Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus-associated oropharyngeal cancer.

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.

Efficacy of transdermal buprenorphine patch for managing withdrawal symptoms in patients with cancer physically dependent on prescription opioids.

BACKGROUND: The physical dependence on prescription opioids among cancer survivors remains an under-investigated area, with a scarcity of well-designed prospective studies. METHODS: This single-arm, phase-2 clinical trial in Korea assessed the efficacy and safety of a transdermal buprenorphine patch (TBP) in managing physical dependence on prescription opioids in cancer survivors, as confirmed through the DSM-5 criteria or psychiatric consultation for opioid withdrawal. This study involved a 4-phase treatment protocol of screening, induction/stabilization, discontinuation, and monitoring. The primary outcome was the rate of successful opioid discontinuation, as measured by a negative urine-drug screening at 8 weeks. Key secondary outcomes included the resumption of prescribed opioids, changes in both the Clinical Opioid Withdrawal Scale (COWS) and morphine equivalent daily dose (MEDD), and assessments related to the psychological and physiological aspects of dependence and safety. RESULTS: Thirty-one participants were enrolled. In the intention-to-treat population, the success rate of opioid discontinuation was 58%, with only 2 participants experiencing a resumption of prescribed opioids. Significant reductions were observed in MEDD, which decreased from 98 to 26 mg/day (P < .001), and COWS scores, which decreased from 5.5 to 2.8 (P < .001). Desire to use opioids reduced from 7.0 to 3.0 on a 10-point numeric rating scale (P < .001). Toxicities related to TBP were mild and manageable, without severe precipitated withdrawal symptoms. CONCLUSION: TBP may be considered as an alternative therapeutic option in cancer survivors physically dependent on prescription opioids, especially where sublingual formulations are unavailable.

Clinical implication of megestrol acetate in metastatic gastric cancer: a big data analysis from Health Insurance Review and Assessment (HIRA) database.

OBJECTIVE: Megestrol acetate (MA) is used to manage anorexia and cachexia in patients with advanced cancer. This study investigated the prescription patterns of MA in patients with metastatic gastric cancer, as well as evaluated its impact on survival outcomes and the incidence of venous thromboembolism (VTE). METHODS: A Health Insurance Review and Assessment (HIRA) service database was used to investigate differences in baseline characteristics, survival, and the incidence of VTE according to MA prescription patterns (i.e., prescription vs. no prescription) in patients diagnosed with metastatic gastric cancer from July 2014 to December 2015. RESULTS: A total of 1938 patients were included in this study. In total, 65% of the patients were prescribed MA. Older age, treatment in tertiary hospitals, and palliative chemotherapy were statistically significant predictive factors for MA prescription. Continuous prescription of MA was observed in 37% of patients. There was no statistically significant difference in survival between the MA and non-MA prescription groups on multivariate analysis. Among the 1427 patients included in the analysis for VTE incidence, 4.3% and 2.9% were diagnosed with VTE during the follow-up period in the MA and non-MA prescription groups, respectively. However, there was no statistically significant difference in VTE diagnosis between the groups on multivariate analysis. CONCLUSION: MA is commonly prescribed for metastatic gastric cancer, especially in elderly patients and those undergoing palliative chemotherapy, without significantly affecting survival or VTE risk.

Information processing in the dorsal pathway: from "where" to "what we do with it".

Visual processing in the brain has been understood as the ventral and dorsal pathways processing "what" and "where" information, respectively. Mocz et al. (Mocz V, Vaziri-Pashkam M, Chun M, Xu Y. J Cogn Neurosci 34: 2406-2435, 2022), however, report that the two pathways code object features in a parallel manner. These results support that information processing in the dorsal pathway is not strictly limited to "where" and that the two pathways work in parallel to process task-relevant information ("what we do with it").

Evaluation of a biotin-based surrogate virus neutralization test for detecting postvaccination antibodies against SARS-CoV-2 variants in sera.

A severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) surrogate virus neutralization test (sVNT) was used to determine the degree of inhibition of binding between human angiotensin converting enzyme 2 (hACE2) and the receptor binding domain (RBD) of spike protein by neutralizing antibodies in a biosafety level 2 facility. Here, to improve the sensitivity and specificity of the commercial sVNT, we developed a new biotin based sVNT using biotinylated RBD and HRP conjugated streptavidin instead of HRP conjugated RBD for direct detection in an ELISA assay that strongly correlated to the FDA approved cPass sVNT commercial kit (R2 = 0.8521) and pseudo virus neutralization test (R2 = 0.9006) (pVNT). The biotin based sVNT was evaluated in 535 postvaccination serum samples corresponding to second and third boosts of AZD1222 and BNT162b2 vaccines of the wild type strain. We confirmed that the neutralizing antibodies against SARS-CoV-2 variants in second vaccination sera decreased after a median of 141.5 days. Furthermore, vaccination sera from BNT162b2-BNT162b2 vaccines maintained neutralizing antibodies for longer than those of AZD1222 only vaccination. In addition, both vaccines maintained high neutralizing antibodies in third vaccination sera against Omicron BA.2 after a median of 27 days, but neutralizing antibodies significantly decreased after a median of 141.5 days. Along with the cPass sVNT commercial kit, biotin based sVNTs may also be suitable for specifically detecting neutralizing antibodies against multiple SARS-CoV-2 variants; however, to initially monitor the neutralizing antibodies in vaccinated sera using high throughput screening, conventional PRNT could be replaced by sVNT to circumvent the inconvenience of a long test time.

Prognostic impact of pretreatment skeletal muscle index and CONUT score in diffuse large B-cell Lymphoma.

BACKGROUND: Although the prognostic value of the Controlling Nutritional Status (CONUT) score in diffuse large B-cell lymphoma (DLBCL) has been reported in several previous studies, its clinical relevance for the presence of sarcopenia has not been assessed. METHODS: In this study, 305 DLBCL patients were reviewed. They were categorized into normal/mild (n = 219) and moderate/severe (n = 86) CONUT groups. Sarcopenia was assessed using the L3-skeletal muscle index measured by baseline computed tomography imaging. Based on CONUT score and sarcopenia, patients were grouped: A (normal/mild CONUT and no sarcopenia), B (either moderate/severe CONUT or sarcopenia, but not both), and C (both moderate/severe CONUT and sarcopenia). RESULTS: The moderate/severe CONUT group showed higher rates of ≥ grade 3 febrile neutropenia, thrombocytopenia, non-hematologic toxicities, and early treatment discontinuation not related to disease progression, compared to the normal/mild CONUT group. The moderate/severe CONUT group had a lower complete response rate (58.1% vs. 80.8%) and shorter median overall survival (18.5 vs. 162.6 months) than the normal/mild group. Group C had the poorest prognosis with a median survival of 8.6 months, while groups A and B showed better outcomes (not reached and 60.1 months, respectively). Combining CONUT score and sarcopenia improved the predictive accuracy of the Cox regression model (C-index: 0.763), compared to the performance of using either CONUT score (C-index: 0.754) or sarcopenia alone (C-index: 0.755). CONCLUSIONS: In conclusion, the moderate/severe CONUT group exhibited treatment intolerance, lower response, and poor prognosis. Additionally, combining CONUT score and sarcopenia enhanced predictive accuracy for survival outcomes compared to individual variables.

Establishment of multicenter COVID-19 therapeutics preclinical test system in Republic of Korea.

Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows: 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.

A Simple New Technique to Peel Epiretinal Membrane Without Removing Silicone Oil.

PURPOSE: To introduce a new surgical technique that can keep constant intraocular pressure of the eyeball during peeling epiretinal membrane under silicone oil status. METHODS: A viscoelastic agent was injected into the air pump of the constellation system via the metal tip. This procedure offers a buffer zone to keep constant pressure within the eyeball without disturbing the surgical field by an air bubble. RESULTS: Three cases were performed efficiently (15 ± 5 minutes) under this technique with improvement in anatomical feature and visual function after the surgery. CONCLUSION: Using this simple yet important technique can provide us the constant intraocular pressure without hypotony and avoid the traditional complicated procedures.

Chemical hazard of robotic hull in-water cleaning discharge on coastal embryonic fish.

