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Sarcopenia is a major component of geriatric syndrome and associated with poor clinical outcomes and mortality. However, diagnosing sarcopenia in the very elderly is difficult, and data on its epidemiology and devastating effects in this group are scarce. Phase angle (PA) is measured using bioimpedance spectroscopy and known to reflect cellular integrity and health. This study aimed to clarify the impact of sarcopenia and PA on mortality risk in very elderly people living in long-term care facilities.This prospective cohort study enrolled elderly residents living in nine long-term care facilities. We collected the participants' data, such as body mass index (BMI), comorbidities and laboratory data, from September to October 2017 and mortality data until October 2019. Nutritional status was evaluated using the Mini Nutritional Assessment (MNA) score, and multifrequency bioimpedance spectroscopy was used to assess body composition including PA. Appendicular skeletal muscle mass was calculated using the body composition monitor-derived equation of Taiwan's researchers. Sarcopenia was diagnosed using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) definition (sarcopenia vs. normal group). We divided the participants into two groups according to the median PA value of 3.65° (high vs. low group) and performed multivariate regression analyses to verify the association with mortality risk according to sarcopenia diagnosis or PA group.A total of 279 elderly participants were enrolled; of them, 238 (85.3%) were diagnosed with sarcopenia according to EWGSOP2 guidelines. The median patient age was 83 years, 211 (75.6%) were female and the median BMI was 20.4 kg/mSarcopenia is prevalent among the very elderly patients in long-term care facilities. Sarcopenia and low PA are significantly associated with higher mortality risk.

There are limited studies on the association of COVID-19 vaccination with neuralgic amyotrophy (NA). Therefore, we evaluated the association between COVID-19 vaccination and the occurrence of NA.We explored unexpected safety signals for NA related to COVID-19 vaccination through disproportionality analysis using VigiBase, the World Health Organization's pharmacovigilance database.On October 15, 2021, 335 cases of NA were identified in the database. The median time to onset of NA after vaccination was around 2 weeks. A significant signal of disproportionality of NA was observed for the ChAdOx1 nCoV-19 vaccine (AstraZeneca) (information component [IC]A weak association was observed between NA and COVID-19 vaccines. However, the risk did not surpass that of influenza vaccines.

To determine the sensitivity and specificity of cutaneous amyloid deposition in relation to patient-reported measures in the earliest disease stage of hereditary ATTR amyloidosis (ATTRv).In a cross-sectional study, we analyzed 88 individuals with TTR mutations, 47 of whom were in the earliest disease stage and without clinically evident neuropathy, 12 healthy controls, and 13 disease controls with diabetes. All participants' neuropathy symptoms and signs were assessed using validated patient and clinician-reported measures and 3-mm skin punch biopsies were immunostained using protein gene product 9.5 and Congo Red.Amyloid can be detected in the earliest disease stages in up to 86% of patients with ATTRv amyloidosis. Amyloid was not detected in healthy individuals or individuals with diabetic peripheral neuropathy supporting a sensitivity of 86% and a specificity of 100%. The cutaneous deposition of amyloid correlates with neuropathy sensory symptoms, measured with the Neuropathy Total Symptom Score-6 (R = 0.46, p 0.01); pain measured with the Brief Pain Symptom Inventory (R = 0.44, p 0.05); autonomic symptoms, measured with the Boston Autonomic Symptom Questionnaire (R = 0.38, p 0.05); and quality of life measured with the Norfolk Diabetic Neuropathy Quality of Life Questionnaire (R = 0.44, p 0.05). Individuals with amyloid deposition were more likely to have sensory symptoms, pain, autonomic impairment, and reduced quality of life than ATTRv patients without amyloid deposition.These findings have implications for understanding the earliest manifestations of the clinical phenotype of ATTRv-associated neuropathy, for the pathophysiological construct of disease staging, and for timing the introduction of disease-modifying therapy.

Extracellular vesicles (EV) have been emerging as potential biomarkers for disease monitoring. In particular, tumor‐derived EV (TDE) are known to carry oncogenic miRNA, so they can be used for diagnosis of early cancer by analyzing the expression levels of EV‐miRNA circulating in the blood. Here, using our novel microfluidic device, we rapidly and selectively isolate cancerous EV expressing breast cancer‐derived surface markers CD49f and EpCAM within 2 minutes. Based on seven candidates of miRNA nominated from The Cancer Genome Atlas (TCGA) database, the expression levels of miRNA in TDE were validated in a total of 82 individuals, including 62 breast cancer patients and 20 healthy controls. Among seven candidates, four miRNAs (miR‐9, miR‐16, miR‐21, and miR‐429) from the EV were highly elevated in early‐stage breast cancer patients compared with healthy donors. The combination of significant miRNAs from specific EV has high sensitivities of 0.90, 0.86, 0.88, and 0.84 of the area under the receiver operating characteristic curve (AUC) in each subtype (luminal A, luminal B, HER‐2, and triple‐negative) of early‐stage breast cancer. Our results suggest that the combination of four miRNA signatures of specific EV could serve as a sensitive and specific biomarker and enable early diagnosis of breast cancer using liquid biopsy., A new combination of miRNA from cancer‐specific extracellular vesicles was proposed for the highly sensitive and specific diagnosis of early‐stage breast cancer in association with a microfluidic‐based immuno‐isolation technique. These findings suggest that miRNA in EV could be used as important biomarkers for the early detection of breast cancer and identification of cancer subtype.

