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Abstract Introduction Brucellosis, a globally distributed zoonotic disease, exhibits diverse clinical manifestations, with Brucella peritonitis being a rare but consequential complication. Methods Analyzing the medical records of four patients with Brucella peritonitis admitted to the First People’s Hospital of Kashi Region from January 2022 to November 2023. A retrospective approach was used to analyze the general data, epidemiological history, clinical features, laboratory tests, and efficacy. All four patients with Brucella peritonitis were farmers. Results All of them were combined with decompensated stage of liver cirrhosis. The main manifestations were poor appetite, fatigue, bloating. Two patients were accompanied by moderate-high fever. All patients presented with mildly elevated C-reactive protein and procalcitonin

Abstract Objective To analyze the clinical characteristics of Brucella endocarditis (BE) and observe the factors related to death to provide guidance for clinical treatment. Methods This study examined all patients with BE admitted to The First People’s Hospital of Kashi Prefecture between January 2017 and November 2023. Clinical characteristics and follow-up outcomes were collected for analysis. Results This study revealed 774 cases of brucellosis and 14 cases of BE, with an overall incidence rate of 1.88%. Most of the patients were male (71.43%) and lived in areas where brucellosis is common. Patients ranged in age from 26 to 68 years. Common symptoms reported among patients included chest tightness and fatigue, and a significant portion also presented with congestive heart failure. Most patients exhibited normal white blood cell counts (WBC) but had elevated levels of C-reactive protein (CRP). Transthoracic ultrasound (TTE) revealed cardiac valve vegetation in all patients, along with positive blood cultures. Six patients (42.86%) completed heart surgery, and ten (71.43%) completed anti-infection treatment. Six patients died, five of whom did not undergo surgery. The other patient with Marfan syndrome died after surgery. Sex, WBC count, neutrophil (NEUT) and total bilirubin (TBIL) were significant factors associated with regression in BE patients (P

Abstract N-methyltransferase (NMT)-catalyzed methylation at the termini of nonribosomal peptides (NRPs) has rarely been reported. Here, we discover a fungal NMT LcsG for the iterative terminal N-methylation of a family of NRPs, leucinostatins. Gene deletion results suggest that LcsG is essential for leucinostatins methylation. Results from in vitro assays and HRESI-MS-MS analysis reveal the methylation sites as NH2, NHCH3 and N(CH3)2 in the C-terminus of various leucinostatins. LcsG catalysis yields new lipopeptides, some of which demonstrate effective antibiotic properties against the human pathogen Cryptococcus neoformans and the plant pathogen Phytophthora infestans. Multiple sequence alignments and site-directed mutagenesis of LcsG indicate the presence of a highly conserved SAM-binding pocket, along with two possible active site residues (D368 and D395). Molecular dynamics simulations show that the targeted N can dock between these two residues. Thus, this study suggests a method for increasing the variety of natural bioactivity of NPRs and a possible catalytic mechanism underlying the N-methylation of NRPs.

BackgroundExercise-induced oxidative stress and inflammation can impair muscular function in humans. The antioxidant and anti-inflammatory properties of molecular hydrogen (H2) highlight its potential to be as an effective nutritional supplement to support muscular function performance in healthy adults. However, the effects of H2 supplementation on muscular endurance performance in trained individuals have not been well characterized. This study aimed to assess the effects of intermittent hydrogen-rich water (HRW) supplementation before, during, and after resistance training on muscular endurance performance, neuromuscular status, and subjective perceptual responses after a 48-h recovery period.MethodsThis randomized, double-blinded, placebo-controlled cross-over study included 18 trained men aged 19.7 ± 0.9 years. Participants in this study were instructed to consume 1,920 mL of HRW or pure water (Placebo) daily for 7 days. Additionally, participants were required to supplement with HRW or pure water five times during the training day (1,260 mL total). This included drinking 210 mL 30 min and 1 min before training, 210 mL between training sets, 210 mL immediately after training, and 420 mL 30 min into the recovery period. Participants performed half-squat exercises with the load set at 70% of one repetition maximum for six sets (half-squat exercise performed to repetitions failure each set). We measured the power output and number of repetitions in the free barbell half-squat used to assess muscular endurance performance in participants. The countermovement jump (CMJ) height, total quality recovery scale (TQRS), and muscle soreness visual analog scale (VAS) scores were measured to assess fatigue recovery status after training, as well as at 24 and 48 h of recovery.ResultsThe total power output (HRW: 50,866.7 ± 6,359.9W, Placebo: 46,431.0 ± 9,376.5W, p = 0.032) and the total number of repetitions (HRW:78.2 ± 9.5 repetitions, Placebo: 70.3 ± 9.5 repetitions, p = 0.019) in the H2 supplemented group were significantly higher than in the placebo group. However, there was no statistically significant difference (p< 0.05) between the H2 and placebo groups in CMJ, TQRS, and VAS.ConclusionEight days of intermittent HRW intake could significantly improve muscular endurance performance in trained individuals, making it a promising strategy for athletes or fitness enthusiasts looking to boost muscular endurance during resistance training or competitions. However, it should be noted that HRW intake alone may not be adequate to accelerate recovery from muscle soreness or fatigue following high-intensity training.

BackgroundPhysical exertion during exercise often leads to increased oxidative stress and inflammatory responses, significantly affecting physical performance. Current strategies to mitigate these effects are limited by their effectiveness and potential side effects. Molecular hydrogen (H₂) has gained attention for its antioxidant and anti-inflammatory properties. Studies have suggested that H2 supplementation contributes to antioxidant potential and anti-fatigue during exercise, but the variance in the observations and study protocols is presented across those studies.ObjectiveThis systematic review and meta-analysis aimed to comprehensively characterize the effects of H₂ supplementation on physical performance (i.e., endurance, muscular strength, and explosive power), providing knowledge that can inform strategies using H2 for enhancing physical performance.MethodsWe conducted a literature search of six databases (PubMed, Web of Science, Medline, Sport-Discus, Embase, and PsycINFO) according to the PRISMA guidelines. The data were extracted from the included studies and converted into the standardized mean difference (SMD). After that, we performed random-effects meta-analyses and used the I2 statistic to evaluate heterogeneity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the quality of the evidence obtained from this meta-analysis.ResultsIn total, 27 publications consisting of 597 participants were included. The search finally included aerobic endurance, anaerobic endurance, muscular strength, lower limb explosive power, rating of perceived exertion (RPE), blood lactate (BLA), and average heart rate (HRavg) in the effect size (ES) synthesis. The ES of H2 on aerobic endurance, including V̇O2max (SMD = 0.09, p = 0.394; I2 = 0%) and aerobic endurance exercise (SMD = 0.04, p = 0.687; I2 = 0%), were not significant and trivial; the ES of H2 on 30 s maximal anaerobic endurance (SMD = 0.19, p = 0.239; I2 = 0%) was not significant and trivial; the ES of H2 on muscular strength (SMD = 0.19, p = 0.265; I2 = 0%) was not significant and trivial; but the ES of H2 on lower limb explosive power (SMD = 0.30, p = 0.018; I2 = 0%) was significant and small. In addition, H2 reduces RPE (SMD = −0.37, p = 0.009; I2 = 58.0%) and BLA (SMD = −0.37, p = 0.001; I2 = 22.0%) during exercise, but not HRavg (SMD = −0.27, p = 0.094; I2 = 0%).ConclusionThese findings suggest that H2 supplementation is favorable in healthy adults to improve lower limb explosive power, alleviate fatigue, and boost BLA clearance, but may not be effectively improving aerobic and anaerobic endurance and muscular strength. Future studies with more rigorous designs are thus needed to examine and confirm the effects of H2 on these important functionalities in humans.Systematic review registrationhttp://www.crd.york.ac.uk/PROSPERO.

