Alveolar osteonecrosis and tooth exfoliation following herpes zoster infection: A case report and review of the literature.

Tooth loss and osteonecrosis of the jaw are a serious and rare oral complications of herpes zoster infection, particularly in immunocompetent individuals. An immunocompetent 58-year-old male patient presented with a sudden exfoliation of almost all the teeth in his right mandible 2 days prior. Three weeks before this event, he had been diagnosed with herpes zoster infection, which led to irreversible necrosis on the right side of his mandible over 3 months. He was subsequently diagnosed with the osteonecrosis of the right mandible following herpes zoster infection and received aggressive treatment including medication, laser therapy and surgery. We present here our insights into the risk factors, differential diagnosis, pathogenesis and treatment options for this rare complication based on our case and latest literature review.

Ruixingdingia sedimenti gen. nov., sp. nov., a novel taxon within the family Paracoccaceae isolated from sediment of Qiantang River.

A Gram-stain-negative bacterium, designated LG-4T, was isolated from sediment of Qiantang River in Zhejiang Province, PR China. Cells were strictly aerobic, non-spore-forming, non-motile and short-rod-shaped (1.0-1.2 µm long and 0.7-0.8 µm wide). Growth occurred at 15-42 °C (optimum, 30 °C), at pH 5.0-9.0 (pH 7.0) and at 0-2.0 % (w/v) NaCl (optimum, 0.5 % NaCl). Strain LG-4T showed 95.75-96.90 % 16S rRNA gene sequence similarity to various type strains of the genera Tabrizicola, Pseudotabrizicola, Phaeovulum, Rhodobacter and Wagnerdoeblera of the family Paracoccaceae, and the most closely related strain was Tabrizicola soli ZQBWT (96.90 % similarity). The phylogenomic tree showed that strain LG-4T clustered in the family Paracoccaceae and was positioned outside of the clade composed of the genera Wagnerdoeblera and Falsigemmobacter. The average nucleotide identity and digital DNA-DNA hybridization values between strain LG-4T and the related type strains were in the range of 74.19-77.56 % and 16.70-25.80 %, respectively. The average amino acid identity (AAI) values between strain LG-4T and related type strains of the family Paracoccaceae were 60.94-69.73 %, which are below the genus boundary (70 %). The evolutionary distance (ED) values between LG-4T and the related genera of the family Paracoccaceae were 0.21-0.34, which are within the recommended standard (≥0.21-0.23) for defining a novel genus in the family Paracoccaceae. The predominant cellular fatty acids were C18 : 1 ω7c, C19 : 0 cyclo ω8c, C18 : 0 and C16 : 0, the isoprenoid quinone was Q-10, and the major polar lipids were phospholipid, phosphatidylglycerol, phosphatidylcholine, aminolipid and two unknown polar lipids. The genome size was 4.7 Mb with 68.6 mol% G+C content. On the basis of distinct phylogenetic relationships, low AAI values and high ED values, and differential phenotypic, physiological and biochemical characteristics, strain LG-4T represents a novel species of a new genus in the family Paracoccaceae, for which the name Ruixingdingia sedimenti gen. nov., sp. nov. is proposed. The type strain is LG-4T (=MCCC 1K08849T=KCTC 8136T).

Constitutive KCC2 Cell- and Synapse-Specifically Regulates NMDA Receptor Activity in the Spinal Cord.

