dNLR-Based Score Predicting Overall Survival Benefit for The Addition of Platinum-Based Chemotherapy to Pembrolizumab in Advanced NSCLC With PD-L1 Tumor Proportion Score ≥50%

Introduction: Both pembrolizumab (P) as a monotherapy or in combination with platinum-based chemotherapy (PCT) represent standard first-line treatment options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS)≥50%. No predictive biomarkers exist to guide treatment decisions.Methods: 423 consecutive patients with EGFR/ALK/ROS1-wild-type PD-L1 TPS≥50% aNSCLC receiving P (n = 302) or PCT (n = 121) as a first-line treatment were identified in the electronic databases of 5 Israeli cancer centers. Overall survival (OS, months [mo]) was assessed in correlation with blood biomarkers (BB: NLR, dNLR, PLR, SII, LIPI, ALI); a predictive score was developed.Results: In the propensity score matching analysis (n = 236; 118 patients in each group matched for age, sex and ECOG PS), mOS was 17.2mo (95% CI, 13.2-36.5) and 21.3mo (95% CI, 14.8-NR) in groups P and PCT, respectively (P = .44). In group P, NLR, dNLR, PLR, LIPI, and ALI significantly correlated with OS in uni- and multivariate COX regression analyses (P < .05), whereas in group PCT, none of the BB demonstrated a significant correlation. A predictive score was developed (each parameter receiving one point): age≥65, female sex, never-smoking status, adenocarcinoma histology, dNLR≥3. In patients with predictive score 3-5, OS was significantly longer with PCT as compared to P: mOS NR (95% CI, 15.3-NR) and 8.7mo (95% CI, 5.8-13.7) (P = .0005), while OS didn't differ significantly in patients with predictive score 0-2 (P = .61).Conclusion: With the limitations of the retrospective analysis, the proposed dNLR-based score appears to predict OS with P and PCT.     

黄芩素调控 NLRP3 / Caspase-1 通路对牙周炎大鼠牙槽骨吸收的影响

目的 探索黄芩素调控核苷酸结合寡聚化结构域样受体蛋白 3 ( nucleotide-binding oligomerization domain-like receptor protein 3, NLRP3) / 半胱氨酸天冬氨酸蛋白酶 1 ( cysteine aspartate protease 1, Caspase1) 通路对牙周炎大鼠牙槽骨吸收的影响。 方法 将 40 只牙周炎大鼠随机分为模型组、 黄芩素组、 激活剂 组、 黄芩素 + 激活剂组, 另取 10 只正常作为对照组。 检测大鼠釉牙骨质界到牙槽嵴顶 (CEJ-AC) 的距离、 血清中白细胞介素-6 (IL-6)、 转化生长因子-β (TGF-β) 含量以及牙周组织病理变化、 IL-6、 TGF-β 阳性 表达和 NLRP3、 Caspase-1 蛋白表达。 结果 模型组大鼠 CEJ-AC、 NLRP3、 Caspase-1、 IL-6、 TGF-β 水平及 阳性表达水平以及蛋白表达水平均升高 (P< 0. 05); 经黄芩素干预后, 各项指标均降低 (P< 0. 05); 引入 激活剂明显削弱了黄芩素对牙周炎大鼠的抗炎作用。 结论 黄芩素通过抑制 NLRP3 / Caspase-1 通路减轻炎性反应, 控制牙槽骨吸收。     

A lethal and rare cause of arthrogryposis: Glyt1 encephalopathy

Glycine encephalopathy with normal serum glycine (MIM #617301), also known as GLYT1 encephalopathy, is an extremely rare disorder caused by biallelic variants in SLC6A9 and characterised by facial dysmorphic features, skeletal findings including contractures, knee hyperextension, and joint dislocations and seizures. To date, only ten patients from five families have been reported and only two of them could survive until childhood. In this study, we report on a consanguineous Turkish couple with a history of six pregnancies with three habitual abortions and three postpartum exitus. While in three pregnancies the babies were born prematurely at 32nd gestational week by emergency ceserean section due to hydrops and fetal distress, the other pregnancy was medically terminated at 16th gestational week due to absent fetal heart activity. The product of all these three pregnancies exhibited similar phenotype including short neck, thoracic kyphosis, hypertrichosis, joint contractures and dislocations, hypertonia, knee hyperextension and facial dysmorphic features. Trio exome sequencing was performed prenatally during the last pregnancy and a novel VUS variant in SLC6A9 and a likely pathogenic variant in MTOR gene were detected. DNA isolation was performed from frozen muscle and adrenal tissue of previously autopsied fetuses with similar clinical features, and the same variants were confirmed in both of them. Our data suggest that SLC6A9 and MTOR variants may be responsible for this extremely lethal phenotype in this family.     