Objective To create an aerosol containment mask (ACM) that contains aerosols during common otolaryngologic endoscopic procedures while protecting patients from environmental aerosols. Study Design Bench testing. Setting Mannequin testing. Methods The mask was designed in SolidWorks and 3-dimensional printed. Mannequins were fitted with a nebulizer to generate aerosols. Commercial particle counters were used to measure mask performance. Results The ACM has 2 ports on either side for instruments and endoscopes, a port for a filter, and a port that can evacuate aerosols contained within the mask via a standard suction pump. The mask contained aerosols on a mannequin with and without facial hair when the suction was set to 18.5 L/min. Other types of masks demonstrated substantial aerosol leakage under similar conditions. In a subsequent experiment, the ACM contained aerosols generated by a nebulizer up to the saturation of the particle detector without measurable leakage with or without suction. Conclusion The ACM will accommodate rigid and flexible endoscopes plus instruments and prevent leakage of patient-generated aerosols, thus avoiding contamination of the room and protecting health care workers from airborne contagions. Level of evidence 2.

Background Recently, pulsed dye laser (PDL) combined with triamcinolone intralesional injection (TAILI) has been introduced for surgical scar prevention. However, little is known about this procedure's effectiveness in preventing hypertrophic scar following surgical scar removal. Objectives This study aimed to evaluate the outcome of early intervention using PDL combined with TAILI after surgical removal of hypertrophic cesarean section (CS) scars. Methods The medical records of 35 patients who underwent early intervention using PDL and TAILI after removal of hypertrophic CS scars were retrospectively reviewed. The scars' average Vancouver Scar Scale (VSS) scores before scar removal and three months after the final treatment were compared. Results The patients received 4.23 treatments on average and were followed up for a mean period of 7.74 months. The mean final VSS was 3.11 ± 1.52 and was significantly lower than that of the previous VSS (9.29 ± 1.74, P = 0.000). VSS of the previous CS scar, and the presence or absence of keloid formation in other areas, were associated with treatment outcome (P = 0.003 and 0.008, respectively). Conclusions Early intervention using PDL combined with TAILI could prevent the recurrence or progression of hypertrophic CS scarring after surgical scar removal.

GC1118 is a monoclonal antibody for epidermal growth factor receptor (EGFR) that is currently under clinical development to treat patients with solid tumors. In this study, the pharmacokinetics (PKs) of GC1118 were modeled in solid tumor patients who received a 2‐h intravenous infusion of GC1118 at 0.3, 1, 3, 5, or 4 mg/kg once‐weekly (Q1W) on days 1, 8, 15, and 22 or 8 mg/kg every other week on days 1 and 15. A target‐mediated drug disposition population PK model adequately described the concentration‐time profiles of GC1118. Monte‐Carlo simulation experiments of the PK profiles and EGFR occupancies (ROs) by GC1118 based on the final model showed that Q1W at 4 or 5 mg/kg will produce a better antitumor effect than Q2W at 8 mg/kg. Because GC1118 was safer at 4 mg/kg than 5 mg/kg in the phase I study, we suggest to test the 4 mg/kg Q1W regimen in further clinical trials with GC1118. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GC1118, a fully human IgG1 monoclonal antibody (mAb) for epidermal growth factor receptor (EGFR), showed a nonlinear pharmacokinetic (PK) profile in monkeys and humans. The total clearance of GC1118 decreased as the dose was increased up to 3–4 mg/kg in humans, beyond which it remained stable. The recommended phase II dose for GC1118 was 4 mg/kg intravenously infused over 2 h once weekly. WHAT QUESTION DID THIS STUDY ADDRESS? We developed a target‐mediated drug disposition (TMDD) population PK model that described the nonlinear PK profile of GC1118 in patients with solid tumors. We also simulated the PK profiles and receptor occupancies for different dosage regimens. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The TMDD population PK model adequately described the nonlinear and multiphasic PK profiles of GC1118 in humans. The simulation experiment showed that once‐weekly GC1118 at 4–5 mg/kg could be more efficacious than the biweekly regimen at 8 mg/kg. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The pharmacometrics analysis could support better informed drug development decisions for GC1118, particularly for determining an optimal dosage regimen.

Cauterization prevents hemorrhage and optimizes the surgical field during endoscopic sinus surgery but may cause injury to nearby structures. The objective of this study is to examine thermal conductance from cauterization equipment across the skull base.Cadaver and animal model.Surgical skills laboratory of an academic tertiary medical institution.A pilot study was conducted with a deidentified cadaver head and expanded to a goat head animal model. Endoscopic dissection was performed to expose the lamina papyracea, ethmoid roof, sphenoid roof, and frontal sinus. Cautery was applied to the frontal sinus of goat heads, and temperatures were measured via thermocouple sensors placed along the intracranial skull base. Surgical instruments studied included monopolar, bipolar, and endoscopic bipolar devices at various power settings.Temperature increase, as averaged across all cautery powers and measurement positions, was highest for the monopolar cautery (17.55 °C) when compared with the bipolar and endoscopic bipolar devices (2 °C for bipolar, Endo-Pen, Stammberger, and Wormald;Thermal conductance across the skull base varies depending on equipment and power of cautery, with monopolar resulting in the largest temperature increase. Choice and implementation of cauterization instruments have implications on inadvertent transmission of thermal energy during endoscopic sinus surgery.

