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OBJECTIVE This study was designed to assess how postoperative opioid prescription dosage could affect patient-reported outcomes after elective spine surgery. METHODS Patients enrolled in the Michigan Spine Surgery Improvement Collaborative (MSSIC) from January 2020 to September 2021 were included in this study. Opioid prescriptions at discharge were converted to total morphine milligram equivalents (MME). A reference value of 225 MME per week was used as a cutoff. Patients were divided into two cohorts based on prescribed total MME: ≤ 225 MME and > 225 MME. Primary outcomes included patient satisfaction, return to work status after surgery, and whether improvement of the minimal clinically important difference (MCID) of the Patient-Reported Outcomes Measurement Information System 4-question short form for physical function (PROMIS PF) and EQ-5D was met. Generalized estimated equations were used for multivariate analysis. RESULTS Regression analysis revealed that patients who had postoperative opioids prescribed with > 225 MME were less likely to be satisfied with surgery (adjusted OR [aOR] 0.81) and achieve PROMIS PF MCID (aOR 0.88). They were also more likely to be opioid dependent at 90 days after elective spine surgery (aOR 1.56). CONCLUSIONS The opioid epidemic is a serious threat to national public health, and spine surgeons must practice conscientious postoperative opioid prescribing to achieve adequate pain control. The authors’ analysis illustrates that a postoperative opioid prescription of 225 MME or less is associated with improved patient satisfaction, greater improvement in physical function, and decreased opioid dependence compared with those who had > 225 MME prescribed.

PURPOSE Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF). METHODS We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape. RESULTS IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients ( P < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P < .0001) and who should therefore be considered for experimental agents. CONCLUSION The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.

A simple stability-indicating reversed-phase high-performance liquid chromatography method has been developed for determination of elobixibat in presence of its potential impurities and degradation products. The chromatographic separation was carried on a Thermo scientific Base Deactivated Silica BDS Hypersil-C18 (150 × 4.6 mm; 5 μm) column using a mobile phase of acetonitrile and phosphate buffer (25 mM, pH 2.5) in a ratio of (70:30, v/v). The experimental conditions were accurately investigated, and the method was validated according to ICH guidelines Q2 (R1). The drug was subjected to various stress conditions including acidic, basic, oxidative, and photolytic conditions. The method successfully separates the drug from the three reported impurities and different degradants. The method was also successfully applied for the determination of elobixibat in laboratory prepared tablets (5.0 mg). Analysis shows no interference from excipients and degradation products. The method was also applied for performing in vitro dissolution testing of elobixibat laboratory prepared tablets. Since elobixibat is recently introduced into the market, there are no previous stability studies and no reported analytical methods for its determination. Thus, this study presents a validated and selective method that can be effectively employed in routine quality control studies.

Cancer cells display DNA hypermethylation at specific CpG islands in comparison with their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T cells and that display a reciprocal association with H3K27me3 binding. In addition, we reveal that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in preleukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent decitabine. Altogether, we provide conceptual evidence for the involvement of a preleukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.Significance:We developed a DNA methylation signature that reveals the epigenetic history of thymocytes during T-cell transformation. This human signature was recapitulated by murine self-renewing preleukemic thymocytes that build an age-related CpG island hypermethylation phenotype, providing conceptual evidence for the involvement of a preleukemic thymic phase in human T-cell leukemia.This article is highlighted in the In This Issue feature, p. 215

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Loss-of-function mutations of EZH2, the enzymatic component of PRC2, have been associated with poor outcome and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL). Using isogenic T-ALL cells, with and without CRISPR/Cas9–induced EZH2-inactivating mutations, we performed a cell-based synthetic lethal drug screen. EZH2-deficient cells exhibited increased sensitivity to structurally diverse inhibitors of CHK1, an interaction that could be validated genetically. Furthermore, small-molecule inhibition of CHK1 had efficacy in delaying tumor progression in isogenic EZH2-deficient, but not EZH2 wild-type, T-ALL cells in vivo, as well as in a primary cell model of PRC2-mutant ALL. Mechanistically, EZH2 deficiency resulted in a gene-expression signature of immature T-ALL cells, marked transcriptional upregulation of MYCN, increased replication stress, and enhanced dependency on CHK1 for cell survival. Finally, we demonstrate this phenotype is mediated through derepression of a distal PRC2-regulated MYCN enhancer. In conclusion, we highlight a novel and clinically exploitable pathway in high-risk EZH2-mutated T-ALL.Significance:Loss-of-function mutations of PRC2 genes are associated with chemotherapy resistance in T-ALL, yet no specific therapy for this aggressive subtype is currently clinically available. Our work demonstrates that loss of EZH2 activity leads to MYCN-driven replication stress, resulting in increased sensitivity to CHK1 inhibition, a finding with immediate clinical relevance.This article is highlighted in the In This Issue feature, p. 890

Supplementary Table 2: Cell viability data from the small-molecule drug screening in EZH2-WT and EZH2-KO1 cells (related to Fig. 1)

Supplementary Table 3: Mutations identified by exome sequencing in Liu et al., 2017 T-ALL cohort (related to Fig. 5G)

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Supplementary Table 1: List of the main targets and number of probes included in the small-molecule inhibitors library (related to Fig. 1)

Supplementary information provided in this work.

