Engineered mischarged transfer RNAs for correcting pathogenic missense mutations.

Missense mutations account for approximately 50% of pathogenic mutations in human genetic diseases, and most lack effective treatments. Gene therapies, gene editing, and RNA therapies, including transfer RNA (tRNA) modalities, are common strategies for genetic disease treatments. However, reported tRNA therapies are for nonsense mutations only. It has not been explored how tRNAs can be engineered to correct missense mutations. Here, we describe missense-correcting tRNAs (mc-tRNAs) as a potential therapeutic for correcting pathogenic missense mutations. Mc-tRNAs are engineered tRNAs charged with one amino acid, but read codons of another in translation. We first developed a series of fluorescent protein-based reporters that indicate the successful correction of missense mutations via restoration of fluorescence. We engineered mc-tRNAs that effectively corrected serine and arginine missense mutations in the reporters and confirmed the amino acid substitution by mass spectrometry and mc-tRNA expression by sequencing. We examined the transcriptome response to mc-tRNA expression and found some mc-tRNAs induced minimum transcriptomic changes. Furthermore, we applied an mc-tRNA to rescue a pathogenic CAPN3 Arg-to-Gln mutant involved in LGMD2A. These results establish a versatile pipeline for mc-tRNA engineering and demonstrate the potential of mc-tRNA as an alternative therapeutic platform for the treatment of genetic disorders.

Aberrant activation of Notch1 signaling in the mouse uterine epithelium promotes hyper-proliferation by increasing estrogen sensitivity.

In mammals, the endometrium undergoes dynamic changes in response to estrogen and progesterone to prepare for blastocyst implantation. Two distinct types of endometrial epithelial cells, the luminal (LE) and glandular (GE) epithelial cells play different functional roles during this physiological process. Previously, we have reported that Notch signaling plays multiple roles in embryo implantation, decidualization, and postpartum repair. Here, using the uterine epithelial-specific Ltf-iCre, we showed that Notch1 signaling over-activation in the endometrial epithelium caused dysfunction of the epithelium during the estrous cycle, resulting in hyper-proliferation. During pregnancy, it further led to dysregulation of estrogen and progesterone signaling, resulting in infertility in these animals. Using 3D organoids, we showed that over-activation of Notch1 signaling increased the proliferative potential of both LE and GE cells and reduced the difference in transcription profiles between them, suggesting disrupted differentiation of the uterine epithelium. In addition, we demonstrated that both canonical and non-canonical Notch signaling contributed to the hyper-proliferation of GE cells, but only the non-canonical pathway was involved with estrogen sensitivity in the GE cells. These findings provided insights into the effects of Notch1 signaling on the proliferation, differentiation, and function of the uterine epithelium. This study demonstrated the important roles of Notch1 signaling in regulating hormone response and differentiation of endometrial epithelial cells and provides an opportunity for future studies in estrogen-dependent diseases, such as endometriosis.

Efficacy of melatonin in the treatment of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

This study investigated the effect of melatonin on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). We searched PubMed, the Web of Science, the Cochrane Library, Ovid MEDLINE, and Clinicaltrials.gov for randomized controlled trials (RCTs) published before September 11, 2021. Only RCTs that compared the clinical efficacy of melatonin with a placebo in the treatment of patients with COVID-19 were included. The primary outcome measure was the clinical recovery rate. We included three RCTs in this meta-analysis. Melatonin 3 mg three times daily was administered in one RCT, and 3 or 6 mg daily before bedtime in the other two trials. Treatment duration was 14 days in two RCTs and 7 days in one trial. The clinical recovery rates were 94.2% (81/86) and 82.4% (70/85) in the melatonin and control groups, respectively. Overall, patients receiving melatonin had a higher clinical recovery rate than did the controls (odds ratio [OR]: 3.67; 95% CI: 1.21-11.12; I2 = 0%, p = 0.02). The risk of intensive care unit admission was numerically lower in the melatonin group than in the control group (8.3% [6/72] vs. 17.6% [12/68], OR: 0.45; 95% CI: 0.16-1.25; I2 = 0%, p = 0.13), and the risk of mortality was numerically lower in the melatonin group than in the control group (1.4% [1/72] vs. 4.4% [3/68], OR: 0.32; 95% CI: 0.03-3.18; I2 = 0%, p = 0.33). In conclusion, melatonin may help improve the clinical outcomes of patients with COVID-19.