Background The aim of this study was to estimate the incidence of and risk factors for Pneumocystis pneumonia (PCP) infection in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Methods The medical records of 739 DLBCL patients who received R-CHOP between May 2004 and January 2019 were retrospectively evaluated. Patients were divided into two groups: those who received primary PCP prophylaxis (prophylaxis group) and those who did not (control group). The incidence rate of PCP in each group was calculated, and risk factors for PCP were evaluated in the control group. Results Baseline characteristics were significantly different between the two groups. Compared to the 602 patients who did not receive prophylaxis, the prophylaxis group (n = 137) had poor prognostic factors of older age, high lactate dehydrogenase (LDH) levels, advanced Ann Arbour stage, and high International Prognostic Index (IPI) risk scores. None of the patients receiving PCP prophylaxis developed PCP, while the incidence of PCP in the control group was 8.1% (definite cases 5.5% and probable cases 2.7%). Out of the 49 patients who developed PCP, 10 patients (20.4%) were admitted to the intensive care unit, and the PCP-related death rate was 16.3% (8/49). Conclusion This study showed that PCP prophylaxis is highly effective against PCP infection and may help guide prevention of PCP during R-CHOP treatment in DLBCL patients.

Traumatic events during early life have been linked with later life psychopathology. To understand this risk factor, researchers have studied the effects of prenatal and postnatal early life stress on neurochemical changes. Here we review the rodent literature on sex differences and sex-specific impact of early life stress on frontal cortex neurochemistry. This region is implicated in regulating motivation and emotion, which are often disrupted in psychological disorders. The prefrontal cortex (PFC) in particular is one of the last brain regions to develop, and there are sex differences in the rate of this development. To draw direct comparisons between sexes, our review of the literature was restricted to studies where the effects of prenatal or postnatal stress had been described in male and female littermates. This literature included research describing glutamate, γ-amino butyric acid (GABA), corticosteroids, monoamines, and cannabinoids. We found that sex-dependent effects of stress are mediated by the age at which stress is experienced, age at test, and type of stress endured. More research is required, particularly into the effects of adolescent stress on male and female littermates. We hope that a greater understanding of sex-specific susceptibilities in response to stress across development will help to uncover risk factors for psychological disorders in vulnerable populations.

Previous research has established associations between early life stress (ELS) and altered pituitary gland volume (PGV) growth during adolescence. The pituitary gland, however, is composed of an anterior and a posterior lobe with distinct histological and neuroendocrinological properties. While the anterior (but not posterior) pituitary gland is directly involved in the hypothalamic-pituitary-adrenal axis (HPAA) stress response, no studies have examined the effects of ELS on anterior PGV (aPGV). The present study investigated whether previously reported associations between ELS and PGV development during adolescence were driven by aPGV versus posterior PGV (pPGV). Ninety-one adolescents (49 males) were included from a longitudinal, community-based adolescent development study investigating risk for psychopathology. ELS (maternal affective behavior, childhood maltreatment, stressful life events) was assessed during early adolescence. Participants underwent two waves of structural magnetic resonance imaging during mid- and late-adolescence, and aPGV and pPGV were manually traced. Regression analyses showed that childhood maltreatment predicted greater aPGV growth in females. This finding was stronger than that previously reported for PGV. No associations were found between ELS and pPGV development. Neither aPGV nor pPGV changes mediated associations between ELS and psychopathology. Results suggest that ELS may accelerate aPGV (but not pPGV) growth throughout adolescence. Investigating the development of aPGV, rather than PGV, represents a novel approach to studying the effects of stress on HPAA functioning.

BACKGROUND & AIMS Regorafenib demonstrated a clinical benefit for patients with unresectable hepatocellular carcinoma (uHCC) in the phase III RESORCE trial. Considering the heterogeneity of uHCC and discrepancies in its characteristics between prospective trials and daily practice, real-life evidence is necessary. METHODS This multicentre, retrospective analysis was performed by the Korean Cancer Study Group. In total, 440 patients who received regorafenib between January 2017 and November 2019 were identified in nine tertiary referral hospitals in Korea. RESULTS All patients received prior sorafenib, and the median time-to-progression (TTP) on sorafenib was 3.9 months (range, 0.2-71.6). Regorafenib was used as the second, third and fourth to seventh lines of therapy in 305 (69.3%), 115 (26.1%) and 20 (4.5%) patients respectively. According to the RECIST v1.1, the overall response rate was 7.7% (n = 34), and the median progression-free survival (PFS) and overall survival (OS) were 3.2 (95% CI, 2.8-3.5) and 12.1 (95% CI, 9.7-14.5) months respectively. Immune checkpoint inhibitors (ICIs) were given in 115 patients (26.1%) prior to regorafenib. There were no differences in PFS and OS with regorafenib according to the prior use of ICIs (PFS, P = .61; OS, P = .63). The occurrence of hand-foot skin reaction (HFSR) was associated with a better OS (P < .001). CONCLUSIONS The real-life clinical outcomes of regorafenib for patients who progressed on prior systemic therapy including ICIs were consistent with the phase III trial results. HFSR was significantly associated with better OS with regorafenib.

