Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial.

It remains unclear whether metronomic chemotherapy is superior to conventional chemotherapy when combined with immune checkpoint blockade. Here we performed a phase 2 clinical trial of metronomic chemotherapy combined with PD-1 blockade to compare the efficacy of combined conventional chemotherapy and PD-1 blockade using Bayesian adaptive randomization and efficacy monitoring. Eligible patients had metastatic HER2-negative breast cancer and had not received more than one prior line of standard chemotherapy. Patients (total n = 97) were randomized to receive (1) metronomic vinorelbine (NVB) monotherapy (n = 11), (2) NVB plus anti-PD-1 toripalimab (n = 7), (3) anti-angiogenic bevacizumab, NVB and toripalimab (n = 27), (4) conventional cisplatin, NVB and toripalimab (n = 26), or (5) metronomic cyclophosphamide, capecitabine, NVB and toripalimab (the VEX cohort) (n = 26). The primary endpoint was disease control rate (DCR). Secondary objectives included progression-free survival (PFS) and safety. The study met the primary endpoint. The VEX (69.7%) and cisplatin (73.7%) cohorts had the highest DCR. The median PFS of patients in the VEX cohort was the longest, reaching 6.6 months, followed by the bevacizumab (4.0 months) and cisplatin (3.5 months) cohorts. In general, the five regimens were well tolerated, with nausea and neutropenia being the most common adverse events. An exploratory mass cytometry analysis indicated that metronomic VEX chemotherapy reprograms the systemic immune response. Together, the clinical and translational data of this study indicate that metronomic VEX chemotherapy combined with PD-1 blockade can be a treatment option in patients with breast cancer. ClinicalTrials.gov Identifier: NCT04389073 .

Primary pulmonary myxoid sarcoma in the interlobar fissure of the left lung lobe: a case report.

BACKGROUND: Primary pulmonary myxoid sarcoma (PPMS) is a rare, low-grade malignant tumor, constituting approximately 0.2% of all lung tumors. Despite its rarity, PPMS possesses distinctive histological features and molecular alterations, notably the presence of EWSR1-CREB1 gene fusion. However, its precise tissue origin remains elusive, posing challenges in clinical diagnosis. CASE DEMONSTRATION: A 20-year-old male patient underwent a routine physical examination 6 months prior, revealing a pulmonary mass. Following surgical excision, microscopic evaluation unveiled predominantly short spindle-shaped tumor cells organized in a fascicular, beam-like, or reticular pattern. The stromal matrix exhibited abundant mucin, accompanied by lymphocytic and plasma cell infiltration, with Russell bodies evident in focal areas. Immunophenotypic profiling revealed positive expression of vimentin and epithelial membrane antigen in tumor cells, whereas smooth muscle actin and S-100, among others, were negative. Ki-67 proliferation index was approximately 5%. Subsequent second-generation sequencing identified the characteristic EWSR1-CREB1 gene fusion. The definitive pathological diagnosis established PPMS. The patient underwent no adjuvant chemotherapy or radiotherapy and remained recurrence-free during a 30-month follow-up period. CONCLUSIONS: We report a rare case of PPMS located within the left lung lobe interlobar fissure, featuring Russell body formation within the tumor stroma, a novel finding in PPMS. Furthermore, the histomorphological characteristics of this case highlight the diagnostic challenge it poses, as it may mimic inflammatory myofibroblastic tumor, extraskeletal myxoid chondrosarcoma, or hemangiopericytoma-like fibrous histiocytoma. Therefore, accurate diagnosis necessitates an integrated approach involving morphological, immunohistochemical, and molecular analyses.

Case Report: Primary malignant mesothelioma of the left atrium easily misdiagnosed as myxoma.

