Mapping quantitative trait loci associated with self-(in)compatibility in goji berries (Lycium barbarum).

BACKGROUND: Goji (Lycium barbarum L.) is a perennial deciduous shrub widely distributed in arid and semiarid regions of Northwest China. It is highly valued for its medicinal and functional properties. Most goji varieties are naturally self-incompatible, posing challenges in breeding and cultivation. Self-incompatibility is a complex genetic trait, with ongoing debates regarding the number of self-incompatible loci. To date, no genetic mappings has been conducted for S loci or other loci related to self-incompatibility in goji. RESULTS: We used genome resequencing to create a high-resolution map for detecting de novo single-nucleotide polymorphisms (SNP) in goji. We focused on 229 F1 individuals from self-compatible '13-19' and self-incompatible 'new 9' varieties. Subsequently, we conducted a quantitative trait locus (QTL) analysis on traits associated with self-compatibility in goji berries. The genetic map consisted of 249,327 SNPs distributed across 12 linkage groups (LGs), spanning a total distance of 1243.74 cM, with an average interval of 0.002 cM. Phenotypic data related to self-incompatibility, such as average fruit weight, fruit rate, compatibility index, and comparable compatibility index after self-pollination and geitonogamy, were collected for the years 2021-2022, as well as for an extra year representing the mean data from 2021 to 2022 (2021/22). A total of 43 significant QTL, corresponding to multiple traits were identified, accounting for more than 11% of the observed phenotypic variation. Notably, a specific QTL on chromosome 2 consistently appeared across different years, irrespective of the relationship between self-pollination and geitonogamy. Within the localization interval, 1180 genes were annotated, including Lba02g01102 (annotated as an S-RNase gene), which showed pistil-specific expression. Cloning of S-RNase genes revealed that the parents had two different S-RNase alleles, namely S1S11 and S2S8. S-genotype identification of the F1 population indicated segregation of the four S-alleles from the parents in the offspring, with the type of S-RNase gene significantly associated with self-compatibility. CONCLUSIONS: In summary, our study provides valuable insights into the genetic mechanism underlying self-compatibility in goji berries. This highlights the importance of further positional cloning investigations and emphasizes the importance of integration of marker-assisted selection in goji breeding programs.

Synthesis of oligosaccharides from terminal B. pertussis LPS pentasaccharide and definition of the minimal epitope recognized by anti-pertussis antibodies.

Pertussis vaccines have been very effective in controlling whooping-cough epidemics but are ineffective in controlling circulation in older children and adults, thus facilitating the onset of future outbreaks. Antibodies against the lipopolysaccharide could reduce the carriage of the bacteria, its circulation, and transmission. The oligosaccharide fragments from the lipopolysaccharide may become a potential complement to existing vaccines in the form of protein glycoconjugates. An important step in the development of this type of vaccine is defining the minimal oligosaccharide epitope recognized by B. pertussis anti-lipopolysaccharide antibodies. This paper describes the complete synthesis of oligosaccharides containing two to five monosaccharide units corresponding to the pentasaccharide at the nonreducing end of the lipooligosaccharide and their recognition by mice and rabbit antibodies elicited against whole-cell B. pertussis. For the first time, we report that the terminal disaccharide, α-D-GlcNAcp-(1 → 4)-(2,3-di-NAc)-D-ManAp acid is the minimal structure recognized by antibodies induced by B. pertussis.

Percutaneous endoscopic interlaminar discectomy for high-grade migrated lumbar disc herniation: clinical efficacy and safety assessment.

PURPOSE: This study aimed to assess the clinical effectiveness and safety of percutaneous endoscopic interlaminar discectomy (PEID) in the management of high-grade migrated Lumbar disc herniation (LDH). METHODS: A total of 328 patients who underwent PEID for high-grade migrated LDH between May 2020 and January 2023 in our hospital were selected. Patients were categorized into high-grade migrated group and low-grade migrated group according to preoperative MRI findings. The preoperative and postoperative evaluations of clinical outcomes, such as Visual Analogue Scale (VAS) for lower backs and legs, Oswestry Disability Index (ODI), and modified MacNab criteria for surgical success, were compared between groups. RESULTS: No statistically significant differences were found in hospitalization time, surgery time, intraoperative hemorrhage, number of intraoperative fluoroscopies, or incision length between the two groups. The lower back and leg VAS scores and ODI exhibited a statistically significant decrease in both groups across all postoperative time intervals. However, the difference between the two groups was not statistically significant. Postoperative nerve root stimulation symptoms were reported in two and three cases in the high-grade migrated group and low-grade migrated group, respectively. One patient in the high-grade migrated group underwent reoperation due to re-herniation at the same segment. There was no significant difference in the rate of excellent-good cases between the two groups, with an overall rate of 94.7%. CONCLUSION: In treating high-grade migrated disc herniation, PEID offers advantages such as reduced trauma, small incision, quicker recovery and satisfactory clinical safety and efficacy.