Aims We sought to determine if non-terminal respiratory unit (TRU) type adenocarcinoma of lung with invasive mucinous adenocarcinoma (IMA) morphology shows gastric differentiation. Methods and results We reviewed whole-section images of 489 cases of lung adenocarcinoma from The Cancer Genome Atlas (TCGA). TCGA data were classified into 426 TRU type adenocarcinoma, 49 IMA and 14 unclassifiable. Their RNA sequencing data was analysed by DESeq2 and WGCNA R packages. Gene expression in patients' samples was measured by NanoString assay. Overexpression of genes including REG4, TFF2, MUCL3, FER1L6, B3GALT5, ANXA10 was observed by TCGA analysis in IMA compared to TRU type adenocarcinoma. Many of these genes are those expressed in normal gastric glands and selected for NanoString experiment on 14 IMA and 10 TRU type adenocarcinoma cases. The expression of genes, including ANXA10, FER1L6, HNF4a, MUC5AC, REG4, TFF1, TFF2 and VSIGI, was increased> 15-fold in IMA. Immunohistochemistry of ANXA10, TFF2 and FER1L6 performed on 31 IMA and 135 TRU type adenocarcinomas showed a predominant expression in IMA, but are not in TRU type adenocarcinoma. Conclusion Our results showed the level of genes expressed in stomach mucosa was increased in IMA compared to TRU type adenocarcinoma, supporting gastric differentiation of IMA. This finding may help the understanding of the pathogenesis of IMA and discovery of therapeutic targets.

Aims Interaction between programmed death-1 ligand (PD-L1) and its receptor programmed death 1 (PD-1) on T cells inactivates antitumour immune responses. PD-L1 expression has been associated with poor prognosis in renal cell carcinoma (RCC) and predicts adverse outcome. This study was designed to evaluate the impact of PD-L1 expression and the immune microenvironment on the clinical outcome in Xp11 translocation renal cell carcinoma (TRCC) and, therefore, their potential relevance as prognostic biomarkers. Methods and results The present retrospective analysis investigated expression of PD-L1 and immune cells CD8, CD4, CD3, forkhead box protein 3 (FoxP3) and PD-1 in TRCC compared to other types of RCC. FFPE specimens were collected between 2011 and 2017 from 311 patients who underwent nephrectomy at our institution for RCC. Specimens were immunostained for PD-L1, CD8, CD4, CD3, FoxP3 and PD-1, and an outcome analysis was conducted. PD-L1 expression rate was highest in TRCC (68%, 16 of 25), followed by mucinous tubular and spindle cell RCC and collecting duct carcinoma (33%, one of three), papillary RCC (27%, seven of 26), clear cell RCC (16%, 29 of 233), chromophobe RCC (11%, two of 18) and multilocular cystic RCC (0%, none of three). In TRCC, PD-L1 expression was associated with poor recurrence-free survival (RFS) (P = 0.041). The CD4high and FoxP3high groups showed a significantly shorter RFS (P = 0.05 and P = 0.031, respectively) compared to CD4low and FOXPlow groups. Conclusion PD-L1 expression was higher in TRCC than in other types of RCC. High PD-L1 tumour cell expression and tumour infiltration by CD4+ and FoxP3+ immune cells were associated with poor RFS in TRCC.

Background A bioabsorbable nasal valve implant (NVI) was introduced in 2016 as a minimally invasive solution to nasal valve collapse. Historically the introduction of less invasive procedures performable in-office has resulted in an increase in volume. Our objective is to evaluate this trend as it relates to nasal vestibular repair, and its impact on healthcare utilization. Methods We interrogated the Medicare Part B national database for nasal vestibular repair (CPT code: 30465), Unlisted nasal procedure (30999) and septoplasty (30520) from 2010 to 2017. Septoplasty was used as a surrogate for overall nasal procedural rate. Linear regression modeling was used to examine the changes in reported vestibular repair rate adjusting for septoplasty rate. Results In the Medicare population, the rate of septoplasty was stable from 2010 to 2017, increasing from 26,962 to 30,194 at an annual rate of 1.5%. Coding for unlisted nasal procedure increased from 272 to 333 at an adjusted annual rate of 1.1% over this time period. Coding for nasal vestibular repair increased from 2026 to 5331 over this interval at an adjusted annual rate of 0.9% from 2010 to 2016 but significantly increased to 5% between 2016 to 2017 (P Conclusion The reported volume of nasal vestibular repair increased significantly in the year following Food and Drug Administration approval of NVIs. In the absence of a corresponding increase in septoplasty, this temporal relationship suggests that the introduction of NVIs impacted the utilization of this procedural code. Level of evidence N/A Laryngoscope, 2020.

This study investigates the effects of distance restrictions on Korean coffee shops' survival. Restrictions were implemented by South Korea's Fair Trade Commission to limit the headquarters' opening of new shops to protect franchisees' territorial rights. Using extended Cox proportional hazard regression analyses, we find that the hazard rates of all coffee shops decreased significantly under the radius restriction, with more substantial decreases for young stores, attenuating over store ages. However, selective restrictions on five big brands influencing interbrand competition might have changed the coffee franchise industry's landscape and thereby widening the gap between exempted brand coffee shops and the rest. (JEL D22, L40, L66)

