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Background Involvement in cervical ligamentum flavum is a rare manifestation of the calcium pyrophosphate dihydrate deposition disease. Only few cases of this condition have been reported. We revealed eighteen cases of CPPD in cervical ligamentum flavum that diagnosed at a single medical center. In our case series, clinical characteristics and magnetic resonance imaging findings of patients are described. Methods We retrospectively reviewed the medical charts and imaging studies of the eighteen patients with pseudogout attack of the cervical ligamentum flavum. In addition, we discussed the differences between this disease and ossification of ligamentum flavum in image manifestations. Results There were fourteen men and four women aged between 59 and 87 years. Diabetes mellitus and hypertension were the most common comorbidities. Myelopathy and neck pain were presented in most patients. C4–5 and C5–6 were attacked most frequently, and multiple- rather than single-level involvement could be observed in our series. “Acute on chronic phenomenon” was a specific magnetic resonance image finding in patients whose symptom durations were between 2 to 5 months. Compared to ossification of ligamentum flavum, calcium pyrophosphate dihydrate crystal deposition had different image signs, including morphology, side of the involved ligament, no continuity with the lamina, acute on chronic phenomenon, and presence of retro-odontoid mass. Conclusions Nodular calcifications in cervical ligamentum flavum raise highly suspicion for calcium pyrophosphate dihydrate deposition and must be diagnosed by histological examination and polarized light microscopy. This disease is different from ossification of ligamentum flavum, and it could be recognized by specific image features.

Background BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations. Methods We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial. Results BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10–4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months. Conclusion Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. Trial registration: Chictr.org.cn ChiCTR1800018143.

Background Isobutanol is considered a potential biofuel, thanks to its high-energy content and octane value, limited water solubility, and compatibility with gasoline. As its biosynthesis pathway is known, a microorganism, such as Saccharomyces cerevisiae, that inherently produces isobutanol, can serve as a good engineering host. Isobutanol’s toxicity, however, is a major obstacle for bioproduction. This study is to understand how yeast tolerates isobutanol. Results A S. cerevisiae gene-deletion library with 5006 mutants was used to screen genes related to isobutanol tolerance. Image recognition was efficiently used for high-throughput screening via colony size on solid media. In enrichment analysis of the 161 isobutanol-sensitive clones identified, more genes than expected were mapped to tryptophan biosynthesis, ubiquitination, and the pentose phosphate pathway (PPP). Interestingly, adding exogenous tryptophan enabled both tryptophan biosynthesis and PPP mutant strains to overcome the stress. In transcriptomic analysis, cluster analysis of differentially expressed genes revealed the relationship between tryptophan and isobutanol stress through some specific cellular functions, such as biosynthesis and transportation of amino acids, PPP, tryptophan metabolism, nicotinate/nicotinamide metabolism (e.g., nicotinamide adenine dinucleotide biosynthesis), and fatty acid metabolism. Conclusions The importance of tryptophan in yeast’s tolerance to isobutanol was confirmed by the recovery of isobutanol tolerance in defective strains by adding exogenous tryptophan to the growth medium. Transcriptomic analysis showed that amino acid biosynthesis- and transportation-related genes in a tryptophan biosynthesis-defective host were up-regulated under conditions similar to nitrogen starvation. This may explain why ubiquitination was required for the protein turnover. PPP metabolites may serve as precursors and cofactors in tryptophan biosynthesis to enhance isobutanol tolerance. Furthermore, the tolerance mechanism may also be linked to tryptophan downstream metabolism, including the kynurenine pathway and nicotinamide adenine dinucleotide biosynthesis. Both pathways are responsible for cellular redox balance and anti-oxidative ability. Our study highlights the central role of tryptophan in yeast’s isobutanol tolerance and offers new clues for engineering a yeast host with strong isobutanol tolerance.

BackgroundNaïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. However, the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive.ResultsWe examine the regulation of telomere maintenance, retrotransposon activity, and genomic stability of primed PSCs and compare them with naïve PSCs. Surprisingly, primed PSCs only minimally maintain telomeres and show fragile telomeres, associated with declined DNA recombination and repair activity, in contrast to naïve PSCs that robustly elongate telomeres. Also, we identify LINE1 family integrantL1Md_Tas naïve-specific retrotransposon and ERVK family integrantIAPEzto define primed PSCs, and their transcription is differentially regulated by heterochromatic histones and Dnmt3b. Notably, genomic instability of primed PSCs is increased, in association with aberrant retrotransposon activity.ConclusionsOur data suggest that fragile telomere, retrotransposon-associated genomic instability, and declined DNA recombination repair, together with reduced function of cell cycle and mitochondria, increased apoptosis, and differentiation properties may link to compromised developmental potency of primed PSCs, noticeably distinguishable from naïve PSCs.