A Versatile Theranostic Nanoplatform with Aggregation-Induced Emission Properties: Fluorescence Monitoring, Cellular Organelle Targeting, and Image-Guided Photodynamic Therapy.

Photosensitizers (PSs) play a key role in the photodynamic therapy (PDT) of tumors. However, commonly used PSs are prone to intrinsic fluorescence aggregation-caused quenching and photobleaching; this drawback severely limits the clinical application of PDT, necessitating new phototheranostic agents. Herein, a multifunctional theranostic nanoplatform (named TTCBTA NP) is designed and constructed to achieve fluorescence monitoring, lysosome-specific targeting, and image-guided PDT. TTCBTA with a twisted conformation and D-A structure is encapsulated in amphiphilic Pluronic F127 to form nanoparticles (NPs) in ultrapure water. The NPs exhibit biocompatibility, high stability, strong near-infrared emission, and desirable reactive oxygen species (ROSs) production capacity. The TTCBTA NPs also show high-efficiency photo-damage, negligible dark toxicity, excellent fluorescent tracing, and high accumulation in lysosome for tumor cells. Furthermore, TTCBTA NPs are used to obtain fluorescence images with good resolution of MCF-7 tumors in xenografted BALB/c nude mice. Crucially, TTCBTA NPs present a strong tumor ablation ability and image-guided PDT effect by generating abundant ROSs upon laser irradiation. These results demonstrate that the TTCBTA NP theranostic nanoplatform may enable highly efficient near-infrared fluorescence image-guided PDT.

Synthesizing studies for comparing different treatment sequences in clinical trials.

With advances in cancer treatments and improved patient survival, more patients may go through multiple lines of treatment. It is of clinical importance to choose a sequence of effective treatments (eg, lines of treatment) for individual patients with the goal of optimizing their long-term clinical outcome (eg, survival). Several important issues arise in cancer studies. First, cancer clinical trials are usually conducted by each line of treatment. For a treatment sequence, we may have first line and second line treatment data from two different studies. Second, there is typically a treatment initiation period varying from patient to patient between progression of disease and the start of the second line treatment due to administrative reasons. Additionally, the choice of the second line treatment for patients with progression of disease may depend on their characteristics. We address all these issues and develop semiparametric methods under the potential outcome framework for the estimation of the overall survival probability for a treatment sequence and for comparing different treatment sequences. We establish the large sample properties of the proposed inferential procedures. Simulation studies and an application to a colorectal clinical trial are provided.

Nitrogen-Doped Bismuth Nanosheet as an Efficient Electrocatalyst to CO2 Reduction for Production of Formate.

Electrochemical CO2 reduction (CO2RR) to produce high value-added chemicals or fuels is a promising technology to address the greenhouse effect and energy challenges. Formate is a desirable product of CO2RR with great economic value. Here, nitrogen-doped bismuth nanosheets (N-BiNSs) were prepared by a facile one-step method. The N-BiNSs were used as efficient electrocatalysts for CO2RR with selective formate production. The N-BiNSs exhibited a high formate Faradic efficiency (FEformate) of 95.25% at -0.95 V (vs. RHE) with a stable current density of 33.63 mA cm-2 in 0.5 M KHCO3. Moreover, the N-BiNSs for CO2RR yielded a large current density (300 mA cm-2) for formate production in a flow-cell measurement, achieving the commercial requirement. The FEformate of 90% can maintain stability for 14 h of electrolysis. Nitrogen doping could induce charge transfer from the N atom to the Bi atom, thus modulating the electronic structure of N-Bi nanosheets. DFT results demonstrated the N-BiNSs reduced the adsorption energy of the *OCHO intermediate and promoted the mass transfer of charges, thereby improving the CO2RR with high FEformate. This study provides a valuable strategy to enhance the catalytic performance of bismuth-based catalysts for CO2RR by using a nitrogen-doping strategy.

