Impact of ambient temperature on respiratory disease: a case-crossover study in Seoul.

BACKGROUND: Respiratory diseases contribute to global morbidity and mortality, and temperature is a significant factor. We investigated the association between ambient temperature and emergency department (ED) visits for various respiratory diseases in Seoul, South Korea. METHODS: Using data from the National Emergency Department Information System (2008-2017), we analysed 1,616,644 ED visits for respiratory diseases, categorised according to the Korean Standard Classification of Diseases 7th revision codes (J00-J99). Using a time-stratified case-crossover design and a distributed lag nonlinear model, we investigated the effect of temperature exposure on ED visits for respiratory diseases, calculating the relative risk (RR) for the maximum risk temperature (MaxRT) of both cold and hot extremes compared to the minimum risk temperature (MinRT). RESULTS: Cold temperatures (MaxRT: -9.0 °C) resulted in a 2.68-fold increase (RR = 2.68, 95% CI = 2.26-3.14) in ED visits for total respiratory diseases, while hot temperatures (MaxRT: 29.4 °C) led to a 1.26-fold increase (RR = 1.26, 95% CI = 1.11-1.42) compared to the MinRT (24.8 °C). Cold temperatures increased the risk of most respiratory diseases, except interstitial lung disease, whereas hot temperatures increased ED visits for acute upper respiratory infections and influenza. Cold temperatures increased ED visits for all age groups, especially those aged 18-64 (RR = 3.54, 95% CI = 2.90-4.33), while hot temperatures significantly affected those < 18 (RR = 1.45, 95% CI = 1.27-1.66). The risk levels were similar in both males and females, regardless of hot and cold temperatures. CONCLUSION: Our findings underscore the significant impact of both cold and heat exposure on ED visits for respiratory diseases, with varying intensities and risk profiles across different population groups.

CRISPRi-based programmable logic inverter cascade for antibiotic-free selection and maintenance of multiple plasmids.

Antibiotics have been widely used for plasmid-mediated cell engineering. However, continued use of antibiotics increases the metabolic burden, horizontal gene transfer risks, and biomanufacturing costs. There are limited approaches to maintaining multiple plasmids without antibiotics. Herein, we developed an inverter cascade using CRISPRi by building a plasmid containing a single guide RNA (sgRNA) landing pad (pSLiP); this inhibited host cell growth by repressing an essential cellular gene. Anti-sgRNAs on separate plasmids restored cell growth by blocking the expression of growth-inhibitory sgRNAs in pSLiP. We maintained three plasmids in Escherichia coli with a single antibiotic selective marker. To completely avoid antibiotic use and maintain the CRISPRi-based logic inverter cascade, we created a novel d-glutamate auxotrophic E. coli. This enabled the stable maintenance of the plasmid without antibiotics, enhanced the production of the terpenoid, (-)-α-bisabolol, and generation of an antibiotic-resistance gene-free plasmid. CRISPRi is therefore widely applicable in genetic circuits and may allow for antibiotic-free biomanufacturing.

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation.

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

Multiparametric myocardial mapping using cardiac magnetic resonance imaging in healthy dogs: Reproducibility, repeatability, and differences across slices, segments, and sequences.

Myocardial mapping in humans has been widely studied and applied to understand heart disease, facilitate early diagnosis, and determine therapeutic targets; however, the reproducibility, repeatability, and protocol-dependent differences in myocardial mapping in dogs remain unknown, which limits its application in dogs. This study investigated the reproducibility and test-retest repeatability of myocardial mapping in dogs and evaluated the differences according to slice, segment, and sequence. Precontrast T1 (native T1), T2 (T2), and T2* relaxation time (T2*), and extracellular volume (ECV) were measured at the base, midventricle, and apex of the left ventricle in six healthy beagles. To compare the sequences, the saturation recovery-based (SMART1) and inversion recovery-based (MOLLI) sequences were used for native T1 and ECV mapping. The intraclass correlation coefficient was measured to evaluate reproducibility and repeatability using the coefficient of variation and Bland-Altman analysis. All parameters showed good to excellent intra- and interobserver reproducibility and test-retest repeatability. The apex slice showed the lowest repeatability among the slices, whereas ECV had the lowest repeatability among the parameters. Native T1, ECV, and T2* did not differ according to slice, but T2 significantly increased from the base to the apex. Native T1 was significantly higher in SMART1 than in MOLLI, whereas ECV did not differ between the two sequences. Our results suggest that myocardial mapping is applicable in dogs with high reproducibility and repeatability, although slice and sequence differences should be considered. This study can serve as a guide for myocardial mapping studies in dogs with heart disease.