Background: Malignant mesothelioma (MM) is a rare and aggressive tumor that is found in the pleura and peritoneum. A few cases of MM in the pericardium and tunica vaginalis testis have been reported. Moreover, primary occurrence in the atrium is extremely rare. The visual appearance of this tumor is similar to that of a common atrial myxoma, which makes it challenging for clinicians and radiologists to diagnose and treat this disease. Case demonstration: An 18-year-old woman presented with symptoms of chest pain, shortness of breath, cough, and expectoration for 7 days. Echocardiography was performed on the patient, which revealed an atrial mass. Myxoma was one of the differential diagnoses. The tumor was an elliptical mass with tips, and the cut surface was jelly-like, similar to myxoma. After surgery, a pathologic examination of the biopsied tumor confirmed epithelial-type MM. During postoperative follow-up, no recurrence of the tumor was observed. Conclusions: MM originating in the atrium is considered to be extremely rare. Consequently, clinicians can easily misdiagnose atrial MM as a myxoma. Moreover, to confirm the diagnosis, histopathologic biopsy, histomorphological characterization, immunohistochemistry, and molecular genetic testing are required. Therefore, clinical diagnosis and treatment of MM are challenging.

Astragaloside IV alleviates renal fibrosis by inhibiting renal tubular epithelial cell pyroptosis induced by urotensin II through regulating the cAMP/PKA signaling pathway.

OBJECTIVE: To explore the molecular mechanism of Astragaloside IV (AS-IV) in alleviating renal fibrosis by inhibiting Urotensin II-induced pyroptosis and epithelial-mesenchymal transition of renal tubular epithelial cells. METHODS: Forty SD rats were randomly divided into control group without operation: gavage with 5ml/kg/d water for injection and UUO model group: gavage with 5ml/kg/d water for injection; UUO+ AS-IV group (gavage with AS-IV 20mg/kg/d; and UUO+ losartan potassium group (gavage with losartan potassium 10.3mg/kg/d, with 10 rats in each group. After 2 weeks, Kidney pathology, serum Urotensin II, and cAMP concentration were detected, and the expressions of NLRP3, GSDMD-N, Caspase-1, and IL-1ß were detected by immunohistochemistry. Rat renal tubular epithelial cells were cultured in vitro, and different concentrations of Urotensin II were used to intervene for 24h and 48h. Cell proliferation activity was detected using the CCK8 assay. Suitable concentrations of Urotensin II and intervention time were selected, and Urotensin II receptor antagonist (SB-611812), inhibitor of PKA(H-89), and AS-IV (15ug/ml) were simultaneously administered. After 24 hours, cells and cell supernatants from each group were collected. The cAMP concentration was detected using the ELISA kit, and the expression of PKA, α-SMA, FN, IL-1ß, NLRP3, GSDMD-N, and Caspase-1 was detected using cell immunofluorescence, Western blotting, and RT-PCR. RESULTS: Renal tissue of UUO rats showed renal interstitial infiltration, tubule dilation and atrophy, renal interstitial collagen fiber hyperplasia, and serum Urotensin II and cAMP concentrations were significantly higher than those in the sham operation group (p <0.05). AS-IV and losartan potassium intervention could alleviate renal pathological changes, and decrease serum Urotensin II, cAMP concentration levels, and the expressions of NLRP3, GSDMD-N, Caspase-1, and IL-1ß in renal tissues (p <0.05). Urotensin II at a concentration of 10-8 mol/L could lead to the decrease of cell proliferation, (p<0.05). Compared with the normal group, the cAMP level and the PKA expression were significantly increased (p<0.05). After intervention with AS-IV and Urotensin II receptor antagonist, the cAMP level and the expression of PKA were remarkably decreased (p<0.05). Compared with the normal group, the expression of IL-1ß, NLRP3, GSDMD-N, and Caspase-1 in the Urotensin II group was increased (p<0.05), which decreased in the AS-IV and H-89 groups. CONCLUSION: AS-IV can alleviate renal fibrosis by inhibiting Urotensin II-induced pyroptosis of renal tubular epithelial cells by regulating the cAMP/PKA signaling pathway.