Cellular Uptake, Organelle Enrichment, and In Vitro Antioxidation of Fullerene Derivatives, Mediated by Surface Charge.

Hydrophilic fullerene derivatives get notable performance in various biological applications, especially in cancer therapy and antioxidation. The biological behaviors of functional fullerenes are much dependent on their surface physicochemical properties. The excellent reactive oxygen species-scavenging capabilities of functional fullerenes promote their outstanding performances in inhibiting pathological symptoms associated with oxidative stress, including neurodegenerative diseases, cardiovascular diseases, acute and chronic kidney disease, and diabetes. Herein, fullerene derivatives with reversed surface charges in aqueous solutions are prepared: cationic C60-EDA and anionic C60-(EDA-EA). Under the driving force of membrane potential (negative inside) in the cell and mitochondria, C60-EDA is much rapidly taken in by cells and transported into mitochondria compared with C60-(EDA-EA) that is enriched in lysosomes. With high cellular uptake and mitochondrial enrichment, C60-EDA exhibits stronger antioxidation capabilities in vitro than C60-(EDA-EA), indicating its better performance in the therapy of oxidation-induced diseases. It is revealed that the cellular uptake rate, subcellular location, and intracellular antioxidation behavior of fullerene derivatives are primarily mediated by their surface charges, providing new strategies for the design of fullerene drugs and their biological applications.

Design, Synthesis and Biological Activity of (20S,21S)-7-Cyclohexyl-21-fluorocamptothecin Carbamates as Potential Antitumor Agents.

(20S,21S)-7-Cyclohexyl-21-fluorocamptothecin was discovered by a fluorine drug design strategy with potent antitumor activity and increased metabolic stability. In continuous efforts to find novel antitumor agents derived from natural product camptothecin, 20-carbamates of the active compound (20S,21S)-7-cyclohexyl-21-fluorocamptothecin have been designed and synthesized. Among them, one compound with the diethylamino group showed greater antiproliferative activity than the other 20-carbamate derivatives. The following biological activity assays indicated that the above compound is a valuable lead compound with excellent Topo I inhibitory activity and solution stability.

Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen.

Percutaneous full endoscopic posterior decompression of thoracic myelopathy caused by ossification of the ligamentum flavum.

PURPOSE: Ossification of ligamentum flavum (OLF) is the leading cause of progressive thoracic myelopathy (TM) in East Asian countries. Surgical decompression is the general treatment for TM. This study investigated the application of percutaneous full endoscopic posterior decompression (PEPD) for the treatment of thoracic OLF. METHODS: Eighteen patients with TM were treated by PEPD under local anaesthesia. Patients had an average age of 59.1 years and single-level lesions mostly at the lower thoracic vertebrae. Computed tomography and magnetic resonance imaging were used to classify the OLF. The pre- and postoperative neurological statuses were evaluated using the American Spinal Injury Association (ASIA) sensory and motor score, modified Japanese Orthopaedic Association (mJOA) score and Frankel grade. RESULTS: OLF for all patients was classed as lateral, extended, and enlarged types without comma and tram track signs. Decompression was completed, and a dome-shaped laminotomy was performed through limited laminectomy and flavectomy. Dural tears in 2 patients were the only observed complication. The average score of ASIA sensory and motor, mJOA, as well as the Frankel grade improved significantly after surgery at an average follow-up time of 17.4 months. The average recovery rate (RR) was 47.5% as calculated from the mJOA scores. According to RR, 10 cases were classified as good, 4 cases fair, and 4 cases unchanged. CONCLUSIONS: For patients with thoracic OLF at a single level and lateral, extended, and enlarged types without comma and tram track signs, it is safe and reliable to perform PEPD, which has satisfactory clinical results. These slides can be retrieved under Electronic Supplementary Material.

A multicenter case registry study on medication-related osteonecrosis of the jaw in patients with advanced cancer.

