroscopic fibers with high strength, while their capability in suppressing crack propagation when subject to damage is hindered by their limited length. Herein, we employed an approach to directly convert bulk wood into fibers with a high aspect ratio and nanosized branching structures. Particularly, the length of microfibers surpassed 1 mm with that of the nanosized branches reaching up to 300 µm. The presence of both interwoven micro- and nanofibers endowed the product with substantially improved tensile strength (393.99 MPa) and toughness (19.07 MJ m-3). The unique mechanical properties arose from mutual filling and the hierarchical deformation facilitated by branched nanofibers, which collectively contributed to effective energy dissipation. Hence, the nanotransformation strategy opens the door toward a facial, scalable method for building high-strength film or macroscopic fibers available in various advanced applications.

The effects of the predictability of acclimatory temperature on the growth and thermal tolerance of juvenile Spinibarbus sinensis.

Heated effluent injection, cold hypolimnetic water inputs from dams, and extreme weather events can lead to unpredictable temperature fluctuations in natural waters, impacting fish performance and fitness. We hypothesized that fish exposed to such unpredictable fluctuations would exhibit weaker growth and enhanced thermal tolerance compared to predictable conditions. Qingbo (Spinibarbus sinensis) was selected as the experimental subject in this study. The qingbo were divided into a constant temperature group (C, 22 ± 0.5 °C), a predictable temperature fluctuation group (PF, 22 ± 4 °C, first warming, then cooling within a day) and an unpredictable temperature fluctuation group (UF, 22 ± 4 °C, the order of warming or cooling is random). After 40 days of temperature acclimation, the growth, metabolic rate, spontaneous activity, thermal tolerance, plasma cortisol concentration and liver hsp70 level of the fish were measured. Unexpectedly, neither the PF nor the UF group showed decreased growth compared to the C group. This could be attributed to the fact that temperature variation did not lead to a substantial increase in basic energy expenditure. Furthermore, feeding rates increased due to temperature fluctuations, although the difference was not significant. Both the PF and UF groups exhibited increased upper thermal tolerance, but only the UF group exhibited improved lower thermal tolerance and higher liver hsp70 levels compared to the C group. The qingbo that experienced unpredictable temperature fluctuations had the best thermal tolerance among the 3 groups, which might have occurred because they had the highest level of hsp70 expression. This may safeguard fish against the potential lethal consequences of extreme temperatures in the future. These findings suggested that qingbo exhibited excellent adaptability to both predictable and unpredictable temperature fluctuations, which may be associated with frequent temperature fluctuations in its natural habitat.

Factors Influencing Adherence to the Risk Management Program for Women With a Genetic Predisposition to Breast Cancer: Real-World Data from a French Multicenter Program.

BACKGROUND: Risk management programs targeting women with genetic predispositions to breast cancer (BC), eg, BRCA1 and BRCA2, are effective assuming full adherence with the program protocol. However, high risk to BC in women and equal access to care may not result in high and uniform adherence with the program. OBJECTIVE: To elucidate factors influencing adherence with screening program in women with genetic predispositions to BC. MATERIAL AND METHODS: We retrieved data from a multicenter pathogenic-related BC surveillance program across 4 French regions. We used multilevel logistic modeling to analyze factors of adherence with the program, with "on-time" or postponed screening as the dependent variable. RESULTS: Seven hundred and seventy-eight participants were followed for a 4.7-year median. We observed 2796 annual screening rounds and 5.4% postponed rounds with a 6-month margin. Women with prevalent BC and carriers of BRCA1 and BRCA2 mutations did not have on-time annual screenings any more than women low cancer risk. Better adherence was observed with screenings after the 2nd round, with higher total number of rounds. Having one or more recalls was significantly associated with worse adherence. No contextual factors affected adherence. Furthermore, postponed rounds increased between 2018 and 2020 compared to 2015 and 2017. CONCLUSION: Having a higher BC risk status does not result in better adherence to the risk management program. However, factors directly related to screening rounds reduced postponements. Future research should address the benefits of screening-related organizational factors that contribute to adherence improvement.

SmEIL1 transcription factor inhibits tanshinone accumulation in response to ethylene signaling in Salvia miltiorrhiza.