Time-restricted eating (TRE) is a circadian rhythm-based intermittent fasting intervention that has been used to treat obesity. However, the efficacy and safety of TRE for fat loss have not been comprehensively examined and the influences of TRE characteristics on such effects are unknown. This systematic review and meta-analysis comprehensively characterized the efficacy and safety of TRE for fat loss in adults with overweight and obese, and it explored the influence of TRE characteristics on this effect. Methods: A search strategy based on the PICOS principle was used to find relevant publications in seven databases. The outcomes were body composition, anthropometric indicators, and blood lipid metrics. Twenty publications (20 studies) with 1288 participants, covering the period from 2020 to 2024, were included. Results: Compared to the control group, TRE safely and significantly reduced body fat percentage, fat mass, lean mass, body mass, BMI, and waist circumference (MDpooled = −2.14 cm, 95% CI = −2.88~−1.40, p < 0.001), and increased low-density lipoprotein (LDL) (MDpooled = 2.70, 95% CI = 0.17~5.22, p = 0.037), but it did not alter the total cholesterol, high-density lipoprotein, and triglycerides (MDpooled = −1.09~1.20 mg/dL, 95% CI −4.31~5.47, p > 0.05). Subgroup analyses showed that TRE only or TRE-caloric restriction with an eating window of 6 to 8 h may be appropriate for losing body fat and overall weight. Conclusions: This work provides moderate to high evidence that TRE is a promising dietary strategy for fat loss. Although it may potentially reduce lean mass and increase LDL, these effects do not pose significant safety concerns. This trial was registered with PROSPERO as CRD42023406329.

ObjectiveExercise-induced oxidative stress affects multiple neurophysiological processes, diminishing the exercise performance. Hydrogen (H2) can selectively reduce excessive free radicals, but studies observed its “dual effects” on exercise-induced oxidative stress, that is, increasing or decreasing the oxidative stress. Therefore, we here conducted a systematic review and meta-analysis to quantitatively assess the influence of H2 on exercise-induced oxidative stress in healthy adults.MethodsWe conducted a systematic review of publications across five databases. The following keywords were used for search strategy: [“hydrogen”[Mesh] or “molecular hydrogen” or “hydrogen rich water” or “hydrogen-rich water” or “hydrogen rich saline”] and [“Oxidative Stress”[Mesh] or “Antioxidative Stress” or “Oxidative Damage” or “Oxidative Injury” or “Oxidative Cleavage”] and [“randomized controlled trial”[Mesh] or “randomized” or “RCT”]. We included trials reporting the effects of H2 on exercise-induced oxidative stress and potential antioxidant capacity post-exercise in healthy adults. Additionally, subgroup analyses were conducted to explore how various elements of the intervention design affected those outcomes.ResultsSix studies, encompassing seven experiments with a total of 76 participants, were included in our analysis. Among these studies, hydrogen-rich water, hydrogen bathing, and hydrogen-rich gas were three forms used in H2 administration. The H2 was applied in different timing, including before, during, or after exercise only, both before and after exercise, and repeatedly over days. Single-dose, multi-dose within 1 day and/or multiple-dose over days were implemented. It was observed that compared to placebo, the effects of H2 on oxidative stress (diacron-reactive oxygen metabolites, d-ROMs) was not significant (SMD = −0.01, 95%CI-0.42 to 0.39, p = 0.94). However, H2 induced greater improvement in antioxidant potential capacity (Biological Antioxidant Potential, BAP) (SMD = 0.29, 95% CI 0.04 to 0.54, p = 0.03) as compared to placebo. Subgroup analyses revealed that H2 supplementation showed greater improvement (SMD = 0.52, 95%CI 0.16 to 0.87, p = 0.02) in the antioxidant potential capacity of intermittent exercises than continuous exercise.ConclusionH2 supplementation can help enhance antioxidant potential capacity in healthy adults, especially in intermittent exercise, but not directly diminish the levels of exercise-induced oxidative stress. Future studies with more rigorous design are needed to examine and confirm these findings.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=364123, Identifier CRD42022364123.

Abstract Ovarian cancer (OC) is the most lethal gynecologic tumor and is characterized by a high rate of metastasis. Challenges in accurately delineating the metastatic pattern have greatly restricted the improvement of treatment in OC patients. An increasing number of studies have leveraged mitochondrial DNA (mtDNA) mutations as efficient lineage-tracing markers of tumor clonality. We applied multiregional sampling and high-depth mtDNA sequencing to determine the metastatic patterns in advanced-stage OC patients. Somatic mtDNA mutations were profiled from a total of 195 primary and 200 metastatic tumor tissue samples from 35 OC patients. Our results revealed remarkable sample-level and patient-level heterogeneity. In addition, distinct mtDNA mutational patterns were observed between primary and metastatic OC tissues. Further analysis identified the different mutational spectra between shared and private mutations among primary and metastatic OC tissues. Analysis of the clonality index calculated based on mtDNA mutations supported a monoclonal tumor origin in 14 of 16 patients with bilateral ovarian cancers. Notably, mtDNA-based spatial phylogenetic analysis revealed distinct patterns of OC metastasis, in which a linear metastatic pattern exhibited a low degree of mtDNA mutation heterogeneity and a short evolutionary distance, whereas a parallel metastatic pattern showed the opposite trend. Moreover, a mtDNA-based tumor evolutionary score (MTEs) related to different metastatic patterns was defined. Our data showed that patients with different MTESs responded differently to combined debulking surgery and chemotherapy. Finally, we observed that tumor-derived mtDNA mutations were more likely to be detected in ascitic fluid than in plasma samples. Our study presents an explicit view of the OC metastatic pattern, which sheds light on efficient treatment for OC patients.

Abstract Background Epithelial ovarian cancer (EOC) heavily relies on oxidative phosphorylation (OXPHOS) and exhibits distinct mitochondrial metabolic reprogramming. Up to now, the evolutionary pattern of somatic mitochondrial DNA (mtDNA) mutations in EOC tissues and their potential roles in metabolic remodelling have not been systematically elucidated. Methods Based on a large somatic mtDNA mutation dataset from private and public EOC cohorts (239 and 118 patients, respectively), we most comprehensively characterised the EOC‐specific evolutionary pattern of mtDNA mutations and investigated its biological implication. Results Mutational profiling revealed that the mitochondrial genome of EOC tissues was highly unstable compared with non‐cancerous ovary tissues. Furthermore, our data indicated the delayed heteroplasmy accumulation of mtDNA control region (mtCTR) mutations and near‐complete absence of mtCTR non‐hypervariable segment (non‐HVS) mutations in EOC tissues, which is consistent with stringent negative selection against mtCTR mutation. Additionally, we observed a bidirectional and region‐specific evolutionary pattern of mtDNA coding region mutations, manifested as significant negative selection against mutations in complex V (ATP6/ATP8) and tRNA loop regions, and potential positive selection on mutations in complex III (MT‐CYB). Meanwhile, EOC tissues showed higher mitochondrial biogenesis compared with non‐cancerous ovary tissues. Further analysis revealed the significant association between mtDNA mutations and both mitochondrial biogenesis and overall survival of EOC patients. Conclusions Our study presents a comprehensive delineation of EOC‐specific evolutionary patterns of mtDNA mutations that aligned well with the specific mitochondrial metabolic remodelling, conferring novel insights into the functional roles of mtDNA mutations in EOC tumourigenesis and progression.

