Supplementary Material for: Ultrathin Bronchoscopy for the Diagnosis of Peripheral Pulmonary Lesions: A Meta-Analysis

Background: Ultrathin bronchoscopy (external diameter, ≤3.5 mm) is useful for the diagnosis of peripheral pulmonary lesions because of its good accessibility. Objectives: We performed a meta-analysis to investigate the diagnostic yield of ultrathin bronchoscopy for peripheral pulmonary lesions. Methods: We performed a systematic search of MEDLINE and EMBASE (from inception to May 2021), and meta-analysis was performed using R software. The diagnostic yield was evaluated by dividing the number of successful diagnoses by the total number of lesions, and subgroup analysis was performed to identify related factors. Results: Nineteen studies with a total of 1,977 peripheral pulmonary lesions were included. The pooled diagnostic yield of ultrathin bronchoscopy was 0.65 (95% confidence interval, 0.60–0.70). Significant heterogeneity was observed among studies (χ2, 87.75; p I2, 79.5%). In a subgroup analysis, ultrathin bronchoscopy with 1.2 mm channel size showed a diagnostic yield of 0.61 (95% confidence interval, 0.53–0.68), whereas ultrathin bronchoscopy with 1.7 mm channel size showed 0.70 (95% confidence interval, 0.66–0.74) (χ2, 5.35; p = 0.02). In addition, there was a significant difference in diagnostic yield based on lesion size, histologic diagnosis (malignant vs. benign), bronchus sign, and lesion location from the hilum, whereas no significant difference was found based on lobar location. The overall complication rate of ultrathin bronchoscopy was 2.7% (pneumothorax, 1.1%). Conclusions: Ultrathin bronchoscopy is an excellent tool for peripheral pulmonary lesion diagnosis with a low complication rate. The diagnostic yield of ultrathin bronchoscopy was significantly higher with larger channel size, which might be attributed to the availability of radial endobronchial ultrasound

Supplementary Material for: Tracking Cognitive Decline in Amnestic Mild Cognitive Impairment and Early-Stage Alzheimer Dementia: Mini-Mental State Examination versus Neuropsychological Battery

<p><b><i>Background/Aims:</i></b> Although the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SOB), and neuropsychological batteries are widely used for evaluating cognitive function, it remains elusive which instrument best reflects the longitudinal disease progression in amnestic mild cognitive impairment (aMCI) and probable Alzheimer disease (AD). We investigated whether changes in these three instruments over time correlate with loss of cortical gray matter volume (cGMV). <b><i>Methods:</i></b> We retrospectively investigated 204 patients (aMCI, <i>n</i> = 114; AD, <i>n</i> = 90) who had undergone MMSE, CDR-SOB, the dementia version of the Seoul Neuropsychological Screening Battery (SNSB-D), and 3-dimensional T1-weighted magnetic resonance images at least twice. We investigated the partial correlation between annual decline in test scores and percent change of cGMV. <b><i>Results:</i></b> In aMCI patients, changes in the SNSB-D total score (<i>r</i> = 0.340, <i>p</i> < 0.001) and CDR-SOB (<i>r</i> = 0.222, <i>p</i> = 0.020), but not MMSE, showed a correlation with cGMV loss, with the SNSB-D total score showing the strongest correlation. In AD patients, decline in all three test scores correlated significantly with cGMV loss, with MMSE exhibiting the strongest correlation (<i>r</i> = 0.464, <i>p</i> < 0.001). <b><i>Conclusion:</i></b> In aMCI patients, neuropsychological battery, though time-consuming, was the most adequate tool in tracking disease progression. In AD patients, however, MMSE may be the most effective longitudinal monitoring tool when considering cost-effectiveness.</p

Supplementary Material for: Glycoconjugate-specific developmental changes in the horse vomeronasal organ