This work presented a novel racemic imprinting process employing the chiral properties of chitosan monomer. The preparation of racemic ketoprofen (RS-KTP) imprinted polymer (RS-MIP) was conducted using glutaraldehyde as a crosslinker. The nature of elution solvent affected the % desorption ratio suggesting a heterogenous nature of the formed binding sites. Good imprinting was indicated by an imprinting factor of 3.50 for S-KTP. The enantioselectivity of the RS-MIP was indicated by enantioselectivity coefficient of 2.31 and % enantiomeric excess (%ee) of 28.55%. A SPE cartridge packed with RS-MIP enabled resolution of RS-KTP using gradient elution solvent system. Scatchard plot revealed two binding sites types of different affinity towards S-KTP and density observed for the RS-MIP. The binding capacity of RS-MIP showed observed dependence on the % ee of S-KTP indicating its enantioselectivity. The success of using racemic template for the preparation of enantioselective MIP brings a new possibility to achieve enantioseparation of racemic mixtures having very expensive or unavailable pure enantiomers.

Background: Favipiravir is an antiviral drug that was recently approved for the management of COVID-19 infection. Aim: This work aimed to develop a new method, using sugaring-out induced homogeneous liquid–liquid microextraction followed by HPLC/UV for the determination of favipiravir in human plasma. Materials & methods: The optimum extraction conditions were attained using 500 μl of tetrahydrofuran as an extractant and 1400 mg of fructose as a phase-separating agent. Results: The developed method was validated according to the US FDA bioanalytical guidelines and was found linear in the range of 25-80,000 ng/ml with a correlation coefficient of 0.999. Conclusion: These results showed that the developed method was simple, easy, valid and adequately sensitive for determination of favipiravir in plasma for bioequivalence studies.

Purpose To evaluate the pan-immune-inflammation value (PIV) and systemic immune-inflammation index (SII) in patients with cutaneous melanoma (CM) under immune checkpoint inhibitor (ICI) therapy. Methods PIV and SII were calculated before the start of ICI therapy and at time of progression/death in patients with metastatic CM (stage III/IV). Sex–age-matched CM patients in stage I/II and healthy subjects (HC) served as controls. Results The median PIV of stage III/IV patients was significantly (P = 0.0011) higher than in stage I/II patients and HC. SII was significantly (P = 0.00044) lower in HC than in CM patients. At baseline, PIV and SII did significantly correlate with lactate dehydrogenase (P = 0.045/0.017). However, ROC curve statistics revealed that SII and PIV were not significantly associated with clinical parameters, including best response to ICI treatment (P = 0.87/0.64), progression-free survival (P = 0.73/0.91), and melanoma-specific survival (P = 0.13/0.17). Moreover, there were no significant changes of PIV and SII from baseline to progression/death (P = 0.38/0.52). Conclusions Even though both immune-inflammation biomarkers showed some power to differentiate between CM stages and HC, respectively, PIV and SII seem not to be significant predictors for clinical outcome measures of CM patients under ICI therapy.

This article presents a comprehensive treatment to the subject of designing ridge waveguide radial combiners. A theoretical framework for the design process is first presented paving the way to a straightforward design procedure for radial combiners with both moderate and very wide bandwidths (BWs) realized in ridge waveguides. Two types of ridge waveguide radial combiners are presented, one with linearly tapered ridged sections and the other with staircase-like ridged sections. The methodology to design the radial combiner is presented. It starts with designing the individual ridge waveguide input ports, and then designing an equivalent transformer section that provides matching between the individual ridge waveguide ports and a common coaxial line output port. Design considerations for the different cross sections make it possible to achieve the required impedance levels for good matching across wide BWs. Three complete design examples are presented. Two proof-of-concept prototypes were designed, simulated, fabricated, and tested demonstrating excellent measured results without any tuning.

Google Trends has been extensively used in different sectors from finance to tourism, the economy, fashion, the fun industry, the oil trade, and healthcare. This scoping review aims to summarize the role of Google Trends as a monitoring and a predicting tool in the COVID-19 pandemic. Inclusion criteria for this scoping review were original English-language peer-reviewed research articles on the COVID-19 pandemic conducted in 2020 using Google Trends as a search tool. Articles that were in a language other than English, were only in abstract form, or did not discuss the role of Google Trends during the COVID-19 pandemic were excluded. According to these criteria, a total of 81 studies were included to cover the period of the first year after the emergence of the crisis. Google Trends can potentially help health authorities to plan and control pandemics earlier and to decrease the risk of infection among people.