Thyroid papillary carcinoma combined with primary follicular lymphoma: a case report.

BACKGROUND: Papillary thyroid carcinoma (PTC) stands out as the most prevalent epithelial malignant thyroid tumor. Thyroid primary follicular lymphoma (PFL) represents a rare malignant tumor originating from mesenchymal tissues. The concurrent occurrence of PTC and PFL is exceptionally rare, particularly in the context of Hashimoto's thyroiditis, presenting significant challenges in clinical diagnosis and treatment. CASE DEMONSTRATION: A 44-year-old female patient presented with a neck mass persisting for over 1 month. The patient underwent surgery, and the incised tissues were subjected to pathology examinations, along with immunohistochemistry and next-generation sequencing tests suggestive of an EZH2 gene mutation in the tumor cells. The final pathological diagnosis confirmed the presence of PTC combined with PFL. Following a 27-month follow-up, the patient displayed no signs of recurrence or metastasis. CONCLUSIONS: The concurrent occurrence of PTC and PFL poses notable challenges in clinical practice, requiring careful consideration in diagnosis and treatment. Herein, we present a rare case of PTC combined with PFL featuring an EZH2 gene mutation, which can be easily overlooked in the context of Hashimoto's thyroiditis. The patient's favorable response to surgical and radiotherapeutic interventions underscores the importance of accurate diagnosis and tailored treatment strategies in similar cases.

Ultrasound-guided core needle biopsy combined with immunohistochemistry and molecular testing improve the diagnostic accuracy of bone metastases from follicular thyroid carcinoma, two case reports and analyses.

Key Clinical Message: Ultrasound-guided core needle biopsy combined with immunohistochemistry and molecular testing could improve the diagnostic accuracy of bone metastases from follicular thyroid carcinoma, help to predict distant metastasis and prognosis. Abstract: Metastatic thyroid follicular carcinoma presenting initially with bone lesion is uncommon, its prime symptom is gradual onset, localized pain. Patient with bone metastasis who were diagnosed before thyroidectomy had a higher rate of mortality, clinician should be cautious in eliciting the clinical history and this insidious symptom in middle age group, carry out further examination. We are presenting two case reports of a follicular thyroid carcinoma with bone metastasis, ultrasound-guided core needle biopsy combined with immunohistochemistry (IHC) were carried out by our clinical team to determine the source and nature of the tumor, relevant literature was reviewed, molecular testing was discussed, we believe core needle biopsy combined with IHC and molecular testing improve the diagnostic accuracy of bone metastases from follicular thyroid carcinoma.

Association between a metabolic score for insulin resistance and hypertension: results from National Health and Nutrition Examination Survey 2007-2016 analyses.

Background: The Metabolic Score for Insulin Resistance (METS-IR) offers a promising and reliable non-insulin-based approach to assess insulin resistance and evaluate cardiometabolic risk. However, evidence for the association between METS-IR and hypertension was still limited. Methods: Participants from the National Health and Nutrition Examination Survey (NHANES) database from 2007-2016 were selected for weighted multivariable regression analyses, subgroup analyses and restricted cubic spline (RCS) modeling to assess the association between the METS-IR and hypertension, as well as systolic blood pressure (SBP) and diastolic blood pressure (DBP). Results: This study enrolled 7,721 adults aged ≥20 years, 2,926 (34.03%) of whom was diagnosed as hypertension. After adjusting for all potential covariates, an increased METS-IR (log2 conversion, denoted as log2METS-IR) was independently associated with a higher prevalence of hypertension (odd ratio [OR] 3.99, 95% confidence interval [CI] 3.19~5.01). The OR for hypertension in subjects with the highest quartile of METS-IR was 3.89-fold (OR 3.89, 95% CI 3.06~4.94) higher than that in those with the lowest quartile of METS-IR. This positive correlation became more significant as METS-IR increased (p for trend < 0.001). Log2METS-IR was significantly correlated with increase in SBP (ß 6.75, 95% CI 5.65~7.85) and DBP (ß 5.59, 95% CI 4.75~6.43) in a fully adjusted model. Consistent results were obtained in subgroup analyses. Hypertension, SBP and DBP all exhibited a non-linear increase with the rise in METS-IR. The minimal threshold for the beneficial association of METS-IR with hypertension, SBP and DBP were all identified to be 46.88. Conclusion: The findings of this study revealed a significant positive association between METS-IR and hypertension among US adults, suggesting METS-IR as a potential tool for assessing hypertension risk.