K+-Cl- cotransporter-2 (KCC2) critically controls neuronal chloride homeostasis and maintains normal synaptic inhibition by GABA and glycine. Nerve injury diminishes synaptic inhibition in the spinal cord via KCC2 impairment. However, how KCC2 regulates nociceptive input to spinal excitatory and inhibitory neurons remains elusive. Here, we show that basal GABA reversal potentials were significantly more depolarized in vesicular GABA transporter (VGAT)-expressing inhibitory neurons than those in vesicular glutamate transporter-2 (VGluT2)-expressing excitatory neurons in spinal cords of male and female mice. Strikingly, inhibiting KCC2 with VU0463271 increased currents elicited by puff NMDA and the NMDAR-mediated frequency of mEPSCs in VGluT2, but not in VGAT, dorsal horn neurons. Notably, VU0463271 had no effect on EPSCs monosynaptically evoked from the dorsal root in VGluT2 neurons. Furthermore, VU0463271 augmented α2δ-1-NMDAR interactions and their protein levels in spinal cord synaptosomes. In Cacna2d1 KO mice, VU0463271 had no effect on puff NMDA currents or the mEPSC frequency in dorsal horn neurons. Disrupting α2δ-1-NMDAR interactions with α2δ-1 C-terminus mimicking peptide diminished VU0463271-induced potentiation in the mEPSC frequency and puff NMDA currents in VGluT2 neurons. Additionally, intrathecal injection of VU0463271 reduced mechanical and thermal thresholds in wild-type mice, but not in Cacna2d1 KO mice. VU0463271-induced pain hypersensitivity in mice was abrogated by co-treatment with the NMDAR antagonist, pregabalin (an α2δ-1 inhibitory ligand), or α2δ-1 C-terminus mimicking peptide. Our findings suggest that KCC2 controls presynaptic and postsynaptic NMDAR activity specifically in excitatory dorsal horn neurons. KCC2 impairment preferentially potentiates nociceptive transmission between spinal excitatory interneurons via α2δ-1-bound NMDARs.Significance statementImpaired function of potassium-chloride cotransporter-2 (KCC2), a key regulator of neuronal inhibition, in the spinal cord plays a major role in neuropathic pain. This study unveils that KCC2 controls spinal nociceptive synaptic strength via NMDA receptors in a cell type- and synapse type-specific manner. KCC2 inhibition preferentially augments presynaptic and postsynaptic NMDA receptor activity in spinal excitatory interneurons via α2δ-1 (previously known as a calcium channel subunit). Importantly, spinal KCC2 impairment triggers pain hypersensitivity through α2δ-1-coupled NMDA receptors. These findings pinpoint the cell and molecular substrates for the reciprocal relationship between spinal synaptic inhibition and excitation in chronic neuropathic pain. Targeting both KCC2 and α2δ-1­NMDA receptor complexes could be an effective strategy in managing neuropathic pain conditions.

CD4+ T cell calibration of antigen-presenting cells optimizes antiviral CD8+ T cell immunity.

Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-ß (IFNα/ß)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/ß or CD40 alone. These responses are critical for the acquisition of antiviral CD8+ T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.

Sphingomonas caeni sp. nov., a phenolic acid-degrading bacterium isolated from activated sludge.

A Gram-stain-negative, rod-shaped, polar flagellated or stalked and non-spore-forming bacterium, designated LB-2T, was isolated from activated sludge. Growth was observed at 20-30 °C (optimum 28 °C), pH 6.0-8.0 (optimum pH 7.0) and salinity of 0-0.5% (w/v; optimum 0.5%). Phylogenetic analysis based on the 16S rRNA gene indicated that strain LB-2T belongs to the genus Sphingomonas and showed the highest sequence similarity (96.7%) and less than 96.7% similarities to other type strains. The genome size of strain LB-2T was 4.10 Mb, with 66.8 mol% G + C content. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strains LB-2T and S. canadensis FWC47T were 77.8% and 21%, respectively. The predominant cellular fatty acids were summed feature 8 (C18:1ω7c and/or C18 : 1ω6c) and C16:0. The major polar lipids were aminolipid, glycolipid, sphingoglycolipid, phosphatidylcholine, phosphatidylglycerol, four unidentified lipids, glycophospholipid, phosphatidylethanolamine and diphosphatidylglycerol. The predominant respiratory quinone was Q-10 and the major polyamine was sym-homospermidine. On the basis of phenotypic, genotypic and phylogenetic evidences, strain LB-2T represents a novel species in the genus Sphingomonas, for which the name Sphingomonas caeni sp. nov. is proposed. The type strain is LB-2T (GDMCC 1.3630T = NBRC 115,102T).

Radiomics Can Distinguish Pediatric Supratentorial Embryonal Tumors, High-Grade Gliomas, and Ependymomas.