Background Accurate prognosis and identification of cancer subtypes at molecular level are important steps towards effective and personalised treatments of breast cancer. To this end, many computational methods have been developed to use gene (mRNA) expression data for breast cancer subtyping and prognosis. Meanwhile, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been extensively studied in the last 2 decades and their associations with breast cancer subtypes and prognosis have been evidenced. However, it is not clear whether using miRNA and/or lncRNA expression data helps improve the performance of gene expression based subtyping and prognosis methods, and this raises challenges as to how and when to use these data and methods in practice. Results In this paper, we conduct a comparative study of 35 methods, including 12 breast cancer subtyping methods and 23 breast cancer prognosis methods, on a collection of 19 independent breast cancer datasets. We aim to uncover the roles of miRNAs and lncRNAs in breast cancer subtyping and prognosis from the systematic comparison. In addition, we created an R package, CancerSubtypesPrognosis, including all the 35 methods to facilitate the reproducibility of the methods and streamline the evaluation. Conclusions The experimental results show that integrating miRNA expression data helps improve the performance of the mRNA-based cancer subtyping methods. However, miRNA signatures are not as good as mRNA signatures for breast cancer prognosis. In general, lncRNA expression data does not help improve the mRNA-based methods in both cancer subtyping and cancer prognosis. These results suggest that the prognostic roles of miRNA/lncRNA signatures in the improvement of breast cancer prognosis needs to be further verified.

Background We assessed whether a postoperative bilateral, ultrasound-guided, posterior transversus abdominis plane (TAP) block could reduce 24 h rescue tramadol requirement compared with placebo in patients undergoing elective laparoscopic colorectal cancer surgery. Methods Patients scheduled to undergo elective laparoscopic surgery following the diagnosis of colorectal cancer were included in this study and randomized into Group and Group Control. The patients received a postoperative bilateral, ultrasound-guided, posterior TAP block in either 20 mL of 0.5% ropivacaine (Group TAP) per side or an equivalent volume of normal saline (Group Control). The primary outcome was the cumulative consumption of rescue tramadol within 24 h after the surgery. Secondary endpoints included (1) resting and movement numerical rating scale (NRS) pain scores at 2, 4, 6, 12, 24, 48, and 72 h; (2) incidences of related side effects; (3) time to the first request for rescue tramadol; (4) patient satisfaction regarding postoperative analgesia; (5) time to restoration of intestinal function; (6) time to mobilization; and (7) the length of hospital stay. Results In total, 92 patients were randomized, and 82 patients completed the analysis. The total rescue tramadol requirement (median [interquartile range]) within the first 24 h was lower in Group TAP (0 [0, 87.5] mg) than in Group Control (100 [100, 200] mg), P P P = 0.002), which was similar on days 2 (P = 0.702) and 3 (P = 0.551), compared with the Group Control. A few incidences of opioid-related side effects (P Conclusions A postoperative bilateral, ultrasound-guided, posterior TAP block resulted in better pain management and a faster recovery in patients undergoing laparoscopic colorectal cancer surgery, without adverse effects. Trial registration The study was registered at http://www.chictr.org.cn (ChiCTR-IPR-17012650; Sep 12, 2017).

Background People living with dementia seem to be more likely to experience delirium following hip fracture. The association between mental disorders (MD) and hip fracture remains controversial. We conducted a nationwide study to examine the prevalence of MD in geriatric patients with hip fractures undergoing surgery and conducted a related risk factor analysis. Material and methods This retrospective cohort study used data from Taiwan’s National Health Insurance Research Database between 2000 and 2012 and focused on people who were older than 60 years. Patients with hip fracture undergoing surgical intervention and without hip fracture were matched at a ratio of 1:1 for age, sex, comorbidities, and index year. The incidence and hazard ratios of age, sex, and multiple comorbidities related to MD and its subgroups were calculated using Cox proportional hazards regression models. Results A total of 1408 patients in the hip fracture group and a total of 1408 patients in the control group (no fracture) were included. The overall incidence of MD for the hip fracture and control groups per 100 person-years were 0.8 and 0.5, respectively. Among MD, the incidences of transient MD, depression, and dementia were significantly higher in the hip fracture group than in the control group. Conclusions The prevalence of newly developed MD, especially transient MD, depression, and dementia, was higher in the geriatric patients with hip fracture undergoing surgery than that in the control group. Prompt and aggressive prevention protocols and persistent follow-up of MD development is highly necessary in this aged society.

