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Background The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson’s disease (PD). Peripheral inflammation and gut microbiota are closely associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD. Porphyromonas gingivalis (Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD. Methods In this study, live Pg were orally administrated to animals, three times a week for 1 month. Pg-derived lipopolysaccharide (LPS) was used to stimulate mononuclear cells in vitro. The effects of oral Pg administration on the gut and brain were evaluated through behaviors, morphology, and cytokine expression. Results Dopaminergic neurons in the substantia nigra were reduced, and activated microglial cells were increased in R1441G mice given oral Pg. In addition, an increase in mRNA expression of tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) as well as protein level of α-synuclein together with a decrease in zonula occludens-1 (Zo-1) was detected in the colon in Pg-treated R1441G mice. Furthermore, serum interleukin-17A (IL-17A) and brain IL-17 receptor A (IL-17RA) were increased in Pg-treated R1441G mice. Conclusions These findings suggest that oral Pg-induced inflammation may play an important role in the pathophysiology of LRRK2-associated PD.

Background: Previous studies suggested an association of sleep disorders with inflammatory bowel disease (IBD) and indicated that using pharmacological treatments for the modulation of circadian rhythms might prevent IBD pathogenesis or aggravation, but whether the effect of sleep traits on IBD was causal is inconclusive and, therefore, prevents drug repurposing based on the previous studies. We aimed to examine the causal effect of different sleep traits on the pathogenesis of IBD. Methods: Genetic instruments for sleep traits were selected from the largest GWAS studies available in the UK Biobank ( n = 449,734) and the 23andMe Research ( n = 541,333). A two-sample Mendelian randomization (MR) study was conducted to examine the association of the genetic instruments with IBD (12,882 cases and 21,770 controls), ulcerative colitis (6,968 cases, 20,464 controls), and Crohn’s disease (5,956 cases and 14,927 controls). We applied the inverse-variance weighted (IVW) method to estimate causal effects, and we used the weighted median and MR-Egger method for sensitivity analyses. Results: We found that sleep duration (OR, 1.00, 95% CI 1.00–1.01), short sleep duration (OR, 1.07, 95% CI 0.41–2.83), morningness (OR, 1.05, 95% CI 0.87–1.27), daytime napping (OR, 1.64, 95% CI 0.62–4.4), frequent insomnia (OR, 1.17, 95% CI 0.8–1.72), any insomnia (OR, 1.17, 95% CI 0.69–1.97), and snoring (OR, 0.31, 95% CI 0.06–1.54) had no causal effect on IBD, and these sleep traits had no causal effect on ulcerative colitis and Crohn’s disease either. Most of the sensitivity analyses showed consistent results with those of the IVW method. Conclusion: Our MR study did not support the causal effect of sleep traits on IBD. Pharmacological modulation of circadian rhythms for the prevention of IBD pathogenesis was unwarranted.

Background: Probiotic and low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet are two commonly used management approaches for patients with irritable bowel syndrome (IBS). We aimed to evaluate the most effective combinations and components among different probiotics or low FODMAP diet through component network meta-analysis (NMA). Methods: We searched Embase, Ovid Medline, and Web of Science from inception to 21 January 2021. Randomized controlled trials (RCTs) examining the efficacy of probiotics and low FODMAP diet for IBS were included, with placebo, sham diet, or conventional treatments as controls. Binary outcomes were compared among treatments using the relative ratio (RR). A minimally contextualized framework recommended by the GRADE group was used to evaluate the certainty of evidence. The primary efficacy outcome was the relief of global IBS symptoms, and the secondary efficacy outcome was the reduction in IBS symptom scores or abdominal pain scores. Key Results: We included 76 RCTs (n = 8058) after screening 1940 articles. Eight RCTs were classified as low risk of bias. Standard network meta-analysis (NMA) showed that Lactobacillus (RR 1.74, 95% CI 1.22–2.48) and Bifidobacterium (RR 1.76, 95% CI 1.01–3.07) were the most effective for the primary efficacy outcome (high certainty evidence); component NMA showed that Bacillus (RR 5.67, 95% CI 1.88 to 17.08, p = 0.002) and Lactobacillus (RR 1.42, 95% CI 1.07 to 1.91, p = 0.017) were among the most effective components. The results of standard NMA and CNMA analysis of the improvement of overall IBS symptom scores or abdominal pain scores were consistent with this finding. Conclusion: Lactobacillus was the most effective component for the relief of IBS symptoms; Bifidobacterium and Bacillus were possibly effective and need further verification. Systematic Review Registration: website, identifier registration number.