BACKGROUND AND PURPOSE: Pediatric supratentorial tumors such as embryonal tumors, high-grade gliomas, and ependymomas are difficult to distinguish by histopathology and imaging because of overlapping features. We applied machine learning to uncover MR imaging-based radiomics phenotypes that can differentiate these tumor types. MATERIALS AND METHODS: Our retrospective cohort of 231 patients from 7 participating institutions had 50 embryonal tumors, 127 high-grade gliomas, and 54 ependymomas. For each tumor volume, we extracted 900 Image Biomarker Standardization Initiative-based PyRadiomics features from T2-weighted and gadolinium-enhanced T1-weighted images. A reduced feature set was obtained by sparse regression analysis and was used as input for 6 candidate classifier models. Training and test sets were randomly allocated from the total cohort in a 75:25 ratio. RESULTS: The final classifier model for embryonal tumor-versus-high-grade gliomas identified 23 features with an area under the curve of 0.98; the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.85, 0.91, 0.79, 0.94, and 0.89, respectively. The classifier for embryonal tumor-versus-ependymomas identified 4 features with an area under the curve of 0.82; the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.93, 0.69, 0.76, 0.90, and 0.81, respectively. The classifier for high-grade gliomas-versus-ependymomas identified 35 features with an area under the curve of 0.96; the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 0.82, 0.94, 0.82, 0.94, and 0.91, respectively. CONCLUSIONS: In this multi-institutional study, we identified distinct radiomic phenotypes that distinguish pediatric supratentorial tumors, high-grade gliomas, and ependymomas with high accuracy. Incorporation of this technique in diagnostic algorithms can improve diagnosis, risk stratification, and treatment planning.

[Intravesical instillations for inflammatory and sensory chronic bladder diseases: Literature review and guide to clinical practice]. / Instillations endovésicales pour les cystopathies chroniques inflammatoires et douloureuses : revue de la littérature et guide de la pratique clinique.

INTRODUCTION: Inflammatory and sensory chronic bladder diseases have a significant impact on quality of life. These pathologies share alteration of the layer between urine and urothelium, making the use of topical agents appropriate. OBJECTIVES: Review the efficacy and tolerance of intravesical treatments for these pathologies. Give practical guidelines for the use of agents currently available in France. METHOD: A narrative review was performed in March 2021 using PubMed/MEDLINE, Google Scholar and the international guidelines. Pharmaceutical companies and pharmacies were interviewed. RESULTS: Although numerous molecules were tested over the last 5 decades, only dimethylsulfoxyde and glycosaminoglycans are available in France today. Results are promising: response rates are up to 95% and 84% respectively in bladder pain syndrome. In urinary tract infections, glycosaminoglycans could decrease annual number of cystitis by 2.56 (95% confidence interval (CI) -3.86, -1.26; P<0.001) and increase the time to first cystitis recurrence by 130 days (95% CI: 5.84 - 254.26; P=0.04). In radiation cystitis, results could be comparable to hyperbaric oxygen regarding pain and frequency of voiding (-1.31±1.3 visual analogic scale et -1.5±1.4 voiding per day, respectively, at 12 months, P<0.01). However, literature has a low level of evidence. CONCLUSION: Chronic bladder diseases have limited treatment options. Intravesical agents are a good alternative, although their cost is significant and their outcome uncertain.

Diagnosis and Management of Pediatric Hypereosinophilic Syndrome.

Hypereosinophilic syndrome (HES) is a diverse group of disorders characterized by peripheral blood eosinophilia of 1.5 × 109/L (1,500/µL) or greater with evidence of end-organ damage attributable to eosinophilia and no other cause of the end-organ damage. The HES is rare, especially in children. This review aims to provide best practices in diagnosis and treatment of HES in children, including how to differentiate between primary and secondary causes of hypereosinophilia; how to distinguish the differences in clinical presentation, treatment, and prognosis of HES in children and adults; and how to identify key steps in the evaluation and management of HES in children.

Panobinostat reverses HepaCAM gene expression and suppresses proliferation by increasing histone acetylation in prostate cancer.