PURPOSE: This observational case registry study was designed to describe the natural history of cancer patients with medication-related osteonecrosis of the jaw (ONJ) and evaluate the ONJ resolution rate. METHODS: Adults with a diagnosis of cancer and with a new diagnosis of ONJ were enrolled and evaluated by a dental specialist at baseline and every 3 months for 2 years and then every 6 months for 3 years until death, consent withdrawal, or loss to follow-up. The primary endpoint was the rate and time course of ONJ resolution. Secondary endpoints included frequency of incident ONJ risk factors, ONJ treatment patterns, and treatment patterns of antiresorptive agents for subsequent ONJ. RESULTS: Overall, 327 patients were enrolled; 207 (63%) were continuing on study at data cutoff. Up to 69% of evaluable patients with ONJ had resolution or improvement during the study. ONJ resolution (AAOMS ONJ staging criteria) was observed in 114 patients (35%); median (interquartile range) time from ONJ onset to resolution was 7.3 (4.5-11.4) months. Most patients (97%) had received antiresorptive medication before ONJ development, 9 patients (3%) had not; 68% had received zoledronic acid, 38% had received denosumab, and 10% had received pamidronate (56% had received bisphosphonates only, 18% had received denosumab only, and 21% had exposure to both). CONCLUSIONS: These results are consistent with those observed in clinical trials evaluating skeletal-related events in patients with advanced malignancy involving bone. Longer follow-up will provide further information on ONJ recurrence and resolution rates between medically and surgically managed patients.

Polymorphisms of human leukocyte antigen B*27 on clinical phenotype of spondyloarthritis in Chinese.

BACKGROUND: In recent years, an ever-increasing number of alleles of human leukocyte antigen B*27 (HLA-B*27) have been identified. This study aimed to establish an updated method for HLA-B*27 subtyping, and to investigate the impact of HLA-B*27 polymorphisms on the clinical phenotype of spondyloarthritis (SpA). METHODS: Overall, 184 SpA patients were recruited for analyzing diversity of HLA-B*27 via an updated high-resolution polymerase chain reaction amplification with sequence specific primers (PCR-SSP). RESULTS: The prevalence of HLA-B*27 was 94.0%, and four subtypes were identified including HLA-B*2704 (77.5%), B*2705 (20.2%), B*2707 (1.7%), and B*2724 (0.6%). There was an obvious male predominance (P=.05) and markedly elevated C-reaction protein (CRP) in B*27 positive SpA (P<.01). In multivariate linear regression analysis, the elevated CRP was positively associated with HLA-B*27 positivity (regression coefficient B=46.1, P=.0003), grade of sacroiliitis (B=47.5, P=.0032), and male gender (B=20.4, P=.0041). Notably, a male predilection was also found in B*2705 positive SpA while B*2707 was associated with older age, higher positive family history, and higher prevalence of extra-articular features (all P<.05). CONCLUSIONS: In this study, an updated PCR-SSP technique to identify increasing alleles of HLA-B*27 was developed and their different effects on clinical manifestations of SpA were demonstrated. Genotyping of HLA-B*27 would shed light on our understanding of the pathogenesis of SpA.

Inhalable gadofullerenol/[70] fullerenol as high-efficiency ROS scavengers for pulmonary fibrosis therapy.

Pulmonary fibrosis has become a fatal disease for its high incidence and few effective drugs available in clinic. In this study, gadofullerenol (GF-OH) and [70] fullerenol (C70-OH) nanoparticles (NPs) prepared by a one-pot reaction were designed as nanomedicines to treat this fatal disease. It was revealed that the inhalation of gadofullerenols and [70] fullerenols substantially alleviates the collagen deposition induced by acute lung injury. Based on detailed studies of oxidative stress parameters and transforming growth factor-ß1 (TGF-ß1), we demonstrated they owned the antioxidant and anti-inflammatory functions for the modulation of ROS-mediated inflammation process. Thus the therapeutic effect may be associated with synergistic mechanism of scavenging free radicals and indirectly modulating TGF-ß1 expression. Moreover, GF-OH NPs were observed to show the superiority to C70-OH NPs both in vitro and in vivo due to the structural distinction. These results suggest the inhalable fullerenols are highly potential for clinical therapy of pulmonary fibrosis.

Distribution of endotoxins in full scale pharmaceutical wastewater treatment plants and its relationship with microbial community structure.