Background How to perform minimally-invasive surgery on Tile C pelvic fractures is very difficult, and it is also a hot topic in orthopedic trauma research. We applied minimally-invasive treatment using an anterior internal fixator combined with sacroiliac screws. Objectives To compare the biomechanical properties of different fixation models in pelvic facture specimens, using an internal fixation system or a steel plate combined with sacroiliac screws. Methods Sixteen fresh adult cadaver pelvic specimens were randomly separated into four groups named A, B, C, and D. The four groups were respectively stabilized using a two-screwed, three-screwed, or four-screwed anterior internal fixator or a steel plate with sacroiliac screws. All models were tested in both standing and sitting positions. Vertical loads of 600 N were applied increasingly. Shifts of bilateral sacroiliac joints and pubis rupture were measured. Results The shifts in sacroiliac joints and pubis rupture in the standing position were all less than 3.5 mm, and the shifts in the sitting position were all less than 1 mm. In the standing position, the results of shifts in the sacroiliac joints were group C < group D < group B < group A. For comparisons between A:B and C:D, P > 0.05. For comparisons between A, B:C, and D, P < 0.05. The results of shifts in pubis ruptures were group D < group C < group B < group A. In the comparison between C:D, P > 0.05; for comparisons between A:B, A:C, A:D, B:C, and B:D, P < 0.05. In the sitting posture, the results of shifts in the sacroiliac joints were group C < group D < group B < group A, and the shifts in the pubis ruptures were group D < group C < roup B < group A. For comparison between C:D, P > 0.05. For comparisons between A:B, A:C, A:D, B:C, and B:D, P < 0.05. Conclusion Use of an anterior internal fixator combined with sacroiliac screws effectively stabilized Tile C3 pelvic fractures. The stability of specimens increased as the number of screws in the internal fixator increased.

Background DNA methylation, as an essential epigenetic modification found in mammals and plants, has been implicated to play an important role in insect reproduction. However, the functional role and the regulatory mechanism of DNA methylation during insect organ or tissue development are far from being clear. Results Here, we found that DNA methylation inhibitor (5-aza-dC) treatment in newly molted pupae decreased the chitin content of pupal wing discs and adult wings and resulted in wing deformity of Bombyx mori. Transcriptome analysis revealed that the up-regulation of chitinase 10 (BmCHT10) gene might be related to the decrease of chitin content induced by 5-aza-dC treatment. Further, the luciferase activity assays demonstrated that DNA methylation suppressed the promoter activity of BmCHT10 by down-regulating the transcription factor, homeobox protein araucan (Bmara). Electrophoretic mobility shift assay, DNA pull-down and chromatin immunoprecipitation demonstrated that Bmara directly bound to the BmCHT10 promoter. Therefore, DNA methylation is involved in keeping the structural integrity of the silkworm wings from unwanted chitin degradation, as a consequence, it promotes the wing development of B. mori. Conclusions This study reveals that DNA methylation plays an important role in the wing development of B. mori. Our results support that the indirect transcriptional repression of a chitin degradation-related gene BmCHT10 by DNA methylation is necessary to keep the proper wing development in B. mori.

Background Variability in the anatomy and orientation of the triangle of Koch (TK) complicates ablation procedures involving the atrioventricular (AV) node. We used CT angiography (CTA) to assess the anatomical TK orientation, the CS ostium direction, and the relationship between the two, and we validated an individualized CS-guided projection during ablation procedures. Methods In 104 patients without structural heart disease undergoing computed tomography (CT) angiography, TK orientations were determined in relation to the coronary sinus ostium (CSo) as well as two standard right anterior oblique (RAO) projection angles (30o and 45o) commonly used in ablation procedures. Results A CS-guided RAO projection (RAOCS) was shown to best track the orientation of the TK compared to RAO30° and 45°, with TK orientation strongly correlating with the CSo direction (r = 0.86, P Conclusion In hearts with a normal structure, the CSo direction offers a reliable predictor of the TK orientation which can be used to guide the projection of the TK during ablation procedures.