The purpose of this study was to explore the efficacy, safety, and tolerability of a novel cyclosporine formulation for dry eye disease (DED). This is an exploratory, multicenter, single-blind, randomized, positive-controlled Phase II clinical trial between cyclosporine ophthalmic gel (CyclAGel) and an open-label comparator (Restasis, positive control). A total of 240 eligible patients with moderate to severe DED were randomized to 4 study groups: CyclAGel 0.05%/once daily (QD) (n = 59), CyclAGel 0.05%/BID (n = 60), CyclAGel 0.1%/QD (n = 60), and Restasis 0.05%/BID (n = 61). After receiving BID dosing of hypromellose eye drops during a 2-week run-in period, patients were randomized to the respective treatment group and dosed QD or BID for 12 weeks. Efficacy was assessed based on a number of sign and symptom end points, including eye dryness score (visual analog scale), 6 other parameters of symptoms for dryness (burning/stinging, itching, foreign body sensation, discomfort, sensitivity to light, and pain), and corneal fluorescein staining. The Schirmer test was used to assess dry eye symptoms (visual analog scale severity) at visit 3 (week 2), visit 4 (week 6), and visit 5 (week 12). CyclAGel showed a consistent improvement in eye dryness score and the 6 other parameters of symptoms for dryness, corneal fluorescein staining, breakup time, and Schirmer test scores compared with Restasis over the 12-week treatment period. However, there were no statistically significant differences between CyclAGel and Restasis after baseline corrections were made, and the results of the full analysis set remained consistent with those of the per-protocol set (P > 0.05). Moreover, each CyclAGel-treated group (0.05%/QD, 0.05%/BID, and 0.1%/QD) exerted better effects than the Restasis group, and CyclAGel 0.05%/QD showed the most significant improvement. The number of ocular-related treatment-emergent adverse events was low in all treatment groups, with no serious drug-related treatment-emergent adverse events. CyclAGel showed excellent safety, tolerability, and comfort profiles at 2 concentrations and frequency in moderate to severe DED. [Display omitted] •Dry eye disease (DED) is a most common chronic disease.•The pathogenesis of DED is contributed to multiple factors.•CyclAGel (0.05%/qd) will be selected as the drug of clinical phase III trial study to further expand the sample size and verify the effectivity and safety in the treatment of the patients with moderate to severe dry eye disease.

Purpose: Chinese herbal medicine (CHM) is an important complementary and alternative therapy for the management of irritable bowel syndrome (IBS). Previous meta-analyses suggested that CHM is effective for IBS; nonetheless, its effectiveness is inconclusive owing to repeated significance testing. We aimed to examine the efficacy and safety of CHM for IBS through a meta-analysis and trial sequential analysis (TSA). Methods: We searched OVID Medline, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from January 1, 1980, to September 20, 2020. The primary outcome was adequate relief of global IBS symptoms. The secondary outcomes included relief of abdominal pain and treatment-related adverse events. The relative ratio (RR) and required information size (RIS) were calculated for each outcome. Results: Ten trials recruiting 2,501 participants were included. Seven (70%) trials were at low risk of bias (RoB). Compared with placebo, CHM was associated with a significantly higher proportion of adequate relief of global IBS symptoms [RR 1.76 (95% confidence interval (95%CI), 1.33–2.33); I 2 = 81.1%; p < 0.001]. The RIS was 1,083 for the primary outcome, and the accrued information size was 1,716. The analysis of the relief of abdominal pain (three trials with 916 participants) showed similar results compared with placebo [RR 1.85 (95%CI, 1.59–2.14); I 2 = 0%; p < 0.001; RIS = 197 participants]. CHM was associated with a higher proportion of adverse events compared with placebo [RR 1.51 (95%CI, 1.14–2); I 2 = 0%; p = 0.004]. Conclusion: CHM was effective in relieving IBS symptoms but caused a higher adverse event rate than placebo. TSA analysis confirmed the findings with sufficient information size.

To investigate the effect and timing of subconjunctival bevacizumab injection on inhibiting corneal neovascularization (CorNV) in patients after chemical burns. Patients with CorNV secondary to chemical burns were involved. Two subconjunctival injections of bevacizumab (2.5 mg/0.1 mL per involved quadrant) with an interval of 4 weeks were administered, and followed up a year. The area occupied by neovascular vessels (NA), accumulative neovascular length (NL), mean neovascular diameter (ND), best-corrected visual acuity (BCVA) and intraocular pressure (IOP) were evaluated. Complication was also recorded. Eleven patients with CorNV were involved. Eight patients had a history of surgery (four had amniotic grafts, one had keratoplasty, and three had amniotic grafts and keratoplasty). Decreasing in NA, NL, and ND were statistically significant at each time point compared to the baseline ( 0.01). CorNV that developed within 1 month was considerably regressed, and vessels with fibrovascular membranes were found to be narrower and shorter than pretreatment. BCVA improved in five patients (from one to five lines), remained unchanged in five patients, and decreased in one patient compared to pretreatment. Subconjunctival bevacizumab injection has a particular potential for the regression of CorNV, especially newly formed within 1 month in patients after chemical burns.