Influence of Nonalcoholic Fatty Liver Disease With Increased Liver Enzyme Levels on the Risk of Cirrhosis and Hepatocellular Carcinoma.

BACKGROUND & AIMS: The influence of nonalcoholic fatty liver disease (NAFLD) on the long-term risk of cirrhosis and hepatocellular carcinoma (HCC) in Asian populations has not been widely investigated. METHODS: We enrolled 129,374 adults aged 30 years and older, all of whom participated in a health screening program from 2008 through 2013, were seronegative for hepatitis B surface antigen and anti-hepatitis C virus antibodies, and had limited daily alcohol consumption (<20 g/d for men and <10 g/d for women). Abdominal ultrasonography was performed to determine the presence of NAFLD. The participants were divided into the following groups: NAFLD with increased or normal liver enzyme levels, and non-NAFLD with normal liver enzyme levels. The incidences of cirrhosis and HCC were determined through computerized data linkage with nationwide registries. Cox proportional hazard models were used to estimate the hazard ratios of NAFLD on the risks of cirrhosis and HCC. RESULTS: The incidence rates of cirrhosis and HCC increased as follows: non-NAFLD with normal liver enzyme levels (n = 66,801; 51%), NAFLD with normal liver enzyme levels (n = 41,461; 32%), and NAFLD with increased liver enzyme levels (n = 21,112; 16%). In the NAFLD group with increased liver enzyme levels and the NAFLD group with normal liver enzyme levels, the corresponding multivariate-adjusted hazard ratios for cirrhosis were 3.51 (95% confidence interval [CI]: 2.36-5.22) and 0.73 (95% CI: 0.46-1.16), and for HCC were 1.91 (95% CI: 1.08-3.38) and 0.57 (95% CI: 0.31-1.04), respectively, compared with the non-NAFLD group (P for trend < .001). The findings were consistent after restricting the analysis to nonobese individuals (body mass index, <25 kg/m2) and nonobese individuals without diabetes (P < .05). CONCLUSIONS: Individuals with NAFLD and increased liver enzyme levels showed significantly higher risks for cirrhosis and HCC and should be monitored.

Clonal hematopoiesis in the donor does not adversely affect long-term outcomes following allogeneic hematopoietic stem cell transplantation: result from a 13-year follow-up.

Donor clonal hematopoiesis may be transferred to the recipient through allogeneic hematopoietic stem cell transplantation (HSCT), but the potential for adverse long-term impact on transplant outcomes remains unknown. A total of 744 samples from 372 recipients who received HSCT and the corresponding donors were included. Bar-coded error-corrected sequencing using a modified molecular inversion probe capture protocol was performed, which targeted 33 genes covering mutations involved in clonal hematopoiesis with indeterminate potential (CHIP) and other acute myeloid leukemia-related mutations. A total of 30 mutations were detected from 25 donors (6.7%): the most frequently mutated gene was TET2 (n=7, 28%), followed by DNMT3A (n=4, 16%), SMC3 (n=3, 12%) and SF3B1 (n=3, 12%). With a median follow-up duration of 13 years among survivors, the presence of CHIP in the donor was not associated with recipient overall survival (P=0.969), relapse incidence (P=0.600) or non-relapse mortality (P=0.570). Donor CHIP did not impair neutrophil (P=0.460) or platelet (P=0.250) engraftment, the rates of acute (P=0.490), or chronic graft-versus-host disease (P=0.220). No significant difference was noted for secondary malignancy following HSCT between the two groups. The present study suggests that the presence of CHIP in allogeneic stem donors does not adversely affect transplant outcomes after HSCT. Accordingly, further study is warranted to reach a clearer conclusion on whether molecular profiling to determine the presence of CHIP mutations is necessary for the pretransplant evaluation of donors prior to stem cell donation.

