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The validity and reliability of the Lafayette stability platform are well-established for double leg testing. However, no evaluation of single leg (SL) stance on the platform was discovered yet. Therefore, this study aimed to investigate the reliability of conducting the SL stance on the Lafayette platform. Thirty-six healthy and active university students (age 23.2 ± 3.2 years; BMI 21.1 ± 3.1 kg/m2) were tested twice, one week apart (week 1; W1, week 2; W2). They stood on their dominant leg with eyes-open (EO) and eyes-closed (EC) in random order. Three successful trials of 20 seconds each were recorded. The duration during which the platform was maintained within 0° of tilt was referred to as time in balance (TIB). At all-time points, TIB was consistently longer in EO (EOW1: 17.02 ± 1.04s; EOW2: 17.32 ± 1.03s) compared to EC (ECW1: 11.55 ± 1.73s; ECW2: 13.08 ± 1.82s). A ±10 seconds difference was demonstrated in the Bland-Altman analysis in both EO and EC. Lower standard error of measurement (SEM) and coefficient of variation (CV) indicated consistent output. High intraclass correlation coefficient (ICC) values were seen between weeks (EO = 0.74; EC = 0.76) and within weeks (EOW1 = 0.79; EOW2 = 0.86; ECW1 = 0.71; ECW2 = 0.71). Although statistical measures (i.e., SEM, CV, and ICC) indicated good reliability of Lafayette for SL tasks, the wide agreement interval is yet to be clinically meaningful. Factors underlying the wide variation need to be identified before Lafayette is used for TIB assessment.

Tuberculosis and COVID-19 are among the infectious diseases that constitute a public health concern. Therefore, this study aims to examine the recent epidemiology of tuberculosis and COVID-19 in East Java Province, Indonesia, in 2020. Case-based surveillance data were acquired with a retrospective design between January and December 2020 by the East Java Health Officer. The data were analyzed using Quantum Geographic Information System (QGIS) for mapping, and Microsoft Excel for recording. Furthermore, the statistical analysis (Spearman correlation test) was carried out via Statistical Package for Social Science (SPSS) applications. A total number of 38,089 confirmed cases of tuberculosis was recorded, with an incidence rate of 95.49/100,000 population, a case fatality rate (CFR) of 3.6%, and an average treatment success rate of 87.78%. COVID-19 is a new viral disease, with a total of 84,133 confirmed COVID-19 cases in East Java, with an incidence rate of 232.9/100,000 population. The highest incidence rate was found in Mojokerto city, while the lowest was found in Sampang. Furthermore, the CFR values of tuberculosis and COVID-19 were 1.4% and 6.8%, respectively. The regional survey in East Java Province showed that the incidence of tuberculosis remains high. This indicated that the search for active cases and preventive promotion was not completed. Therefore, inter-sectoral collaboration can be adapted to provide suitable tuberculosis health care.

In this research paper, thermoelectric generator (TEG) module was embedded inside the oven to harvest electrical energy from heat waste of the kitchen oven. The development of experimental setup was investigated in closed-circuit from room temperature rise to 150°C in 60 min using kitchen oven with custom-made aluminum heatsink with built-in water-cooling tank attached on the TEG module. The maximum voltage output was generated about 1.87V in single TEG module where gradient of TEG was measured about 0.0337V/°C. The harvested output of voltage was demonstrated by charging a single lithium battery ‘AA’ in 110 mins for full-charged and it was able to power a LED torch light.

