Integrative analysis of the ovarian metabolome and transcriptome of the Yaoshan chicken and its improved hybrids.

Introduction: Laying performance is a key factor affecting production efficiency in poultry, but its molecular mechanism is still indistinct. In this study, Yaoshan chickens, a local breed in Guizhou, China, and merchant chickens (GYR) with higher egg yield after the three-line cross improvement hybridization of Yaoshan chickens were used as animal samples. Methods: To explore the regulatory mechanism of the diversities in laying performance, RNA-seq and ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) were used to describe the transcriptional and metabolic profiles of the ovaries of Yaoshan and GYR chickens. Results: At the transcriptional level, 288 differentially expressed genes were upregulated in Yaoshan chickens and 353 differentially expressed genes were upregulated in GYR chickens. In addition, GSEA showed that ECM-receptor interactions and the TGF-ß signaling pathway were restrained, resulting in increased egg production in GYR chickens. Furthermore, the upregulation of thiamine and carnitine was identified by metabolomic analysis to facilitate the laying performance of hens. Finally, comprehensive analyses of the transcriptome and metabolome found that thiamine and carnitine were negatively correlated with ECM-receptor interactions and the TGF-ß signaling pathway, which jointly regulate the laying performance of Yaoshan chickens and GYR chickens. Discussion: Taken together, our research delineates differences in the transcriptional and metabolic profiles of the ovaries of Yaoshan and GYR chickens during the peak egg production period and provides new hypotheses and clues for further research on poultry egg production performance and the improvement of economic benefits.

Wolbachia mediates crosstalk between miRNA and Toll pathways to enhance resistance to dengue virus in Aedes aegypti.

The obligate endosymbiont Wolbachia induces pathogen interference in the primary disease vector Aedes aegypti, facilitating the utilization of Wolbachia-based mosquito control for arbovirus prevention, particularly against dengue virus (DENV). However, the mechanisms underlying Wolbachia-mediated virus blockade have not been fully elucidated. Here, we report that Wolbachia activates the host cytoplasmic miRNA biogenesis pathway to suppress DENV infection. Through the suppression of the long noncoding RNA aae-lnc-2268 by Wolbachia wAlbB, aae-miR-34-3p, a miRNA upregulated by the Wolbachia strains wAlbB and wMelPop, promoted the expression of the antiviral effector defensin and cecropin genes through the Toll pathway regulator MyD88. Notably, anti-DENV resistance induced by Wolbachia can be further enhanced, with the potential to achieve complete virus blockade by increasing the expression of aae-miR-34-3p in Ae. aegypti. Furthermore, the downregulation of aae-miR-34-3p compromised Wolbachia-mediated virus blockade. These findings reveal a novel mechanism by which Wolbachia establishes crosstalk between the cytoplasmic miRNA pathway and the Toll pathway via aae-miR-34-3p to strengthen antiviral immune responses against DENV. Our results will aid in the advancement of Wolbachia for arbovirus control by enhancing its virus-blocking efficiency.

Quality of evidence supporting the role of probiotics for rheumatoid arthritis: an overview of systematic reviews.

Background: To evaluate the methodological quality, report quality, and evidence quality of meta-analysis (MA) and systematic review (SR) on the efficacy of probiotics in the treatment of rheumatoid arthritis (RA). Methods: Databases were used to identify eligible SRs/MAs until February 12, 2024. The methodological quality of the studies was assessed using AMSTAR-2 tool, the quality of the literature reports was scored using PRISMA checklists, and the quality of the evidence was graded using GRADE system. Results: Seven reviews including 21 outcomes were included. Methodological quality of the included reviews was of general low, and the entries with poor scores were 2, 4, and 7. By PRISMA checklists, there were some reporting deficiencies, and quality problems were mainly reflected in the reporting registration and protocol, comprehensive search strategy and additional analysis. GRADE results elevated the quality of evidence to be low or very low overall. Conclusions: Probiotics may have a therapeutic effect on RA, based on the evidence provided by the SRs/MAs in this overview. Nevertheless, there is still a lack of conclusive evidence due to methodological limitations in the included research. To make trustworthy judgments regarding the efficacy of probiotics in the treatment of RA, more large-scale, high-quality randomized controlled trials are still required.

Genetic Foundation of Male Spur Length and Its Correlation with Female Egg Production in Chickens.