Medullary thyroid carcinoma (MTC) accounts up to 10% of all thyroid cancers, but is responsible for a disproportionate number of deaths. While surgery is the only curative treatment for MTC, indications for lateral neck lymph node (LLN) dissection are controversial. We performed a retrospective review to describe clinical outcomes in 93 MTC patients from July 1995 to March 2015. We analyzed their clinicopathologic factors, and cut‐off values of tumor size and calcitonin levels were calculated using a receiver operating characteristic curve. Using the instances of lymph node metastases, the tumor size cut‐off value was 0.95 cm (area under curve, AUC = 0.697) in patients with ipsilateral central lymph node (CLN) metastases, 2.25 cm (AUC = 0.793) in contralateral CLN metastases, and 1.75 cm (AUC = 0.753) in ipsilateral LLN metastases. The cut‐off values of preoperative calcitonin levels were 226.6 pg/mL (AUC = 0.746) in ipsilateral CLN, 755.0 pg/mL (AUC = 0.840) in contralateral CLN metastases, and 237.0 pg/mL (AUC = 0.775) in ipsilateral LLN metastases. This study supports the notion that ipsilateral LLN metastases occur before contralateral CLN metastases. Therefore, ipsilateral LLN dissection should be considered in patients with contralateral CLN metastases. The extent of surgery should be based on the status of LN metastases, preoperative basal calcitonin level, and tumor size to help individualize the extent of surgery.

Balloon sinuplasty utilization has increased significantly since its introduction over a decade ago. However, the most common associated complications are still unknown. The objective of this study was to analyze adverse events related to balloon sinuplasty.Retrospective cross-sectional analysis.Food and Drug Administration's MAUDE database (Manufacturer and User Facility Device Experience; 2008-2018).The MAUDE database was searched for all reports on adverse events involving balloon sinuplasty devices from the 3 leading manufacturers: Acclarent, Entellus, and Medtronic. Reported events were reviewed and categorized.During the study period, there were 211 adverse events from 208 reports divided into the following categories: patient related (n = 102, 48.3%), device related (n = 101, 47.9%), and packaging related (n = 8, 3.8%). Four periprocedural deaths were reported but were not clearly associated with technical complications. The most common device-related complications were guide catheter malfunction (39.6%), balloon malfunction (38.6%), and imprecise navigation (17.8%). The most common patient-related complications were cerebrospinal fluid leak (36.3%), eye swelling (29.4%), and epistaxis (11.8%). A lateral canthotomy was performed in 30.0% of eye-swelling complications. Sixty percent of eye complications occurred during balloon dilation of the maxillary sinus. The years 2014 (n = 48) and 2012 (n = 32) had the highest number of adverse events reported as compared with all other years.The most common adverse events associated with balloon sinuplasty include balloon malfunction, guide catheter malfunction, cerebrospinal fluid leak, and significant eye swelling. Health care providers should discuss these possible complications when consenting patients for balloon sinuplasty.

Previously, we reported induced expression of the p190 Rho guanine nucleotide exchange factor (p190RhoGEF, ARHGEF28) following CD40 stimulation of B cells isolated from mouse spleen. We also reported that p190RhoGEF and a downstream effector molecule RhoA are required for B-cell differentiation, especially for the induction of the plasma cell (PC) differentiation. This study investigates the role of p190RhoGEF in B-cell biology in vivo, using p190RhoGEF transgenic (TG) mice that overexpress a wild-type full gene in B cells. Immunization of these mice with T-cell-dependent antigen showed that populations of germinal center B cells and PCs were significantly increased in TG mice. Furthermore, similar results were shown in recombination activating 1 (Rag1) knockout mice that were reconstituted with B cells isolated from TG mice in combination with T cells isolated from littermate control mice. Analyses of isotype class switching and transcription factors involved in a germinal center reaction and PC differentiation also supported the findings from the cellular responses. These results suggest that p190RhoGEF may play a role in the stage of PC differentiation during T-cell-dependent humoral immune responses.

PURPOSE To determine the accuracy of a digital manufacturing method for dental implant restorations on stock abutments using intraoral scanners and prefabricated stock-abutment libraries. MATERIALS AND METHODS Two dental implants with internal hexagonal connections were placed in the mandibular second premolar and second molar areas of a partially edentulous dentoform model; stock abutments with a diameter of 5 mm, abutment height of 5.5 mm, and gingival cuff height of 2 mm were connected. The study model was scanned 10 times using a reference tabletop scanner and 5 types of intraoral scanners (IOSs). The data collected by 5 types of IOSs were divided into 3 groups, based on the type and matching of stock abutment library data: no library, optical library, and contact library groups. A total of 160 data files were analyzed, including reference data. The resulting data were used to evaluate trueness and precision. RESULTS Trueness and precision values in the group in which library data of the stock abutment were not used were 42.0 to 76.3 µm and 30.5 to 99.7 µm; corresponding values when the library data using an optical scanner were matched were 51.2 to 73.4 µm and 26.3 to 62.8 µm, and those when contact scanner library data were used were 30.1 to 62.4 µm and 15.5 to 55.9 µm. Thus, the accuracy of the contact library group was significantly higher than the accuracies of the no library (p < 0.001) and optical library groups (p < 0.001). CONCLUSION The application of prefabricated library data of stock abutments using a contact scanner improved the accuracy of scan data. Scan accuracy of the stock abutments differed significantly based on the type of scanner.

Extinction is the decrease in emotion to a cue that was previously associated with an emotionally significant event. It involves repeated presentation of the cue without any consequences. In adult animals, extinguished fear to a cue can return if the cue is presented in a different environment/context to where extinction occurred, referred to as renewal. We have previously reported that developing female, but not male, rats show renewal. This study investigates whether the ability of developing female rats to show renewal is related to their ability in fear conditioning to the context. Additionally, facilitation of context conditioning by weaning previously shown in male rats was tested in developing female rats. In experiment 1, postnatal day 25 (P25) and P18 female rats showed renewal. P25 rats show more fear overall, suggesting a weaker extinction recall in this age. Experiment 2 tested context- and cue-elicited fear either immediately or 24 hr following conditioning. At the immediate test, P18 rats showed less context-fear compared with P25 rats. All rats showed low levels of context-fear at the 24 hr test. There were no age differences in cued fear. Weaning at P21 did not affect context or cue memory in P25 female rats. These findings suggest that the ability to form contextual fear memory is unrelated to the expression of renewal in juvenile female rats.