A novel, inhibitor-potentiated disc-diffusion test for detecting extended-spectrum β-lactamases (ESBLS) in bacteria was evaluated. This test uses the principle of augmentation (by ≥10 mm) of inhibition zones produced by ceftazidime, cefotaxime, ceftriaxone or aztreonam discs on Mueller-Hinton agar supplemented with clavulanate (4 mg/L). The test was initially compared with the double-disc synergy test, Kirby-Bauer disc-diffusion test and Etest ESBL screen with a panel of 45 reference strains with known resistance profiles. This panel consisted of 27 ESBL-positive Escherichia coli strains expressing 14 Bush group 2be enzymes and 18 other E. coli and Klebsiella pneumoniae strains (14 non-ESBL β-lactamase producers and four non-β-lactamase producers). The Kirby-Bauer disc-diffusion test was the least sensitive method: 11-44% of the ESBL-positive control strains were misclassified as susceptible to ceftazidime, cefotaxime, ceftriaxone or aztreonam when interpreted by National Committee for Clinical Laboratory Standards (NCCLS) criteria. The sensitivities of the inhibitor-potentiated disc-diffusion test, the double-disc synergy test (when discs were 25 or 30 mm apart) and the Etest ESBL screen (with a breakpoint of >4-fold reduction in ceftazidime MIC in the presence of clavulanate) were 100%, 96% and 89-96%, respectively. The inhibitor potentiated disc-diffusion test was further evaluated with 81 E. coliand K. pneumoniae clinical isolates, which were identified as putative ESBL-producers by the double-disc synergy test. For these isolates, the sensitivity of both the inhibitor-potentiated disc-diffusion test and the Etest ESBL screen was 100%. In conclusion, the inhibitor-potentiated disc-diffusion test is a sensitive, convenient and inexpensive method of screening for ESBLs in E. coli and K. pneumoniae isolates, with potential for incorporation into routine clinical laboratory service. [ABSTRACT FROM PUBLISHER]

There are conflicting data on the relationship between the time of symptom onset during the 24-hour cycle (circadian dependence) and infarct size in ST-elevation myocardial infarction (STEMI). Moreover, the impact of this circadian pattern of infarct size on clinical outcomes is unknown. We sought to study the circadian dependence of infarct size and its impact on clinical outcomes in STEMI.We studied 6,710 consecutive patients hospitalized for STEMI from 2006 to 2009 in a tropical climate with non-varying day-night cycles. We categorized the time of symptom onset into four 6-hour intervals: midnight-6:00 A.M., 6:00 A.M.-noon, noon-6:00 P.M. and 6:00 P.M.-midnight. We used peak creatine kinase as a surrogate marker of infarct size.Midnight-6:00 A.M patients had the highest prevalence of diabetes mellitus (P = 0.03), more commonly presented with anterior MI (P = 0.03) and received percutaneous coronary intervention less frequently, as compared with other time intervals (P = 0.03). Adjusted mean peak creatine kinase was highest among midnight-6:00 A.M. patients and lowest among 6:00 A.M.-noon patients (2,590.8±2,839.1 IU/L and 2,336.3±2,386.6 IU/L, respectively, P = 0.04). Midnight-6:00 A.M patients were at greatest risk of acute heart failure (P

Abstract Background Gail and others developed a model (GAIL) using age-at-menarche, age-at-birth of first live child, number of previous benign breast biopsy examinations, and number of first-degree-relatives with breast cancer as well as baseline age-specific breast cancer risks for predicting the 5-year risk of invasive breast cancer for Caucasian women. However, the validity of the model for projecting risk in South-East Asian women is uncertain. We evaluated GAIL and attempted to improve its performance for Singapore women of Chinese, Malay and Indian origins. Methods Data from the Singapore Breast Screening Programme (SBSP) are used. Motivated by lower breast cancer incidence in many Asian countries, we utilised race-specific invasive breast cancer and other cause mortality rates for Singapore women to produce GAIL-SBSP. By using risk factor information from a nested case-control study within SBSP, alternative models incorporating fewer then additional risk factors were determined. Their accuracy was assessed by comparing the expected cases (E) with the observed (O) by the ratio (E/O) and 95% confidence interval (CI) and the respective concordance statistics estimated. Results From 28,883 women, GAIL-SBSP predicted 241.83 cases during the 5-year follow-up while 241 were reported (E/O=1.00, CI=0.88 to 1.14). Except for women who had two or more first-degree-relatives with breast cancer, satisfactory prediction was present in almost all risk categories. This agreement was reflected in Chinese and Malay, but not in Indian women. We also found that a simplified model (S-GAIL-SBSP) including only age-at-menarche, age-at-birth of first live child and number of first-degree-relatives performed similarly with associated concordance statistics of 0.5997. Taking account of body mass index and parity did not improve the calibration of S-GAIL-SBSP. Conclusions GAIL can be refined by using national race-specific invasive breast cancer rates and mortality rates for causes other than breast cancer. A revised model containing only three variables (S-GAIL-SBSP) provides a simpler approach for projecting absolute risk of invasive breast cancer in South-East Asia women. Nevertheless its role in counseling the individual women regarding their risk of breast cancer remains problematical and needs to be validated in independent data.