Spurs, which mainly appear in roosters, are protrusions near the tarsometatarsus on both sides of the calves of chickens, and are connected to the tarsometatarsus by a bony core. As a male-biased morphological characteristic, the diameter and length of spurs vary significantly between different individuals, mainly related to genetics and age. As a specific behavior of hens, egg-laying also varies greatly between individuals in terms of traits such as age at first egg (AFE), egg weight (EW), and so on. At present, there are few studies on chicken spurs. In this study, we investigated the inheritance pattern of the spur trait in roosters with different phenotypes and the correlations between spur length, body weight at 18 weeks of age (BW18), shank length at 18 weeks of age (SL18), and the egg-laying trait in hens (both hens and roosters were from the same population and were grouped according to their family). These traits related to egg production included AFE, body weight at first egg (BWA), and first egg weight (FEW). We estimated genetic parameters based on pedigree and phenotype data, and used variance analysis to calculate broad-sense heritability for correcting the parameter estimation results. The results showed that the heritability of male left and right spurs ranged from 0.6 to 0.7. There were significant positive correlations between left and right spur length, BW18, SL18, and BWA, as well as between left and right spur length and AFE. We selected 35 males with the longest spurs and 35 males with the shortest spurs in the population, and pooled them into two sets to obtain the pooled genome sequencing data. After genome-wide association and genome divergency analysis by FST, allele frequency differences (AFDs), and XPEHH methods, we identified 7 overlapping genes (CENPE, FAT1, FAM149A, MANBA, NFKB1, SORBS2, UBE2D3) and 14 peak genes (SAMD12, TSPAN5, ENSGALG00000050071, ENSGALG00000053133, ENSGALG00000050348, CNTN5, TRPC6, ENSGALG00000047655,TMSB4X, LIX1, CKB, NEBL, PRTFDC1, MLLT10) related to left and right spur length through genome-wide selection signature analysis and a genome-wide association approach. Our results identified candidate genes associated with chicken spurs, which helps to understand the genetic mechanism of this trait and carry out subsequent research around it.

Phosphorus flow characteristics in the waste system of Poyang Lake Watershed over the past 70 years.

With the intensification of human activities, the amount of phosphorus (P)-containing waste has increased. When such waste is not recycled, P is released into the environment, leading to environmental issues such as the eutrophication of water bodies. In this study, based on the material flow analysis method, a P Waste Flow analysis model (P-WFA) was developed to analyze the P flow in the waste system of Poyang Lake, the largest freshwater lake in China. To address the research gap in long-term P flow analysis at the watershed scale, this study quantified the P content in the waste system of the Poyang Lake Watershed from 1950 to 2020. The analysis revealed that from 1950 to 2020, the total P input into the waste system increased from 5.49 × 104 tons in 1950 to 2.28 × 105 tons in 2020. The breeding industry system was identified as the primary source, accounting for 25.19-41.59 % of the total waste system. Over the past 70 years, P loss to surface water from waste systems has been primarily facilitated by manure from the breeding industry, as well as drainage from crop farming systems (77.74 % in 2020). At the same time, the P recycling rate (PRR) of the waste system exhibited an initial increase followed by a decrease, increasing from 44.14 % to 47.75 % before dropping to 44.41 %. Population growth, urbanization, and changes in consumption levels in Jiangxi Province have led to changes in the dietary structure and fertilizer use, consequently affecting the P cycling pattern. This study presents a comprehensive P flow model for waste systems in the Poyang Lake Watershed. This model can be used as a reference to enhance P cycling and manage P loss in other large freshwater lakes.

An overview of systematic reviews of clinical studies of platelet-rich plasma for venous ulcers.

To evaluate the clinical evidence of platelet-rich plasma (PRP) in the treatment of venous ulcers (VUs). Electronic searches were conducted through the Cochrane Library, Web of Science, Embase and PubMed. AMSTAR-2 was used to assess the methodological quality. The quality of evidence was assessed using the GRADE system. According to AMSTAR-2, the methodological quality of the included reviews was generally inadequate owing to the limitations of entries 2, 4 and 7. Due to bias risk and imprecision, the evidence quality of the outcome measures was inadequate. In conclusion, PRP may have a therapeutic effect on VUs. However, this conclusion must be treated with caution due to methodological flaws of the included systematic reviews and meta-analyses.

Genetic parameter estimation and molecular foundation of chicken beak shape.