Genome-wide association study of occupational attainment as a proxy for cognitive reserve.

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale genome-wide association study of occupational attainment with 248 847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10-8); 12 were novel variants, not associated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986 and rs1627527. The single nucleotide polymorphism-based heritability was estimated to be 8.5% (standard error of the mean = 0.004) and partitioned heritability was enriched in the CNS and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction and neuropsychiatric disorders. In two-sample Mendelian randomization analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65-0.92 in inverse variance weighted method; OR = 0.73, 95% CI = 0.57-0.92 in the weighted median method]. This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic single nucleotide polymorphisms (OR = 0.72, 95% CI = 0.57-0.91 in the inverse variance weighted method; OR = 0.72, 95% CI = 0.53-0.97 in the weighted median method). Multivariable Mendelian randomization confirmed that occupational attainment had an independent effect on the risk for Alzheimer's disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54-0.95 in the inverse variance weighted method; OR = 0.68, 95% CI = 0.48-0.97 in the weighted median method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.

Equilibria of semi-volatile isothiazolinones between air and glass surfaces measured by gas chromatography and Raman spectroscopy.

Trace amounts of semi-volatile organic compounds (SVOCs) of the two isothiazolinones of 2-methylisothiazol-3(2H)-one (MIT) and 2-octyl-4-isothiazolin-3-one (OIT) were detected both in the air and on glass surfaces. Equilibria of SVOCs between air and glass were examined by solid phase microextraction-gas chromatography/mass spectrometry (SPME-GC/MS). Surface to air distribution ratios of Ksa for MIT and OIT were determined to be 5.10 m and 281.74 m, respectively, suggesting more abundant MIT in the gas phase by a factor of ∼55. In addition, a facile method of silver nanocube (AgNC)-assisted surface-enhanced Raman scattering (SERS) has been developed for the rapid and sensitive detection of MIT and OIT on glass surfaces. According to MIT and OIT concentration-correlated SERS intensities of Raman peaks at ∼1585 cm-1 and ∼1125 cm-1, respectively. Their calibration curves have been obtained in the concentration ranges between 10-3 to 10-10 M and 10-3 to 10-11 M with their linearity of 0.9986 and 0.9989 for MIT and OIT, respectively. The limits of detection (LODs) of the two isothiazolinones were estimated at 10-10 M, and 10-11 M for MIT and OIT, respectively. Our results indicate that AgNC-assisted SERS spectra are a rapid and high-ultrasensitive method for the quantification of MIT and OIT in practical applications. The development of analytical methods and determination of the Ksa value obtained in this study can be applied to the prediction of the exposure to MIT and OIT from various chemical products and dynamic behaviors to assess human health risks in indoor environments.

Trends in serum uric acid levels among Korean children and adolescents between 2016 and 2020: a nationwide study.