Lignans and Flavonoids from Cajanus cajan (L.) Millsp. and Their α-Glucosidase Inhibitory Activities.

A pair of new lignan conformers (1-2), one new flavonoid glycoside (3), as well as nineteen known compounds were purified from the twigs and leaves of Cajanus cajan (L.) Millsp.. The planar structures of the unknown compounds were determined via NMR and high-resolution mass spectrometry, while their absolute configurations were elucidated via comparison between their experimental and calculated electronic circular dichroism (ECD) values. All the isolated compounds were assayed for their α-glucosidase inhibitory activities. The results demonstrated that compounds 8-12, 15-16, 18-19, 21-22 had strong inhibition activities, with compound 10 (IC50 =0.4±0.21 µM) most active. The structure-activity relationships were preliminarily summarized. Enzyme kinetics showed that compounds 8, 9, 15-16, 18-19, 21-22 were non-competitive inhibitors and compounds 10-12 were anti-competitive ones.

Reliability, validity and developmental sensitivity of the Language Use Inventory (LUI) in the Chinese context.

BACKGROUND: Pragmatics has generally been defined as the ability to use language in social situations, it is commonly regarded as the third major component of language ability. To date, there is no tool for assessing early pragmatic development of Chinese-speaking children. AIMS: To describe the translation of the Language Use Inventory (LUI) from English to Mandarin Chinese and to report findings on the Chinese version's reliability, validity and developmental sensitivity. METHODS & PROCEDURES: The original English version of the LUI was translated into Mandarin Chinese. Parents of 177 typically developing (TD) toddlers and preschool children completed the inventory to examine its internal reliability and construct validity and how scores differed across ages and sexes. A total of 31 parents out of the 177 completed the LUI-Mandarin, again within 4 weeks, to assess test-retest reliability. To examine discriminative validity, 43 parents of age- and sex-matched TD children and children with autism spectrum disorder (ASD) recruited from Nanjing Brain Hospital affiliated with Nanjing Medical University completed the LUI-Mandarin. OUTCOMES & RESULTS: Cronbach's alpha values for the LUI-Mandarin's three parts and for 11 of 12 LUI-Mandarin subscales were 0.707-0.992, with most values in the 0.825-0.992 range. Test-retest reliability ranged from 0.66 to 0.95, indicating good to excellent reliability. Factor analysis of the LUI-Mandarin revealed two different factors, and the total variance explained was 74.38%. The LUI-Mandarin total scores and subscale scores increased with age for both boys and girls, providing evidence of the inventory's developmental sensitivity. Girls, however, had higher total scores than boys at earlier ages (18-23 months). The results of the discriminant validity study revealed that performance was significantly lower in the ASD group than in the TD group with respect to LUI total scores and subscale scores (except for subscale A). CONCLUSIONS & IMPLICATIONS: The LUI-Mandarin is the first and only questionnaire available in China that evaluates the pragmatic language skills of children aged between 18 and 47 months. The results of the study show that the LUI-Mandarin is a valid and reliable tool for Chinese toddlers and preschool children. WHAT THIS PAPER ADDS: What is already known on this subject The LUI is a parent-report questionnaire that can provide comprehensive information about very young children's communicative competence. It is widely used both for assessment and to guide intervention. Additionally, it has been translated into French, Italian, Polish, Arabic, Portuguese and Norwegian and it shows good reliability and validity. What this paper adds to existing knowledge In the present study we describe the translation of the LUI from English to Mandarin Chinese and report findings on the Chinese version's reliability, validity and developmental sensitivity. What are the potential or actual clinical implications of this work? The LUI-Mandarin is the first and only questionnaire available in China that can evaluate pragmatic language skills of children aged between 18 and 47 months. The results show that the LUI-Mandarin is a valid and reliable tool for use with Chinese toddlers and preschool children.