Increased expression of histone deacetylases (HDACs) affiliated to the epigenetic regulation is common aberration in prostate cancer (PCa). We have confirmed that hepatocyte cell adhesion molecule (hepaCAM), acting as a tumor suppressor gene, is rarely expressed in PCa previously, However, the mechanisms of which is still unknown. The level of histone acetylation reportedly may involve anti-oncogene transcription and expression. In this study, we investigated the effect of panobinostat, the broad-spectrum histone deacetylases inhibitor, on PCa LNCaP and DU145 cell growth, and observed re-expression of hepaCAM when treated with panobinostat. We demonstrated that intranuclear acetylation of lys9 of histone H3 (Ac-H3K9) were increased, while that of both mRNA and protein of HDAC1, HDAC3, and HDAC4 were decreased when the treating concentration of panobinostat increased. We confirmed the relationship between histone acetylation and the expression of hepaCAM and AR in prostate cancer tissues. We also confirmed that panobinostat could overcome the resistance for androgen deprivation therapy (ADT). Further, we combined panobinostat with Ad-hepaCAM, which resulted in significantly increased antitumor activity and significant attenuation of the proliferation-associated genes CCND1 and PCNA compared to each single treatment. In conclusion, panobinostat may enhance the acetylation of lys9 of histone 3 and reverse the hepaCAM expression through its inhibitory effect on HDACs activity in PCa LNCaP and DU145 cells; Ad-hepaCAM combined with panobinostat may synergistically inhibit the growth of LNCaP and DU145 cells, via a potential mechanism associated with the down-regulation of the expression of CCND1 and PCNA. These findings suggest that this therapeutic strategy should be further developed in clinical trials.

[Impact of treatment compliance in chronic hepatitis B].

The incidence rate of chronic hepatitis B remains high in China. Antiviral therapy can significantly reduce the risk of progressive liver disease and hepatocellular carcinoma in patients with chronic hepatitis B. However, all current antiviral treatments can only inhibit HBV replication and not completely eliminate the hepatitis B virus, so antiviral therapy for chronic hepatitis B is probably a long-term or even lifelong treatment. Antiviral therapy compliance is essential for achieving long-term clinical benefits and preventing nucleot(s)ide drugs resistance. Herein, we analyzed the relevant factors of antiviral therapy compliance and their impact on CHB treatment and explored feasible programs that can improve compliance with nucleot(s)ide drug treatment by conducting a literature search using PubMed and Scopus with search terms including hepatitis B, compliance, nucleot(s)ide drugs, antiviral therapy, viral suppression, and drug resistance.

[Mechanism of TRIM27 promoting inflammatory response in lung cancer cells].

Objective: To investigate the mechanism of tripartite motif-containing 27 (TRIM27) expression promoting inflammatory response in non-small lung cancer cells. Methods: Ten cases of lung cancer tissues and their matched normal tissue (the distance was 5 cm of the tumor marginal) from patients underwent resection in the People's Hospital of Pingyang Hospital Affiliated to Wenzhou Medical University were collected. The expression of TRIM27 was identified by using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. TRIM27 knockdown experiment included negative control (NC(TRIM27)) group, TRIM27 short interfering RNA (siRNA) group, NC(TRIM27)+ TNF-α group and TRIM27 siRNA+ TNF-α group. Interlukin-6 (IL-6) knockdown experiment included NC(IL-6) group and IL-6 siRNA group. The protein expressions of TRIM27, TNFR1, TNFR2 and some TNFR related inflammation factors were verified by qRT-PCR and WB. Results: The expression levels of TRIM27 in NSCLC tissues of different stages (stage Ⅰ: 2.81±0.58, stage Ⅱ: 3.32±1.38, stage Ⅲ: 3.67±1.24) was higher than that in the adjacent normal tissues (1.01±0.15, 0.92±0.10 and 1.05±0.12, P<0.05). The expression levels of TRIM27 mRNA in NC(TRIM27) group and NC(TRIM27)+ TNF-α group were 0.94±0.12 and 1.67±0.03, and the expression levels of TRIM27 protein were 0.31±0.02 and 0.38±0.01, respectively (P<0.05). The expression levels of IL-6 mRNA in NC(TRIM27)+ TNF-α group and TRIM27 siRNA+ TNF-α group were 11.35±0.12 and 5.62±0.15, respectively, and the expression levels of VCAM-1 mRNA were 18.75±0.17 and 9.35±0.11, respectively. STAT3 mRNA expression levels were 16.54±0.10 and 8.12±0.10, respectively, with statistical significance (P<0.05). The expression levels of IL-6 mRNA in NC(IL-6) group and IL-6 siRNA group were 1.10±0.07 and 0.52±0.16, respectively, and the expression levels of STAT3 mRNA were 1.01±0.01 and 0.48±0.12, respectively. The expression levels of TRIM27 mRNA were 1.03±0.01 and 0.30±0.11, respectively, with statistical significance (P<0.05). Conclusion: The upregulation of TRIM27 in NSCLC tissue and cells promotes the expression of TNF-α, and may activate inflammatory response by regulating TNF-α-induced IL-6/STAT3 signaling pathway.