Background Escherichia coli are mostly commensals but also contain pathogenic lineages. It is largely unclear whether the commensal E. coli as the potential origins of pathogenic lineages may consist of monophyletic or polyphyletic populations, elucidation of which is expected to lead to novel insights into the associations of E. coli diversity with human health and diseases. Methods Using genomic sequencing and pulsed field gel electrophoresis (PFGE) techniques, we analyzed E. coli from the intestinal microbiota of three groups of healthy individuals, including preschool children, university students, and seniors of a longevity village, as well as colorectal cancer (CRC) patients, to probe the commensal E. coli populations for their diversity. Results We delineated the 2280 fresh E. coli isolates from 185 subjects into distinct genome types (genotypes) by PFGE. The genomic diversity of the sampled E. coli populations was so high that a given subject may have multiple genotypes of E. coli, with the general diversity within a host going up from preschool children through university students to seniors. Compared to the healthy subjects, the CRC patients had the lowest diversity level among their E. coli isolates. Notably, E. coli isolates from CRC patients could suppress the growth of E. coli bacteria isolated from healthy controls under nutrient-limited culture conditions. Conclusions The coexistence of multiple E. coli lineages in a host may help create and maintain a microbial environment that is beneficial to the host. As such, the low diversity of E. coli bacteria may be associated with unhealthy microenvironment in the intestine and hence facilitate the pathogenesis of diseases such as CRC.

Background The present cohort study aims to examine the relationship between fibrinogen (Fib) levels and glucose metabolism [fasting blood glucose (FBG) and hemoglobin A1c (HbA1c)] and investigate the impact of high Fib on cardiovascular outcomes in patients with stable CAD and pre-diabetes mellitus (pre-DM) or diabetes mellitus (DM). Methods This study included 5237 patients from March 2011 to December 2015. Patients were distributed into three groups according to Fib levels (low Fib, median Fib, high Fib) and further categorized by glucose metabolism status [normal glucose regulation (NGR), Pre-DM, DM]. All patients were followed up for the occurrences of major adverse cardiovascular events (MACEs), including cardiovascular mortality, nonfatal MI, stroke, and unplanned coronary revascularization. Results Linear regression analyses showed that FBG and HbA1c levels were positively associated with Fib in overall CAD participants, either with or without DM (all P P 0.001]. Furthermore, DM but not pre-DM was a significant predictor of MACEs (P P > 0.05, respectively). When patients were stratified by both glucose metabolism status and Fib levels, high Fib was associated with a higher risk of MACEs in pre-DM (HR 1.66, 95% CI 1.02–2.71, P P Conclusions The present study suggested that Fib levels were associated with FBG and HbA1c in stable CAD patients. Moreover, elevated Fib was independently associated with MACEs in CAD patients, especially among those with pre-DM and DM, suggesting that Fib may provide incremental value in the cardiovascular risk stratification of pre-DM and DM patients.

Background MicroRNAs (miRNAs), a class of small regulatory RNAs, have been proven to play important roles in plant growth, development and stress responses. Sweet potato (Ipomoea batatas L.) is an important food and industrial crop that ranks seventh in staple food production. However, the regulatory mechanism of miRNA-mediated abiotic stress response in sweet potato remains unclear. Results In this study, we employed deep sequencing to identify both conserved and novel miRNAs from salinity-exposed sweet potato cultivars and its untreated control. Twelve small non-coding RNA libraries from NaCl-free (CK) and NaCl-treated (Na150) sweet potato leaves and roots were constructed for salt-responsive miRNA identification in sweet potatoes. A total of 475 known miRNAs (belonging to 66 miRNA families) and 175 novel miRNAs were identified. Among them, 51 (22 known miRNAs and 29 novel miRNAs) were significantly up-regulated and 76 (61 known miRNAs and 15 novel miRNAs) were significantly down-regulated by salinity stress in sweet potato leaves; 13 (12 known miRNAs and 1 novel miRNAs) were significantly up-regulated and 9 (7 known miRNAs and 2 novel miRNAs) were significantly down-regulated in sweet potato roots. Furthermore, 636 target genes of 314 miRNAs were validated by degradome sequencing. Deep sequencing results confirmed by qRT-PCR experiments indicated that the expression of most miRNAs exhibit a negative correlation with the expression of their targets under salt stress. Conclusions This study provides insights into the regulatory mechanism of miRNA-mediated salt response and molecular breeding of sweet potatoes though miRNA manipulation.

Background Knee osteoarthritis (KOA) is one of the most common bone and joint diseases. As one of the main non-drug therapies, acupuncture is widely used to treat KOA, although the evidence for its efficacy is inconclusive. The objective of this pilot trial is to clarify the clinical efficacy and safety of fire acupuncture in the treatment of mild to moderate KOA and to provide high-quality data for further research. Methods/design This study is a prospective randomized controlled pilot trial in which 120 patients with mild to moderate KOA will be randomly allocated in equal proportions to a fire acupuncture group or a general acupuncture group. They will receive acupuncture for six sessions over 2 weeks. The primary end point is success rate, which will be calculated based on the change from baseline of the pain and function scores in the Western Ontario and McMaster Universities Osteoarthritis Index at 4 weeks. Secondary end points include the proportion of patients achieving clinical improvement based on: (1) the OMERACT-OARSI responder criteria, (2) levels of matrix metalloproteinase 3, interleukin 1β, and tumor necrosis factor α in blood, and (3) a subjective efficacy evaluation from patients. Trial registration Chinese Clinical Trial Registry, ChiCTR1800019162. Registered on 29 October 2018.