The role of urease in the acid stress response and fimbriae expression in Klebsiella pneumoniae CG43

Background/purposeTwo urease operons were identified in Klebsiella pneumoniae CG43, ure-1 and ure-2. This study investigates whether a differential regulation of the expression of ure-1 and ure-2 exists and how urease activity influences the acid stress response and expression of type 1 and type 3 fimbriae.MethodsThe ureA1 and ureA2 gene specific deletion mutants were constructed. Promoter activity was assessed using a LacZ reporter system. The sensitivity to acid stress was determined by assessing the survival after pH 2.5 treatment. The influence on type 1 and type 3 fimbriae expression was assessed using western blotting and mannose-sensitive yeast agglutination and biofilm formation assay, respectively.ResultsBacterial growth analysis in mM9-U or modified Stuart broth revealed that ure-1 was the principal urease system, and ure-2 had a negative effect on ure-1 activity. Deletion of the fur or nac gene had no apparent effect on the activity of P_ure1, P_ure2-1, and P_ure2-2. The P_ure2-2 activity was enhanced by deletion of the hns gene. ureA1 deletion increased acid stress sensitivity, whereas the deleting effect of ureA2 was notable without hns. Deletion of ureA1 or ureA2 significantly induced the expression of type 1 fimbriae but decreased MrkA production and biofilm formation.Conclusionure-1 is the primary expression system in K. pneumoniae CG43, while ure-2 is active in the absence of hns. Impairment of urease activity increases the sensitivity to acid stress, and the accumulation of urea induces the expression of type 1 fimbriae but represses type 3 fimbriae expression.     

Management of blood pressure disorders in individuals with spinal cord injury

Blood pressure regulation is impacted by a spinal cord injury (SCI) due to impaired descending sympathetic vascular control. Common blood pressure problems in the SCI population include persistently low blood pressure with bouts of orthostatic hypotension and autonomic dysreflexia, which are more prevalent in individuals with lesions above the sixth thoracic vertebral level; however, they may occur regardless of the neurological level of injury. Although blood pressure disorders adversely impact daily function and quality of life, most individuals with SCI do not acknowledge this association. Few pharmacological options have been rigorously tested for safety and efficacy to manage blood pressure disorders in the SCI population. Furthermore, clinical management of any one blood pressure disorder may adversely impact others, as such treatment is complicated and not often prioritized.     

Impact of age within younger populations on outcomes following cervical surgery in the ambulatory setting

ObjectiveTo determine the effect of age within the younger population seen at ambulatory surgical centers on patient-reported outcome measures (PROMs) after cervical spine surgery.MethodsPatients of age <65 years undergoing single-level anterior cervical discectomy and fusion (ACDF) or cervical disc replacement (CDR) were included. Patients were divided by mean age of initial population (46 years). PROMs included Patient-reported Outcome Measurement Information System Physical Function (PROMIS-PF), 12-Item Short-Form Physical Component Survey (SF-12 PCS), Visual Analog Scale (VAS) neck, VAS arm, Neck Disability Index (NDI) collected preoperatively and at postoperative time points up to 2 years.Results138 patients were included, with 66 patients <46 years. Both cohorts demonstrated improvement from preoperative baseline with regard to all studied PROMs at multiple time points postoperatively (p ≤ 0.042, all). Between groups, the older cohort demonstrated greater mean PROMIS-PF scores preoperatively and at 6 weeks (p ≤ 0.011, both), while VAS arm scores were lower in the older group at 1 year (p = 0.002), and NDI scores were lower in the older group at 6 weeks and 1 year (p < 0.027, both). Minimal Clinically Important Difference (MCID) achievement rates were greater in the younger group in PROMIS PF at 2 years (p = 0.002), and in the older group in VAS arm score at 1 year (p = 0.007).ConclusionBoth cohorts showed significant improvement at multiple postoperative time points for all PROMs. Between groups, the older group reported more favorable physical function, VAS arm, and NDI scores at several time points. However, MCID achievement rates only significantly differed in two PROMs at singular time points. Difference in age in patients <65 years likely does not significantly affect long-term outcomes after cervical spine surgery.