[Unrelated cord blood stem cell transplantation for high-risk/refractory childhood acute myeloid leukemia: a clinical analysis of 160 cases].

Objective: To retrospectively analyze the clinical outcomes of single unrelated cord blood transplantation (UCBT) in children with high risk and refractory acute myeloid leukemia (AML) . Methods: Between June 2008 and December 2018, a total of 160 consecutive pediatric patients with AML received single UCBT (excluding acute promyelocytic leukemia) . Myeloablative conditioning (MAC) regimen were applied. All patients received a combination of cyclosporine A (CsA) and mycophenolate mofetil (MMF) for the prophylaxis of graft -versus- host disease (GVHD) . Results: The cumulative incidence of neutrophil cells engraftment at day +42 and platelet recovery at day +120 was 95.0% (95% CI 90.0%-97.5%) at a median of 16 days after transplantation (range, 11-38 days) and 85.5% (95%CI 83.3%-93.4%) with a median time to recovery of 35 days (range, 13-158) , respectively. Incidence of grades Ⅱ-Ⅳ and Ⅲ-Ⅳ acute GVHD and chronic GVHD were 37.3% (95%CI 29.3%-45.2%) , 27.3% (95%CI 20.0%-35.0%) and 22.4% (95%CI 15.5%-28.7%) , respectively. The transplant-related mortality (TRM) at 360 day was 13.1% (95%CI 8.4%-18.9%) . The 5-year cumulative incidence of relapse was 13.8% (95%CI 8.5%-20.3%) . The 5-year disease-free survival (DFS) and overall survival (OS) were 71.7% (95%CI 62.7%-77.8%) and 72.2% (95%CI 64.1%-78.7%) , respectively. The 5-year GVHD and relapse free survival (GRFS) was 56.1% (95%CI 46.1%-64.9%) . The 5-year cumulative recurrence rates of CR1, CR2, and NR groups were 5.3%, 19.9%, and 30.9% (P=0.001) , and the 5-year OS rates were 79.9% (95%CI 70.3%-86.7%) , 71.1% (95%CI 50.4%-84.4%) and 52.9% (95%CI 33.0%-69.3%) (χ(2)=7.552, P=0.020) , respectively. Conclusions: For pediatric patients with high risk and refractory AML, UCBT is a safe and effective treatment option, and it is favorable to improve the survival rate in CR1 stage.

[Anatomical study and clinical application of in situ reduction and fixation of anterior medial fenestration approach of femoral head fracture].

Objectives: To explore the feasibility of anterior medial fenestration approach in situ reduction and fixation in the treatment of PipkinⅠ and Ⅱ femoral head fractures,and to explore the clinical effect of this operation. Methods: Hips of two anti-corrosion adult specimens treated with formalin were dissected, then anatomical structures and directional characteristics of anterior medial main muscles,ligaments,blood vessels and nerves were observed.The anterior medial fenestration approach was performed on bilateral hips of four fresh frozen specimens to determine pulling direction of stripped muscles and ligaments required during operation,and to observe and analyze vascular and nerve traction protection directions exposed in the approach.Determine extent of exposure to the approach and assess feasibility of this approach.The clinical data of 12 patients with Pipkin Ⅰ and Ⅱ femoral head fractures who underwent in situ reduction and fixation of anterior medial fenestration at Department of Orthopaedics,Affiliated Hospital of Chengdu University from February 2016 to April 2018 were retrospectively analyzed.There were 3 males and 9 females with an age of 48.5 years(range:37 to 59 years).There were 8 cases of Pipkin type Ⅰ and 4 cases of Pipkin type Ⅱ.The operation time,blood loss,fracture healing time,last Thompson-Epstein evaluation and Harris score were observed. Results: Anterior medial fenestration approach to expose the femoral head in 4 bilateral hips with a total of 8 sides of fresh frozen specimens.The upper boundary of observation fenestration was pubic body (anterior acetabulum),and the outer upper boundary was iliacus and psoas muscle.The lateral boundary is rectus femoris and femoral vessels,the lower boundary was transverse branch of the medial femoral circumflex artery and vein.The medial boundary was pubis muscle,short adductor muscle and long adductor muscle.Pubofemoral and iliofemoral ligament were seen in fenestration. Four quadrants in front of femoral head in fenestration can be seen after cutting switch capsule active hip joint. In 12 patients with femoral head fracture,the operation time was 107.5 minutes(range:90 to 135 minutes),and the intraoperative bleeding volume was 115.0 ml(range:85 to 150 ml).The patients were followed up for 18.6 months(range:12 to 28 months).The fracture healing time of 12 patients was 144.2 days(range:120 to 180 days).The curative effect was evaluated according to Thompson-Epstein standard at the last follow-up:excellent in 6 cases,good in 4 cases and fair in 2 cases.At the last follow-up,the Harris score of hip joints was 85.1(range:75 to 93). Conclusions: Anterior medial fenestration in situ reduction and fixation surgery is feasible for the treatment of Pipkin Ⅰ and Ⅱ femoral head fractures. The short and midterm follow-up reveal satisfactory effect.