BackgroundTaichi is beneficial for functional mobility and balance in older adults. However, such benefits of Taichi when comparing to conventional exercise (CE) are not well understood due to large variance in study protocols and observations.MethodsWe reviewed publications in five databases. Eligible studies that examined the effects of Taichi on the outcomes of functional mobility and balance in healthy older adults as compared to CE were included. Subgroup analyses compared the effects of different types of CE (e.g., single and multiple-type exercise) and different intervention designs (e.g., Taichi types) on those outcomes (Registration number: CRD42022331956).ResultsTwelve studies consisting of 2,901 participants were included. Generally, compared to CE, Taichi induced greater improvements in the performance of Timed-Up-and-Go (SMD = −0.18, [−0.33 to −0.03], p = 0.040, I2 = 59.57%), 50-foot walking (MD = −1.84 s, [−2.62 to −1.07], p

Mitochondrial DNA (mtDNA) somatic mutations play important roles in the initiation and progression of cancer. Although next‐generation sequencing (NGS) of paired tumor and control samples has become a common practice to identify tumor‐specific mtDNA mutations, the unique nature of mtDNA and NGS‐associated sequencing bias could cause false‐positive/‐negative somatic mutation calling. Additionally, there are clinical scenarios where matched control tissues are unavailable for comparison. Therefore, a novel approach for accurately identifying somatic mtDNA variants is greatly needed, particularly in the absence of matched controls. In this study, the ground truth mtDNA variants orthogonally validated by triple‐paired tumor, adjacent nontumor, and blood samples were used to develop mitoSomatic, a random forest‐based machine learning tool. We demonstrated that mitoSomatic achieved area under the curve (AUC) values over 0.99 for identifying somatic mtDNA variants without paired control in three tumor types. In addition, mitoSomatic was also applicable in nontumor tissues such as adjacent nontumor and blood samples, suggesting the flexibility of mitoSomatic's classification capability. Furthermore, analysis of triple‐paired samples identified a small group of variants with uncertain somatic/germline origin, whereas application of mitoSomatic significantly facilitated the prediction of their possible source. Finally, a control‐free evaluation of the public pan‐cancer NGS dataset with mitoSomatic revealed a substantial number of variants that were probably misclassified by conventional tumor‐control comparison, further emphasizing the usefulness of mitoSomatic in application. Taken together, our study demonstrates that mitoSomatic is valuable for accurately identifying somatic mtDNA variants in mtDNA NGS data without paired controls, applicable for both tumor and nontumor tissues.

(1) Background: Hydrogen (H2) may be a potential therapeutic agent for managing Long COVID symptoms due to its antioxidant and anti-inflammatory properties. However, more scientific literature is needed to describe the effects of H2 administration on treating symptoms. A study aimed to investigate the impact of hydrogen-rich water (HRW) administration on the fatigue and dyspnea of Long-COVID patients for 14 consecutive days. (2) Methods: In this randomized, single-blind, placebo-controlled study, 55 participants were recruited, and 23 of them were excluded. A total of 32 eligible participants were randomized into a hydrogen-rich water (HRW) group (n = 16) and a placebo water (PW) group (n = 16) in which they were instructed to consume hydrogen-rich water or placebo water for 14 days, respectively. The participants completed the Fatigue Severity Scale (FSS), Six-Minute Walk Test (6MWT), 30 s Chair Stand Test (30s-CST), Modified Medical Research Council Dyspnea Rating Scale (mMRC), Pittsburgh Sleep Quality Index (PSQI), and depression anxiety stress scale (DASS-21) before and after the intervention. A linear mixed-effects model was used to analyze the effects of HRW. Cohen’s d values were used to assess the effect size when significance was observed. The mean change with 95% confidence intervals (95% CI) was also reported. (3) Results: The effects of HRW on lowering FSS scores (p = 0.046, [95% CI = −20.607, −0.198, d = 0.696] and improving total distance in the 6WMT (p < 0.001, [95% CI = 41.972, 61.891], d = 1.010), total time for the 30s-CST (p = 0.002, [95% CI = 1.570, 6.314], d = 1.190), and PSQI scores (p = 0.012, [95% CI = −5.169, 0.742], d = 1.274) compared to PW were of a significantly moderate effect size, while there was no significant difference in mMRC score (p = 0.556) or DASS-21 score (p > 0.143). (4) Conclusions: This study demonstrates that HRW might be an effective strategy for alleviating fatigue and improving cardiorespiratory endurance, musculoskeletal function, and sleep quality. Still, it does not ameliorate dyspnea among Long-COVID patients.

ObjectiveTo determine the impacts of concurrent aerobic and resistance training on vascular structure (IMT) and function (PWV, FMD, NMD) in type 2 diabetes (T2D).MethodsThe electronic databases PubMed, Web of Science Core Collection, Cochrane Library, Embase, Scopus, CINAHL, and SPORTDiscus were systematically searched for articles on “type 2 diabetes” and “concurrent training” published from inception to August 2, 2022. We included randomized controlled trials that examined the effects of concurrent training versus passive controls on IMT, PWV, FMD and NMD in T2D.ResultsTen studies were eligible, including a total of 361 participants. For IMT, concurrent training showed a slight decrease by 0.05 mm (95% CI −0.11 to 0.01, p > 0.05). concurrent training induced an overall significant improvement in FMD by 1.47% (95% CI 0.15 to 2.79, p < 0.05) and PWV by 0.66 m/s (95% CI −0.89 to −0.43, p < 0.01) in type 2 diabetics. However, concurrent training seemed to exaggerate the impaired NMD (WMD = −2.30%, 95% CI −4.02 to −0.58, p < 0.05).ConclusionsConcurrent training is an effective method to improve endothelial function and artery stiffness in T2D. However, within 24 weeks concurrent training exacerbates vascular smooth muscle dysfunction. More research is needed to explore whether longer and/or higher-intensity concurrent training interventions could enhance the vascular structure and smooth muscle function in this population.Systematic review registrationwww.crd.york.ac.uk/PROSPERO/, identifier CRD42022350604.

Cefquinome is widely used to treat respiratory tract diseases of swine. While extra-label dosages of cefquinome could improve clinical efficacy, they might lead to excessively high residues in animal-derived food. In this study, a physiologically based pharmacokinetic (PBPK) model was calibrated based on the published data and a microdialysis experiment to assess the dosage efficiency and food safety. For the microdialysis experiment, in vitro/in vivo relative recovery and concentration-time curves of cefquinome in the lung interstitium were investigated. This PBPK model is available to predict the drug concentrations in the muscle, kidney, liver, plasma, and lung interstitial fluid. Concentration-time curves of 1000 virtual animals in different tissues were simulated by applying sensitivity and Monte Carlo analyses. By integrating pharmacokinetic/pharmacodynamic target parameters, cefquinome delivered at 3–5 mg/kg twice daily is advised for the effective control of respiratory tract infections of nursery pig, which the bodyweight is around 25 kg. Based on the predicted cefquinome concentrations in edible tissues, the withdrawal interval is 2 and 3 days for label and the extra-label doses, respectively. This study provides a useful tool to optimize the dosage regimen of cefquinome against respiratory tract infections and predicts the concentration of cefquinome residues in edible tissues. This information would be helpful to improve the food safety and guide rational drug usage. Author summary Physiologically-based pharmacokinetic (PBPK) models, a mechanism-based model that incorporate physiological and chemical-specific parameters, can describe the absorption, distribution, metabolism and excretion of chemicals in different organs of animals. It can be applied for chemical risk assessment, dosage optimization and withdrawal intervals determination. The Extra-label use antimicrobial drug is a way to solve the treatment failure resulting from antimicrobial resistance. Integrate with pharmacokinetic/pharmacodynamic (PK/PD) parameters and maximum residual limit, PBPK model can determine a safe and effective dosage. This approach would be helpful to improve the food safety and guide rational drug usage.