Characterization of Citrullination Sites in Neutrophils and Mast Cells Activated by Ionomycin via Integration of Mass Spectrometry and Machine Learning.

Citrullination is an important post-translational modification implicated in many diseases including rheumatoid arthritis (RA), Alzheimer's disease, and cancer. Neutrophil and mast cells have different expression profiles for protein-arginine deiminases (PADs), and ionomycin-induced activation makes them an ideal cellular model to study proteins susceptible to citrullination. We performed high-resolution mass spectrometry and stringent data filtration to identify citrullination sites in neutrophil and mast cells treated with and without ionomycin. We identified a total of 833 validated citrullination sites on 395 proteins. Several of these citrullinated proteins are important components of pathways involved in innate immune responses. Using this benchmark primary sequence data set, we developed machine learning models to predict citrullination in neutrophil and mast cell proteins. We show that our models predict citrullination likelihood with 0.735 and 0.766 AUCs (area under the receiver operating characteristic curves), respectively, on independent validation sets. In summary, this study provides the largest number of validated citrullination sites in neutrophil and mast cell proteins. The use of our novel motif analysis approach to predict citrullination sites will facilitate the discovery of novel protein substrates of protein-arginine deiminases (PADs), which may be key to understanding immunopathologies of various diseases.

The characteristics and factors of the internalizing and externalizing behaviours of children at high risk for autism spectrum disorder.

BACKGROUND: The behavioral characteristics of children with autism spectrum disorder (ASD) are not only affected by their disease, but also by their parenting environment. HR-ASD has the risk of developing internalization and externalization problems. How the early development of these behavioral problems is affected by parent-child interaction is worth exploring. We tested whether parent-child interactions and parenting characteristics were associated with behavioural problems during the infant periods. METHODS: This study collected data from 91 infants at high risk for ASD and 68 matched typically developing (TD) infants, about their internalizing and externalizing behavioural problems and engagement states (i.e. positive, negative, and parent-child interactions), using free play paradigm. Parent measures were assessed using the Broad Autism Phenotypic Questionnaire (BAPQ) and Parenting Stress Index Short Form (PSI-SF) questionnaire. The core symptoms of ASD were assessed using the the Autism Diagnostic Observational Schedule (ADOS). RESULTS: During free play, infants in the HR-ASD group showed more internalizing (P < 0.001) and externalizing (P < 0.05) behaviours and less positive engagement (P < 0.01) than the TD group. In the regression analysis, we found that parenting stress had an impact on the infants' externalizing behaviours (△R2 = 0.215). Parent negative engagement had an impact on the infants' internalizing behaviours (△R2 = 0.451). CONCLUSIONS: The present study revealed that children at high risk for ASD exhibited more severe internalizing and externalizing behavioural problems than TD group. The parent negative engagement is associated with behavioural problems. The findings on the contribution of parents' factors to behavioural problems suggests that the parenting stress and parent-child interactions are important factors for mitigating behavioural problems.