Vomeronasal organ (VNO) is a tubular pheromone sensing organ in which the lumen is covered with sensory and non-sensory epithelia. This study used immunohistochemistry and lectin histochemistry techniques to evaluate developmental changes, specifically of the glycoconjugate profile, in the horse VNO epithelium. Immunostaining analysis revealed PGP9.5 expression in some vomeronasal non-sensory epithelium (VNSE) cells and in the vomeronasal receptor cells of the vomeronasal sensory epithelium (VSE) in fetuses, young foals, and adult horses. OMP expression was exclusively localized in receptor cells of the VSE in fetuses, young foals, and adult horses and absent in VNSE. To identify the glycoconjugate type, lectin histochemistry was performed using 21 lectins. Semi-quantitative analysis revealed that the intensities of glycoconjugates labeled with WGA, DSL, LEL, and RCA120 were significantly higher in adult horse VSE than those in foal VSE, whereas the intensities of glycoconjugates labeled with LCA and PSA were significantly lower in adult horse VSE. The intensities of glycoconjugates labeled with s-WGA, WGA, BSL-II, DSL, LEL, STL, ConA, LCA, PSA, DBA, SBA, SJA, RCA120, jacalin, and ECL were significantly higher in adult horse VNSE than those in foal VNSE, whereas the intensity of glycoconjugates labeled with UEA-I was lower in adult horse VNSE. Histochemical analysis of each lectin revealed that various glycoconjugates in the VSE were present in the receptor, supporting, and basal cells of foal and adult horses. A similar pattern of lectin histochemistry was also observed in the VNSE of foal and adult horses. In conclusion, these results suggest that there are increase in the level of N-acetylglucosamine (labeled by WGA, DSL, LEL) and galactose (labeled by RCA120) in horse VSE during postnatal development, implying that they may influence the function of VNO in adult horses

Supplementary Material for: Age-Dependent Predictors for Recurrent Stroke: The Paradoxical Role of Triglycerides

<b><i>Background:</i></b> Although long-term predictors of mortality and vascular events after ischemic stroke are well defined, the age-dependent differences in predicting outcomes are unknown, particularly for lipid parameters. <b><i>Methods:</i></b> We assessed recurrent stroke and other vascular events in patients with first-ever ischemic strokes who were registered in a prospectively collected hospital-based stroke registry. Patients were classified into a middle-age group (40–64 years old) and an old-age group (65 years and older). <b><i>Results:</i></b> A total of 551 patients comprising 235 middle-age and 316 old-age subjects were investigated. At the mean follow-up of 26.4 months, 49 (8.9%) patients had experienced recurrent stroke. Outcome events in the middle-age group (3.8%) were less frequent than in the old-age group (12.7%). The effects of vascular risk factors were different across age groups. In particular, the hazard ratio direction for triglycerides was significantly different between age groups for recurrent stroke or composite outcomes. <b><i>Conclusions:</i></b> Incidence and predictors of stroke and other vascular events following ischemic stroke are age-dependent. Differential effects of triglycerides on long-term outcomes following ischemic stroke were found to be hazardous at middle age but turned out to be non-significant at old age

Supplementary Material for: The Clinical Stages of Sporadic Creutzfeldt-Jakob Disease with Met/Met Genotype in Korean Patients

<b><i>Background:</i></b> Clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) is currently based on changes occurring in the late disease stages, which limits early-stage detection. Therefore, we investigated the disease course from the vague symptomatic to the terminal phase. <b><i>Methods:</i></b> We retrospectively reviewed 36 sCJD patient records, classifying the disease progression into 4 stages based on clinical manifestations: vague symptomatic, possible CJD, probable CJD and chronic vegetative state. We analyzed findings from diffusion-weighted imaging (DWI), electroencephalography (EEG) and cerebrospinal fluid (CSF) 14-3-3 protein testing performed at each stage. <b><i>Results:</i></b> In stage 1, the most distinctive feature was DWI hyperintensities in the neocortex, even with negative CSF 14-3-3 protein and EEG results. In stage 2, DWI hyperintensities in the limbic cortex were more remarkable. CSF 14-3-3 protein testing yielded positive results in >80% of patients; EEG showed sensitivity in <30% of patients. With progression toward stage 3, DWI hyperintensities in the subcortical nucleus increased, with a sustained higher rate of hyperintensities in the limbic and neocortical regions. With gradual progression to stage 4, the sensitivity of CSF 14-3-3 protein testing and EEG decreased and increased, respectively within limited data. <b><i>Conclusions:</i></b> Understanding disease stage-dependent differences in clinical symptoms and laboratory test results will facilitate early and accurate diagnosis