BACKGROUND There has been a rapid increase in electric motorized scooter (e-scooter) usage after the introduction of dockless, shareable devices. METHODS Case series from three tertiary hospitals in Los Angeles between May-September 2019. RESULTS Five patients had skull base fractures and CSF leaks or pneumocephalus after e-scooter accident, none wore helmets. Two patients were treated with observation alone, two patients were treated with lumbar drain or external ventriculostomy placement, and one patient died of their injuries prior to definitive management. CONCLUSION Without appropriate safety policies in place, the number of such injuries may increase as the use of e-scooters increase. Laryngoscope, 131:E1035-E1037, 2021.

Background and aim Inflammatory bowel diseases is associated with an increased risk for the development of colorectal cancer. However, the mechanism of immune signaling pathways linked to colitis-associated cancer (CAC) has not been fully elucidated. Tauroursodeoxycholic acid (TUDCA) exhibits anti-inflammatory and anti-cancer activities. The aim of this study is to investigate the role of TUDCA in the pathogenesis of CAC. Methods Colitis-associated cancer was induced in mice using azoxymethane and dextran sodium sulfate administration, and TUDCA's effect on tumor development was evaluated. HCT 116 and COLO 205 were treated with TUDCA or vehicle and then stimulated with tumor necrosis factor-α (TNF-α). Expression of interleukin (IL)-8 was determined by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, and IκBα phosphorylation and degradation was evaluated by immunoblot assay. The DNA-binding activity of NF-κB was assessed by electrophoretic mobility shift assay. Cell viability assay and real-time reverse transcription-polymerase chain reaction of bcl-xL, MCL1, c-FLIP-L, and VEGF were performed. Results Tauroursodeoxycholic acid significantly attenuated the development of CAC in mice. Exposure to TUDCA resulted in extensive epithelial apoptosis and reduced levels of phospho-IκB kinase in the colon. In HCT 116 cells stimulated with TNF-α, TUDCA significantly inhibited IL-8 and IL-1α expression and suppressed TNF-α-induced IκBα phosphorylation/degradation and DNA-binding activity of NF-κB. Furthermore, in both HCT 116 and COLO 205 cells, TUDCA reduced cell viability and downregulated the expression of bcl-xL, MCL1, c-FLIP-L, and VEGF. Conclusion These results demonstrated that TUDCA suppresses NF-κB signaling and ameliorates colitis-associated tumorigenesis, suggesting that TUDCA could be a potential treatment for CAC.

Although the introduction of human epidermal growth factor receptor (HER)2-directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T-DM1) in the treatment of HER2-positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2-positive mBC will eventually progress. Poziotinib is an oral pan-HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2-positive mBC who had progressed from more than two HER2-directed therapies. Patients received 12 mg poziotinib once daily on a 14-day on/7-day off schedule. Progression-free survival (PFS) as the primary endpoint, the objective response rate (ORR), overall survival (OS) and safety were evaluated. From April 2015 to February 2016, 106 patients were enrolled in the trial from seven institutes in South Korea. They had a median age of 51 years (range 30-76) and had received a median of four prior therapies including two HER2-directed therapies for advanced or metastatic cancers. The median follow-up duration was 12 months. The median PFS was 4.04 months (95% confidence interval [CI], 2.94-4.40 months), and median overall survival has not been reached. The most common treatment-related adverse events were (total/grade ≥3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%) and rashes (63.21%/3.77%). Poziotinib showed meaningful activity in these heavily treated HER2-positive mBCs. Diarrhea and stomatitis were the major toxicities. Biomarker studies analyzed are warranted to support further evaluation of this treatment in such cases.

Background and Aim Little is known about the risk factors associated with serrated polyps, because the early studies, which occurred before the new World Health Organization classification was introduced, included mixtures of serrated polyps. This study aimed to evaluate the risk factors associated with the presence of sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs) using big data analytics. Methods Using a case-control design, we evaluated the risk factors associated with the presence of SSAs and TSAs. Subjects who underwent colonoscopies from 2002 to 2012 as part of the comprehensive health screening programs undertaken at the Samsung Medical Center, South Korea, participated in this study. Results Of the 48,677 individuals who underwent colonoscopies, 183 (0.4%) had SSAs and 212 (0.4%) had TSAs. The multivariate analysis determined that being aged ≥50 years (odds ratio [OR] 1.91, 95% confidential interval [CI] 1.27–2.90, P=0.002) and a history of CRC among first-degree relatives (OR 3.14, 95% CI 1.57–6.27, P=0.001) were significant risk factors associated with the presence of SSAs, and that being aged ≥50 years (OR 2.61, 95% CI 1.79–3.80, P