Aromatherapy intervention on anxiety and pain during first stage labour in nulliparous women: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to critically evaluate and summarise all available evidence derived from randomised clinical trials (RCTs) regarding aromatherapy's effects on labour pain and anxiety relief. Literature search was performed in MEDLINE/PubMed, Cochrane library, Cochrane Central Register of Controlled Trials (CENTRAL) and Scopus since their respective inception to January 2019. Additionally, Google Scholar was also searched to explore citations of eligible final studies which were subsequently included in the systematic review. The search strategy used was: (pregnancy or pregnant or prenatal or antenatal or perinatal or maternal) AND (aromatherapy or essential oils or aroma therapy). Per inclusion and exclusion criteria established by the current study, nine RCTs were included in the systematic review. Results from the current study suggested that aromatherapy significantly decreased pain and anxiety in the first stage of labour.IMPACT STATEMENTWhat is already known on this subject? Several studies have shown aromatherapy's effectiveness in relieving pain and anxiety for hospitalised patients and on relieving nausea and vomiting for women during pregnancy. Some results have further indicated that aromatherapy was effective in facilitating episiotomy healing and in reducing pain, fatigue and distress. Aromatherapy was also found to play a role in improving maternal moods; reducing post-caesarean pain; and preventing or mitigating stress, anxiety and depression after childbirth. Though most non-pharmaceutical pain management options were considered non-invasive and presumably safe for mothers and their foetuses, their exact efficacies remained unclear due to a lack of high quality evidence.What the results of this study add? This systematic review and meta-analysis summarises all evidence derived from RCTs wherein aromatherapy was performed as a supportive analgesic method during labour. Results of this meta-analysis identified more credible evidence validating that aromatherapy could significantly decrease labour pain both in early active and late active phases.What the implications are of these findings for clinical practice and/or further research? Availability of credible evidence supporting aromatherapy's effectiveness on reducing physiological and psychological stress during pregnancy and childbirth would be useful, both theoretically and practically, for all stakeholders concerned, such as pregnant women, medicine and midwifery students, midwives, nurses, gynaecologists and health policymakers.

Development of a Parallel Reaction Monitoring Mass Spectrometry Assay for the Detection of SARS-CoV-2 Spike Glycoprotein and Nucleoprotein.

There is an urgent need for robust and high-throughput methods for SARS-CoV-2 detection in suspected patient samples to facilitate disease management, surveillance, and control. Although nucleic acid detection methods such as reverse transcription polymerase chain reaction (RT-PCR) are the gold standard, during the current pandemic, the deployment of RT-PCR tests has been extremely slow, and key reagents such as PCR primers and RNA extraction kits are at critical shortages. Rapid point-of-care viral antigen detection methods have been previously employed for the diagnosis of respiratory viruses such as influenza and respiratory syncytial viruses. Therefore, the direct detection of SARS-CoV-2 viral antigens in patient samples could also be used for diagnosis of active infection, and alternative methodologies for specific and sensitive viral protein detection should be explored. Targeted mass spectrometry techniques have enabled the identification and quantitation of a defined subset of proteins/peptides at single amino acid resolution with attomole level sensitivity and high reproducibility. Herein, we report a targeted mass spectrometry assay for the detection of SARS-CoV-2 spike protein and nucleoprotein in a relevant biological matrix. Recombinant full-length spike protein and nucleoprotein were digested and proteotypic peptides were selected for parallel reaction monitoring (PRM) quantitation using a high-resolution Orbitrap instrument. A spectral library, which contained seven proteotypic peptides (four from spike protein and three from nucleoprotein) and the top three to four transitions, was generated and evaluated. From the original spectral library, we selected two best performing peptides for the final PRM assay. The assay was evaluated using mock test samples containing inactivated SARS-CoV-2 virions, added to in vitro derived mucus. The PRM assay provided a limit of detection of ∼200 attomoles and a limit of quantitation of ∼ 390 attomoles. Extrapolating from the test samples, the projected titer of virus particles necessary for the detection of SARS-CoV-2 spike and nucleoprotein detection was approximately 2 × 105 viral particles/mL, making it an attractive alternative to RT-PCR assays. Potentially, mass spectrometry-based methods for viral antigen detection may deliver higher throughput and could serve as a complementary diagnostic tool to RT-PCR. Furthermore, this assay could be used to evaluate the presence of SARS-CoV-2 in archived or recently collected biological fluids, in vitro-derived research materials, and wastewater samples.

Correlation of serum N-Acetylneuraminic acid with the risk and prognosis of acute coronary syndrome: a prospective cohort study.