The aim of this study was to examine trends in serum uric acid (SUA) levels over a recent 5-year period according to age, sex, obesity, and abdominal obesity among Korean children and adolescents. We conducted a serial cross-sectional analysis using nationally representative data from the Korea National Health and Nutritional Examination Survey from 2016 to 2020. The study outcome was trends in SUA levels. SUA trends were analyzed by survey-weighted linear regression analysis considering the survey year as a continuous variable. SUA trends were also analyzed for subgroups based on age, sex, abdominal obesity, or obesity. This study included 3,554 children and adolescents aged 10-18 years. SUA increased significantly over the study period in boys (p for trend = 0.043), but not in girls (p for trend = 0.300). In age-specific analyses, SUA increased significantly in the 10-12 years group (p for trend = 0.029). After adjusting for age, SUA increased significantly in the obese group of both boys (p for trend = 0.026) and girls (p for trend = 0.023), but not in the overweight, normal, or under-weight groups of either sex. After adjusting for age, SUA increased significantly in the abdominal obesity group of boys (p for trend = 0.017) and girls (p for trend = 0.014), but not in the non-abdominal obesity group of either sex.   Conclusion: In the current study, SUA levels significantly increased in both boys and girls with obesity or abdominal obesity. Further studies of the effect of SUA on health outcomes in boys and girls with obesity or abdominal obesity are needed. What is Known: • High serum uric acid (SUA) is a risk factor for various metabolic diseases, including gout, hypertension, and type 2 diabetes. What is New: • SUA levels increased in boys and the 10-12 years group of Korean children and adolescents. • SUA levels increased significantly in Korean children and adolescents with obesity or central obesity.

Long-term exposure to particulate air pollution and incidence of Parkinson's disease: A nationwide population-based cohort study in South Korea.

There has been increasing interest in the neurological impact of particulate matter (PM). However, its association with the incidence of Parkinson's disease (PD) remains unclear. We selected 313,355 participants satisfying inclusion criteria from the National Health Insurance Service-National Sample Cohort based on the nationwide population of South Korea, and followed them up from January 2007 through December 2015. Individual-level long-term PM exposure was assessed as the five time-varying average concentrations estimated for the previous 1, 2, 3, 4 and 5 years on each year (until censored or event occurred) at the district-level residential addresses of participants using a previously validated prediction model. Incident PD was defined as the first diagnosis accompanied by anti-PD medication prescription from 2007 through 2015. Time-varying Cox proportional hazards models were employed to estimate the hazard ratio (HR) of incident PD for long-term PM exposure, adjusting for individual- and area-level covariates. During the 8 years (2,745,389 person-years) of follow-up for a total of 313,355 participants (mean [range] age, 48.9 [19-87] years; 169,571 males [54.1%]), 2621 participants (0.8%) developed PD. The HR of incident PD per interquartile range (3.3 µg/m3) increase in fine PM (PM2.5) for the previous 1 year was 1.08 (95% confidence interval: 1.01-1.19). In subgroup-specific analyses, HRs for PM2.5 were significant among older participants, males, participants living in metropolitan cities, ibuprofen users, and participants with comorbidities (HR: 1.10-1.20). Long-term exposure to PM2.5 might play a role in PD development.

Analysis of semi-volatile organic compounds in indoor dust and organic thin films by house type in South Korea.

In this study, semi-volatile organic compounds (SVOCs) in samples of indoor dust and organic thin films obtained from 100 residential houses in South Korea, were examined, based on both target analysis using gas chromatography-mass spectrometry (GC-MS) and non-target analysis by gas chromatography-quadrupole time-of flight mass spectrometry (GC-QTOF-MS) screening. In the targeted approach, phthalates and polycyclic aromatic hydrocarbons (PAHs) were analyzed in dust and organic film samples, to find that both these classes of SVOCs were detected in dust and organic film samples, with the median concentrations of eight phthalates (Σ8 phthalate) and 16 PAHs (Σ16 PAH) being 1015.93 µg/g and 1824.97 ng/g in the dust samples, and 75.79 µg/m2 and 2252.78 ng/m2 in the organic film samples, respectively. Among the phthalates, in all house types. bis(2-ethylhexyl) phthalate (DEHP) was detected at the highest concentration, followed by dibutyl phthalate (DBP) and diisobuthyl phthalate (DiBP), with DEHP levels found to be highest in dwelling houses. DEHP levels were found to be significantly associated with building age and renovation status. Lower levels of DEHP were detected in houses less than 10 years old or that had undergone renovation in the previous 10 years. Among the assessed PAHs, a significant correlation was detected between benzo(a)pyrene in dust and building age (p < 0.05). These findings imply that the inhabitants of older houses are at a greater risk of exposure to SVOCs originating from indoor dust and organic films. Non-target screening of selected dust and organic film samples using GC-QTOF-MS data revealed the presence of numerous SVOC compounds, including triphenylphosphine oxide, (Z)-9-octadecenamide, and cyclosiloxanes, along with certain organophosphate flame retardants including tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloroisopropyl) phosphate (TDCPP), and plasticizers. These compounds identified in the non-target screening are of emerging concern, and their presence in dust and organic films needs to be estimated.