The bird beak is mainly functioned as feeding and attacking, and its shape has extremely important significance for survival and reproduction. In chickens, since beak shape could lead to some disadvantages including pecking and waste of feed, it is important to understand the inheritance of chicken beak shape. In the present study, we firstly established 4 indicators to describe the chicken beak shapes, including upper beak length (UL), lower beak length (LL), distance between upper and lower beak tips (DB) and upper beak curvature (BC). And then, we measured the 4 beak shape indicators as well as some production traits including body weight (BW), shank length (SL), egg weight (EW), eggshell strength (ES) of a layer breed, Rhode Island Red (RIR), in order to estimate genetic parameters of chicken beak shape. The heritabilities of UL and LL were 0.41 and 0.37, and the heritabilities of DB and BC were 0.22 and 0.21, indicating that beak shape was a highly or mediumly heritable. There were significant positive genetic and phenotypic correlations among UL, LL, and DB. And UL was positively correlated with body weight (BW18) and shank length (SL18) at 18 weeks of age in genetics, and DB was positively correlated with BC in terms of genetics and phenotype. We also found that layers of chicken cages played a role on beak shape, which could be attributed to the difference of lightness in different cage layers. By a genome-wide association study (GWAS) for the chicken UL, we identified 9 significant candidate genes associated with UL in RIR. For the variants with low minor allele frequencies (MAF <0.01) and outside of high linkage disequilibrium (LD) regions, we also conducted rare variant association studies (RVA) and GWAS to find the association between genotype and phenotype. We also analyzed transcriptomic data from multiple tissues of chicken embryos and revealed that all of the 9 genes were highly expressed in beak of chicken embryos, indicating their potential function for beak development. Our results provided the genetic foundation of chicken beak shape, which could help chicken breeding on beak related traits.

Genetic parameter estimation and molecular foundation of chicken egg-laying trait.

The age of first egg (AFE) in chicken can affect early and even life-time egg production performance to some extent, and therefore is an important economic trait that affects production efficiency. To better understand the genetic patterns of AFE and other production traits including body weight at first egg (BWA), first egg weight (FEW), and total egg number from AFE to 58 wk of age (total-EN), we recorded the production performance of 2 widely used layer breeds, white leghorn (WL) and Rhode Island Red (RIR) and estimated genetic parameters based on pedigree and production data. The results showed that the heritability of AFE in both breeds ranged from 0.4 to 0.6, and AFE showed strong positive genetic and phenotypic correlations to BWA as well as FEW, while showing strong negative genetic and phenotypic correlations with total-EN. Furtherly, by genome-wide association analysis study (GWAS), we identified 12 and 26 significant SNPs to be related to AFE in the 2-layer breeds, respectively. A total of 18 genes were identified that could affect AFE based on the significant SNP annotations obtained, but there were no gene overlapped in the 2 breeds indicating the genetic foundation of AFE could differ from breed to breed. Our results provided a deeper understanding of genetic patterns and molecular basement of AFE in different breeds and could help in the selection of egg production traits.

Molecular genetic foundation of a sex-linked tailless trait in Hongshan chicken by whole genome data analysis.

As a Chinese local chicken breed, Hongshan chickens have 2 kinds of tail feather phenotypes, normal and taillessness. Our previous studies showed that taillessness was a sex-linked dominant trait. Abnormal development of the tail vertebrae could be explained this phenomenon in some chicken breeds. However, the number of caudal vertebrae in rumpless Hongshan chickens was normal, so rumplessness in Hongshan chicken was not related to the development of the caudal vertebrae. Afterwards, we found that rumplessness in Hongshan was due to abnormal development of tail feather rather than abnormal development of caudal vertebrae. In order to understand the genetic foundation of the rumplessness of Hongshan chickens, we compared and reanalyzed 2 sets of data in normal and rumpless Hongshan chickens from our previous studies. By joint analysis of genome-wide selection signature analysis and genome-wide association approach, we found that 1 overlapping gene (EDIL3) and 16 peak genes (ENSGALG00000051843, ENSGALG00000053498, ENSGALG00000054800, KIF27, PTPRD, ENSGALG00000047579, ENSGALG00000041052, ARHGEF28, CAMK4, SERINC5, ENSGALG00000050776, ERCC8, MCC, ADAMTS19, ENSGALG00000053322, CHRNA8) located on the Z chromosome was associated with the rumpless trait. The results of this study furtherly revealed the molecular mechanism of the rumpless trait in Hongshan chickens, and identified the candidate genes associated with this trait. Our results will help to improve the shape of chicken tail feathers and to rise individual economic value in some specific market in China.