Salmonella spp. is one of the most important foodborne pathogens. Typhoid fever and enteritis caused by Salmonella enterica are associated with 16–33 million infections and 500,000 to 600,000 deaths annually worldwide. The eradication of Salmonella is becoming increasingly difficult because of its remarkable capacity to counter antimicrobial agents. In addition to the intrinsic and acquired resistance of Salmonella, increasing studies indicated that its non-inherited resistance, which commonly mentioned as biofilms and persister cells, plays a critical role in refractory infections and resistance evolution. These remind the urgent demand for new therapeutic strategies against Salmonella. This review starts with escape mechanisms of Salmonella against antimicrobial agents, with particular emphasis on the roles of the non-inherited resistance in antibiotic failure and resistance evolution. Then, drug design or therapeutic strategies that show impressive effects in overcoming Salmonella resistance and tolerance are summarized completely, such as overcoming the barrier of outer membrane by targeting MlaABC system, reducing persister cells by limiting hydrogen sulfide, and applying probiotics or predatory bacteria. Meanwhile, according to the clinical practice, the advantages and disadvantages of above strategies are discussed. Finally, we further analyze how to deal with this tricky problems, thus can promote above novel strategies to be applied in the clinic as soon as possible. We believed that this review will be helpful in understanding the relationships between tolerance phenotype and resistance of Salmonella as well as the efficient control of antibiotic resistance.

BackgroundFatigue is oftentimes induced by high-intensity exercise potentially via the exceeded amount of reactive oxygen species, leading to diminished functions (e.g., aerobic capacity) and increased risk of injuries. Studies indicate that molecular hydrogen (H2), with antioxidant and anti-inflammatory properties, may be a promising strategy to alleviate fatigue and improve aerobic capacity. However, such effects have not been comprehensively characterized.ObjectiveTo systematically assess the effects of in taking H2 on fatigue and aerobic capacity in healthy adults.MethodsThe search was conducted in August 2022 in five databases. Studies with randomized controlled or crossover designs that investigated the rating of perceived exertion (RPE), maximal oxygen uptake (VO2max), peak oxygen uptake (VO2peak), and endurance performance were selected. The data (mean ± standard deviation and sample size) were extracted from the included studies and were converted into the standardized mean difference (SMD). Random-effects meta-analyses were performed. Subgroup analysis was used to analyze potential sources of heterogeneity due to intervention period, training status, and type of exercise.ResultsSeventeen publications (19 studies) consisting of 402 participants were included. The pooled effect sizes of H2 on RPE (SMDpooled = −0.38, 95%CI −0.65 to −0.11, p = 0.006, I2 = 33.6%, p = 0.149) and blood lactate (SMDpooled = −0.42, 95% CI −0.72 to −0.12, p = 0.006, I2 = 35.6%, p = 0.114) were small yet significant with low heterogeneity. The pooled effect sizes of H2 on VO2max and VO2peak (SMDpooled = 0.09, 95% CI −0.10 to 0.29, p = 0.333, I2 = 0%, p = 0.998) and endurance performance (SMDpooled = 0.01, 95% CI −0.23 to 0.25, p = 0.946, I2 = 0%, p > 0.999) were not significant and trivial without heterogeneity. Subgroup analysis revealed that the effects of H2 on fatigue were impacted significantly by the training status (i.e., untrained and trained), period of H2 implementation, and exercise types (i.e., continuous and intermittent exercises).ConclusionsThis meta-analysis provides moderate evidence that H2 supplementation alleviates fatigue but does not enhance aerobic capacity in healthy adults.Systematic review registrationwww.crd.york.ac.uk/PROSPERO/, identifier: CRD42022351559.

Objective: This study examined the effects of 12-week complex training (CT) programs on professional firefighters’ occupational activities, strength, and power.Methods: Thirty men professional firefighters were randomly assigned to the CT group (n = 15) and control group (n = 15). The CT group performed complex training and the control group completed resistance training (RT) twice a week over 12 weeks. The occupational activities, strength, and power were assessed at baseline and immediately after the intervention by measuring the performance of 100 m load-bearing run (100 m LR), 60 m shoulder ladder run (60 m SLR), 5 m × 20 m shuttle run (5 m × 20 m SR), 4th-floor climbing rope (4th-floor CR), countermovement jump with arm swing (CMJas), seated medicine-ball throw (SMT), one-repetition maximum bench press (1RM BP), and one-repetition maximum back squat (1RM BS).Results: The results showed that compared to RT, CT induced significantly greater improvements in 60 m SLR (p = 0.007), 4th-floor CR (p = 0.020), CMJas (p = 0.001), and SMT (p < 0.001).Conclusion: These findings suggest that CT is a novel intervention with great promise of improving professional firefighters’ occupational activities, strength, and power.

ObjectiveTo evaluate the effectiveness of a new tracer (S)-1-(4-(6-(dimethylamino)quinoxalin-2-yl)phenoxy)-3-fluoropropan-2-ol ([18F]-S16), in distinguishing patients with AD from HCs.MethodsPaired [18F]-S16 and [18F]-THK5317 scans were acquired in five patients with AD, six HCs, one subject with a semantic variant of primary progressive aphasia (sv-PPA) and one subject with probable progressive supranuclear palsy (PSP). Dynamic PET scanning was performed over 90 min after injection of the tracers. Standardized uptake values (SUV) and cortical-to-cerebellum standardized uptake value ratios (SUVRs) were used for tau deposition semi-quantization. A voxel-based analysis was employed to assess the uptake difference between populations.Results[18F]-S16 exhibited excellent blood-brain-barrier penetration. AD patients showed increased cortical [18F]-THK5317 and [18F]-S16 binding. Compared to HCs, AD patients showed significantly increased cortical [18F]-S16 uptake in the bilateral occipital cortex, posterior cingulated cortex/precuneus, and lateral frontal cortex. Notable [18F]-S16 uptake was observed in the basal ganglia and brainstem compared to the neocortex. A substantial [18F]-S16 signal was detected in the basal ganglia and midbrain in a patient with probable PSP and in the bilateral anterior temporal cortex in a sv-PPA patient.Conclusion[18F]-S16 might be of help to detect tau protein in vivo.

IntroductionAccurately predicting the competitive performance of elite athletes is an essential prerequisite for formulating competitive strategies. Women’s all-around speed skating event consists of four individual subevents, and the competition system is complex and challenging to make accurate predictions on their performance.ObjectiveThe present study aims to explore the feasibility and effectiveness of machine learning algorithms for predicting the performance of women’s all-around speed skating event and provide effective training and competition strategies.MethodsThe data, consisting of 16 seasons of world-class women’s all-around speed skating competition results, used in the present study came from the International Skating Union (ISU). According to the competition rules, distinct features are filtered using lasso regression, and a 5,000 m race model and a medal model are built using a fivefold cross-validation method.ResultsThe results showed that the support vector machine model was the most stable among the 5,000 m race and the medal models, with the highest AUC (0.86, 0.81, respectively). Furthermore, 3,000 m points are the main characteristic factors that decide whether an athlete can qualify for the final. The 11th lap of the 5,000 m, the second lap of the 500 m, and the fourth lap of the 1,500 m are the main characteristic factors that affect the athlete’s ability to win medals.ConclusionCompared with logistic regression, random forest, K-nearest neighbor, naive Bayes, neural network, support vector machine is a more viable algorithm to establish the performance prediction model of women’s all-around speed skating event; excellent performance in the 3,000 m event can facilitate athletes to advance to the final, and athletes with outstanding performance in the 500 m event are more likely competitive for medals.