[Current concerns and considerations regarding mesenchymal stem cells therapy in perplexing severe liver diseases].

Stem cells are type of cells that have unlimited self-renewal and multi-differentiation potential under specific conditions. Stem cell-based therapeutic techniques can provide new methods for the treatment of perplexing severe liver diseases. Umbilical cord mesenchymal stem cells are currently considered as ideal stem cells due to their low immunogenicity, convenient materials, abundant sources and advantage of no ethical controversy in the clinical treatment of diseases. Presently, there is a large number of basic and clinical application evidence, which suggests that mesenchymal stem cells can significantly improve the condition and outcome of end-stage liver diseases such as liver cirrhosis and liver failure, and its mechanism of action may include hepatocyte-like cells differentiation, immune function regulation, exosome secretion, etc. This paper briefly summarizes the current theories and clinical research status of mesenchymal stem cells application, as well as the therapeutic clinical trial issues and concerns that needs to be resolved during the perplexing severe liver diseases process.

[Establishment of an early risk prediction model for bloodstream infection and analysis of its predictive value in patients with extremely severe burns].

Objective: To establish an early prediction model for bloodstream infection in patients with extremely severe burns based on the screened independent risk factors of the infection, and to analyze its predictive value. Methods: A retrospective case-control study was conducted. From January 1, 2010 to December 31, 2019, 307 patients with extremely severe burns were admitted to the Department of Burns and Plastic Surgery of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medcine, including 251 males and 56 females, aged from 33 to 55 years. According to the occurrence of bloodstream infection, the patients were divided into non-bloodstream infection group (221 cases) and bloodstream infection group (86 cases). The gender, age, body mass index, outcome, length of hospital stay of patients were compared between the two groups, and the detection of bacteria in blood microbial culture of patients was analyzed in bloodstream infection group. The included 307 patients were divided into modeling group (219 cases) and validation group (88 cases) according to the random number table with a ratio of about 7∶3. The gender, age, body mass index, total burn area, full-thickness burn area, combination of inhalation injury, implementation of mechanical ventilation, days of mechanical ventilation, days of intensive care unit (ICU) stay, outcome, length of hospital stay, complication of bloodstream infection of patients were compared between the two groups. According to the occurrence of bloodstream infection, the patients in modeling group were divided into bloodstream infection subgroup (154 cases) and non-bloodstream infection subgroup (165 cases). The total burn area, full-thickness burn area, combination of inhalation injury, implementation of mechanical ventilation, days of mechanical ventilation, and days of ICU stay of patients were compared between the two subgroups. The above-mentioned data between two groups were statistically analyzed with one-way analysis of independent sample t test, chi-square test, and Mann-Whitney U test to screen out the factors with statistically significant differences in the subgroup univariate analysis of modeling group. The factors were used as variables, and binary multivariate logistic regression analysis was performed to screen out the independent risk factors of bloodstream infection in patients with extremely severe burns, based on which the prediction model for bloodstream infection in patients with extremely severe burns of modeling group was established. The receiver operating characteristic (ROC) curve of the prediction model predicting the risk of bloodstream infection of patients in modeling group was drawn, and the area under the ROC curve was calculated. The sensitivity, specificity, and the best prediction probability were calculated according to the Youden index. According to the occurrence of bloodstream infection, the patients in validation group were divided into bloodstream infection subgroup (21 cases) and non-bloodstream infection subgroup (67 cases). The prediction probability >the best prediction probability of model was used as the judgment standard of bloodstream infection. The prediction model was used to predict the occurrence of bloodstream infection of patients in the two subgroups of validation group, and the