Understanding the social-emotional components of our "number sense": insights from a novel non-symbolic numerical comparison task.

Introduction: A large body of work has identified a core sense of number supported by the Approximate Number System (ANS) that is present in infancy and across species. Although it is commonly assumed that the ANS directly processes perceptual input and is relatively independent from affective factors, some evidence points at a correlation between ANS performance and math anxiety. However, the evidence is mixed. We tested whether giving participants active control in completing a numerical task would change the relationship between math anxiety on performance. Methods: Adult participants (N = 103) completed a novel four-alternative-forced-choice non-symbolic numerical comparison task. In a repeated-measures design, participants either passively viewed different dot arrays or actively chose to view each array (i.e., active information-seeking) before deciding on the largest quantity. Participants also provided confidence judgments during the passive version of the task. Results: We replicated the ratio-dependent signature in participants' accuracy in both the passive and active versions of the task using this novel paradigm, as well as in trial-level confidence judgments and information-seeking behavior. Participants' self-reported math anxiety significantly correlated with their accuracy on the passive version of the task. Critically, the correlation disappeared in the active version of the task. Gender also emerged as a predictor of confidence judgments and a moderator of the effect of task on overall accuracy and the effect of active information seeking on accuracy in the active version of the task. Exploratory analysis of estimated Weber Fraction suggests that these results may be driven by auxiliary factors instead of changes in ANS acuity. Conclusion: These findings have implications for understanding the relationship between math anxiety and performance on numerical tasks.

Assess different fermentation characteristics of 54 lager yeasts based on group classification.

Saccharomyces pastorianus, hybrids of Saccharomyces cerevisiae and Saccharomyces eubayanus, were generally regarded as authentic lager beer yeasts. In recent years, with more new findings of other Saccharomyces genus hybrids, yeasts used in lager beer brewing have been proved much more complicated than previous cognition. In this study, we analyzed the different fermentation characteristics of 54 yeast strains used for lager brewing in normal and very high gravity brewing based on group classification. The difference between Group Ⅰ and Group Ⅱ lager yeasts were more striking in very high gravity brewing. However, during our research progress, we realized that some yeasts used in this study were actually hybrids of S. cerevisiae and Saccharomyces kudriavzevii. Features of these hybrids could be beneficial to very high gravity brewing. We further discussed about the mechanism behind their outstanding characteristics and the reason why group classification methods of lager beer yeasts had limitations. Hybridization in yeasts is constantly getting richer. Lager yeasts could have more possibilities based on better understandings of their genetic background and roles of other Saccharomyces genus hybrids. Their heterosis shed light on innovation in brewing and other diverse fermentation industries.

"Catastrophic" set size limits on infants' capacity to represent objects: A systematic review and Bayesian meta-analysis.