Summary: Background: Mitochondrial DNA (mtDNA) mutations alter mitochondrial function in oxidative metabolism and play an important role in tumorigenesis. A series of studies have demonstrated that the mtDNA control region (mtCTR), which is essential for mtDNA replication and transcription, represents a mutational hotspot in human tumors. However, a comprehensive pan-cancer evolutionary pattern analysis of mtCTR mutations is urgently needed. Methods: We generated a comprehensive combined dataset containing 10026 mtDNA somatic mutations from 4664 patients, covering 20 tumor types based on public and private next-generation sequencing data. Findings: Our results demonstrated a significantly higher and much more variable mutation rate in mtCTR than in the coding region across different tumor types. Moreover, our data showed a remarkable distributional bias of tumor somatic mutations between the hypervariable segment (HVS) and non-HVS, with a significantly higher mutation density and average mutation sites in HVS. Importantly, the tumor-specific mutational pattern between mtCTR HVS and non-HVS was identified, which was classified into three evolutionary selection types (relaxed, moderate, and strict constraint types). Analysis of substitution patterns revealed that the prevalence of CH > TH in non-HVS greatly contributed to the mutational selection pattern of mtCTR across different tumor types. Furthermore, we found that the mutational pattern of mtCTR in the four tumor types was clearly associated with mitochondrial biogenesis, mitochondrial oxidative metabolism, and the overall survival of patients. Interpretation: Our results suggest that somatic mutations in mtCTR may be shaped by tumor-specific selective pressure and are involved in tumorigenesis. Fundings: National Natural Science Foundation of China [grants 82020108023, 81830070, 81872302], and Autonomous Project of State Key Laboratory of Cancer Biology, China [grants CBSKL2019ZZ06, CBSKL2019ZZ27].

Next-generation sequencing technology has been commonly applied to detect mitochondrial DNA (mtDNA) mutations, which are reported to be strongly associated with cancers. However, several key challenges still exist regarding bioinformatics analysis of mtDNA sequencing data that greatly affect the detection accuracy of mtDNA mutations. Here we comprehensively evaluated several key analysis procedures in three different sample types. We found that a trimming procedure was essential for improving mtDNA mapping performance in plasma but not tissue samples. Mapping with a revised Cambridge reference sequence and human genome 19 reference was strongly suggested for mtDNA mutation detection in plasma samples because of the extreme abundance of nuclear DNA of mitochondrial origin. Moreover, our results showed that a setting of 3 mismatches was most appropriate for mtDNA mutation calling. Importantly, we revealed the presence of a negative logarithmic relationship between mtDNA site sequencing depth and minimum detectable mutation frequency and built an innovative and efficient filtering strategy to increase the accuracy and sensitivity of mutation detection. Finally, we verified that higher sequencing depth was required for a PCR-based compared with a capture-based enrichment strategy. We established an innovative data analysis strategy that is of great significance for improving the accuracy of mtDNA mutation detection for different types of tumor samples.

Mitochondrial DNA (mtDNA) mutations are closely implicated in the pathogenesis of multiple cancers, making circulating cell-free mtDNA (ccf-mtDNA) as a potential non-invasive tumor biomarker. However, an effective approach to comprehensively profile ccf-mtDNA mutations is still lacking. In this study, we first characterized ccf-mtDNA by low-depth whole-genome sequencing (WGS) and found that plasma DNA samples exhibited a dramatic decrease in mtDNA copy number when compared with fresh tumor tissues. Further analysis revealed that plasma ccf-mtDNA had a biased distribution of fragment size with a peak around 90 bp. Based on these insights, we developed a robust captured-based mtDNA deep-sequencing approach that enables accurate and efficient detection of plasma ccf-mtDNA mutations by systematic optimization of probe quantity and length, hybridization temperature, and PCR amplification cycles. Moreover, we found that placement of isolated plasma for 6 h at both 4°C and room temperature (RT) led to a dramatic decrease of ccf-mtDNA stability, highlighting the importance of proper plasma sample processing. We further showed that the optimized approach can successfully detect a substantial fraction of tumor-specific mtDNA mutations in plasma ccf-mtDNA specifically from hepatocellular carcinoma (HCC) patients but not from colorectal cancer (CRC) patients, suggesting the presence of a potential cancer-specific difference in the abundance of tumor-derived mtDNA in plasma.

ObjectiveThe studies showed the benefits of virtual reality training (VRT) for functional mobility and balance in older adults. However, a large variance in the study design and results is presented. We, thus, completed a systematic review and meta-analysis to quantitatively examine the effects of VRT on functional mobility and balance in healthy older adults.MethodsWe systematically reviewed the publications in five databases. Studies that examine the effects of VRT on the measures of functional mobility and balance in healthy older adults were screened and included if eligible. Subgroup analyses were completed to explore the effects of different metrics of the intervention design (e.g., session time) on those outcomes related to functional mobility and balance.ResultsFifteen studies of 704 participants were included. The quality of these studies was good. Compared to traditional physical therapy (TPT), VRT induced greater improvement in TUG (MD = −0.31 s, 95% CI = −0.57 to −0.05, p = 0.02, I2 = 6.34%) and one-leg stance with open eyes (OLS-O) (MD = 7.28 s, 95% CI = 4.36 to 10.20, p = 0.00, I2 = 36.22%). Subgroup analyses revealed that immersive VRT with more than 800 min of total intervention time over 8 weeks and at least 120 min per week and/or designed by the two motor-learning principles was optimal for functional mobility and balance.ConclusionVirtual reality training can significantly improve functional mobility and balance in healthy older adults compared to TPT, and the findings provided critical knowledge of the optimized design of VRT that can inform future studies with more rigorous designs.Systematic Review Registration[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021297085].

BackgroundRecently, considerable research has been conducted to study the effects of traditional Chinese exercises (TCEs) on cognitive function in older adults with MCI. We completed a comprehensive systematic review and meta-analysis to assess the efficacy of TCEs on cognitive function in this population.MethodsA search strategy based on the PICOS principle was used to find the literatures in the databases of PubMed, Web of Science, MEDLINE, SPORT-Discus, PsycINFO, Cochrane Central Register of Controlled Trials, Ovid. The quality and risk of bias in the studies were independently assessed by two researchers.ResultsNine trials with 1,290 participants were included. The effect size of TCEs on global cognitive function was small (SMD = 0.29, 95% CI 0.15–0.44, p < 0.001) when compared to the active control and was moderate (SMD = 0.58, 95% CI 0.21–0.94, p = 0.002) compared to the inactive control; statistically significant effects were also found for short-term memory (SMD = 0.22, 95% CI 0.05–0.39, p = 0.013), long-term memory (SMD = 0.53, 95% CI 0.20–0.86, p = 0.002), shifting (SMD = −0.39, 95% CI −0.54 to −0.25, p < 0.001), language ability (SMD = 0.32, 95% CI 0.13–0.51, p = 0.001), visuospatial perception (SMD = 0.31, 95% CI 0.15–0.46, p < 0.001).ConclusionThis meta-analysis provides clinicians with moderate evidence to recommend that TCEs hold potential to enhance both global cognitive function and multiple domains of cognitive function, which, however, needs to be confirmed and further examined in futures studies. The results of this work provide critical knowledge for the design of future studies implementing TCEs as well as its clinical practice. Future RCTs with rigorous designs are needed to help obtain more definitive conclusions on the effects of TCEs on cognitive function in older adults with MCI.