Endotoxins are potential toxics impacting human health through respiration derived in wastewater treatment plants (WWTPs), yet the formation of endotoxins during wastewater treatment processes is still lacking research. In our study, the distribution of endotoxins and bacterial community structure in the wastewater of three full scale pharmaceutical WWTPs were explored using the limulus amebocyte lysate (LAL) test and MiSeq technique. Results showed that higher endotoxin activities in the influent of Plant A and Plant C (560 and 1140 EU/mL), stemming from the fermentation process, were found compared to that of Plant B (135 EU/mL), coming from the process of chemical synthesis. During the anaerobic treatment and the cyclic activated sludge system (CASS) in the three WWTPs, the endotoxin activity increased, while it declined in the aerobic treatment system. In all bioreactors, the relative abundance of Gram-negative bacteria accounted for 50.0-94.6%. Bacteria with high lipopolysaccharide (LPS) in LAL assay were found at the genus level of Bacteroides, Enterococcus, Desulfovibrio, and Megasphaera.

Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-free survival-2.

PURPOSE: Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2). PATIENTS AND METHODS: Women with recurrent disease (platinum-free interval<12months) were randomized to receive intravenous paclitaxel 80mg/m(2) (3weeks on/1week off) plus intravenous trebananib 15mg/kg or placebo, weekly. OS in the intent-to-treat population was a key secondary endpoint. Exploratory analysis of PFS-2 was conducted according to guidance by the European Medicines Agency. RESULTS: Median OS was not significantly improved with trebananib compared with placebo (19.3 versus 18.3months; HR, 0.95; 95% CI, 0.81-1.11; P=0.52) in the intent-to-treat population (n=919). In subgroup analysis, trebananib improved median OS compared with placebo (14.5 versus 12.3months; HR, 0.72; 95% CI, 0.55-0.93; P=0.011) in patients with ascites at baseline (n=295). In the intent-to-treat population, trebananib significantly improved median PFS-2 compared with placebo (12.5 versus 10.9months; HR, 0.85; 95% CI, 0.74-0.98; P=0.024). The incidence and type of adverse events in this updated analysis was consistent with that described in the primary analysis; no new safety signals were detected. CONCLUSIONS: OS was not significantly longer in the intent-to-treat population, although there was an improvement in OS in patients with ascites receiving trebananib. PFS-2 confirmed that the PFS benefit associated with trebananib was maintained through the second disease progression independent of the choice of subsequent therapy.

Hierarchical Bayesian approaches for detecting inconsistency in network meta-analysis.

Network meta-analysis (NMA), also known as multiple treatment comparisons, is commonly used to incorporate direct and indirect evidence comparing treatments. With recent advances in methods and software, Bayesian approaches to NMA have become quite popular and allow models of previously unanticipated complexity. However, when direct and indirect evidence differ in an NMA, the model is said to suffer from inconsistency. Current inconsistency detection in NMA is usually based on contrast-based (CB) models; however, this approach has certain limitations. In this work, we propose an arm-based random effects model, where we detect discrepancy of direct and indirect evidence for comparing two treatments using the fixed effects in the model while flagging extreme trials using the random effects. We define discrepancy factors to characterize evidence of inconsistency for particular treatment comparisons, which is novel in NMA research. Our approaches permit users to address issues previously tackled via CB models. We compare sources of inconsistency identified by our approach and existing loop-based CB methods using real and simulated datasets and demonstrate that our methods can offer powerful inconsistency detection. Copyright © 2016 John Wiley & Sons, Ltd.

Proton Pump Inhibitor Therapy for the Treatment of Laryngopharyngeal Reflux: A Meta-Analysis of Randomized Controlled Trials.

GOALS: To compare the treatment effect of proton pump inhibitor (PPI) therapy and placebo for patients with laryngopharyngeal reflux (LPR). STUDY: PubMed, Cochrane Library, and EMBASE were searched from the date of conception to August 2014. Randomized controlled clinical trials (RCTs) were included in this meta-analysis if they compared the treatment response of PPI therapy and placebo among patients with LPR. The risk difference, the standard mean difference (SMD), and their corresponding 95% confidence intervals (CIs) were calculated for the endpoints evaluated. RESULTS: Fourteen eligible RCTs with 771 participants were identified and analyzed in this meta-analysis. By pooling all eligible data, we found that patients treated with PPI therapy had a significantly higher response rate than those who received placebo (risk difference=0.15; 95% CI, 0.01-0.30). Compared with placebo, PPI therapy could also improve the total reflux symptom index significantly (SMD=1.65; 95% CI, 0.15-3.14), but results of the reflux symptom index varied for specific symptoms. However, PPI therapy did not show any advantage over placebo in the improvement of the reflux finding score (SMD=0.62; 95% CI, -0.96-2.19). CONCLUSIONS: In this meta-analysis of 14 eligible RCTs, we found that in patients with LPR, PPI therapy could improve reflux symptoms significantly compared with placebo.