BACKGROUND: N-acetylneuraminic acid (Neu5Ac) is a functional metabolite involved in coronary artery disease (CAD). We aimed to evaluate the relationship between serum Neu5Ac and the risk and prognosis of acute coronary syndrome (ACS) in a real-world prospective study. METHODS: Patients with suspected ACS who underwent coronary angiography were included. Serum Neu5Ac was measured at admission. Coronary lesion severity was evaluated by Gensini Score. GRACE risk stratification was performed at admission. Major adverse cardiac events (MACEs) were recorded during follow-up. RESULTS: A total of 766 patients, including 537 with unstable angina (UAP), 100 with myocardial infarction (MI), and 129 without CAD were included. The circulating Neu5Ac level was significantly higher in patients with MI (median [1QR]: 297[220, 374] ng/ml) than in those with UAP (227 [114, 312] ng/ml) or without CAD (207 [114, 276] ng/ml; both p < 0.001). Serum level of Neu5Ac was positively correlated with age, hypertension, serum uric acid, creatinine, MB isoform of creatine kinase (CK-MB), and Gensini score (all p < 0.05). Receiver operating characteristic curve analysis showed that a higher serum Neu5Ac was potentially associated with MI and high-risk GRACE stratification in ACS patients. Logistic analysis identified only elevated serum Neu5Ac as an independent predictor of MACEs in these patients (odds ratio [OR]: 1.003, 95% confidence interval [CI]: 1.002-1.005, p < 0.001). CONCLUSIONS: Serum Neu5Ac is associated with myocardial injury, GRACE risk category, and prognosis in ACS patients.

TVT-O vs TVT-S for female stress urinary incontinence: A systematic review and meta-analysis.

BACKGROUND: Tension-free vaginal tape obturator (TVT-O) and tension-free vaginal tape secur (TVT-S) are common surgeries for the treatment of stress urinary incontinence (SUI), several randomised controlled trials (RCTs) have compared the effects of TVT-O and TVT-S, yet the results remained inconsistent. Therefore, we attempted to conduct this systematic review and meta-analysis to analyse the role of TVT-O and TVT-S in patients with SUI. METHODS: We searched PubMed databases from inception date to Jan 15, 2020 for RCTs that compared TVT-O and TVT-S in SUI patients. Two authors independently screened and extracted data from the published articles. Summary odd ratios (OR) or mean differences (MD) with 95% confidence intervals (95% CI) were calculated for each outcome by fixed- or random-effects model. RESULTS: Seven RCTs with a total of 755 patients were identified, with 373 patients for TVT-O and 382 patients for TVT-S. TVT-O preceded TVT-S in the objective cure at 12 months (OR = 1.72, 95% CI 1.21-2.45), subjective cure (OR = 1.98, 95% CI 1.08-3.62); but TVT-S have more advantage in the incidence of postoperative thigh pain (OR = 18.94, 95% CI 7.01-51.15); no significant differences on the duration of operative procedure (OR = -1.09, 95% CI -2.37-0.18), urinary retention (OR = 0.77, 95% CI 0.36-1.62) and urinary infection (OR = 1.80, 95% CI 0.63-5.13) were found. CONCLUSIONS: TVT-O should be preferred for patients with SUI even though with higher risks of postoperative thigh pain when compared with TVT-S, more related studies are needed to identify the role of TVT-O and TVT-S for the treatment of SUI.

Evaluate five different diagnostic tests for dry mouth assessment in geriatric residents in long-term institutions in Taiwan.