Background We have previously identified 11 promising candidate genes for milk composition traits by resequencing the whole genomes of 8 Holstein bulls with extremely high and low estimated breeding values for milk protein and fat percentages (high and low groups), including FCGR2B, CENPE, RETSAT, ACSBG2, NFKB2, TBC1D1, NLK, MAP3K1, SLC30A2, ANGPT1 and UGDH those contained 25 indels between high and low groups. In this study, the purpose was to further examine whether these candidates have significant genetic effects on milk protein and fat traits. Results With PCR product sequencing, 13 indels identified by whole genome resequencing were successfully genotyped. With association analysis in 769 Chinese Holstein cows, we found that the indel in FCGR2B was significantly associated with milk yield, protein yield and protein percentage (P = 0.0041 to 0.0297); five indels in CENPE and one indel in MAP3K1 were markedly relevant to milk yield, fat yield and protein yield (P

Background The role of Salmonella virulence factor (VF) allelic variation in modulating pathogenesis or host specificity has only been demonstrated in a few cases, mostly through serendipitous findings. Virulence factor (VF) alleles from Salmonella enterica subsp. enterica genomes were compared to identify potential associations with the host-adapted invasive serovars Typhi, Dublin, Choleraesuis, and Gallinarum, and with the broad host-range intestinal serovars Typhimurium, Enteritidis, and Newport. Results Through a bioinformatics analysis of 500 Salmonella genomes, we have identified allelic variants of 70 VFs, many of which are associated with either one of the four host-adapted invasive Salmonella serovars or one of the three broad host-range intestinal serovars. In addition, associations between specific VF alleles and intra-serovar clusters, sequence types (STs) and/or host-adapted FimH adhesins were identified. Moreover, new allelic VF associations with non-typhoidal S. Enteritidis and S. Typhimurium (NTS) or invasive NTS (iNTS) were detected. Conclusions By analogy to the previously shown association of specific FimH adhesin alleles with optimal binding by host adapted Salmonella serovars, lineages or strains, we predict that some of the identified association of other VF alleles with host-adapted serovars, lineages or strains will reflect specific contributions to host adaptation and/or pathogenesis. The identification of these allelic associations will support investigations of the biological impact of VF alleles and better characterize the role of allelic variation in Salmonella pathogenesis. Most relevant functional experiments will test the potential causal contribution of the detected FimH-associated VF variants in host adapted virulence. Electronic supplementary material The online version of this article (10.1186/s12864-019-5809-8) contains supplementary material, which is available to authorized users.

Background Breast cancer is one the most common cancers, making it the second leading cause of cancer-related death among women. Long non-coding RNAs (lncRNAs), with tightly regulated expression patterns, also serve as tumor suppressor during tumorigenesis. The present study aimed to elucidate the role of LINC00968 in breast cancer via WNT2-mediated Wnt2/β-catenin signaling pathway. Methods Breast cancer chip GSE26910 was utilized to identify differential expression in LINC00968 and WNT2. The possible relationship among LINC00968, transcriptional repressor HEY and WNT2 was analyzed and then verified. Effects of LINC00968 on activation of the Wnt2/β-catenin signaling pathway was also tested. Drug resistance, colony formation, cell migration, invasion ability and cell apoptosis after transfection were also determined. Furthermore, tumor xenograft in nude mice was performed to test tumor growth and weight in vivo. Results WNT2 expression exhibited at a high level, whereas LINC00968 at a low expression in breast cancer which was also associated with poor prognosis in patients. LINC00968 targeted and negatively regulated WNT2 potentially via HEY1. Either overexpressed LINC00968 or silenced inhibited activation of the Wnt2/β-catenin signaling pathway, thereby reducing drug resistance, decreasing colony formation ability, as well as suppressing migration and invasion abilities of breast cancer cells in addition to inducing apoptosis. Lastly, in vivo experiment suggested that LINC00968 overexpression also suppressed transplanted tumor growth in nude mice. Conclusion Collectively, overexpressed LINC00968 contributes to reduced drug resistance in breast cancer cells by inhibiting the activation of the Wnt2/β-catenin signaling pathway through silencing WNT2. This study offers a new target for the development of breast cancer treatment.