Decades of research has revealed that humans can concurrently represent small quantities of three-dimensional objects as those objects move through space or into occlusion. For infants (but not older children or adults), this ability apparently comes with a significant limitation: when the number of occluded objects exceeds three, infants experience what has been characterized as a "catastrophic" set size limit, failing to represent even the approximate quantity of the hidden array. Infants' apparent catastrophic representational failures suggest a significant information processing limitation in the first years of life, and the evidence has been used as support for prominent theories of the development of object and numerical cognition. However, the evidence for catastrophic failure consists of individual small-n experiments that use null hypothesis significance testing to obtain null results (i.e., p > 0.05). Whether catastrophic representational failures are robust or reliable across studies, methods, and labs is not known. Here we report a systematic review and Bayesian meta-analysis to examine the strength of the evidence in favor of catastrophic representational failures in infancy. Our analysis of 22 experiments across 12 reports, with a combined total of n = 367 infants aged 10-20 months, revealed strong support for the evidence for catastrophic set size limits. A complementary analysis found moderate support for infants' success when representing fewer than four objects. We discuss the implications of our findings for theories of object and numerical cognitive development. RESEARCH HIGHLIGHTS: Previous work has suggested that infants are unable to concurrently represent four or more objects-a "catastrophic" set size limit. We reviewed this work and conducted a Bayesian meta-analysis to examine the robustness of this limit across individual small-n experiments. We found strong support for the evidence for catastrophic set size limits, and moderate support for infants' success when representing fewer than four objects.

Predictors and prognosis of early neurological outcomes on patients with Vertebrobasilar artery occlusion undergoing endovascular treatment.

BACKGROUND: This research explored the factors influencing early neurological outcomes (ENO) in patients who had vertebrobasilar artery occlusion (VBAO) and received endovascular treatment (EVT), as well as examining the causal influence of ENO on the prognosis of VBAO patients. METHODS: A retrospective review was carried out on patients from 65 Chinese stroke centers, all within 24 hours of the estimated occlusion time. ENO includes early neurological improvement (ENI) and early neurological deterioration (END), defined as a decrease or an increase of at least 4 points in NIHSS score between baseline and 24 hours after EVT. Death within 24 hours after EVT also consider as END. END was further divided into explainable END and unexplainable END (unEND). Independent predictors of ENO and the association between ENO and outcomes in patients with VBAO were determined using center-adjusted analyses. The study developed a multivariate logistic regression model to examine the comparative risk of unEND versus explainable END on the clinical outcomes in VBAO patients. RESULTS: A total of 2257 patients were included. Glasgow Coma Scale (GCS) (OR 1.16, 95% CI 1.03-1.30) and successful reperfusion (OR 1.15, 95% CI 1.02-1.30) were associated with ENI. Baseline NIHSS (OR 0.60, 95% CI 0.53-0.68), successful reperfusion (OR 0.79, 95% CI 0.71-0.89) and puncture to reperfusion time (OR 1.17, 95% CI 1.03-1.33) were associated with END. When examining three-month prognostic indexes, both END and ENI were found to be linked to the three-month outcomes, but in opposite directions. A subgroup analysis of END suggested that unexplained END typically demonstrated a more favorable prognosis compared to explained END, although the prognosis remained generally unfavorable. CONCLUSIONS: ENO, whether they manifested as early improvement or deterioration, were linked to the prognosis of VBAO patients undergoing EVT. The outcomes after unEND were more favorable than those following explained END.

Utility of Goal Attainment Scaling (GAS) in evaluating a multicomponent exercise programme for community-dwelling pre-frail older adults.