incidence, specificity, and sensitivity for predicting bloodstream infection were calculated. In addition, the ROC curve of the prediction model predicting the risk of bloodstream infection of patients in validation group was drawn, and the area under the ROC curve was calculated. Results: Compared with those of non-bloodstream infection group, the mortality of patients in bloodstream infection group was significantly higher (χ2=8.485, P<0.01), the length of hospital stay was significantly increased (Z=-3.003, P<0.01), but there was no significant change in gender, age, or body mass index (P>0.05). In patients of bloodstream infection group, 110 strains of bacteria were detected in blood microbial culture, among which Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii were the top three bacteria, accounting for 35.45% (39/110), 26.36% (29/110), and 13.64% (15/110), respectively. Gender, age, body mass index, total burn area, full-thickness burn area, proportion of combination of inhalation injury, proportion of implementation of mechanical ventilation, days of mechanical ventilation, days of ICU stay, outcome, length of hospital stay, and proportion of complication of bloodstream infection of patients were similar between modeling group and validation group (P>0.05). Compared with those of non-bloodstream infection subgroup in modeling group, the total burn area, full-thickness burn area, proportion of combination of inhalation injury, proportion of implementation of mechanical ventilation, days of mechanical ventilation, and days of ICU stay of patients in bloodstream infection subgroup were significantly increased (Z=-4.429, t=-4.045, χ2=7.845, 8.845, Z=-3.904, -4.134, P<0.01). Binary multivariate logistic regression analysis showed that total burn area, days of ICU stay, and combination of inhalation injury were the independent risk factors for bloodstream infection of patients in modeling group (odds ratio=1.031, 1.018, 2.871, 95% confidence interval=1.004-1.059, 1.006-1.030, 1.345-6.128, P<0.05 or P<0.01). In modeling group, the area under the ROC curve was 0.773 (95% confidence interval=0.708-0.838); the sensitivity was 64.6%, the specificity was 77.9%, and the best prediction probability was 0.335 when the Youden index was 0.425. The bloodstream infection incidence of patients predicted by the prediction model in validation group was 27.27% (24/88), with specificity of 82.09% (55/67) and sensitivity of 57.14% (12/21). The area under the ROC curve in validation group was 0.759 (95% confidence interval=0.637-0.882). Conclusions: The total burn area, days of ICU stay, and combination of inhalation injury are the risk factors of bloodstream infection in patients with extremely severe burns. The early prediction model for bloodstream infection risk in patients with extremely severe burns based on these factors has certain predictive value for burn centers with relatively stable treatment methods and bacterial epidemiology.

A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer.

INTRODUCTION: MEK inhibition is a potential therapeutic strategy in non-small cell lung cancer (NSCLC). This phase I study evaluates the MEK inhibitor binimetinib plus carboplatin and pemetrexed in stage IV non-squamous NSCLC patients (NCT02185690). METHODS: A standard 3 + 3 dose-escalation design was used. Binimetinib 30 mg BID (dose level 1 [DL1]) or 45 mg BID (dose level 2 [DL2]) was given with standard doses of carboplatin and pemetrexed using an intermittent dosing schedule. The primary outcome was determination of the recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomes included efficacy, pharmacokinetics, and an exploratory analysis of response based on mutation subtype. RESULTS: Thirteen patients (6 DL1, 7 DL2) were enrolled: 7 KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg BID. Eight patients (61.5%) had grade 3/4 adverse events, with dose limiting toxicities in 2 patients at DL2. Twelve patients were evaluated for response, with an investigator-assessed objective response rate (ORR) of 50% (95% CI 21.1%-78.9%; ORR 33.3% by independent-review, IR), and disease control rate 83.3% (95% CI 51.6%-97.9%). Median progression free survival (PFS) was 4.5 months (95% CI 2.6 months-NA), with a 6-month and 12-month PFS rate of 38.5% (95% CI 19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 25% in KRAS/NRAS wild-type patients. In MAP2K1-mutated patients, the ORR was 42.8%. CONCLUSION: The addition of binimetinib to carboplatin and pemetrexed appears to have manageable toxicity with evidence of activity in advanced non-squamous NSCLC.

Excess mortality and life-years lost in people with bipolar disorder: an 11-year population-based cohort study.