In-water cleaning (IWC) involves the removal of biofilms and foulants from the hull of a ship using brush or water jet. During IWC, several factors associated with the harmful chemical contaminants release to the marine environment, which can create "hotspots" of chemical contamination in coastal areas. To elucidate the potential toxic effects of IWC discharge, we investigated developmental toxicity in embryonic flounder, which are sensitive life stage to chemical exposure. Zinc and copper were the dominant metals, while zinc pyrithione was the most abundant biocide associated with IWC discharge in two remotely operated IWC. Discharge from IWC carried by both remotely operated vehicles (ROVs) produced developmental malformations including pericardial edema, spinal curvature, and tail-fin defects. In an analyses of differential gene expression profiles (fold-change of genes with a cutoff < 0.05) as assessed by high-throughput RNA sequencing, genes associated with muscle development were commonly and significantly changed. The gene ontology (GO) of embryos exposed to IWC discharge from ROV A activities highly enriched muscle and heart development, while cell signaling and transport were evident in embryos exposed to IWC discharge of ROV B. We analyzed the gene network by significant GO terms. In the network, TTN, MYOM1, CASP3, and CDH2 genes appeared to be key regulators of the toxic effects on muscle development. In embryos exposed to ROV B discharge, HSPG2, VEGFA, and TNF genes related to the nervous system pathway were affected. These results shed light on the potential impacts of muscle and nervous system development in non-target coastal organisms exposed to contaminants found in IWC discharge.

A comparison of conceptual frameworks to examine health inequities in End-of-Life care.

AIMS: To discuss existing conceptual frameworks that can be applied to the examination of health inequities in end-of-life care and related health outcomes. We used the Fawcett and Desanto-Madeya evaluation technique modified by the National Institute on Minority Health and Health Disparities Research Framework to include individual, interpersonal, community, and societal levels of influence. DESIGN: Discussion paper. DATA SOURCES: We performed a systematic review of PubMed, CINAHL and Embase for conceptual frameworks of health inequities in end-of-life care and health outcomes published as of February 2022. IMPLICATIONS FOR NURSING: There is a strong need for research that can address multiple factors influencing end-of-life care inequities and health outcomes. To mitigate the complex nature of social determinants of health and structural inequities, researchers, clinicians, educators and administrators should have solid conceptualizations of these multi-level factors. Based on sound and comprehensive frameworks, nurses with interdisciplinary partnerships can promote health equity with a broader health care scope through addressing social determinants of health. CONCLUSION: We identified and reviewed three frameworks. We concluded all three frameworks have the potential for use in the examination of health inequities in end-of-life care and health outcomes. However, the Conceptual Framework of Minority Access to End-of-Life Care was more applicable to diverse studies and settings when adapted to include fundamental characteristics such as sex and gender. IMPACT: Despite the substantial rise in end-of-life care delivery, health inequities persist in end-of-life care access and utilization. Though some studies have been conducted to promote health equity by addressing social determinants of health, progress is hampered by their complex and multi-faceted nature. Through a concrete conceptual framework, researchers can comprehensively examine multi-level factors influencing health inequities in end-of-life care. NO PATIENT OR PUBLIC CONTRIBUTION: This discussion paper focused on reviewing existing evidence.

Naegleria fowleri Extracellular Vesicles Induce Proinflammatory Immune Responses in BV-2 Microglial Cells.

Extracellular vesicles (EVs) of protozoan parasites have diverse biological functions that are essential for parasite survival and host-parasite interactions. In this study, we characterized the functional properties of EVs from Naegleria fowleri, a pathogenic amoeba that causes a fatal brain infection called primary amoebic meningoencephalitis (PAM). N. fowleri EVs (NfEVs) have been shown to be internalized by host cells such as C6 glial cells and BV-2 microglial cells without causing direct cell death, indicating their potential roles in modulating host cell functions. NfEVs induced increased expression of proinflammatory cytokines and chemokines such as TNF-α, IL-1α, IL-1ß, IL-6, IL-17, IFN-γ, MIP-1α, and MIP-2 in BV-2 microglial cells; these increases were initiated via MyD88-dependent TLR-2/TLR-4. The production levels of proinflammatory cytokines and chemokines in NfEVs-stimulated BV-2 microglial cells were effectively downregulated by inhibitors of MAPK, NF-κB, or JAK-STAT. Phosphorylation levels of JNK, p38, ERK, p65, JAK-1, and STAT3 were increased in NfEVs-stimulated BV-2 microglial cells but were effectively suppressed by each corresponding inhibitor. These results suggest that NfEVs could induce proinflammatory immune responses in BV-2 microglial cells via the NF-κB-dependent MAPK and JAK-STAT signaling pathways. Taken together, these findings suggest that NfEVs are pathogenic factors involved in the contact-independent pathogenic mechanisms of N. fowleri by inducing proinflammatory immune responses in BV-2 microglial cells, further contributing to deleterious inflammation in infected foci by activating subsequent inflammation cascades in other brain cells.

Expression, Purification, and Characterization of Plasmodium vivax Lactate Dehydrogenase from Bacteria without Codon Optimization.