SummaryAim Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) has been managed as low-risk malignancy. Recently, a proposal was made to reclassify this tumor type as a premalignant lesion and rename it noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). However, a comprehensive study on molecular genotype-phenotype correlations of encapsulated FVPTC is lacking. Methods and results This study consisted of 177 consecutive FVPTCs from January 2014 to April 2016. These were classified into noninvasive (n=74), invasive (n=51) encapsulated FVPTC, and infiltrative FVPTC (n=52) according to standard criteria by two independent pathologists. Genetic alterations and other clinicopathologic information were compared. A BRAFV600E mutation was found in 12.2% (noninvasive) and 11.8% (invasive) of encapsulated FVPTCs and 34.6% of infiltrative FVPTCs (P=0.001). Mutation in encapsulated FVPTCs was limited to cases with rare or abortive papillae. RET/PTC1 and RET/PTC3 rearrangements were present (11.5%) only in infiltrative FVPTC. In contrast, N-, H-, and KRAS mutations were observed predominantly in encapsulated FVPTCs (48.6% in noninvasive and 66.7% in invasive) compared to infiltrative FVPTCs (15.4%) (P

Background and aim The present study evaluated the clinical characteristics of Korean patients with Crohn's disease (CD) according to their age at diagnosis in a nationwide multicenter cohort study. Methods A total of 1224 patients diagnosed with CD between 1982 and 2008 in 32 hospitals were included, and age at diagnosis was categorized as ≤ 16 (G1), 17-40 (G2), 41-59 (G3) and ≥ 60 (G4) years old. The baseline characteristics, medication, and intestinal resection were compared according to the age at diagnosis. Results The number of patients in each age group was 155 (G1; 12.7%), 919 (G2; 75.1%), 120 (G3; 9.8%), and 30 (G4; 2.5%). The frequencies of ileocolonic disease in the late adult onset and elderly onset groups were lower than those in the other groups (P Conclusions Elderly onset CD may be related to favorable outcomes in Korea. Thus, the heterogeneity of this disease should be considered when developing a tailored strategy for the treatment of CD.

Resectable pancreatic cancer has a high recurrence rate after curative surgery. Biomarkers are needed for distinguishing patients who may benefit from curative resection. In this study, we sought to analyze the prognostic value of p21-activated kinase 1 (PAK1), p21-activated kinase 4 (PAK4), human equilibrative nucleoside transporter 1 (hENT1), and thymidylate synthase (TS) in surgically resected pancreatic ductal adenocarcinomas. A total of 160 pancreatic cancer patients who underwent surgery with curative intent were retrospectively reviewed. Tissue microarrays were constructed and immunohistochemical stains were performed for PAK1, PAK4, hENT1, and TS. The absence of PAK4 expression in pancreatic adenocarcinomas was associated with poorer histologic differentiation (p < 0.001), shorter overall survival [hazard ratio (HR) = 2.86, 95% confidence interval (CI) 1.43-5.71; p = 0.003], and disease-free survival (HR = 2.29, 95% CI: 1.11-4.74; p = 0.025) on univariate analyses. In addition, more frequent venous invasion and lymph node metastases were seen in PAK4-negative tumors although not statistically significant. PAK1, hENT1, and TS expression status did not have significant influences on patient survival. In conclusion, PAK4 of the markers tested in this study may be a potential prognostic biomarker for pancreatic adenocarcinomas.

Since the first description of Guillain-Barre syndrome (GBS) 100 years ago, the concept of this syndrome has changed remarkably. The purpose of our study was to identify and characterize the most-cited articles that have contributed to advancing the understanding of GBS. Based on the database of Journal Citation Reports, we selected 554 journals that were considered as potential sources of reports on studies related to clinical neurology and general medicine. The Web of Science search tools were used to identify the most-cited articles relevant to GBS or other variants in the selected journals. Of the selected articles, 18 were review articles and the remainder were original articles or included only a few case series. Among the original articles, 13 described basic research associated with immunological pathogenesis involving anti-ganglioside antibodies. Most of the original studies (42/64, 66%) published after 1990 evaluated anti-ganglioside antibodies that mediated axonal GBS or Miller Fisher syndrome, with only a small number of the papers involving electrodiagnostic medicine (n = 4). Our bibliometric analysis has yielded a detailed list of the top-100 cited articles in the field of GBS.

Background There was a difficulty for detecting Central lymph node metastasis (CLNM) in papillary thyroid carcinoma (PTC) patients. Therefore, the purpose of this study was to design a nomogram for predicting CLNM. Methods A total of 10,763 PTC patients who underwent total thyroidectomy with central neck dissection (CND) in Samsung Medical Center were randomly assigned to the training set (n = 7,535) and to the internal validation set (n = 3,228). And, a total of 2,514 PTC patients who underwent total thyroidectomy with CND at Seoul National University Hospital were assigned to the external validation set. Results The values of the area under the receiver operating characteristic curve in the training set, internal validation set, and external validation set were 0.721 (95% confidence interval [CI], 0.709–0.732), 0.706 (95%CI, 0.688–0.724), and 0.706 (95%CI, 0.685–0.727), respectively. Conclusions We recommend the use of our nomogram to enable clinicians and patients to easily personalize and quantify the probability of CLNM during the both pre- and postoperative period. Clinicians may consider the prophylactic CND and meticulous postoperative evaluation in PTC patients with a high nomogram score. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

Background and Aim It is generally assumed that gastric cancer (GC) in young patients has different clinicopathologic characteristics than that of elderly patients. Although recurrence is an important factor in determining prognosis, traditional clinicopathological factors are sometimes inadequate for predicting recurrence in individuals. Therefore, we aimed to identify miRNAs with the potential to predict recurrence in young patients. Methods Young patients (age 3.35, had a sensitivity and specificity of 86.7% and 65.5%, respectively, for predicting recurrence, with an area under the ROC curve of 0.723. Conclusions miR-21-5p may be useful as a predictor of recurrence in young GC patients whose tumors contain a high proportion of intratumoral stroma. The combination of this miRNA with conventional clinicopathological factors should allow patient prognoses to be more accurately predicted.