Background: The goal of this study was to report a fully automated radiosynthetic procedure of a novel tau tracer [18F]-S16 and its safety, biodistribution, and dosimetry in healthy volunteers as well as the potential utility of [18F]-S16 positron emission tomography (PET) in Alzheimer’s disease (AD).Methods: The automated radiosynthesis of [18F]-S16 was performed on a GE Tracerlab FX2 N module. For the biodistribution and dosimetry study, healthy volunteers underwent a series of PET scans acquired at 10, 60, 120, and 240 min post-injection. The biodistribution and safety were assessed. For the AD study, both AD and healthy controls (HCs) underwent dynamic [18F]-S16 and static [18F]-FDG PET imaging. [18F]-S16 binding was assessed quantitatively using standardized uptake value ratios (SUVRs) measured at different regions of interest (ROIs). [18F]-S16 SUVRs were compared between the AD patients and HCs using the Mann–Whitney U-test. In AD patients with all cortical ROIs, Spearman rank-correlation analysis was used to calculate the voxel-wise correlations between [18F]-S16 and [18F]-FDG.Results: The automated radiosynthesis of [18F]-S16 was finished within 45 min, with a radiochemical yield of 30 ± 5% (n = 8, non-decay-corrected). The radiochemical purity was greater than 98%, and the specific activity was calculated to be 1,047 ± 450 GBq/μmol (n = 5), and [18F]-S16 was stable in vitro. In the healthy volunteer study, no adverse effect was observed within 24 h post-injection, and no defluorination was observed in vivo. The radiotracer could pass through the blood–brain barrier easily and was rapidly cleared from the circulation and excreted through the hepatic system. The whole-body mean effective dose was 15.3 ± 0.3 μSv/MBq. In AD patients, [18F]-S16 accumulation was identified as involving the parietal, temporal, precuneus, posterior cingulate, and frontal lobes. No specific [18F]-S16 cerebral uptake was identified in HCs. The SUVR of AD patients was significantly higher than that of HCs. No specific binding uptake was found in the choroid plexus, venous sinus, and white matter. A significant correlation was found between [18F]-S16 binding and hypometabolism across neocortical regions.Conclusion: [18F]-S16 could be synthesized automatically, and it showed favorable biodistribution and safety in humans. [18F]-S16 PET indicated a high image quality for imaging tau deposition in AD and distinguishing AD from HCs.

Diaveridine (DVD) is widely used for the prevention and treatment of coccidiosis and leucocytozoonosis infections in food-producing animals. To gain a better understanding of DVD metabolism and pharmacokinetics in healthy Landrace/Doric Cross castrated male pigs and both female and male Cobb 500 broiler chickens, a method involving radioactive tracing coupled with LC/MS-IT-TOF was developed for the identification and quantitation of DVD and its metabolites in pig and chicken plasma, and then was applied to investigate DVD pharmacokinetics. A simple MCX solid phase extraction procedure was adopted for sample preparation. After a single oral administration of 3H-DVD (10 mg/kg BW), three radioactive compounds (D0: DVD; D1: 3′-desmethyl-DVD; and D2: monoglucuronide of 3′-desmethyl-DVD) were identified in pig plasma, while only two radioactive compounds (D0 and D2) were identified in chicken plasma. In both species, the Cmax values for all detected compounds were reached at 2 h after dosing. The Cmax order was D2 (1.38 μg/ml) > D0 (0.49 μg/ml) > D1 (0.24 μg/ml) in pigs and D0 (1.55 μg/ml) > D2 (0.27 μg/ml) in chickens. The longer t1/2 (elimination half-life) of D0 contributed to the slow elimination of DVD-related compounds. The t1/2β of D0 in pigs (66.41 h) was significantly longer than that in chickens (48.30 h), but the t1/2 of total DVD-related metabolites in pigs (42.86 h) was lower than that in chickens (56.11 h). These findings suggested that the metabolism and pharmacokinetics of DVD in pigs and chickens were significantly different, and that this would affect its effectiveness, toxicology, and food safety in these animals.

According to the United Nations (UN), about 70% of the world’s population projected to live in urban areas by 2050. Therefore, cities are experiencing an enormous urban transition the world has ever seen, accounting for 80% of global carbon dioxide emissions, consuming over two-thirds of the world’s energy, and producing 1.3 billion tons of waste per year. Leaders, governments, architects, urban designers, developers, planners and business leaders need to make decisions and find solutions for how billions of urbanites will live in the future. Therefore, future cities will require new design principles to face their urban challenges and problems such as pollution, poverty, poor environment, land use management, green-house gas emissions and socio-economic and environmental risks. In this context, the case study area of this paper will be El Raval district, which is in a medieval quarter of Barcelona. This area considered as one of the oldest and a significant part of the city that contains many heritage buildings and unique traditional urban context going back to hundreds of years. The district has an influx of immigrants, which has transformed its label from an industrial neighbourhood into a residential one and low rents that have attracted many people of low income, making it a vibrant and multicultural community. Therefore, the main aim of this paper is to address the implementation of innovative solutions, advanced technologies, ICT and IoT that might enhance people participation in the urban design processes and respond to urban futures challenges. The result of this research will lead to creating a platform to resolve the conflicting values of architectural heritage and smart cities principles, sourcing new sustainable technologies and the integration of the smart infrastructure systems.DOI: https://doi.org/10.20365/disegnarecon.23.2019.14

Veterinary antibiotics are widely used in animal agriculture. Owing to its good absorption in the gastrointestinal tract, strong tissue permeability, and long biological half-life, doxycycline (DOX) is widely used to treat bacterial infections; however, this use can pose an environmental risk. The adsorption/desorption and degradation of DOX in three agricultural soils were investigated. DOX rapidly adsorbed to the soils, with an adsorption equilibrium time of 12 h for the three soils. The Freundlich equation was used to fit the adsorption and desorption of DOX in soils. A high Freundlich affinity coefficient (KF) was obtained from Freundlich isotherms, indicating strong sorption of DOX to agricultural soils and weak mobility to aquatic environment. Soil organic matter, the clay ratio and the cation exchange capacity were significantly positively correlated with KF (P

In our previous study, enrofloxacin-loaded docosanoic acid solid lipid nanoparticles (SLNs) could be effectively delivered to cells in vitro. In this study, its properties and exploitation as possible oral and intramuscular sustained release formulations for pigs were studied after being made into suspension. The re-dispersed time and sedimentation rate of the nanosuspension were 55 s and 1, respectively. It showed good stability when stored away from light and sustained release in pH = 7.4 PBS buffer. The suspension exhibited no irritation at the injection site and good palatability. Compared with commercial injection and soluble powder, the nanosuspension increased the bioavailability of enrofloxacin by 1.63 and 2.38 folds, and extended the mean residence time (MRT) of the drug from 11.27 and 12.33 to 37.76 and 35.15 h after intragastric and intramuscular administration, respectively. These results suggest that docosanoic acid SLN suspension (DAS) might be a promising oral and intramuscular sustained release formulation to enhance the pharmacological activity of enrofloxacin.