Among the bioactive compounds, lipid-soluble tanshinone is present in Salvia miltiorrhiza, a medicinal plant species. While it is known that ethephon has the ability to inhibit the tanshinones biosynthesis in the S. miltiorrhiza hairy root, however the underlying regulatory mechanism remains obscure. In this study, using the transcriptome dataset of the S. miltiorrhiza hairy root induced by ethephon, an ethylene-responsive transcriptional factor EIN3-like 1 (SmEIL1) was identified. The SmEIL1 protein was found to be localized in the nuclei, and confirmed by the transient transformation observed in tobacco leaves. The overexpression of SmEIL1 was able to inhibit the tanshinones accumulation to a large degree, as well as down-regulate tanshinones biosynthetic genes including SmGGPPS1, SmHMGR1, SmHMGS1, SmCPS1, SmKSL1 and SmCYP76AH1. These are well recognized participants in the tanshinones biosynthesis pathway. Further investigation on the SmEIL1 was observed to inhibit the transcription of the CPS1 gene by the Dual-Luciferase (Dual-LUC) and yeast one-hybrid (Y1H) assays. The data in this work will be of value regarding the involvement of EILs in regulating the biosynthesis of tanshinones and lay the foundation for the metabolic engineering of bioactive ingredients in S. miltiorrhiza.

Positive buttress reduction in femoral neck fractures: a literature review.

BACKGROUND: Femoral neck fractures (FNFs) in young adults are usually caused by high-energy trauma, and their treatment remains a challenging issue for orthopedic surgeons. The quality of reduction is considered an important factor in improving the poor prognosis of patients with FNFs. In recent years, positive buttress closed reduction technique has received widespread attention in the treatment of FNFs. This comprehensive literature review is designed to encapsulate the impacts of both non-anatomic and anatomic reduction on the biomechanical stability, clinical outcomes, and postoperative complications in the management of FNFs, conjecture the efficacy of positively braced reduction techniques and provide a thorough summarization of the clinical outcomes. METHODS: In this literature review, we have examined all clinical and biomechanical studies related to the treatment of FNFs using non-anatomical reduction or positive and negative buttress reduction. PubMed, Web of Science, Google Scholar and Embase Library databases were searched systematically for studies published before September 1, 2023. Published literature on fracture reduction techniques for treating FNFs was reviewed. In addition, we evaluated the included literature using the MINORs tool. RESULTS: Although the "arch bridge" structure formed by the positive buttress reduction technique improved the support to the cortical bone and provided a more stable biomechanical structure, no significant differences were noted in the clinical efficacy and incidence of postoperative complications between the positive buttress reduction and anatomical reduction. CONCLUSION: Positive buttress reduction is an effective treatment method for young patients with FNFs. When facing difficult-to-reduce FNF, positive buttress reduction should be considered first, followed by anatomical reduction. However, negative buttress reduction should be avoided.

Intrinsic capacity assessment using World Health Organization Integrated Care for Older People Step 1, and the association with frailty in community dwelling older adults.

AIM: This study aimed to investigate the association between intrinsic capacity (IC) and frailty in community-dwelling older adults. Specifically, we examined the utility of the World Health Organization's Integrated Care for Older People Step 1 screen for identifying frail older persons in the community. METHODS: This is a cross-sectional analysis of a community frailty screening initiative. IC loss was ascertained using the World Health Organization's Integrated Care for Older People Step 1 questions. The Clinical Frailty Scale was used to categorize participants as robust (Clinical Frailty Scale S1-3) or frail (Clinical Frailty Scale ≥4). Logistic regression was used to analyze the association of individual and cumulative IC losses with frailty, adjusting for confounders. Additionally, the diagnostic performance of using cumulative IC losses to identify frailty was assessed. RESULTS: This study included 1164 participants (28.2% frail). Loss in locomotion (adjusted odds ratio [AOR] 1.47, 95% CI 1.07-2.02), vitality (AOR 1.58, 95% CI 1.04-2.39), sensory (AOR 1.99, 95% CI 1.51-2.64) and psychological capacities (AOR 1.92, 95% CI 1.45-2.56) were significantly associated with frailty. Loss in more than three IC domains was associated with frailty. Using loss in at least three ICs identifies frailty, with sensitivity of 38.6%, specificity of 83.5% and positive predictive value of 47.4%. Using loss in at least four ICs improved specificity to 96.9%, and is associated with the highest positive predictive value of 57.6% and highest positive likelihood ratio of 3.55 for frailty among all cut-off values. The area under the receiver operating characteristic curve was 0.64 (95% CI 0.61-0.68). CONCLUSIONS: IC loss as identified through World Health Organization's Integrated Care for Older People Step 1 is associated with frailty community-dwelling older adults. Geriatr Gerontol Int 2024; 24: 457-463.