Effect of the personal protective equipment donning and doffing program for nurses in military hospitals.

This study aimed to develop and verify the effect of a new personal protective equipment donning and doffing program for nurses in military hospitals. A total of 40 nurses (20 experimental group, 20 control group) participated in this nonequivalent control group experimental study. The new program consisted of the description of the design modification of the inner and outer boundary marks of coveralls and a video with verbal instructions and footswitch that the participants could watch at their own pace. Data collection was carried out before, immediately after, and 2 weeks after the intervention. The effects of the program on accuracy, self-efficacy, and time were analyzed using a generalized estimating equation. PPE donning and doffing accuracy, self-efficacy, and time were significantly increased in the experimental group compared to those in the control group, both immediately after and 2 weeks after intervention. As this program has been confirmed to be effective in improving PPE donning and doffing accuracy and self-efficacy, we recommend using this program for training nurses on donning and doffing of PPE.

Mortality and Prognostic Factors of Nontuberculous Mycobacterial Infection in Korea: A Population-based Comparative Study.

BACKGROUND: Population-based studies on the mortality burden of nontuberculous mycobacteria (NTM) infection are lacking. We compared the long-term mortality of NTM-infected patients with tuberculosis (TB)-patients and the general population, and investigated mortality-associated factors. METHODS: We analyzed nationwide-data from the Korean National Health Insurance and Korea-Statistical Office between 2002 and 2017. NTM infection was identified using the International Classification of Disease, Tenth Revision code, with one-to-one matching to TB patients and general population controls. RESULTS: A total of 530 401 individuals were analyzed, including 183 267 with NTM infections; 166 666 with TB; and 180 468 controls. The overall 6-, 10-, and 14-year cumulative survival probabilities in the NTM group were 86.3%, 80.8%, and 77.1%, respectively, which were significantly lower than those of the TB or control groups (log-rank P < .0001). In cases of NTM and TB coinfection, the overall 6-, 10-, and 14-year cumulative survival probabilities were 75.1%, 65.4%, and 57.0%, respectively. Multivariable analysis indicated that old age, male gender, province, and various respiratory or nonrespiratory comorbidities were significantly associated with mortality of NTM infection. The use of a macrolide (more than 1 year) negatively correlated with mortality of NTM infection (adjusted hazard ratio [aHR] 0.61, 95% confidence interval [CI] .53-.71), regardless of azithromycin (aHR 0.60, 95% CI .43-.85) or clarithromycin use (aHR 0.63, 95% CI .53-.75). CONCLUSIONS: NTM-infected patients had poor prognosis when compared to TB patients or the general population, especially for NTM and TB coinfection. NTM mortality was associated with certain demographic characteristics, but long-term use of macrolides may provide survival benefits.

Syntrophic co-culture of a methanotroph and heterotroph for the efficient conversion of methane to mevalonate.

As the bioconversion of methane becomes increasingly important for bio-industrial and environmental applications, methanotrophs have received much attention for their ability to convert methane under ambient conditions. This includes the extensive reporting of methanotroph engineering for the conversion of methane to biochemicals. To further increase methane usability, we demonstrated a highly flexible and efficient modular approach based on a synthetic consortium of methanotrophs and heterotrophs mimicking the natural methane ecosystem to produce mevalonate (MVA) from methane. In the methane-conversion module, we used Methylococcus capsulatus Bath as a highly efficient methane biocatalyst and optimized the culture conditions for the production of high amounts of organic acids. In the MVA-synthesis module, we used Escherichia coli SBA01, an evolved strain with high organic acid tolerance and utilization ability, to convert organic acids to MVA. Using recombinant E. coli SBA01 possessing genes for the MVA pathway, 61 mg/L (0.4 mM) of MVA was successfully produced in 48 h without any addition of nutrients except methane. Our platform exhibited high stability and reproducibility with regard to cell growth and MVA production. We believe that this versatile system can be easily extended to many other value-added processes and has a variety of potential applications.