Whole genome resequencing reveals genomic regions related to red plumage in ducks.

Plumage color is a characteristic trait of ducks that originates as a result of natural and artificial selection. As a conspicuous phenotypic feature, it is a breed characteristic. Previous studies have identified some genes associated with the formation of black and white plumage in ducks. However, studies on the genetic basis underlying the red plumage phenotype in ducks are limited. Here, genome-wide association analysis (GWAS) and selection signal detection (Fst, θπ ratio, and cross-population composite likelihood ratio [XP-CLR]) were conducted to identify candidate regions and genes underlying duck plumage color phenotype. Selection signal detection revealed 29 overlapping genes (including ENPP1 and ULK1) significantly associated with red plumage color in Ji'an Red ducks. ENSAPLG00000012679, ESRRG, and SPATA5 were identified as candidate genes associated with red plumage using GWAS. Selection signal detection revealed that 19 overlapping genes (including GMDS, PDIA6, and ODC1) significantly correlated with light brown plumage in Brown Tsaiya ducks. GWAS to narrow down the significant regions further revealed nine candidate genes (AKT1, ATP6V1C2, GMDS, LRP4, MAML3, PDIA6, PLD5, TMEM63B, and TSPAN8). Notably, in Brown Tsaiya ducks, GMDS, ODC1, and PDIA6 exhibit significantly differentiated allele frequencies among other feather-colored ducks, while in Ji'an Red ducks, ENSAPLG00000012679 has different allele frequency distributions compared with that in other feather-colored ducks. This study offers new insights into the variation and selection of the red plumage phenotype using GWAS and selective signals.

Artificial intelligence in cardiology: a bibliometric study.

OBJECTIVES: To perform a comprehensive bibliometric analysis of global publications on the applications of artificial intelligence (AI) in cardiology. METHODS: Documents related to AI in cardiology published between 2002 and 2022 were retrieved from Web of Science Core Collection. R package "bibliometrix", VOSviewers and Microsoft Excel were applied to perform the bibliometric analysis. RESULTS: A total of 4332 articles were included. United States topped the list of countries publishing articles, followed by China and United Kingdom. The Harvard University was the institution that contributed the most to this field, followed by University of California System and University of London. Disease risk prediction, diagnosis, treatment, disease detection, and prognosis assessment were the research hotspots for AI in cardiology. CONCLUSIONS: Enhancing cooperation between different countries and institutions is a critical step in leading to breakthroughs in the application of AI in cardiology. It is foreseeable that the application of machine learning and deep learning in various areas of cardiology will be a research priority in the coming years.

Intragrain impurity annihilation for highly efficient and stable perovskite solar cells.

Intragrain impurities can impart detrimental effects on the efficiency and stability of perovskite solar cells, but they are indiscernible to conventional characterizations and thus remain unexplored. Using in situ scanning transmission electron microscopy, we reveal that intragrain impurity nano-clusters inherited from either the solution synthesis or post-synthesis storage can revert to perovskites upon irradiation stimuli, leading to the counterintuitive amendment of crystalline grains. In conjunction with computational modelling, we atomically resolve crystallographic transformation modes for the annihilation of intragrain impurity nano-clusters and probe their impacts on optoelectronic properties. Such critical fundamental findings are translated for the device advancement. Adopting a scanning laser stimulus proven to heal intragrain impurity nano-clusters, we simultaneously boost the efficiency and stability of formamidinium-cesium perovskite solar cells, by virtual of improved optoelectronic properties and relaxed intra-crystal strain, respectively. This device engineering, inspired and guided by atomic-scale in situ microscopic imaging, presents a new prototype for solar cell advancement.

Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons.

The KCNT1 gene encodes the sodium-activated potassium channel Slack (KCNT1, KNa1.1), a regulator of neuronal excitability. Gain-of-function mutations in humans cause cortical network hyperexcitability, seizures, and severe intellectual disability. Using a mouse model expressing the Slack-R455H mutation, we find that Na+-dependent K+ (KNa) and voltage-dependent sodium (NaV) currents are increased in both excitatory and inhibitory cortical neurons. These increased currents, however, enhance the firing of excitability neurons but suppress that of inhibitory neurons. We further show that the expression of NaV channel subunits, particularly that of NaV1.6, is upregulated and that the length of the axon initial segment and of axonal NaV immunostaining is increased in both neuron types. Our study on the coordinate regulation of KNa currents and the expression of NaV channels may provide an avenue for understanding and treating epilepsies and other neurological disorders.