Background Acupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis. Methods We searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach. Results A total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23). Conclusion Acupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence. Highlights Acupuncture showed better improvement than sham acupuncture in reducing headache frequency of tension-type headache (TTH), but the lack of comparisons between acupuncture and first-line drugs impedes recommendation of acupuncture for TTH. Our indirect treatment comparison meta-analysis found similar effect between acupuncture and tricyclic antidepressants (TCAs) in reducing TTH frequency with very low certainty of evidence. Similar effect between acupuncture and TCAs were also observed in reducing headache intensity with very low certainty of evidence. Acupuncture had a lower rate of adverse events than amitriptyline with very low certainty of evidence.

Purpose To investigate the safety and efficacy of femtosecond laser-assisted penetrating keratoplasty (FLAK) versus conventional penetrating keratoplasty (CPK). Methods A literature search of PubMed, Cochrane, Embase, Web of Science, and Clinicaltrials.gov was conducted for comparative studies published from January 2007 to October 2019. Studies that involved both FLAK and CPK groups and reported on the relevant efficacy and/or safety parameters were included. The Newcastle–Ottawa quality assessment scale was used to analyse the methodological quality of these studies. Further, weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated. Results From the screened articles, a total of 1991 eyes from nine comparative studies were included. FLAK was not statistically superior for twelve-month postoperative best corrected visual acuity (WMD = − 0.06; 95% CI [− 0.16, 0.04]; P  = 0.22), corneal astigmatism (WMD = − 0.81; 95% CI [− 1.63, 0.01]; P  = 0.05) or six-month postoperative uncorrected visual acuity (WMD = − 0.11; 95% CI [− 0.27, 0.06]; P  = 0.21). There were no significant differences in corneal graft rejection rate and the graft failure between FLAK and CPK at twelve months postoperative. However, best-corrected visual acuity (BCVA) and corneal astigmatism corrected with FLAK were better than those with CPK six months postoperative after elimination of data heterogeneity. Conclusion Visual outcomes improvement in FLAK was better than that in CPK at six months postoperative, but not twelve months postoperative. This review recommends selecting a technique based on patients’ work demands and economic burdens.

The polarization fields in c-plane InGaN/(In)GaN multiple quantum well (MQW) structures grown on sapphire substrate by metal-organic chemical vapor deposition are investigated in this paper. The indium composition in the quantum wells varies from 14.8 to 26.5% for different samples. The photoluminescence wavelengths are calculated theoretically by fully considering the related effects and compared with the measured wavelengths. It is found that when the indium content is lower than 17.3%, the measured wavelengths agree well with the theoretical values. However, when the indium content is higher than 17.3%, the measured ones are much shorter than the calculation results. This discrepancy is attributed to the reduced polarization field in the MQWs. For the MQWs with lower indium content, 100% theoretical polarization can be maintained, while, when the indium content is higher, the polarization field decreases significantly. The polarization field can be weakened down to 23% of the theoretical value when the indium content is 26.5%. Strain relaxation is excluded as the origin of the polarization reduction because there is no sign of lattice relaxation in the structures, judging by the X-ray diffraction reciprocal space mapping. The possible causes of the polarization reduction are discussed.

Proper development of mammalian skeletal muscle relies on precise gene expression regulation. Our previous studies revealed that muscle development is regulated by both mRNA and long non-coding RNAs (lncRNAs). Accumulating evidence has demonstrated that N 6 -methyladenosine (m 6 A) plays important roles in various biological processes, making it essential to profile m 6 A modification on a transcriptome-wide scale in developing muscle. Patterns of m 6 A methylation in lncRNAs in developing muscle have not been uncovered. Here, we reveal differentially expressed lncRNAs and report temporal m 6 A methylation patterns in lncRNAs expressed in mouse myoblasts and myotubes by RNA-seq and methylated RNA immunoprecipitation (MeRIP) sequencing. Many lncRNAs exhibit temporal differential expression, and m 6 A-lncRNAs harbor the consensus m 6 A motif “DRACH” along lncRNA transcripts. Interestingly, we found that m 6 A methylation levels of lncRNAs are positively correlated with the transcript abundance of lncRNAs. Overexpression or knockdown of m 6 A methyltransferase METTL3 alters the expression levels of these lncRNAs. Furthermore, we highlight that the function of m 6 A genic lncRNAs might correlate to their nearby mRNAs. Our work reveals a fundamental expression reference of m 6 A-mediated epitranscriptomic modifications in lncRNAs that are temporally expressed in developing muscle.