IL-25 Elicits Innate Lymphoid Cells and Multipotent Progenitor Type 2 Cells That Reduce Renal Ischemic/Reperfusion Injury.

IL-25 is an important immune regulator that can promote Th2 immune response-dependent immunity, inflammation, and tissue repair in asthma, intestinal infection, and autoimmune diseases. In this study, we examined the effects of IL-25 in renal ischemic/reperfusion injury (IRI). Treating IRI mice with IL-25 significantly improved renal function and reduced renal injury. Furthermore, IL-25 treatment increased the levels of IL-4, IL-5, and IL-13 in serum and kidney and promoted induction of alternatively activated (M2) macrophages in kidney. Notably, IL-25 treatment also increased the frequency of type 2 innate lymphoid cells (ILC2s) and multipotent progenitor type 2 (MPP(type2)) cells in kidney. IL-25-responsive ILC2 and MPP(type2) cells produced greater amounts of Th2 cytokines that associated with the induction of M2 macrophages and suppression of classically activated (M1) macrophages in vitro. Finally, adoptive transfer of ILC2s or MPP(type2) cells not only reduced renal functional and histologic injury in IRI mice but also induced M2 macrophages in kidney. In conclusion, our data identify a mechanism whereby IL-25-elicited ILC2 and MPP(type2) cells regulate macrophage phenotype in kidney and prevent renal IRI.

Evaluation of an ICD-10 algorithm to detect osteonecrosis of the jaw among cancer patients in the Danish National Registry of Patients.

PURPOSE: This study aimed to validate a predefined algorithm for osteonecrosis of the jaw (ONJ) among cancer patients in the Danish National Registry of Patients and to assess the nature of clinical information recorded in medical charts of ONJ patients. METHODS: We identified potential ONJ cases recorded in 2005-2010 among cancer patients at the hospital Departments of Oral and Maxillofacial Surgery (DOMS) in three Danish regions, using a set of codes from the International Classification of Diseases, 10th revision (ICD-10). We abstracted DOMS charts of the potential cases, had the ONJ status adjudicated by an expert ONJ adjudication committee (ONJAC), and computed positive predictive values. For patients with ONJAC-confirmed ONJ, we abstracted the charts for information on ONJ clinical course. Sensitivity of the algorithm was computed using a separate sample of 101 known ONJ cases accrued in 2005-2011. RESULTS: We identified 212 potential ONJ cases, of which 197 (93%) had charts available for abstraction. Eighty-three potential cases were confirmed by ONJAC, with a positive predictive value of 42% (95% confidence interval [CI] 35%-49%). DOMS charts of these 83 cases contained complete information on ONJ clinical course. Information about antiresorptive treatment was recorded for 84% of the patients. Among the 101 known ONJ cases, 74 had at least one prespecified ICD-10 code recorded in the Danish National Registry of Patients within ±90 days of the ONJ diagnosis (sensitivity 73%; 95%CI [64%-81%]). CONCLUSIONS: The predefined algorithm is not adequate for monitoring ONJ in pharmacovigilance studies. Additional case-finding approaches, coupled with adjudication, are necessary to estimate ONJ incidence accurately.

Guidance on the implementation and reporting of a drug safety Bayesian network meta-analysis.

The Drug Information Association Bayesian Scientific Working Group (BSWG) was formed in 2011 with a vision to ensure that Bayesian methods are well understood and broadly utilized for design and analysis and throughout the medical product development process, and to improve industrial, regulatory, and economic decision making. The group, composed of individuals from academia, industry, and regulatory, has as its mission to facilitate the appropriate use and contribute to the progress of Bayesian methodology. In this paper, the safety sub-team of the BSWG explores the use of Bayesian methods when applied to drug safety meta-analysis and network meta-analysis. Guidance is presented on the conduct and reporting of such analyses. We also discuss different structural model assumptions and provide discussion on prior specification. The work is illustrated through a case study involving a network meta-analysis related to the cardiovascular safety of non-steroidal anti-inflammatory drugs.