Plasmodium vivax is the most widespread cause of malaria, especially in subtropical and temperate regions such as Asia-Pacific and America. P. vivax lactate dehydrogenase (PvLDH), an essential enzyme in the glycolytic pathway, is required for the development and reproduction of the parasite. Thus, LDH from these parasites has garnered attention as a diagnostic biomarker for malaria and as a potential molecular target for developing antimalarial drugs. In this study, we prepared a transformed Escherichia coli strain for the overexpression of PvLDH without codon optimization. We introduced this recombinant plasmid DNA prepared by insertion of the PvLDH gene in the pET-21a(+) expression vector, into the Rosetta(DE3), an E. coli strain suitable for eukaryotic protein expression. The time, temperature, and inducer concentration for PvLDH expression from this E. coli Rosetta(DE3), containing the original PvLDH gene, were optimized. We obtained PvLDH with a 31.0 mg/L yield and high purity (>95%) from this Rosetta(DE3) strain. The purified protein was characterized structurally and functionally. The PvLDH expressed and purified from transformed bacteria without codon optimization was successfully demonstrated to exhibit its potential tetramer structure and enzyme activity. These findings are expected to provide valuable insights for research on infectious diseases, metabolism, diagnostics, and therapeutics for malaria caused by P. vivax.

Diagnostic performance and clinical feasibility of a novel one-step RT-qPCR assay for simultaneous detection of multiple severe acute respiratory syndrome coronaviruses.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Other coronaviruses (CoVs) can also infect humans, although the majority cause only mild respiratory symptoms. Because early diagnosis of SARS-CoV-2 is critical for preventing further transmission events and improving clinical outcomes, it is important to be able to distinguish SARS-CoV-2 from other SARS-related CoVs in respiratory samples. Therefore, we developed and evaluated a novel reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay targeting the genes encoding the spike (S) and membrane (M) proteins to enable the rapid identification of SARS-CoV-2, including several new circulating variants and other emerging SARS-like CoVs. By analysis of in vitro-transcribed mRNA, we established multiplex RT-qPCR assays capable of detecting 5 × 10° copies/reaction. Using RNA extracted from cell culture supernatants, our multiple simultaneous SARS-CoV-2 assays had a limit of detection of 1 × 10° TCID50/mL and showed no cross-reaction with human CoVs or other respiratory viruses. We also validated our method using human clinical samples from patients with COVID-19 and healthy individuals, including nasal swab and sputum samples. This novel one-step multiplex RT-qPCR assay can be used to improve the laboratory diagnosis of human-pathogenic CoVs, including SARS-CoV-2, and may be useful for the identification of other SARS-like CoVs of zoonotic origin.

Population genetic analyses inferred a limited genetic diversity across the pvama-1 DI domain among Plasmodium vivax isolates from Khyber Pakhtunkhwa regions of Pakistan.

BACKGROUND: Plasmodium vivax apical membrane antigen-1 (pvama-1) is an important vaccine candidate against Malaria. The genetic composition assessment of pvama-1 from wide-range geography is vital to plan the antigen based vaccine designing against Malaria. METHODS: The blood samples were collected from 84 P. vivax positive malaria patients from different districts of Khyber Pakhtunkhwa (KP) province of Pakistan. The highly polymorphic and immunogenic domain-I (DI) region of pvama-1 was PCR amplified and DNA sequenced. The QC based sequences raw data filtration was done using DNASTAR package. The downstream population genetic analyses were performed using MEGA4, DnaSP, Arlequin v3.5 and Network.5 resources. RESULTS: The analyses unveiled total 57 haplotypes of pvama-1 (DI) in KP samples with majorly prevalent H-14 and H-5 haplotypes. Pairwise comparative population genetics analyses identified limited to moderate genetic distinctions among the samples collected from different districts of KP, Pakistan. In context of worldwide available data, the KP samples depicted major genetic differentiation against the Korean samples with Fst = 0.40915 (P-value = 0.0001), while least distinction was observed against Indian and Iranian samples. The statistically significant negative values of Fu and Li's D* and F* tests indicate the evidence of population expansion and directional positive selection signature. The slow LD decay across the nucleotide distance in KP isolates indicates low nucleotide diversity. In context of reference pvama-1 sequence, the KP samples were identified to have 09 novel non-synonymous single nucleotide polymorphisms (nsSNPs), including several trimorphic and tetramorphic substitutions. Few of these nsSNPs are mapped within the B-cell predicted epitopic motifs of the pvama-1, and possibly modulate the immune response mechanism. CONCLUSION: Low genetic differentiation was observed across the pvama-1 DI among the P. vivax isolates acquired from widespread regions of KP province of Pakistan. The information may implicate in future vaccine designing strategies based on antigenic features of pvama-1.