BACKGROUND: Residents in long-term care (LTC) institutions require care plans to effectively resolve dry mouth. Simple and easily comprehensible dry mouth indices must be developed to assist care professionals in determining dry mouth among residents. Therefore, this study aim of the study was to evaluate five different diagnostic tests for dry mouth assessment. METHODS: A total of 568 residents were recruited from several LTC institutions in central Taiwan. The research instruments and tools comprised of the characteristics of the residents, state of oral health care, self-perceived ability to chew food, Taiwanese short-form of the Oral Health Impact Profile (OHIP-7 T), self-perceived levels of dry mouth, oral moisture checking, and a repetitive saliva swallowing test (RSST). The data collected were analyzed through demographic analysis, Correlation coefficient and chi-squared automatic interaction detection. RESULTS: Results of the decision tree analysis indicated that RSST results, tooth brushing frequency, and age were the three indices that exerted the greatest influence on oral moisture levels. Specifically, in residents with relatively high RSST results, a daily tooth brushing frequency > 1, and an age < 68 years exhibited more favorable oral moisture levels. The results indicated that residents' self-perceived oral status was not associated with their oral moisture levels. CONCLUSION: The three indices can be provided to LTC institutions for on-site assessment of dry mouth among residents to facilitate early detection of those with dry mouth.

Transcriptome profiling analysis reveals metabolic changes across various growth phases in Bacillus pumilus BA06.

BACKGROUND: Bacillus pumilus can secret abundant extracellular enzymes, and may be used as a potential host for the industrial production of enzymes. It is necessary to understand the metabolic processes during cellular growth. Here, an RNA-seq based transcriptome analysis was applied to examine B. pumilus BA06 across various growth stages to reveal metabolic changes under two conditions. RESULTS: Based on the gene expression levels, changes to metabolism pathways that were specific to various growth phases were enriched by KEGG analysis. Upon entry into the transition from the exponential growth phase, striking changes were revealed that included down-regulation of the tricarboxylic acid cycle, oxidative phosphorylation, flagellar assembly, and chemotaxis signaling. In contrast, the expression of stress-responding genes was induced when entering the transition phase, suggesting that the cell may suffer from stress during this growth stage. As expected, up-regulation of sporulation-related genes was continuous during the stationary growth phase, which was consistent with the observed sporulation. However, the expression pattern of the various extracellular proteases was different, suggesting that the regulatory mechanism may be distinct for various proteases. In addition, two protein secretion pathways were enriched with genes responsive to the observed protein secretion in B. pumilus. However, the expression of some genes that encode sporulation-related proteins and extracellular proteases was delayed by the addition of gelatin to the minimal medium. CONCLUSIONS: The transcriptome data depict global alterations in the genome-wide transcriptome across the various growth phases, which will enable an understanding of the physiology and phenotype of B. pumilus through gene expression.

Using the CRISPR/Cas9 system to eliminate native plasmids of Zymomonas mobilis ZM4.

The CRISPR/Cas system can be used to simply and efficiently edit the genomes of various species, including animals, plants, and microbes. Zymomonas mobilis ZM4 is a highly efficient, ethanol-producing bacterium that contains five native plasmids. Here, we constructed the pSUZM2a-Cas9 plasmid and a single-guide RNA expression plasmid. The pSUZM2a-Cas9 plasmid was used to express the Cas9 gene cloned from Streptococcus pyogenes CICC 10464. The single-guide RNA expression plasmid pUC-T7sgRNA, with a T7 promoter, can be used for the in vitro synthesis of single-guide RNAs. This system was successfully employed to knockout the upp gene of Escherichia coli and the replicase genes of native Z. mobilis plasmids. This is the first study to apply the CRISPR/Cas9 system of S. pyogenes to eliminate native plasmids in Z. mobilis. It provides a new method for plasmid curing and paves the way for the genomic engineering of Z. mobilis.