AIMS: Bipolar disorder is associated with premature mortality, but evidence is mostly derived from Western countries. There has been no research evaluating shortened lifespan in bipolar disorder using life-years lost (LYLs), which is a recently developed mortality metric taking into account illness onset for life expectancy estimation. The current study aimed to examine the extent of premature mortality in bipolar disorder patients relative to the general population in Hong Kong (HK) in terms of standardised mortality ratio (SMR) and excess LYLs, and changes of mortality rate over time. METHODS: This population-based cohort study investigated excess mortality in 12 556 bipolar disorder patients between 2008 and 2018, by estimating all-cause and cause-specific SMRs, and LYLs. Trends in annual SMRs over the 11-year study period were assessed. Study data were retrieved from a territory-wide medical-record database of HK public healthcare services. RESULTS: Patients had higher all-cause [SMR: 2.60 (95% CI: 2.45-2.76)], natural-cause [SMR: 1.90 (95% CI: 1.76-2.05)] and unnatural-cause [SMR: 8.63 (95% CI: 7.34-10.03)] mortality rates than the general population. Respiratory diseases, cardiovascular diseases and cancers accounted for the majority of deaths. Men and women with bipolar disorder had 6.78 (95% CI: 6.00-7.84) years and 7.35 (95% CI: 6.75-8.06) years of excess LYLs, respectively. The overall mortality gap remained similar over time, albeit slightly improved in men with bipolar disorder. CONCLUSIONS: Bipolar disorder is associated with increased premature mortality and substantially reduced lifespan in a predominantly Chinese population, with excess deaths mainly attributed to natural causes. Persistent mortality gap underscores an urgent need for targeted interventions to improve physical health of patients with bipolar disorder.

Expression of tricellular tight junction proteins and the paracellular macromolecule barrier are recovered in remission of ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) has a relapsing and remitting pattern, wherein the underlying mechanisms of the relapse might involve an enhanced uptake of luminal antigens which stimulate the immune response. The tricellular tight junction protein, tricellulin, takes charge of preventing paracellular passage of macromolecules. It is characterized by downregulated expression in active UC and its correct localization is regulated by angulins. We thus analyzed the tricellulin and angulin expression as well as intestinal barrier function and aimed to determine the role of tricellulin in the mechanisms of relapse. METHODS: Colon biopsies were collected from controls and UC patients who underwent colonoscopy at the central endoscopy department of Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin. Remission of UC was defined basing on the clinical appearance and a normal Mayo endoscopic subscore. Intestinal barrier function was evaluated by electrophysiological and paracellular flux measurements on biopsies mounted in Ussing chambers. RESULTS: The downregulated tricellulin expression in active UC was recovered in remission UC to control values. Likewise, angulins were in remission UC at the same levels as in controls. Also, the epithelial resistance which was decreased in active UC was restored in remission to the same range as in controls, along with the unaltered paracellular permeabilities for fluorescein and FITC-dextran 4 kDa. CONCLUSIONS: In remission of UC, tricellulin expression level as well as intestinal barrier functions were restored to normal, after they were impaired in active UC. This points toward a re-sealing of the impaired tricellular paracellular pathway and abated uptake of antigens to normal rates in remission of UC.

Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature.

Brain metastases (BMs) are the most common intracranial malignancy with poor prognosis. Patients with intracranial tumors are at greater risk for thrombotic complications and intracranial hemorrhage. Rivaroxaban is a potent oral anticoagulant with the high selectivity of direct factor Xa inhibition. The incidence and severity of rivaroxaban-triggered intratumoral hemorrhage (ITH) in patients with BMs remain unknown. A 57-year-old woman was diagnosed with multiple lung, bone, and BMs from unknown primary cancer origin, and refused any invasive procedures to confirm tumor pathology. However, this patient had a relatively favorable outcome after treating with cabozantinib, an inhibitor of multiple tyrosine kinases. The patient survived over 2 years and developed deep vein thrombosis of right lower limb. Oral rivaroxaban was prescribed, and the multifocal catastrophic ITH was encountered after 1 week. The last head computed tomography imaging revealed a rare but typical image of diffuse hemorrhagic metastases. Hemorrhagic-prone BMs, therapeutic rivaroxaban, and cabozantinib treatment increase risks to develop ITH. In this case rivaroxaban was the trigger to this terminal event. This case is a miserable lesson and keeps reminding us to stay vigilant in clinical practice even when there is a potential benefit for anticoagulation in such population.