Treatment of diabetic foot with moxibustion: Clinical evidence from meta-analysis.

To assess the efficacy of moxibustion for diabetic foot, and compile the findings of randomised clinical trials. China National Knowledge Infrastructure Database, Medicine, WanFang Database, Embase, Chinese Scientific Journal Database and Web of Science were from the establishment to January, 2024 were searched. Randomised controlled trials, which evaluated the effects of moxibustion were included. A total of 12 randomised controlled trials involving 1196 patients were included. According to the pooled results of this meta-analysis, effective rate (relative risk 1.16, 95% confidence intervals, CI [1.11, 1.22]), healing time (mean difference [MD] -6.27, 95% CI [-8.68, -3.86]), wound area (MD 3.46, 95% CI [0.84, 6.09]), and ankle brachial index (MD 0.14, 95% CI [0.03, 0.24]) were statistically significant compared to the control group. This study suggests that moxibustion treatment has the potential for improving symptoms of diabetic foot. However, future in-depth research on the benefits and harms of moxibustion for the diabetic foot is needed before it can be accepted as an evidence-based treatment.

Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators.

Neuronal activity stimulates mRNA translation crucial for learning and development. While FMRP (Fragile X Mental Retardation Protein) and CYFIP1 (Cytoplasmic FMR1 Interacting Protein 1) regulate translation, the mechanism linking translation to neuronal activity is not understood. We now find that translation is stimulated when FMRP and CYFIP1 translocate to the potassium channel Slack (KCNT1, Slo2.2). When Slack is activated, both factors are released from eIF4E (Eukaryotic Initiation Factor 4E), where they normally inhibit translation initiation. A constitutively active Slack mutation and pharmacological stimulation of the wild-type channel both increase binding of FMRP and CYFIP1 to the channel, enhancing the translation of a reporter for ß-actin mRNA in cell lines and the synthesis of ß-actin in neuronal dendrites. Slack activity-dependent translation is abolished when both FMRP and CYFIP1 expression are suppressed. The effects of Slack mutations on activity-dependent translation may explain the severe intellectual disability produced by these mutations in humans. HIGHLIGHTS: Activation of Slack channels triggers translocation of the FMRP/CYFIP1 complexSlack channel activation regulates translation initiation of a ß-actin reporter constructA Slack gain-of-function mutation increases translation of ß-actin reporter construct and endogenous cortical ß-actinFMRP and CYFIP1 are required for Slack activity-dependent translation. IN BRIEF: Malone et al . show that the activation of Slack channels triggers translocation of the FMRP/CYFIP1 complex from the translation initiation factor eIF4E to the channel. This translocation releases eIF4E and stimulates mRNA translation of a reporter for ß-actin and cortical ß-actin mRNA, elucidating the mechanism that connects neuronal activity with translational regulation.

Analysis of Epidemiological and Issues Encountered in Case Reports on Echinococcosis - China, 2022.

What is already known about this topic?: Echinococcosis is classified as a Class C infectious disease in China. It is endemic in 370 counties located in the agricultural and pastoral regions of western China. What is added by this report?: This report provides a comprehensive overview of the cases of echinococcosis reported in China in 2022. Following a thorough evaluation conducted by provincial CDCs, it was identified that 105 new cases were not reported through the National Notifiable Disease Reporting System. Furthermore, there were 1,051 cases that were reported among patients who had been previously diagnosed with echinococcosis. What are the implications for public health practice?: The reported cases of echinococcosis in non-endemic counties of provincial-level administrative divisions where the disease is endemic need to be given more attention, as there is a potential risk of it spreading within the non-endemic areas. Inadequate reporting practices by clinical medical institutions are hindering the subsequent investigations carried out by CDCs. It is important to implement enhanced health promotion efforts that focus on high-risk populations to address unhealthy lifestyles.

Synthesis of high-crystallinity Zeolite A from rare earth tailings: Investigating adsorption performance on typical pollutants in rare earth mines.