OBJECTIVES: This study aimed to investigate the effectiveness of Goal Attainment Scaling (GAS) in assessing an intervention for pre-frail senior citizens. Additionally, the study aimed to explain how the GAS goals were established based on the International Classification of Functioning, Disability and Health (ICF) categories, including body function, activity and participation and environmental factors. METHODS: In this study, 220 pre-frail older adults were randomly selected to participate in a controlled trial. The intervention group engaged in multicomponent exercise three times a week, once at a community health service location and twice at home. The control group received advice on physical activity but did not have supervised exercise. Participants in both groups selected individualised GAS goals from 23 goals developed based on ICF by focus group discussion. The study used generalised estimating equations to analyse the differences between the groups. RESULTS: The study included 144 participants, 72 in the exercise group and 72 in the control group. The top three individualised goals for all participants were vestibular functions (53.5%), pain management (43.1%) and lifting and carrying objects (31.9%). Both groups saw a significant increase in GAS scores at week 8 and week 24 of the intervention (p<0.05), but the exercise group showed a more significant improvement (p<0.05). The participants living alone were associated with lower postintervention improvements in the GAS scores. In contrast, the participants who were using a smartphone were likely to get higher postintervention improvements in the GAS scores. CONCLUSIONS: GAS can be a valuable tool for setting and evaluating individualised and meaningful goals in body functions, activity and participation and environmental factors. The multicomponent exercise interventions can help pre-frail older adults achieve their expected goals as measured by the GAS.

Neuroimaging of neuropsychological disturbances following ischaemic stroke (CONNECT): a prospective cohort study protocol.

INTRODUCTION: Neuropsychiatric distubance is a common clinical manifestation in acute ischemic stroke. However, it is frequently overlooked by clinicians. This study aimed to explore the possible aetiology and pathogenesis of neuropsychiatric disturbances following ischaemic stroke (NDIS) from an anatomical and functional perspective with the help of neuroimaging methods. METHOD AND ANALYSIS: CONNECT is a prospective cohort study of neuroimaging and its functional outcome in NDIS. We aim to enrol a minimum of 300 individuals with first-ever stroke. The neuropsychological disturbances involved in this study include depression, anxiety disorder, headache, apathy, insomnia, fatigue and cognitive impairment. Using scales that have been shown to be effective in assessing the above symptoms, the NDIS evaluation battery requires at least 2 hours at baseline. Moreover, all patients will be required to complete 2 years of follow-up, during which the NDIS will be re-evaluated at 3 months, 12 months and 24 months by telephone and 6 months by outpatient interview after the index stroke. The primary outcome of our study is the incidence of NDIS at the 6-month mark. Secondary outcomes are related to the severity of NDIS as well as functional rehabilitation of patients. Functional imaging evaluation will be performed at baseline and 6-month follow-up using specific sequences including resting-state functional MRI, diffusion tensor imaging, T1-weighted imaging, T2-weighted imaging, diffusion-weighted imaging, arterial spin labelling, quantitative susceptibility mapping and fluid-attenuated inversion recovery imaging. In addition, we collect haematological information from patients to explore potential biological and genetic markers of NDIS through histological analysis. ETHICS AND DISSEMINATION: The CONNECT Study was approved by the Ethics Review Committee of the First Hospital of the University of Science and Technology of China (2021-ky012) and written informed consent will be obtained from all participants. Results will be disseminated via a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2100043886.

Functional connectome hierarchy of thalamus impacts fatigue in acute stroke patients.

This study aimed to explore the topographic features of thalamic subregions, functional connectomes and hierarchical organizations between thalamus and cortex in poststroke fatigue patients. We consecutively recruited 121 acute ischemic stroke patients (mean age: 59 years) and 46 healthy controls matched for age, sex, and educational level. The mean age was 59 years (range 19-80) and 38% of acute stroke patients were females. Resting-state functional and structural magnetic resonance imaging were conducted on all participants. The fatigue symptoms were measured using the Fatigue Severity Scale. The thalamic functional subdivisions corresponding to the canonical functional network were defined using the winner-take-all parcellation method. Thalamic functional gradients were derived using the diffusion embedding analysis. The results suggested abnormal functional connectivity of thalamic subregions primarily located in the temporal lobe, posterior cingulate gyrus, parietal lobe, and precuneus. The thalamus showed a gradual increase from the medial to the lateral in all groups, but the right thalamus shifted more laterally in poststroke fatigue patients than in non- poststroke fatigue patients. Poststroke fatigue patients also had higher gradient scores in the somatomotor network and the right medial prefrontal and premotor thalamic regions, but lower values in the right lateral prefrontal thalamus. The findings suggested that poststroke fatigue patients had altered functional connectivity and thalamocortical hierarchical organizations, providing new insights into the neural mechanisms of the thalamus.