Precise transformations of natural products (NPs) can fine-tune their physicochemical properties while preserving inherently complex and evolutionarily optimized parent scaffolds. Here, we report an unprecedented lactone-to-lactam transformation on bilobalide, thus improving its stability and paving the way for biological exploration of previously inaccessible chemical space that is highly representative of the parent structure. This late-stage molecular editing of bilobalide enables facile access to a unique library of lactam analogues with altered pharmacology. Through phenotypic screening, we identify BB10 as a hit compound with unexpected inhibition of ferroptotic cell death. We further reveal that BB10 suppresses ferroptosis by restoring the expression of glutathione peroxidase 4 (GPX4) in brain cells. This study highlights that even subtle changes on NP scaffolds can confer new pharmacological properties, inspiring the exploration of simple yet critical transformations on complex NPs., Competing Interests: The authors declare the following competing financial interest(s): B.W.-L.N. is an inventor on a U.S. non-provisional patent application submitted by The Chinese University of Hong Kong that covers the described analogues in this manuscript., (© 2024 The Authors. Published by American Chemical Society.)

Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization. Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer's disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson's disease (PD)-Lewy body dementia (LBD) model. An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia; it disproportionally affects women in terms of both incidence rates and severity of progression. The cellular and molecular mechanisms underlying this clinical phenomenon remain elusive and ill-defined., Methods: In-depth analyses were performed with multiple human LOAD single-nucleus transcriptome datasets to thoroughly characterize cell populations in the cerebral cortex. ROSMAP bulk human brain tissue transcriptome and DNA methylome datasets were also included for validation. Detailed assessments of microglial cell subpopulations and their relevance to sex-biased changes at the tissue level were performed. Clinical trait associations, cell evolutionary trajectories, and transcription regulon analyses were conducted., Results: The relative numbers of functionally defective microglia were aberrantly increased uniquely among affected females. Substratification of the microglia into different subtypes according to their transcriptomic signatures identified a group of female-enriched and disease-associated microglia (FDAMic), the numbers of which were positively associated with disease severity. Phenotypically, these cells exhibit transcriptomic signatures that support active proliferation, MHC class II autoantigen presentation and amyloid-β binding, but they are also likely defective in phagocytosis. FDAMic are likely evolved from female activated response microglia (ARMic) with an APOE4 background and compromised estrogen receptor (ER) signaling that is deemed to be active among most subtypes of microglia., Conclusion: This study offered important insights at both the cellular and molecular levels into how ER signaling affects microglial heterogeneity and function. FDAMic are associated with more advanced pathologies and severe trends of cognitive decline. Their emergence could, at least in part, explain the phenomenon of greater penetrance of the APOE4 genotype found in females. The biases of FDAMic emergence toward female sex and APOE4 status may also explain why hormone replacement therapy is more effective in APOE4 carriers. The pathologic nature of FDAMic suggests that selective modulations of these cells may help to regain brain neuroimmune homeostasis, serving as a new target for future drug development., (© 2023. The Author(s).)