Role of early short-term cardiac rehabilitation in patients undergoing pacemaker implantation.

Exercise-based cardiac rehabilitation (CR) improves the clinical outcomes in patients with cardiovascular diseases. However, few data exist regarding the role of early short-term CR in patients undergoing pacemaker (PM) implantation. We assessed whether short-term CR following PM implantation was sufficient to improve both physical function and quality of life (QOL). A total of 27 patients with a 6-minute walking distance (6MWD) of less than 85% of the predicted value on the day following PM implantation were randomly assigned to either the CR group (n = 12, 44.4%) or the non-CR group (n = 15, 55.6%). The CR group involved individualized exercise-based training with moderate intensity for 4 weeks after PM implantation. Cardiopulmonary exercise test (CPET), 6MWD, muscle strength, and Short Form (SF)-36 were assessed at baseline and at the 4-week follow-up. After a mean follow-up period of 38.3 days, both groups showed significantly improved 6MWD. Peak oxygen uptake improved in both groups on CPET, but the difference was not statistically significant. Knee extension power and handgrip strength were similar in both groups. Regarding QOL, only the CR group showed improved SF-36 scores in the items of vitality and mental health. There was no difference in any subscale in the non-CR group. Neither lead dislodgement nor significant changes in PM parameters were observed in any patient. Early short-term CR following PM implantation was associated with improved psychological subscales and can be safely performed without increasing the risk of procedure-related complications.

Roadmap to resuming care for liver diseases after coronavirus disease-2019.

The global pandemic of coronavirus disease-2019 (COVID-19) has led to significant disruptions in healthcare delivery. Patients with chronic liver diseases require a high level of care and are therefore particularly vulnerable to disruptions in medical services during COVID-19. Recent data have also identified chronic liver disease as an independent risk factor for COVID-19 related hospital mortality. In response to the pandemic, national and international societies have recommended interim changes to the management of patients with liver diseases. These modifications included the implementation of telehealth, postponement or cancelation of elective procedures, and other non-urgent patient care-related activities. There is concern that reduced access to diagnosis and treatment can also lead to increased morbidity in patients with liver diseases and we may witness a delayed surge of hospitalizations related to decompensated liver disease after the COVID-19 pandemic has receded. Therefore, it is paramount that liver practices craft a comprehensive plan for safe resumption of clinical operations while minimizing the risk of exposure to patients and health-care professionals. Here, we provide a broad roadmap for how to safely resume care for patients with chronic liver disease according to various phases of the pandemic with particular emphasis on outpatient care, liver transplantation, liver cancer care, and endoscopy.

Secular trend of treatment uptake in patients with chronic hepatitis B: A territory-wide study of 135 395 patients from 2000 to 2017.