Efficacy of vasopressin-epinephrine compared to epinephrine alone for out of hospital cardiac arrest patients: A systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to conduct a meta-analysis to evaluate the efficacy of vasopressin-epinephrine compared to epinephrine alone in patients who suffered out-of-hospital cardiac arrest (OHCA). METHODS: Relevant studies up to February 2017 were identified by searching in PubMed, EMBASE, the Cochrane Library, Wanfang for randomized controlled trials(RCTs) assigning adults with cardiac arrest to treatment with vasopressin-epinephrine (VEgroup) vs adrenaline (epinephrine) alone (E group). The outcome point was return of spontaneous circulation (ROSC) for patients suffering from OHCA. Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were explored. RESULTS: Individual patient data were obtained from 5047 participants who experienced OHCA in nine studies. Odds ratios (ORs) were calculated using a random-effects model and results suggested that vasopressin-epinephrine was associated with higher rate of ROSC (OR=1.67, 95% CI=1.13-2.49, P<0.00001, and total I2=83%). Subgroup showed that vasopressin-epinephrine has a significant association with improvements in ROSC for patients from Asia (OR=3.30, 95% CI=1.30-7.88); but for patients from other regions, there was no difference between vasopressin-epinephrine and epinephrine alone (OR=1.07, 95% CI=0.72-1.61). CONCLUSION: According to the pooled results of the subgroup, combination of vasopressin and adrenaline can improve ROSC of OHCA from Asia, but patients from other regions who suffered from OHCA cannot benefit from combination of vasopressin and epinephrine.

No association between fiber intake and prostate cancer risk: a meta-analysis of epidemiological studies.

BACKGROUND: The findings of epidemiologic studies on the association between fiber intake and prostate cancer risk remain conflicting. We aimed to examine this association by conducting a meta-analysis of epidemiological studies. METHODS: Relevant studies were identified by PubMed (1966 to March 2015) and Embase (1974 to March 2015) database search through March 2015. We included epidemiological studies that reported relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) for the association between dietary fiber intake and prostate cancer risk. Random effects models were used to calculate the summary risk estimates. RESULTS: For the highest compared with the lowest dietary fiber intake, a significantly decreased risk with prostate cancer was observed in case-control studies (OR = 0.82; 95% CI, 0.68-0.96), but not in cohort studies (RR = 0.94; 95% CI, 0.77-1.11). The combined risk estimate of all studies was 0.89 (95% CI, 0.77, 1.01). A significant heterogeneity was observed across studies (p = 0.005). There was no evidence of significant publication bias based on Begg's funnel plot (p = 0.753) or Egger's test (p = 0.946). CONCLUSIONS: This meta-analysis suggests the absence of evidence for association between dietary fiber intake and prostate cancer risk.

Genetic insights into gut microbiota and risk of prostatitis: a Mendelian randomization study.

Background: The dysbiosis of gut microbiota (GM) is considered a contributing factor to prostatitis, yet the causality remains incompletely understood. Methods: The genome-wide association study (GWAS) data for GM and prostatitis were sourced from MiBioGen and FinnGen R10, respectively. In the two-sample Mendelian randomization (MR) analysis, inverse variance weighting (IVW), MR-Egger, weighted median, simple mode, weighted mode, and maximum likelihood (ML) methods were utilized to investigate the causal relationship between GM and prostatitis. A series of sensitivity analysis were conducted to confirm the robustness of the main results obtained from the MR analysis. Results: According to the IVW results, genus Sutterella (OR: 1.37, 95% CI: 1.09-1.71, p = 0.006) and genus Holdemania (OR: 1.21, 95% CI: 1.02-1.43, p = 0.028) were associated with an increased risk of prostatitis. The phylum Verrucomicrobia (OR: 0.76, 95% CI: 0.58-0.98, p = 0.033) and genus Parasutterella (OR: 0.84, 95% CI: 0.70-1.00, p = 0.045) exhibited a negative association with prostatitis, indicating a potential protective effect. Sensitivity analysis showed that these results were not affected by heterogeneity and horizontal pleiotropy. Furthermore, the majority of statistical methods yielded results consistent with those of the IVW analysis. Conclusions: In this study, we identified two GM taxon that might be protective against prostatitis and two GM taxon that could increase the risk of developing prostatitis. These findings could potentially provide a valuable theoretical basis for the future development of preventive and therapeutic strategies for prostatitis.

Citrus fruit intake and incidence of renal cell carcinoma: A meta-analysis of observational studies.