Infections caused by extended-spectrum β-lactamase-producing Enterobacterales have increased rapidly and are mainly attributed to the production of CTX-M enzymes. This study evaluated the NG-Test ® CTX-M MULTI lateral flow assay (CTX-M LFA) and the Rapid ESBL NP ® test (ESBL NP test) for rapid detection of CTX-M-producing Enterobacterales directly in midstream urine (MSU) samples. Testing was performed on 277 clinical MSU samples in a hospital microbiology laboratory from November 2022 to January 2023; 60 of these samples (30 positive for ESBL producers and 30 positive for non-ESBL producers) were tested retrospectively after the identification and susceptibility results were obtained, and 217 samples were tested prospectively immediately after a Gram stain showing the presence of Gram-negative bacilli. The results were compared against phenotypic detection of ESBL and molecular testing as the reference methods. Overall, 67 of the 277 samples were culture-positive for ESBL-producing Enterobacterales. PCR for the bla CTX-M gene was positive for all ESBL-producing Enterobacterales isolates. All CTX-M LFA results were interpretable, while three of the ESBL NP test results were noninterpretable. The sensitivity of the CTX-M LFA (100%, 95% CI 94.6-100%) was higher than that of the ESBL NP test (86.6%, 95% CI 76.0-93.7%). Both tests had high specificities (CTX-M LFA, 99.1%, 95% CI 96.6-99.9% and ESBL NP test, 100%, 95% CI 98.2-100%). In conclusion, both the CTX-M LFA and the ESBL NP test can deliver rapid results that could improve antimicrobial stewardship for urinary tract infections.

Objectives: This retrospective study analyzed the susceptibility levels of Bacteroides fragilis group (BFG) in a hospital-based laboratory where disk diffusion test (DDT) was routinely performed. Isolates non-susceptible to imipenem and metronidazole by DDT were further investigated using a gradient method., Methods: The DDT and MIC susceptibility data of clindamycin, metronidazole, moxifloxacin and imipenem obtained on Brucella blood agar for 1264 non-duplicated isolates during 2020-2021 were analyzed. Species identification was obtained by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and 16S rRNA sequencing. Interpretative agreement of DDT results using the 2015 EUCAST tentative and 2021 CA-SFM breakpoints was compared against MIC as the reference., Results: The dataset included 604 B. fragilis (483 division I, 121 division II isolates), 415 non-fragilis Bacteroides, 177 Phocaeicola and 68 Parabacteroides. Susceptibility rates for clindamycin (22.1-62.1%) and moxifloxacin (59.9-80.9%) were low and many had no inhibition zones. At the EUCAST and CA-SFM breakpoints, 83.0 and 89.4% were imipenem-susceptible, and 89.6% and 97.4 were metronidazole-susceptible. MIC testing confirmed 11.4% and 2.8% isolates as imipenem-non-susceptible and metronidazole-resistant, respectively. Significant numbers of false-susceptibility and/or false-resistance results were observed at the CA-SFM breakpoint but not the EUCAST breakpoint. Higher rates of imipenem and/or metronidazole resistance were detected in B. fragilis division II, B. caccae, B. ovatus, B. salyersiae, B. stercoris and Parabacteroides. Co-resistance to imipenem and metronidazole was detected in 3 B. fragilis division II isolates., Conclusions: The data demonstrated emerging BFG resistance to several important anti-anaerobic antibiotics and highlights the importance of anaerobic susceptibility testing in clinical laboratories to guide therapy., Competing Interests: Declaration of competing interest All the authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cerebellar ataxia is often the first and irreversible outcome in the disease of ataxia-telangiectasia (A-T), as a consequence of selective cerebellar Purkinje neuronal degeneration. A-T is an autosomal recessive disorder resulting from the loss-of-function mutations of the ataxia-telangiectasia-mutated ATM gene. Over years of research, it now becomes clear that functional ATM-a serine/threonine kinase protein product of the ATM gene-plays critical roles in regulating both cellular DNA damage response and central carbon metabolic network in multiple subcellular locations. The key question arises is how cerebellar Purkinje neurons become selectively vulnerable when all other cell types in the brain are suffering from the very same defects in ATM function. This review intended to comprehensively elaborate the unexpected linkages between these two seemingly independent cellular functions and the regulatory roles of ATM involved, their integrated impacts on both physical and functional properties, hence the introduction of selective vulnerability to Purkinje neurons in the disease will be addressed., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers., (© 2023. The Author(s).)