Supplementary Material for: Three Novel Pathogenic Mutations in KATP Channel Genes and Somatic Imprinting Alterations of the 11p15 Region in Pancreatic Tissue in Patients with Congenital Hyperinsulinism

<p><b><i>Background/Aims:</i></b> This study was performed to investigate the molecular pathology underlying focal and diffuse congenital hyperinsulinism (CHI). <b><i>Methods:</i></b> The <i>ABCC8</i> and <i>KCNJ11</i> genes were analyzed in 3 patients with focal CHI and in 1 patient with diffuse CHI. Immunohistochemistry, real-time PCR, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and microsatellite marker analyses of the 11p15 region were performed on both normal tissues and adenomatous hyperplasia lesions. <b><i>Results:</i></b> The 3 patients with focal CHI harbored paternally inherited <i>ABCC8</i> or <i>KCNJ11</i> mutations. Compound heterozygous <i>ABCC8</i> mutations were identified in the patient with diffuse CHI. In the 3 patients with focal CHI, homozygous <i>ABCC8</i> or <i>KCNJ11</i> mutations were identified within the lesions. MLPA and real-time PCR revealed the presence of two copies of 11p15. MS-MLPA and microsatellite analyses demonstrated abnormal imprinting patterns and focal loss of maternal 11p13-15 within the lesions. In contrast, parental heterozygosity was preserved in the normal tissue. In the patient with diffuse CHI, the two <i>ABCC8</i> mutations were conserved, and imprinting patterns at 11p15 were normal. <b><i>Conclusions:</i></b> The epigenetic alteration at the 11p15 region plays a central role in developing focal CHI by paternally derived mutations of the K_ATP channel and maternal allelic loss at this region. MS-MLPA and microsatellite analyses are useful to investigate the molecular etiology of CHI.</p

Supplementary Material for: Limited Role of Random Skin Biopsy in the Diagnosis of Intravascular Lymphoma in Adult Patients with Hemophagocytic Lymphohistiocytosis

<strong><em>Background/Aims:</em></strong> This study examined the role of random normal skin biopsy in the diagnosis of intravascular lymphoma (IVL) in adult Western patients with clinically diagnosed hemophagocytic lymphohistiocytosis (HLH). <b><i>Methods:</i></b> In a retrospective chart review study, we analyzed a total of 59 skin biopsies that were performed to diagnose IVL in 21 adult patients with HLH seen at Stanford Hospital between 2004 and 2016. <b><i>Results:</i></b> Out of the 59 skin biopsies, 42 were taken from clinically normal-appearing skin and 17 from clinically abnormal-appearing skin. None of the 59 biopsies revealed a diagnosis of primary or metastatic malignancy, regardless of the malignancy history, clinical presentation, and biopsy and histopathologic characteristics. A review of 8 positive IVL cases at Stanford Hospital including 1 case associated with HLH showed 1 positive diagnosis by a targeted skin biopsy and other positive diagnoses by bone marrow (<i>n</i> = 4), lung (<i>n</i> = 2), brain (<i>n</i> = 2), muscle (<i>n</i> = 1), and nerve (<i>n</i> = 1). <b><i>Conclusion:</i></b> Random skin biopsies have a limited role in diagnosing IVL in adult patients with HLH, in the setting of a single academic institution in the USA. A review of the literature emphasizes the role of a full body skin exam with a selective skin biopsy in these patients

Supplementary Material for: Fibroblasts and Mesenchymal Stromal/Stem Cells Are Phenotypically Indistinguishable