Background With great changes over the past 10 years in China, especially the rapid economic development, population mobility, urbanization and aging, dynamic change on risk of delay, to our knowledge, has not been well studied in China. The study was to explore risk of delay in diagnosis of new pulmonary tuberculosis (PTB) and dynamic changes in risk of delay in Northwest China. Methods From January 1, 2008 to December 31, 2017, a total of 13,603 people with new PTB registered in Yulin city of Shaanxi province were included. The median delay time was estimated by Kaplan-Meier survival curve. Time delay curves of year-, gender-year-, age-year- and smear-year specific were examined using log-rank test. Two-level mixed-effects survival model was used to calculate the hazard ratio (HR) and 95% confidence interval (95%CI) for factors associated with diagnostic delay. Time delay was defined as time interval between the onset of PTB symptoms and being diagnosed. The outcome variable of interest was defined as “being diagnosed” in survival analysis. Results The 10-year delay time was 33 days (Interquartile Range, 16–65). Annual median delay time gradually decreased from 60 days to 33 days during the past 10 years. The probability that individuals were diagnosed since onset of PTB symptoms increased by 1.29 times in 2017 when compared to 2008. Female (Hazard Ratio (HR), 95%CI, 0.95(0.91–0.99)), age>45 years (HR, 95%CI, 0.87(0.82–0.93)) and smear positive (HR, 95%CI, 0.86(0.78–0.95)) were associated with increased risk of diagnostic delay over 10-year timespan. However, Age>45 years and smear positive showed trend to be protective factors in the past 5 years. Conclusions Time and risk of delay in diagnosis of new PTB had declined over the past 10 years. However, more attentions should be paid to the fact that female still suffered from higher risk of diagnostic delay. We noted a potential reversal in traditional risk factors such as age>45 and smear positive. Those dynamic changes deserved further attention.

Background: Carbapenem resistance in Acinetobacter baumannii in China was mainly mediated by OXA-23-like carbapenemases, while OXA-24/40-like carbapenemases were rarely identified. OXA-72 is one variant of OXA-24/40-like carbapenemases. This study aimed to demonstrate the epidemiology and characterizations of OXA-72-producing A. baumannii in a Chinese hospital.Methods: A total of 107 clinical A. calcoaceticus-A. baumannii (Acb) complex isolates were collected in a Chinese hospital during between 2014 and 2016. These isolates were identified using Vitek 2 system and gyrB multiplex PCR. Vitek 2 system was used for antibiotic susceptibility testing. Genes encoding for major classes of carbapenemases were investigated by PCR. Rep-PCR was used for genotyping of all the A. baumannii isolates. The risk factors for carriage of OXA-72-producing or OXA-23-producing A. baumannii were analyzed through univariate and multivariate logistic regression.Results: Of the 107 Acb isolates collected, 101 isolates (94.4%) and 6 isolates (5.6%) were identified as A. baumannii and A. pittii, respectively. 78 A. baumannii isolates (77.2%) were carbapenem resistant and mainly cultured from intensive care unit (ICU). blaOXA-72 and blaOXA-23 genes were identified in 45(57.7%) and 33(42.3%) carbapenem-resistant A. baumannii (CRAB), respectively. Multivariate risk factor analyses showed that prior carbapenem usage and nasogastric intubation were significantly associated with carriage of OXA-72-producing A. baumannii or OXA-23-producing A. baumannii. Rep-PCR analysis showed that 9 and 22 Rep-PCR types were assigned to 78 CRAB isolates and 23 carbapenem-susceptible A. baumannii (CSAB) isolates, respectively. A higher diverstiy of Rep-PCR patterns was observed among OXA-72-producing A. baumannii isolates than OXA-23-producing A. baumannii isolates, but all of them belonged to the same clone complex. MLST analysis suggested that the OXA-72 isolates from this study correspond to CC92/CC2 clone complex.Conclusions: This study demonstrates high prevalence and potential clonal spread of closely related genotypes of OXA-72-producing A. baumannii within a Chinese hospital. Continuous surveillance is necessary to monitor the dissemination of these strains in other healthcare settings to guide infection control policies in order to curb the spread of this bacterium.