The immune system plays a central role in many processes of age-related disorders and it remains unclear if the innate immune system may play roles in shaping extreme longevity. By an integrated analysis with multiple bulk and single cell transcriptomic, so as DNA methylomic datasets of white blood cells, a previously unappreciated yet commonly activated status of the innate monocyte phagocytic activities is identified. Detailed analyses revealed that the life cycle of these monocytes is enhanced and primed to a M2-like macrophage phenotype. Functional characterization unexpectedly revealed an insulin-driven immunometabolic network which supports multiple aspects of phagocytosis. Such reprogramming is associated to a skewed trend of DNA demethylation at the promoter regions of multiple phagocytic genes, so as a direct transcriptional effect induced by nuclear-localized insulin receptor. Together, these highlighted that preservation of insulin sensitivity is a key to healthy lifespan and extended longevity, via boosting the function of innate immune system in advanced ages., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Epithelial-to-mesenchymal transition (EMT) is associated with tumor initiation, metastasis, and drug resistance. However, the mechanisms underlying these associations are largely unknown. We studied several tumor types to identify the source of EMT gene expression signals and a potential mechanism of resistance to immuno-oncology treatment. Across tumor types, EMT-related gene expression was strongly associated with expression of stroma-related genes. Based on RNA sequencing of multiple patient-derived xenograft models, EMT-related gene expression was enriched in the stroma versus parenchyma. EMT-related markers were predominantly expressed by cancer-associated fibroblasts (CAFs), cells of mesenchymal origin which produce a variety of matrix proteins and growth factors. Scores derived from a 3-gene CAF transcriptional signature (COL1A1, COL1A2, COL3A1) were sufficient to reproduce association between EMT-related markers and disease prognosis. Our results suggest that CAFs are the primary source of EMT signaling and have potential roles as biomarkers and targets for immuno-oncology therapies., (© 2023. The Author(s).)

Chronological aging is by far the strongest risk factor for age-related dementia and Alzheimer's disease. Senescent cells accumulated in the aging and Alzheimer's disease brains are now recognized as the keys to describing such an association. Cellular senescence is a classic phenomenon characterized by stable cell arrest, which is thought to be applicable only to dividing cells. Emerging evidence indicates that fully differentiated post-mitotic neurons are also capable of becoming senescent, with roles in contributing to both brain aging and disease pathogenesis. The key question that arises is the identity of the upstream triggers and the molecular mechanisms that underly such changes. Here, we highlight the potential role of persistent DNA damage response as the major driver of senescent phenotypes and discuss the current evidence and molecular mechanisms that connect DNA repair infidelity, cell cycle re-entry and terminal fate decision in committing neuronal cell senescence.

The prevalence and propagation of antimicrobial resistance (AMR) are serious global public health concerns. The large and the ever-increasing use of antibiotics in livestock is also considered a great concern. The extent of the similarity of acquired antibiotic resistance genes (ARGs) between humans and food animals and the driving factors underlying AMR transfer between them are not clear, although a link between ARGs in both hosts was proposed. To address this question, with swine and chicken as examples of food animals, we analyzed over 1,000 gut metagenomes of humans and food animals from over the world. A relatively high abundance and diversity of ARGs were observed in swine compared with those in humans as a whole. Commensal bacteria, particularly species from Clostridiales , contribute the most ARGs associated with mobile genetic elements (MGEs) and were found in both humans and food animals. Further studies demonstrate that overrepresented MGEs, namely, Tn 4451 /Tn 4453 and Tn As3 , are attributed mainly to the sharing between humans and food animals. A member of large resolvase family site-specific recombinases, TnpX, is found in Tn 4451 /Tn 4453 which facilitates the insertions of the transient circular molecule. Although the variance in the transferability of ARGs in humans is higher than that in swine, a higher average transferability was observed in swine than that in humans. In conclusion, the potential antibiotic resistance hot spots with higher transferability in food animals observed in the present study emphasize the importance of surveillance for emerging resistance threats before they spread. IMPORTANCE Antimicrobial resistance (AMR) has proven to be a global public health concern. To conquer this increasingly worrying trend, an overarching, One Health approach has been used that brings together different sectors, but the fundamental knowledge of the relationship between humans, food animals, and their environments is not mature yet or is lacking in some aspect. With swine and chicken as examples of food animals, a large global data set of over 1,000 human and food animal gut metagenomes was analyzed with a focus on acquired antibiotic resistance genes (ARGs) associated with mobile genetic elements (MGEs) to answer this question. Outputs from this work open a new avenue to further our understanding of ARG transferability in food animals. It is a necessary milestone to better equip governmental agencies to monitor and pre-empt antibiotic resistance hot spots. This work will assist and give guidance on how to decipher other links within any One Health initiatives with expected positive feedback to human health.

Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter-methylated adult and pediatric gliomas and neuroblastomas.

Introduction: The emergence of multidrug resistance in Bacteroides fragilis, especially the phylogenetic lineage carrying the carbapenemase gene cfiA, represents an increasing threat to human health. However, knowledge on the diversity of the multidrug-resistant strains and the genetic elements carrying the antibiotic resistance genes (ARGs) remains limited., Aim: The objective of the study was to describe the resistome in cfiA-positive B. fragilis., Methods: A collection of cfiA-positive B. fragilis from diverse human (8 bacteremias, 15 wound infections) and animal (2 chickens, 2 pigs, 6 dogs, 3 cats) sources in Hong Kong, 2015-2017 was analysed by whole genome sequencing., Results: In the 36 isolates, 13 distinct ARGs (total number 83, median 2, range 0-7 per isolate) other than cfiA were detected. ARGs encoding resistance to aminoglycosides, β-lactams, macrolides, sulphonamides and tetracyclines were carried by CTn341-like, CTnHyb-like, Tn5220-like, Tn4555-like and Tn613-like transposons and were detected in phylogenetically diverse isolates of different host sources. Only few ARGs encoding resistance to metronidazole and tetracyclines were localized on plasmids. In two chicken isolates, a novel transposon (designated as Tn6994) was found to be involved in the dissemination of multiple ARGs mediating resistance to multiple antibiotics, including metronidazole and linezolid that are critically important for treatment of anaerobic infections. In mating experiments, Tn6994 and the associated phenotypic resistance could be transferred to Bacteroides nordii recipient., Conclusion: This study illustrates the importance of transposons in the dissemination of ARGs in the cfiA-positive division of B. fragilis. One Health approach is necessary to track the dissemination of ARGs., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objectives: To compare the phylogeny of cfiA-positive Bacteroides fragilis isolates from diverse human and animal sources., Method: Complete genome sequences were obtained from 42 cfiA-positive B. fragilis isolates (Hong Kong, 2015-2017) and additional 24 genomes deposited in the GenBank (multiple countries, 1985-2019) were included. The genomic clusters were constructed using PopPUNK. The CfiA alleles and polymorphism in the cfiA locus were analyzed in silico., Results: The 66 isolates were grouped into 12 genomic clusters (BFSC-1 to 12). Human infection isolates were distributed in diverse clusters, being many of them common to fecal isolates from both human and animals. Thirteen CfiA alleles including 2 novel ones were identified. CfiA-1 (n = 28) is the predominating allele, following by CfiA-13 (n = 8), CfiA-4 (n = 7) and CfiA-14 (n = 6). The other CfiA alleles were identified in 1-3 isolates. Six patterns of gene context were identified in the regions flanking cfiA locus. No consistent association between genomic clusters and CfiA alleles could be detected. Similarly, markedly elevated imipenem MIC was linked to the integration, immediately upstram of cfiA of an IS element but not the CfiA allele or gene context., Conclusion: The phylogeny of cfiA-positive B. fragilis isolates causing human diseases was diverse and overlaped with those from human and animal carriage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors. However, 50%-60% do not respond to single-agent anti-programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6-12 months. This phase Ib trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors., Patients and Methods: Eligible patients ≥18 years without prior anti-PD-1/PD-L1 therapy received LY3300054 monotherapy ( N = 40) or combination ( N = 20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination ( N = 22). LY3300054 (700 mg) and anti-TIM-3 antibody (cycles 1-2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability., Results: Eighty-two patients were enrolled. Most had colorectal ( n = 39, 47.6%) or endometrial ( n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort., Conclusions: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI-H/dMMR tumors., (©2021 American Association for Cancer Research.)