The ecological restoration of rare earth mines and the management of rare earth tailings have consistently posed global challenges, constraining the development of the rare earth industry. In this study, Zeolite A is efficiently prepared from the tailings of an ion-type rare earth mine in the southern Jiangxi Province of China. The resulting Zeolite A boasts exceptional qualities, including high crystallinity, a substantial specific surface area, and robust thermal stability. The optimum conditions for Zeolite synthesis are experimental determination and the adsorption properties of Zeolite A for typical pollutants (Cd2+, Cu2+, NH4+, PO43- and F-) in rare earth mines. The synthesised Zeolite A material is found to have strong adsorption properties. The adsorption mechanism is mainly cation exchange, and the priority of adsorption of pollutants is Cu2+> Cd2+ > NH4+ > PO43- > F-. Notably, the sodium Zeolite A material synthesized at room temperature can be effectively recycled multiple times. In summary, we propose a method to synthesise low cost and high adsorption zeolites using rare earth tailings. This will facilitate the reduction of rare earth tailings and the rehabilitation of rare earth mines. Our method has great potential as a rehabilitation technology for rare earth mines.

Interaction Between HCN and Slack Channels Regulates mPFC Pyramidal Cell Excitability in Working Memory Circuits.

The ability of monkeys and rats to carry out spatial working memory tasks has been shown to depend on the persistent firing of pyramidal cells in the prefrontal cortex (PFC), arising from recurrent excitatory connections on dendritic spines. These spines express hyperpolarization-activated cyclic nucleotide-gated (HCN) channels whose open state is increased by cAMP signaling, and which markedly alter PFC network connectivity and neuronal firing. In traditional neural circuits, activation of these non-selective cation channels leads to neuronal depolarization and increased firing rate. Paradoxically, cAMP activation of HCN channels in PFC pyramidal cells reduces working memory-related neuronal firing. This suggests that activation of HCN channels may hyperpolarize rather than depolarize these neurons. The current study tested the hypothesis that Na+ influx through HCN channels activates Slack Na+-activated K+ (KNa) channels to hyperpolarize the membrane. We have found that HCN and Slack KNa channels co-immunoprecipitate in cortical extracts and that, by immunoelectron microscopy, they colocalize at postsynaptic spines of PFC pyramidal neurons. A specific blocker of HCN channels, ZD7288, reduces KNa current in pyramidal cells that express both HCN and Slack channels, but has no effect on KNa currents in an HEK cell line expressing Slack without HCN channels, indicating that blockade of HCN channels in neurons reduces K+ current indirectly by lowering Na+ influx. Activation of HCN channels by cAMP in a cell line expressing a Ca2+ reporter results in elevation of cytoplasmic Ca2+, but the effect of cAMP is reversed if the HCN channels are co-expressed with Slack channels. Finally, we used a novel pharmacological blocker of Slack channels to show that inhibition of Slack in rat PFC improves working memory performance, an effect previously demonstrated for blockers of HCN channels. Our results suggest that the regulation of working memory by HCN channels in PFC pyramidal neurons is mediated by an HCN-Slack channel complex that links activation HCN channels to suppression of neuronal excitability.

Quality of evidence supporting the role of hyperbaric oxygen therapy for diabetic foot ulcers.

The goal of this overview of systematic reviews (SRs) and meta-analyses (MAs) was to methodically gather, evaluate and summarize the data supporting the use of hyperbaric oxygen therapy (HBOT) to treat diabetic foot ulcers (DFUs). The Cochrane Library, Embase, PubMed, Web of Science and Embase were all searched thoroughly to identify SRs/MAs that qualified. AMSTAR-2 tool, PRISMA checklists and GRADE system were applied by two reviewers independently to assess the methodological quality, reporting and evidence quality of the included SRs/MAs, respectively. Eleven SRs/MAs were enrolled in this overview. According to AMSTAR-2, a very low methodological quality assessment was given to the included SRs/MAs due to the limitations of items 2, 4 and 7. For the PRISMA, the overall quality of reporting is not satisfactory due to missing reporting on protocol, search, as well as additional analysis. The majority of outcomes had low- to moderate-quality evidence, and no high-quality evidence was found to support the role of HBOT for DFUs, according to GRADE. To conclude, the potential of HBOT in treating DFUs is supported by evidence of low to moderate quality. More rigorously designed, high-level studies are needed in the future to determine the evidence for HBOT for DFU, including the timing, frequency and duration of HBOT interventions.

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.