Background Emergence agitation (EA) is a common phenomenon in preschool children during emergence from general anesthesia. This study evaluated the safety and efficacy of dezocine for emergence agitation in preschool children anesthetized with sevoflurane-remifentanil. Methods A total of 100 preschool children, scheduled for elective laparoscopic repair of an inguinal hernia by high ligation of the hernia sac under sevoflurane-remifentanil anesthesia were randomized into two groups: Group C (n = 50) received Ringer’s lactate 10 mL and Group D received Ringer’s lactate 10 mL containing dezocine 0.1 mg/kg, postoperatively. Results Incidence of EA, defined as a score ≥ 3 on Aono’s four point scale or Pediatric Anesthesia Emergence Delirium (PAED) score ≥ 10 in the PACU (10% vs. 76%) and the percentage of patients with severe EA (PAED score ≥ 13) (12% vs. 76%) were significantly lower in Group D compared to Group C (P

Background The incidence of cerebral infarction has been growing year by year in China and around the world. According to clinical observation, acupuncture utilizing the “waking up the spirit” needling method is widely used in patients with cerebral infarction, though the underlying mechanisms remain unclear. Additionally, a number of studies have begun to focus on the relationship between cerebrovascular reserve (CVR) and cerebral infarction. The present study aims to investigate whether CVR is one of potential mechanisms underpinning this effect of acupuncture on patients with cerebral infarction. Methods This is a single-centre, prospective, single-blinded, randomized controlled pilot study. Sixty eligible patients will be randomized into an intervention group (waking up the spirit acupuncture) and a control group (hand and foot 12-meridian acupuncture) in a 1:1 ratio. All treatments will be conducted once a day on weekdays followed by a 2-day rest period on the weekend, over a total treatment course of 2 weeks. The primary outcome measures are cerebrovascular reserve (CVR) capacity and Breath-holding Index (BHI) which will be evaluated at baseline and 2 weeks after the first acupuncture treatment, and the secondary outcome measures are National Institutes of Health Stroke Scale (NIHSS) and Barthel Index scores which will be used to further evaluate the efficacy of the intervention. Discussion Cerebrovascular reserve is an independent risk factor for the occurrence, progression, and recurrence of cerebral infarction that requires attention. This trial aims to investigate whether acupuncture utilizing the waking up the spirit needling method can improve CVR capacity in patients with acute cerebral infarction, thus reducing NIHSS scores and preventing further progression of the disease. Furthermore, data and evidence gained from this study will be utilized in the development of future research projects regarding the effects of acupuncture in patients with acute cerebral infarction. Trial registration ISRCTN, ID: ISRCTN99117074. Registered on 20 April 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2013-5) contains supplementary material, which is available to authorized users.

The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0439-6) contains supplementary material, which is available to authorized users.

Background Previous studies have reported that eEF-2 kinase is associated with tumour cell sensitivity to certain therapies. In the present study, we investigated the relationship between eEF-2 kinase and lapatinib, a dual inhibitor of EGFR and HER-2, in nasopharyngeal carcinoma (NPC) cells. Methods The effect of treatment on the growth and proliferation of NPC cells was measured by three methods: cell counting, crystal violet staining and colony counting. Apoptosis was evaluated by flow cytometry to determine Annexin V-APC/7-AAD and cleaved PARP levels, and the results were further confirmed by Western blot analysis. The expression of eEF-2 kinase and the impacts of different treatments on different signalling pathways were analysed by Western blot analysis. Results The expression of eEF-2 kinase was significantly associated with NPC cell sensitivity to lapatinib. Therefore, suppression of this kinase could increase the cytocidal effect of lapatinib, as well as reduce cell viability and colony formation. Furthermore, inhibition of eEF-2 kinase, by either RNA interference (eEF-2 kinase siRNA or shRNA) or pharmacological inhibition (NH125), enhanced lapatinib-induced apoptosis of NPC cells. The results also showed that lapatinib combined with NH125 had a synergistic effect in NPC cells. In addition, mechanistic analyses revealed that downregulation of the ERK1/2 and Src pathways, but not the AKT pathway, was involved in this sensitizing effect. Conclusions The results of this study suggest that targeting eEF-2 kinase may improve the efficacy of therapeutic interventions such as lapatinib in NPC cells.

Background Different biologic approaches to treat disc regeneration, including growth factors (GFs) application, are currently under investigation. Human annulus fibrosus (hAF) repair or regeneration is one of the key elements for maintenance and restoration of nucleus pulposus function. However, so far there is no effective treatment for this purpose. The aim of the present study was to investigate the response of hAF cells to different combinations of GFs, and develop a protocol for efficient culture expansion. Methods hAF cells were harvested from degenerated disc tissues during surgical intervertebral disc removal, and hAF cells were expanded in a monolayer. The experiments were categorized based on different protocols with transforming growth factor (TGF-β1) and fibroblast growth factor (FGF-2) culture for 14 days: group 1 had no GFs (control group); group 2 received TGF-β1; group 3 received FGF-2; group 4 received both GFs; and group 5 (two-step) received both GFs for the first 10 days and TGF-β1 only for the next 4 days. Cell proliferation, collagen, and noncollagen extracellular matrix (ECM) production and genes expression were compared among these groups. Results At days 3, 7 and 10 of cultivation, groups 4 and 5 had significantly more cell numbers and faster cell proliferation rates than groups 1, 2, and 3. At 14 days of cultivation, significantly more cell numbers were observed in groups 3 and 4 than in group 5. The group 4 had the most cell numbers and the fastest proliferation rate at 14 days of cultivation. After normalization for cell numbers, group 5 (two-step) produced the most collagen and noncollagen ECM at 10 and 14 days of cultivation among the five groups. In group 5, ECM gene expression was significantly upregulated. High expression of matrix metalloproteinase-1 was upregulated with FGF-2 on the different days as compared to the other groups. Annulus fibrosus cell phenotypes were only marginally retained under the different protocols based on quantitative polymerase chain reaction results. Conclusion Taken together, the two-step protocol was the most efficient among these different protocols with the most abundant ECM production after normalization for cell numbers for culture expansion of hAF cells. The protocol may be useful in further cell therapy and tissue engineering approaches for disc regeneration.