Entry inhibition of hepatitis B virus using cyclosporin O derivatives with peptoid side chain incorporation.

Hepatitis B virus (HBV) infection is a serious worldwide health problem causing liver cirrhosis and hepatocellular carcinoma. The development of novel therapeutics targeting distinct steps of the HBV life cycle and combination therapy with approved drugs (i.e., nucleot(s)ides, interferon-α) are considered effective strategies for curing HBV. Among these strategies is the development of entry inhibitors that interfere with the host entry step of HBV to prevent viral infection and transmission. Herein, we generated a novel library of cyclosporin O (CsO) derivatives that incorporate peptoid side chains. Twenty-two CsO derivatives were evaluated for membrane permeability, cytotoxicity, and in vitro HBV entry inhibitory activity. The lead compound (i.e., compound 21) showed the greatest potency in the in vitro HBV entry inhibition assay (IC50 = 0.36 ± 0.01 µM) with minimal cytotoxicity. Our peptide-peptoid hybrid CsO scaffold can readily expand chemical diversity and is applicable for screening various targets requiring macrocyclic chemical entities.

Prognostic implication of serum AFP in patients with hepatocellular carcinoma treated with regorafenib.

Background: This multicenter study investigated the predictive value of baseline AFP and on-treatment AFP response for survival in hepatocellular carcinoma (HCC) patients with regorafenib. Materials & methods: A total of 578 patients with HCC treated with regorafenib from 12 institutions in South Korea and Italy were included. Baseline AFP (cutoff, 400 ng/ml) and AFP response (20% reduction from baseline) were analyzed for overall survival (OS) and progression-free survival (PFS). Results: Baseline AFP below 400 ng/ml was a significant factor that was independently associated with longer OS and PFS. AFP response was also a significant factor independently associated with longer OS and PFS. Conclusion: Baseline AFP and AFP response may be used as prognostic factors for survival in HCC treated with regorafenib.

Regorafenib is standard second-line therapy for patients with hepatocellular carcinoma (HCC) who show failure to sorafenib treatment, but there is no reliable factor to predict survival. In this multicenter, retrospective study with patients from South Korea and Italy, we have found that both baseline AFP level and on-treatment AFP response have independent predictive value for survival in patients with HCC under regorafenib treatment. We observed similar results when the patients were divided according to their nationality (South Korea vs Italy), despite the fact that the baseline characteristics of the patients from the two cohorts were significantly different.

Testosterone deficiency and the risk of anemia: A propensity score-matched analysis.

OBJECTIVE: There are little data on the endogenous testosterone effect on hemoglobin or hematocrit. Moreover, these data are limited by a cross-sectional study design, a small participant number, and no adjustment for confounding factors. Therefore, the present study was conducted to address the aforementioned limitations of previous studies using a large dataset and propensity score matched analysis. MATERIALS AND METHODS: Men who underwent health check-up were analyzed. Participants were divided into two groups using the cut-off testosterone value of 3.5 or 3.0 ng/ml according to a previous definition of testosterone deficiency. Using the cutoff testosterone value of 3.5 ng/ml, 966 cases (testosterone levels <3.5 ng/ml) and 7402 controls (testosterone level ≥3.5 ng/ml) were included, but following propensity score matching, there were 966 cases and 1932 controls. Using the cutoff testosterone value of 3.0 ng/ml, 444 cases (testosterone levels <3.0 ng/ml) and 7924 controls (testosterone level ≥3.0 ng/ml) were included, but following propensity score matching, there were 444 cases and 888 controls. RESULTS: After matching, the groups were evenly distributed with respect to age, body mass index, estimated glomerular filtration rate, hypertension, and diabetes in both data sets. After matching, the mean Hb and Hct were significantly lower and the incidence of anemia was significantly greater in the case compared to the control in both data sets. The relative risk of anemia in the case was 2.4 compared to the control in both data sets. CONCLUSION: Screening for anemia in patients with testosterone deficiency would be needed and vice versa.

Survey of Opioid Risk Tool Among Cancer Patients Receiving Opioid Analgesics.