Observational studies on the association between citrus fruit intake and risk of renal cell carcinoma (RCC) have reported inconsistent results. We quantitatively assessed this association by conducting a meta-analysis. PubMed and Embase databases search was conducted including relevant studies published up to January, 2020. We included epidemiological studies that reported relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) for the association between citrus fruit intake and RCC risk. A total of eight epidemiological studies consisting of five cohort and three case-control studies were included. The overall analysis showed a significantly reduced risk of RCC for high intake of citrus fruit (OR = 0.84, 95% CI 0.73-0.95). No heterogeneity was detected among the included studies (p = 0.497 for heterogeneity; I2 = 0). There was no significant publication bias by Begg's test (p = 0.266) or Egger's test (P = 0.578). A statistically significant association between citrus fruit intake and RCC was observed in case-control studies (OR = 0.84, 95% CI 0.71-0.98), while no association was observed in cohort studies (OR = 0.84, 95% CI 0.64-1.05). In addition, the dose-response analysis indicated that the RCC risk reduced by 13% (95%CI 1.0%-27%, p = 0.04 for heterogeneity) for each 100 grams per day increment of citrus fruit intake. In summary, our findings suggest an inverse association between citrus fruit intake and RCC incidence.

Disease-modifying therapies for diabetic peripheral neuropathy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Alpha-lipoic acid, epalrestat, and mecobalamin are widely used as monotherapies for diabetic peripheral neuropathy. However, whether a triple-combination therapy with these three drugs is superior to monotherapy or dual therapy remains debatable. METHODS: Nine randomized controlled trials were identified through a search on electronic databases such as PubMed, Web of Science, and Cochrane Library. The trial participants (N = 1153) were divided into the experimental group who received the triple-combination therapy and the control group who received conventional or dual therapy with the aforementioned drugs. RESULTS: Therapeutic outcomes were better in the experimental group than in the control group (odds ratio: 3.74; 95 % confidence interval: 2.57-5.45; I2 = 0 %; p < 0.00001). No statistic difference was noted in adverse effects. Compared with the control group, the experimental group exhibited significant improvements in median motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV, and vibration perception thresholds (VPT) in the left and right lower limbs. In the control group, a subgroup analysis by treatment strategy revealed similar improvements in total efficacy, MNCV, and SNCV. CONCLUSIONS: For diabetic peripheral neuropathy, the triple-combination therapy may be more effective than monotherapy or dual therapy.

Enhanced Electrical Conductivity and Mechanical Properties of Stretchable Thermoelectric Generators Formed by Doped Semiconducting Polymer/Elastomer Blends.

Recent research efforts have concentrated on the development of flexible and stretchable thermoelectric (TE) materials. However, significant challenges have emerged, including increased resistance and reduced electrical conductivity when subjected to strain. To address these issues, rigid semiconducting polymers and elastic insulating polymers have been incorporated and nanoconfinement effects have been exploited to enhance the charge mobility. Herein, a feasible approach is presented for fabricating stretchable TE materials by using a doped semiconducting polymer blend consisting of either poly(3-hexylthiophene) (P3HT) or poly(3,6-dithiophen-2-yl-2,5-di(2-decyltetradecyl)-pyrrolo[3,4-c]pyrrole-1,4-dione-alt-thienylenevinylene-2,5-yl) (PDVT-10) as the rigid polymer with styrene-ethylene-butylene-styrene (SEBS) as the elastic polymer. In particular, the blend composition is optimized to achieve a continuous network structure with SEBS, thereby improving the stretchability. The optimized polymer films exhibit well-ordered microstructural aggregates, indicative of good miscibility with FeCl3 and enhanced doping efficiency. Notably, a lower activation energy and higher charge-carrier concentration contribute to an improved electrical conductivity under high tensile strain, with a maximum output power of 1.39 nW at a ΔT of 22.4 K. These findings offer valuable insights and serve as guidelines for the development of stretchable p-n junction thermoelectric generators based on doped semiconducting polymer blends with potential applications in wearable electronics and energy harvesting.