Influence of Cuticular Waxes from Triticale on Rumen Fermentation: A Metabolomic and Microbiome Profiling Study.

Cuticular wax, a critical defense layer for plants, remains a relatively unexplored factor in rumen fermentation. We investigated the impact of cuticular wax on rumen fermentation using triticale as a model. In total, six wax classes were identified, including fatty acids, aldehydes, alkane, primary alcohol, alkyresorcinol, and ß-diketone, with low-bloom lines predominated by 46.05% of primary alcohols and high-bloom lines by 35.64% of ß-diketone. Low-wax addition (2.5 g/kg DM) increased the gas production by 19.25% (P < 0.05) and total volatile fatty acids by 6.34% (P > 0.05), and enriched key carbohydrate-fermenting rumen microbes like Saccharofermentans, Ruminococcus, and Prevotellaceae, when compared to non-wax groups. Metabolites linked to nucleotide metabolism, purine metabolism, and protein/fat digestion in the rumen showed a positive correlation with low-wax, benefiting rumen microbes. This study highlights the intricate interplay among cuticular wax, rumen microbiota, fermentation, and metabolomics in forage digestion, providing insights into livestock nutrition and forage utilization.

Serum uric acid and prognosis of ischemic stroke: Cohort study, meta-analysis and Mendelian randomization study.

INTRODUCTION: The role of serum uric acid (UA) levels in the functional recovery of ischemic stroke remains uncertain. To evaluate whether UA could predict clinical outcomes in patients with ischemic stroke. PATIENTS AND METHODS: A three-stage study design was employed, combining a large-scale prospective cohort study, a meta-analysis and a Mendelian randomization (MR) analysis. Firstly, we conducted a cohort study using data from the Nanjing Stroke Registry Program (NSRP) to assess the association between UA levels and 3-month functional outcomes in ischemic stroke patients. Secondly, the meta-analysis was conducted to integrate currently available cohort evidence. Lastly, MR analysis was utilized to explore whether genetically determined UA had a causal link to the functional outcomes of ischemic stroke using summary data from the CKDGen and GISCOME datasets. RESULTS: In the first stage, the cohort study included 5631 patients and found no significant association between UA levels and functional outcomes at 3 months after ischemic stroke. In the second stage, the meta-analysis, including 10 studies with 14,657 patients, also showed no significant association between UA levels and stroke prognosis. Finally, in the third stage, MR analysis using data from 6165 patients in the GISCOME study revealed no evidence of a causal relationship between genetically determined UA and stroke functional outcomes. DISCUSSION AND CONCLUSION: Our comprehensive triangulation approach found no significant association between UA levels and functional outcomes at 3 months after ischemic stroke.

Enhanced expression of a novel trypsin from Streptomyces fradiae in Komagataella phaffii GS115 through combinational strategies of propeptide engineering and self-degredation sites modification.

This study aimed to enhance the expression level of a novel trypsin gene from Streptomyces fradiae ATCC14544 in Komagataella phaffii GS115 through the combinational use of propeptide engineering and self-degradation residues modification strategies. An artificial propeptide consisted of thioredoxin TrxA, the bovine propeptide DDDDK and the hydrophobic peptide FVEF was introduced to replace the original propeptide while the self-degradation residue sites were predicted and analyzed through alanine screening. The results showed that the quantity and enzymatic activity of asft with engineered propeptide reached 47.02 mg/mL and 33.9 U/mL, which were 9.6 % and 59.29 % higher than those of wild-type (42.9 mg/mL and 13.8 U/mL). Moreover, the introduction of R295A/R315A mutation further enhanced the enzymatic activity (58.86 U/mL) and obviously alleviated the phenomena of self-degradation. The tolerance of trypsin towards alkaline environment was also improved since the optimal pH was shifted from pH 9.0 to pH 9.5 and the half-life value at pH 10 was significantly extended. Finally, the fermentation media composition and condition were optimized and trypsin activity in optimal condition reached 160.58 U/mL, which was 2.73-fold and 11.64-fold of that before optimization or before engineering. The results obtained in this study indicated that the combinational use of propeptide engineering and self-degradation sites modification might have great potential application in production of active trypsins.