BACKGROUND: The risk of opioid-related aberrant behavior (OAB) in Korean cancer patients has not been previously evaluated. The purpose of this study is to investigate the Opioid Risk Tool (ORT) in Korean cancer patients receiving opioid treatment. METHODS: Data were obtained from a multicenter, cross-sectional, nationwide observational study regarding breakthrough cancer pain. The study was conducted in 33 South Korean institutions from March 2016 to December 2017. Patients were eligible if they had cancer-related pain within the past 7 days, which was treated with strong opioids in the previous 7 days. RESULTS: We analyzed ORT results of 946 patients. Only one patient in each sex (0.2%) was classified as high risk for OAB. Moderate risk was observed in 18 males (3.3%) and in three females (0.7%). Scores above 0 were primarily derived from positive responses for personal or familial history of alcohol abuse (in men), or depression (in women). In patients with an ORT score of 1 or higher (n = 132, 14%), the score primarily represented positive responses for personal history of depression (in females), personal or family history of alcohol abuse (in males), or 16-45 years age range. These patients had more severe worst and average pain intensity (proportion of numeric rating scale ≥ 4: 20.5% vs. 11.4%, P < 0.001) and used rescue analgesics more frequently than patients with ORT scores of 0. The proportion of moderate- or high-risk patients according to ORT was lower in patients receiving low doses of long-acting opioids than in those receiving high doses (2.0% vs. 6.6%, P = 0.031). Moderate or high risk was more frequent when ORT was completed in an isolated room than in an open, busy place (2.7% vs. 0.6%, P = 0.089). CONCLUSIONS: The score of ORT was very low in cancer patients receiving strong opioids for analgesia. Higher pain intensity may associate with positive response to one or more ORT item.

Effectiveness of nasotracheal intubation in anterior cervical surgery including C3 lesions.

OBJECTIVE: Anterior approach cervical surgery is widely used for accessing C3 lesions. When operating with an anterior approach, the surgical field is obstructed by mandible. Neck extension is popular method to secure better surgical field but risk devastating neurological damage. To overcome this limited surgical field without neck extension, we adopted nasotracheal intubation and evaluated its efficiency. METHODS: We retrospectively analyzed 16 patients who underwent anterior cervical discectomy or corpectomy of C3 lesions via nasotracheal intubation. We enrolled an additional 29 patients who underwent anterior cervical discectomy or corpectomy of C3 lesions via orotracheal intubation as a control group. All patients had been diagnosed with cervical spondylotic myelopathy or ossification of the posterior longitudinal ligament. We measured the mandibular-cervical angle, which is the angle between the lower mandibular line and anterior vertebral line. RESULTS: The mandibular-cervical angle was increased by 7.3 with nasotracheal intubation compared to orotracheal intubation. CONCLUSIONS: Nasotracheal intubation is an effective surgical option for securing the surgical field without neck extension in anterior cervical surgery including C3 lesions.

Naegleria fowleri Cathepsin B Induces a Pro-Inflammatory Immune Response in BV-2 Microglial Cells via NF-κB and AP-1 Dependent-MAPK Signaling Pathway.

Naegleria fowleri is a ubiquitous protozoa parasite that can cause primary amoebic meningoencephalitis (PAM), a fatal brain infection in humans. Cathepsin Bs of N. fowleri (NfCBs) are multifamily enzymes. Although their pathogenic mechanism in PAM is not clearly understood yet, NfCBs have been proposed as pathogenic factors involved in the pathogenicity of amoeba. In this study, the immune response of BV-2 microglial cells induced by NfCB was analyzed. Recombinant NfCB (rNfCB) evoked enhanced expressions of TLR-2, TLR-4, and MyD88 in BV-2 microglial cells. This enzyme also induced an elevated production of several pro-inflammatory cytokines such as TNF-α, IL-1α, IL-1ß, and IL-6 and iNOS in cells. The inhibition of mitogen-activated protein kinases (MAPKs), including JNK, p38, and ERK, effectively reduced the production of these pro-inflammatory cytokines. The rNfCB-induced production of pro-inflammatory cytokines in BV-2 microglial cells was suppressed by inhibiting NF-kB and AP-1. Phosphorylation and nuclear translocation of p65 in cells were also enhanced by rNfCB. These results suggest that NfCB can induce a pro-inflammatory immune response in BV-2 microglial cells via the NF-κB- and AP-1-dependent MAPK signaling pathways. Such a NfCB-induced pro-inflammatory immune response in BV-2 microglial cells might contribute to the pathogenesis of PAM caused by amoeba, by exacerbating deleterious immune responses and tissue damages in N. fowleri-infected foci of the brain.