<b><i>Background/Aims:</i></b> Human mesenchymal stromal/stem cells (MSCs), derived from many different tissues, are characterized by a fibroblast-like morphology, the expression of certain cell surface markers and their ability to differentiate into adipocytes, chondrocytes and osteoblasts. A number of studies have shown that MSCs share many characteristics with fibroblasts; however, there is no well-defined set of phenotypic characteristics that could distinguish between these 2 types of cells. <b><i>Methods:</i></b> We used 4 well-established human fibroblast strains from 3 different tissue sources and several human MSC strains from 2 different tissue sources to compare the phenotypic and immunological characteristics of these cells. <b><i>Results:</i></b> Fibroblast strains had a similar morphology to MSCs, expressed the same cell surface markers as MSCs and could also differentiate into adipocytes, chondrocytes and osteoblasts. Also, similar to MSCs, these fibroblasts were capable of suppressing T cell proliferation and modulating the immunophenotype of macrophages. We also show that MSCs deposit extracellular matrices of collagen type I and fibronectin, and express FSP1 in patterns similar to fibroblasts. <b><i>Conclusions:</i></b> Based on currently accepted definitions for cultured human MSCs and fibroblasts, we could not find any immunophenotypic property that could make a characteristic distinction between MSCs and fibroblasts

Supplementary Material for: Recovery of Food Intake after Gastrectomy for Gastric Cancer: Based on a Large-Scale Gastric Cancer Cohort

<p><b><i>Background:</i></b> This study was aimed at evaluating the food intake and nutritional status of patients who underwent gastrectomy for gastric cancer based on a large-scale gastric cancer cohort. <b><i>Methods:</i></b> An observational prospective cohort study for gastric cancer has been conducted since 2010. From the cohort data, we selected the data for patients who completed at least 2 days of 3-day diet diaries and who underwent subtotal gastrectomy (STG) or total gastrectomy (TG). As a control group, patients who underwent endoscopic submucosal dissection were also included. The collected diet data were converted to macro- and micronutrients using computerized software, and the nutrient intakes were compared. <b><i>Results:</i></b> Among 6,556 patients who participated in the cohort study from 2011 to 2016, 1,289 patients who completed at least 2 days of 3-day diet diaries were included in this study. During the postoperative 3-month period, body weight was significantly decreased in the and TG groups. However, there was no difference in nutrient intake among the 3 groups except vitamin D and calcium intake. Similar results were observed during the postoperative 12 months period. <b><i>Conclusions:</i></b> Postoperative body weight loss and anemia might originate from altered absorptive function and metabolic change after gastrectomy rather than decreased nutrient intake.</p

Supplementary Material for: Age and sex disparities in cardiovascular risk factor management prior to stroke: Linked registry and general practice data

Introduction: There is limited evidence about the management of cardiovascular risk factors within 12 months before stroke/transient ischaemic attack (TIA) in Australian general practices. We evaluated whether age and sex disparities in cardiovascular risk factor management for primary prevention exist in general practice. Methods: A retrospective cohort study using data from the Australian Stroke Clinical Registry (2014-2018) linked with general practice data from three primary health networks in Victoria, Australia. We included adults who had ≥2 encounters with a general practitioner within 12 months immediately before the first stroke/TIA. Cardiovascular risk factor management within 12 months before stroke/TIA was evaluated in terms of: assessment of risk factors (blood pressure [BP], serum lipids, blood glucose, body weight); prescription of prevention medications (BP, lipid-, glucose-lowering, antithrombotic agents); and attainment of risk factor targets. Results: Of 2,880 patients included (median age 76.5 years, 48.4% women), 80.9% were assessed for BP, 49.9% serum lipids, 46.8% blood glucose, and 39.3% body weight. Compared to patients aged 65-84 years, those aged <65 or ≥85 years were less often assessed for risk factors, with women aged ≥85 years assessed for significantly fewer risk factors than their male counterparts. The most prescribed prevention medications were BP-lowering (64.9%) and lipid-lowering agents (42.0%). There were significant sex differences among those aged <65 years (34.7% women vs. 40.2% men) and ≥85 years (34.0% women vs. 44.3% men) for lipid-lowering agents. Risk factor target attainment was generally poorer in men than women, especially among those aged <65 years. Conclusion: Age-sex disparity exists in risk factor management for primary prevention in general practice, and this was more pronounced among younger patients and older women