Non-small cell lung cancer with bone metastasis and pneumocystis pneumonia in a pregnant woman: a case report and literature review.

BACKGROUND: Cancer case during pregnancy is rare, but it is the second leading cause of maternal mortality. CASE PRESENTATION: A-32-year old pregnant woman with a gestational age of 37 weeks was admitted to the hospital due to repeated coughing for 5 months. She received Veno-Venous Extracorporeal Membrane Oxygenation (V-V ECMO) treatment for severe hypoxemia after delivery. She was diagnosed with non-small cell lung cancer (NSCLC) with bone metastasis and pneumocystis pneumonia (PCP). She subsequently received anti-tumor therapy and anti-infective therapy. After treatment, her condition improved and she was weaned from ECMO. Two weeks after weaning ECMO, her condition worsened again. Her family chose palliative treatment, and she ultimately died. CONCLUSIONS: NSCLC is rare during pregnancy. At present, there is still a lack of standardized methods to manage these cases. For theses cases, the clinician should be wary of opportunistic infections, such as pneumocystis jirovecii (P. jirovecii) and Elizabethkingia spp. Specialized medical teams with abundant experience and multidisciplinary discussions from the perspectives of the patient's clinical characteristics as well as preferences are crucial for developing individualized and the best approach.

Characterization of color, metabolites and microbial community dynamics of doubanjiang during constant temperature fermentation.

This study aimed to elaborate the effect of temperature on doubanjiang fermentation. Two batches of constant-temperature groups were prepared and their physicochemical parameters, color formation, metabolites and microbial community dynamics during fermentation were determined and compared with those of natural temperature fermentation group. The results showed that fermentation at 40 °C could accelerate the accumulation of amino nitrogen, reducing sugar, amino acids, organic acids and various volatile metabolites while it was able to inhibit the growth of conditionally pathogenic bacteria, such as Klebsiella and Salmonella. However, high concentrations of total acids and biogenic amines, protrusive burnt flavor and darker color were observed in constant temperature fermentation, which were unfavorable for doubanjiang quality. Higher fermentation temperature lowered the diversity of bacterial community and favored the growth of Bacillus genus. The correlation between key microbial genera and doubanjiang quality indexes were significantly different among different temperatures. This study would deep our understanding of the roles of temperature ondoubanjiangfermentation.

Fatal invasive pulmonary aspergillosis in non-immunocompromised host: A case report.

RATIONALE: Invasive pulmonary aspergillosis (IPA) is an uncommon but life-threatening disease. The disease often occurs in immunocompromised patients or critically ill patients. Here, we reported that IPA occurred in a non-immunocompromised host. PATIENT CONCERNS: A 45-year-old man was admitted to the hospital for 1 week due to fever and cough. He was engaged in waste recycling and lived in a dark and humid environment for a long time. DIAGNOSIS: Invasive pulmonary aspergillosis. INTERVENTIONS: Next generation sequencing and pathological examination of alveolar lavage fluid indicated aspergillus infection. He received voriconazole infusion after admission. After 5 weeks of antifungal treatment, his condition improved significantly and discharged. OUTCOME: One week after discharge, his condition deteriorated again and returned to the hospital. Unfortunately, he died. LESSON: The immunocompetent adults can develop invasive pulmonary aspergillosis if they are exposed to high-risk environments. IPA in non-immunocompromised host should arouse the vigilance of clinicians.