The hollow fiber cartridge has the advantages of good semi-permeability, high surface area to volume ratio, convenient operation, and so on. Its application in chemical analysis, drug in vitro experiment, hemodialysis, and other fields has been deeply studied. This paper introduces the basic structure of hollow fiber cartridge, compares the advantages and disadvantages of a hollow fiber infection model constructed by a hollow fiber cartridge with traditional static model and animal infection model and introduces its application in drug effects, mechanism of drug resistance, and evaluation of combined drug regimen. The principle and application of hollow fiber bioreactors for cell culture and hollow fiber dialyzer for dialysis and filtration were discussed. The hollow fiber cartridge, whether used in drug experiments, artificial liver, artificial kidney, etc., has achieved controllable experimental operation and efficient and accurate experimental results, and will provide more convenience and support for drug development and clinical research in the future.

Model informed drug development is a valuable tool for drug development and clinical application due to its ability to integrate variability and uncertainty of data. This study aimed to determine an optimal dosage of ceftiofur against P. multocida by ex vivo pharmacokinetic/pharmacodynamic (PK/PD) model and validate the dosage regimens by Physiological based Pharmacokinetic-Pharmacodynamic (PBPK/PD) model. The pharmacokinetic profiles of ceftiofur both in plasma and bronchoalveolar lavage fluid (BALF) are determined. PD performance of ceftiofur against P. multocida was investigated. By establishing PK/PD model, PK/PD parameters and doses were determined. PBPK model and PBPK/PD model were developed to validate the dosage efficacy. The PK/PD parameters, AUC0–24 h/MIC, for bacteriostatic action, bactericidal action and elimination were determined as 44.02, 89.40, and 119.90 h and the corresponding dosages were determined as 0.22, 0.46, and 0.64 mg/kg, respectively. AUC24 h/MIC and AUC 72 h/MIC are simulated by PBPK model, compared with the PK/PD parameters, the therapeutic effect can reach probability of target attainment (PTA) of 90%. The time-courses of bacterial growth were predicted by the PBPK/PD model, which indicated the dosage of 0.46 mg/kg body weight could inhibit the bacterial growth and perform good bactericidal effect.

ABSTRACT: Background: DNAs released from tumor cells into blood (circulating tumor DNAs, ctDNAs) carry tumor-specific genomic aberrations, providing a non-invasive means for cancer detection. In this study, we aimed to leverage somatic copy number aberration (SCNA) in ctDNA to develop assays to detect early-stage HCCs. Methods: We conducted low-depth whole-genome sequencing (WGS) to profile SCNAs in 384 plasma samples of hepatitis B virus (HBV)-related HCC and cancer-free HBV patients, using one discovery and two validation cohorts. To fully capture the robust signals of WGS data from the complete genome, we developed a machine learning-based statistical model that is focused on detection accuracy in early-stage HCC. Findings: We built the model using a discovery cohort of 209 patients, achieving an overall area under curve (AUC) of 0.893, with 0.874 for early-stage (Barcelona clinical liver cancer [BCLC] stage 0-A) and 0.933 for advanced-stage (BCLC stage B-D). The performance of the model was then assessed in two validation cohorts (76 and 99 patients) that only consisted of patients with stage 0-A HCC. Our model exhibited a robust predictive performance, with an AUC of 0.920 and 0.812 for the two validation cohorts. Further analyses showed the impact of tumor sample heterogeneity in model training on detecting early-stage tumors, and a refined model addressing the heterogeneity in the discovery cohort significantly increased model performance in validation. Interpretation: We developed an SCNA-based, machine learning-driven model in the non-invasive detection of early-stage HCC in HBV patients and demonstrated its performance through strict independent validations.

Magnesium matrix composites are considered a desired solution for lightweight applications. As an attractive thermal management material, diamond particle-reinforced Mg matrix (Mg/diamond) composites generally exhibit thermal conductivities lower than expected. To exploit the potential of heat conduction, a combination of Cr coating on diamond particles and squeeze casting was used to prepare Mg/diamond (Cr) composites. The thickness of the Cr coating under different coating processes (950 °C/30 min, 950 °C/60 min, 950 °C/90 min, 1000 °C/30 min, and 1050 °C/30 min) was measured by FIB-SEM to be 1.09–2.95 μm. The thermal conductivity (TC) of the Mg/diamond composites firstly increased and then decreased, while the coefficient of thermal expansion (CTE) of Mg/diamond (Cr) composite firstly decreased and then increased with the increase in Cr coating thickness. The composite exhibited the maximum TC of 202.42 W/(m·K) with a 1.20 μm Cr coating layer, while a minimum CTE of 5.82 × 10−6/K was recorded with a coating thickness of 2.50 μm. The results clearly manifest the effect of Cr layer thickness on the TC and CTE of Mg/diamond composites.

Antimicrobial resistance is a major public health issue. The pharmacokinetic/pharmacodynamic (PK/PD) model is an essential tool to optimize dosage regimens and alleviate the emergence of resistance. The semi-mechanistic PK/PD model is a mathematical quantitative tool to capture the relationship between dose, exposure, and response, in terms of the mechanism. Understanding the different resistant mechanisms of bacteria to various antibacterials and presenting this as mathematical equations, the semi-mechanistic PK/PD model can capture and simulate the progress of bacterial growth and the variation in susceptibility. In this review, we outline the bacterial growth model and antibacterial effect model, including different resistant mechanisms, such as persisting resistance, adaptive resistance, and pre-existing resistance, of antibacterials against bacteria. The application of the semi-mechanistic PK/PD model, such as the determination of PK/PD breakpoints, combination therapy, and dosage optimization, are also summarized. Additionally, it is important to integrate the PD effect, such as the inoculum effect and host response, in order to develop a comprehensive mechanism model. In conclusion, with the semi-mechanistic PK/PD model, the dosage regimen can be reasonably determined, which can suppress bacterial growth and resistance development.

Streptococcus suis (S. suis), a zoonotic pathogen, causes severe diseases in both pigs and human beings. Cefquinome can display excellent antibacterial activity against gram-negative and gram-positive bacteria. The aim of this study was to derive an optimal dosage of cefquinome against S. suis with a pharmacokinetic/pharmacodynamic (PK/PD) integration model in the target infection site and to investigate the cutoffs monitoring the changes of resistance. The minimum inhibitory concentration (MIC) distribution of cefquinome against 342 S. suis strains was determined. MIC50 and MIC90 were 0.06 and 0.25 μg/mL, respectively. The wild-type cutoff was calculated as 1 μg/mL. A two-compartmental model was applied to calculate the main pharmacokinetic parameters after 2 mg/kg cefquinome administered intramuscularly. An optimized dosage regimen of 3.08 mg/kg for 2-log10 CFU reduction was proposed by ex vivo PK/PD model of infected swine. The pharmacokinetic-pharmacodynamic cutoff was calculated as 0.06 μg/mL based on PK/PD targets. Based on the clinical effectiveness study of pathogenic MIC isolates, the clinical cutoff was calculated as 0.5 μg/mL. A clinical breakpoint was proposed as 1 μg/mL. In conclusion, the results offer a reference for determining susceptibility breakpoint of cefquinome against S. suis and avoiding resistance emergence by following the optimal dosage regimen.