BACKGROUND AND AIMS: The uptake of antiviral treatment for patients with chronic hepatitis B (CHB) has been suboptimal. We aimed to determine the secular trend of treatment uptake in the territory-wide CHB cohort in Hong Kong from 2000 to 2017 and the factors for no treatment despite fulfilling treatment criteria. METHODS: Chronic hepatitis B patients under public clinics and hospitals were identified through electronic medical records. The treatment indications were defined according to the Asian-Pacific guidelines published at the time of patients' first appearance in four periods: 2000-2004, 2005-2009, 2010-2013, and 2014-2017. RESULTS: There were 135 395 CHB patients were included; 1493/12472 (12.0%), 7416/43426 (17.1%), 10 129/46559 (21.8%), 8051/32 938 (24.4%) patients fulfilled treatment criteria in the four periods, respectively. The treatment uptake rate increased with time: 35.1%, 43.4%, 60.2%, and 68.6% respectively. High fibrosis indices (APRI, FIB-4, and Forns indices) appeared to be the main factors for treatment indication in non-cirrhotic patients, with over 90% fulfilling treatment criteria due to high fibrosis indices alone. Of those fulfilling treatment criteria by high fibrosis indices, less than 60% of patients (25.2%, 36.1%, 46.0%, and 58.9%, respectively) had antiviral treatment initiated. Normal platelet count (odds ratio 0.42, P < 0.001) was the independent factor associated with not initiating antiviral treatment in patients fulfilling treatment criteria. CONCLUSIONS: Treatment uptake rates have been increasing over time. Normal platelet count, which reflects less advanced liver disease, precludes patients from receiving antiviral treatment even if treatment indication is fulfilled. Hence, the importance to identify non-cirrhotic patients with significant liver fibrosis should be emphasized.

Analysis of laboratory parameters for optimal autologous peripheral blood stem cell collection from lymphoma and myeloma patients.

BACKGROUND: Peripheral blood stem cell (PBSC) collection is important for successful hematopoietic stem cell transplantation. This study aimed to investigate the laboratory parameters associated with the optimal timing of autologous PBSC collection from lymphoma and multiple myeloma patients. METHODS: We retrospectively evaluated data from 1105 PBSC apheresis procedures performed on 379 adult patients at the National Cancer Center between June 2005 and December 2019. Laboratory parameters, including cutoff values for the number of hematopoietic progenitor cells (HPCs) and circulating CD34+ cells, were analyzed to determine their association with CD34+ cell yield. RESULTS: The pre-apheresis HPC and CD34+ cell count were statistically significant variables associated with harvested CD34+ cell in lymphoma and MM patients. The optimal cutoff values were 18 × 106 /L for pre-HPC count (66.8% sensitivity, 66.4% specificity) and 11/µL for pre-CD34+ cell count (85.8% sensitivity, 87.2% specificity), to achieve CD34+ cell yields ≥ 1.0 × 106 /kg for each apheresis procedure. Moreover, the optimal cutoff values were 23 × 106 /L for pre-HPC count (71.0% sensitivity, 69.0% specificity) and 18/µL for pre-CD34+ cell count (87.5% sensitivity, 86.3% specificity) to achieve CD34+ cell yields ≥ 2.0 × 106 /kg for each apheresis procedure. CONCLUSION: HPC count is a potential surrogate marker for monitoring the starting time for PBSC collection. Applying cutoff values for the number of HPC and CD34+ cells may be clinically useful for optimizing the timing of PBSC collection.

Current Use of Total Body Irradiation in Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation.

Total body irradiation (TBI) is included in the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT), with unique advantages such as uniform distribution over the whole body and decreased exposure to cytotoxic chemotherapeutic agents. For individuals who lack matched sibling or matched unrelated donors, the use of haploidentical donors has been increasing despite challenges such as graft rejection and graft-versus-host disease (GVHD). Although a limited number of studies have been performed to assess the clinical role of TBI in haploidentical HSCT, TBI-based conditioning showed comparable results in terms of survival outcomes, rate of relapse, and GVHD in diverse hematologic malignancies such as leukemia, lymphoma, and multiple myeloma. Advances in supportive care, along with recent technical improvements such as restriction of maximum tolerated dose, appropriate fractionation, and organ shielding, help to overcome diverse adverse events related to TBI. Post-transplantation cyclophosphamide was used in most studies to reduce the risk of GVHD. Additionally, it was found that post-transplantation rituximab may improve outcomes in TBI-based haploidentical HSCT, especially in patients with B-cell lymphoma. Along with the advances of techniques and strategies, the expansion of age restriction would be another important issue for TBI-based haploidentical HSCT considering the current tendency toward increasing age limitation and lack of matched donors. This review article summarizes the current use and future perspectives of TBI in haploidentical HSCT.

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma.

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.