Background RNA interference (RNAi) is a robust tool for inhibiting specific gene expression, but it is limited by the uncertain efficiency of siRNA or shRNA constructs. It has been shown that the overexpression of ARGONAUTE 2 (AGO2) protein increases silencing efficiency. However, the key elements required for AGO2-mediated enhancement of gene silencing in lentiviral vector has not been well studied. Results To explore the application of AGO2-based shRNA system in mammalian cells, we designed shRNA vectors targeting the EGFP reporter gene and evaluated the effects of various factors on silencing efficiency including stem length, loop sequence, antisense location as well as the ratio between AGO2 and shRNA. We found that 19 ~ 21-bp stem and 6- or 9-nt loop structure in the sense-loop-antisense (S-L-AS) orientation was an optimal design in the AGO2-shRNA system. Then, we constructed a single lentiviral vector co-expressing shRNA and AGO2 and demonstrated that the simultaneous expression of shRNA and AGO2 can achieve robust silencing of exogenous DsRed2 and endogenous ID1 and P65 genes. However, the titers of packaged lentivirus from constitutive expression of AGO2 vector were extremely low, severely limiting its broad application. For the first time, we demonstrated that the problem can be significantly improved by using the inducible expression of AGO2 lentiviral system. Conclusions We reported a novel lentiviral vector with an optimal design of shRNA and inducible AGO2 overexpression which provides a new tool for RNAi research.

Lysobacter arseniciresistens ZS79T is a highly arsenic-resistant,rod-shaped, motile, non-spore-forming, aerobic, Gram-negative bacterium. In this study, four Lysobacter type strains were sequenced and the genomic information of L. arseniciresistens ZS79T and the comparative genomics results of the Lysobacter strains were described. The draft genome sequence of the strain ZS79T consists of 3,086,721 bp and is distributed in 109 contigs. It has a G+C content of 69.5 % and contains 2,363 protein-coding genes including eight arsenic resistant genes. Electronic supplementary material The online version of this article (doi:10.1186/s40793-015-0070-5) contains supplementary material, which is available to authorized users.

To compare the clinical outcomes of external fixator (EF) and intramedullary nails (IN) in the treatment of open tibial fractures. We searched seven electronic databases (PubMed, MEDLINE, EMBASE, OVID, Cochrane library, CNKI, and CBM) for trials of tibial fracture fixation published from 1980 to 2013. The indicators including postoperative infection, malunion, nonunion, soft tissue injury, delayed healing, and healing time were used for quantitative outcome assessments. A total of nine trials involving 532 patients (EF, n = 253; IN, n = 279) with open tibia fractures were included in this meta-analysis. The results indicated that the patients undergoing IN had lower incidence of postoperative infection (risk radio [RR] = 3.85; 95% confidence intervals [CI], 2.67–5.54; P

Salmonella arizonae (also called Salmonella subgroup IIIa) is a Gram-negative, non-spore-forming, motile, rod-shaped, facultatively anaerobic bacterium. S. arizonae strain RKS2983 was isolated from a human in California, USA. S. arizonae lies somewhere between Salmonella subgroups I (human pathogens) and V (also called S. bongori; usually non-pathogenic to humans) and so is an ideal model organism for studies of bacterial evolution from non-human pathogen to human pathogens. We hence sequenced the genome of RKS2983 for clues of genomic events that might have led to the divergence and speciation of Salmonella into distinct lineages with diverse host ranges and pathogenic features. The 4,574,836 bp complete genome contains 4,203 protein-coding genes, 82 tRNA genes and 7 rRNA operons. This genome contains several characteristics not reported to date in Salmonella subgroup I or V and may provide information about the genetic divergence of Salmonella pathogens.