Enrofloxacin (ENR) granules were developed to prevent and control the infections caused by foodborne zoonotic intestinal pathogens in our previous studies. To promote the further development of ENR granules and standardize their usage in pigs, a physiologically based pharmacokinetic (PBPK) model of the ENR granule in pigs was built to determine the withdrawal time (WT) and evaluate the toxicity to pigs. Meanwhile, the population WT was determined by a Monte Carlo analysis to guarantee pork safety. The fitting results of the model showed that the tissue residual concentrations of ENR, ciprofloxacin, and ENR plus ciprofloxacin were all well predicted by the built PBPK model (R2 > 0.82). When comparing with the EMA’s WT1.4 software method, the final WT (6 d) of the ENR granules in the population of pigs was well predicted. Moreover, by combining the cytotoxicity concentration (225.9 µg/mL) of ENR against pig hepatocytes, the orally safe dosage range (≤130 mg/kg b.w.) of the ENR granules to pigs was calculated based on the validated PBPK model. The well-predicted WTs and a few uses in animals proved that the PBPK model is a potential tool for promoting the judicious use of antimicrobial agents and evaluating the toxicity of the veterinary antimicrobial products.

Zoonotic intestinal pathogens threaten human health and cause huge economic losses in farming. Enrofloxacin (ENR) shows high antibacterial activity against common intestinal bacteria. However, its poor palatability and low aqueous solubility limit the clinical application of ENR. To obtain an ENR oral preparation with good palatability and high solubility, a granule containing an amorphous ENR solid dispersion (ENR-SD) was prepared. Meanwhile, a PBPK model of ENR in pigs was built based on the physiological parameters of pigs and the chemical-specific parameters of ENR to simulate the pharmacokinetics (PK) of ENR-SD granules in the intestinal contents. According to the results of parameter sensitivity analysis (PSA) and the predicted PK parameters at different doses of the model, formulation strategies and potential dose regimens against common intestinal infections were provided. The DSC and XRD results showed that no specific interactions existed between the excipients and ENR during the compatibility tests, and ENR presented as an amorphous form in ENR-SD. Based on the similar PK performance of ENR-SD granules and the commercial ENR soluble powder suggesting continued enhancement of the solubility of ENR, a higher drug concentration in intestinal contents could not be obtained. Therefore, a 1:5 ratio of ENR and stearic acid possessing a saturated aqueous solubility of 1190 ± 7.71 µg/mL was selected. The predictive AUC24h/MIC90 ratios against Campylobacter jejuni, Salmonella, and Escherichia coli were 133, 266 and 8520 (>100), respectively, suggesting that satisfactory efficacy against common intestinal infections would be achieved at a dose of 10 mg/kg b.w. once daily. The PSA results indicated that the intestinal absorption rate constant (Ka) was negatively correlated with the Cmax of ENR in the intestine, suggesting that we could obtain higher intestinal Cmax using P-gp inducers to reduce Ka, thus obtaining a higher Cmax. Our studies suggested that the PBPK model is an excellent tool for formulation and dose design.

Haemophilus parasuis can cause high morbidity and mortality in swine. Cefquinome possesses excellent antibacterial activity against pathogens causing diseases of the respiratory tract. This study aimed to establish the clinical breakpoint (CBP) of cefquinome against H. parasuis and to monitor the resistance change. Referring to the minimum inhibitory concentration (MIC) distribution of cefquinome against 131 H. parasuis isolates, the MIC50 and MIC90 were determined to be 0.125 and 1 μg/mL, respectively. And the epidemiological cutoff (ECOFF) value was 1 μg/mL. HPS42 was selected as a representative strain for the pharmacodynamic (PD) experiment, pharmacokinetic (PK) experiment and clinical experiments. The PK/PD index values, area under concentration-time curve (AUC)/MIC, of the bacteriostatic, bactericidal, and bacterial elimination effects were 23, 41, and 51 h, respectively. The PK/PD cutoff was calculated as 0.125 μg/mL by Monte Carlo simulation (MCS), and the clinical cutoff was 0.25−4 μg/mL by WindoW. Combing these three values, the CBP of cefquinome against H. parasuis was found to be 1 μg/mL. In conclusion, this was the first study to integrate various cutoffs to establish the CBP in the laboratory. It is helpful to distinguish wild type H. parasuis and reduce the probability of treatment failure.

Developing a targeted oral delivery system to improve the efficacy of veterinary antibiotics and reduce their consumption and environmental risks is urgent. To achieve the duodenum-targeted release of tilmicosin, the enteric granule containing tilmicosin-loaded solid lipid nanoparticles (TIL-SLNs) was prepared based on its absorption site and transport characteristics. The in vitro release, release mechanisms, stability, palatability, and pharmacokinetics of the optimum enteric granules were studied. The intestine perfusion indicated that the main absorption site of tilmicosin was shifted to duodenum from ileum by TIL-SLNs, while, the absorption of TIL-SLNs in the duodenum was hindered by P-glycoprotein (P-gp). In contrast with TIL-SLNs, the TIL-SLNs could be more effectively delivered to the duodenum in intact form after enteric coating. Its effective permeability coefficient was enhanced when P-gp inhibitors were added. Compared to commercial premix, although the TIL-SLNs did not improve the oral absorption of tilmicosin, the time to reach peak concentration (Tmax) was obviously shortened. After the enteric coating of the granules containing SLNs and P-gp inhibitor of polysorbate-80, the oral absorption of tilmicosin was improved 2.72 fold, and the Tmax was shortened by 2 h. The combination of duodenum-targeted release and P-gp inhibitors was an effective method to improve the oral absorption of tilmicosin.

The Staphylococcus aureus (S. aureus) cow mastitis causes great losses to the cow industry. In order to improve the treatment effect of tilmicosin against cow mastitis, the combination of solid lipid nanoparticle (SLN) technology with in situ hydrogel technology was used to prepare the self-assembly tilmicosin nanogel (TIL-nanogel). The physicochemical characteristics, in vitro release, antibacterial activity and in vivo treatment efficacy of TIL-SLNs and TIL-nanogel were studied, respectively. The results showed the loading capacity (LC), encapsulation efficiency (EE), size, zeta potential and poly dispersion index (PDI) of TIL-nanogel were 23.33 ± 0.77%, 67.89 ± 3.01%, 431.57 ± 12.87 nm, 8.3 ± 0.06 mv and, 0.424 ± 0.032, respectively. The TIL-nanogel showed stronger sustained release in vitro than TIL-SLNs and commercial injection. The cure rate of half dosage and normal dosage of TIL-nanogel was 58.3% and 75.0%, which was higher than that of commercial injection (50.0%) at normal dosage. The results suggest that the treatment dosage of tilmicosin for cow mastitis could be reduced by TIL-nanogel. The novel TIL-nanogel will be beneficial by decreasing the usage of tilmicosin and the treatment costs of cow mastitis.

Mastitis is one of the most widespread infectious diseases that adversely affects the profitability of the dairy industry worldwide. Accurate diagnosis and identification of pathogens early to cull infected animals and minimize the spread of infection in herds is critical for improving treatment effects and dairy farm welfare. The major pathogens causing mastitis and pathogenesis are assessed first. The most recent and advanced strategies for detecting mastitis, including genomics and proteomics approaches, are then evaluated . Finally, the advantages and disadvantages of each technique, potential research directions, and future perspectives are reported. This review provides a theoretical basis to help veterinarians select the most sensitive, specific, and cost-effective approach for detecting bovine mastitis early. [ABSTRACT FROM AUTHOR]