Background The purpose of this study was to describe how the up-front transoral robotic surgery (TORS) approach could be used to individually tailor adjuvant therapy based on surgical pathology. Methods Between January 2009 and December 2013, 76 patients received TORS for oropharyngeal squamous cell carcinoma (OPSCC). Clinical predictors of adjuvant therapy were analyzed and comparisons were made between recommended treatment guidelines for up-front surgery versus definitive nonsurgical approaches. Results Advanced N classification, human papillomavirus (HPV)-positive tumor, extracapsular spread (ECS; 26 of 76), perineural invasion (PNI; 14 of 76), and positive margins (7 of 76) were significant predictors of adjuvant chemoradiotherapy (CRT) (p < .05). Up-front TORS deintensified adjuvant therapy; 76% of stage I/II and 46% of stage III/IV patients avoided CRT. Conversely, pathologic staging resulted in 33% of patients who would have received radiotherapy (RT) alone based on clinical staging, to be intensified to receive adjuvant CRT. Conclusion The TORS approach deintensifies adjuvant therapy and provides valuable pathologic information to intensify treatment in select patients. TORS may be less effective in deintensification of adjuvant therapy in patients with clinically advanced N classification disease. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

Background Persistent hypercalcitoninemia is reported in 40% to 60% of patients with medullary thyroid cancer (MTC) after initial therapy, but their clinical outcomes have not been clearly studied. We evaluated the outcomes of MTC with hypercalcitoninemia and assessed the cutoffs of postoperative serum calcitonin for predicting structural recurrence. Methods A dynamic risk assessment system was used to categorize clinical outcomes in this retrospective study. Receiver operating characteristic (ROC) curve analysis was used to calculate the calcitonin cutoffs for predicting structural recurrence. Results Among 120 patients operated on, 30 (25%) had persistent hypercalcitoninemia. Of that group, 18 (60%) had biochemical persistent disease and 11 (37%) developed structural identified disease, including 1 death (3%). Postoperative calcitonin

Background and Purpose There is currently no medication approved specifically to treat cocaine addiction. Behavioural interventions such as cue exposure therapy (CET) rely heavily on new learning. Antagonism of the metabotropic glutamate 5 (mGlu5) receptor has emerged as a potential treatment, by reducing the reinforcing properties of cocaine. However, mGlu5 receptor activity is necessary for learning; therefore, such agents could interfere with behavioural treatments. We used a novel rodent model of CET to test the effects of mGlu5 negative and positive allosteric modulators (NAM and PAM) on behavioural therapy. Experimental Approach Rats were trained to press a lever for cocaine in the presence of a discrete cue [conditioned stimulus (CS)] and then extinguished in the absence of the CS. Following lever extinction, half the rats received CS extinction in the same chambers but with the levers withdrawn; the remaining rats received no CS extinction. Before this session, rats received a systemic administration of either vehicle or a mGlu5 NAM (MTEP, experiment 1) or PAM (CDPPB, experiment 2). Cue-induced reinstatement was tested in a drug-free session the following day. Key Results At reinstatement, rats that had received CS extinction showed reduced responding. This effect was attenuated by MTEP treatment before CS extinction. In contrast, administration of CDPPB (PAM) led to decreased reinstatement the following day, regardless of extinction condition. Conclusion and Implications These results suggest that mGlu5 receptor activity is both necessary and sufficient for efficient extinction of a cocaine-associated CS. Therefore, mGlu5 PAMs could enhance the efficacy of CET.

Background While fine-needle aspiration cytology (FNAC) using conventional smear has been widely accepted as the primary diagnostic tool for thyroid lesions, liquid-based preparations (LBPs) are increasingly replacing it. A new automated LBP method, EASYPREP® (EP), was recently introduced and has shown relevant diagnostic efficacy in gynecologic samples. We compared the diagnostic utility of EP and SurePath® (SP), a more widely established LBP method, in thyroid FNAC. Methods Under the ultrasonographic guidance, 253 thyroid FNAC samples were collected by sample-splitting manner. Three pathologists made cytologic diagnoses of EP and SP according to the Bethesda system independently and compared the cytomorphologic parameters. Cytohistologic correlation was performed in 30 resected cases. Results Fifteen (5.9%) and 21 (8.3%) samples were unsatisfactory in SP and EP, respectively, owing to the unequal sample-splitting. Cytologic diagnoses of SP and EP were consistent in 228 cases (90.1%), and inconsistent in remainder mostly owing to the unequal distribution of pathognomic cells. While cytomorphologic parameters were not significantly different between two methods, EP showed less three-dimensional configuration in benign lesions. Cytohistologic correlation showed no significant differences in sensitivity (100% vs. 95.5%) and specificity (100% vs. 100%) between SP and EP. Labor time for processing 48 cases was 42% shorter with EP than with SP (28 min vs. 48 min). Conclusions The diagnostic utility of EP in thyroid FNAC was comparable to that of SP. EP allowed better visibility owing to better fragmentation of follicular clusters. The automated system of EP has the advantages of a shorter labor time for batch processing. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.