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Background There are few studies demonstrating how the effectiveness of various extents of Non-Pharmaceutical Interventions (NPIs) before and after vaccination periods. The study aimed to demonstrate such an effectiveness in the alteration of the epidemic curves from theory to practice. Methods The empirical data on the daily reported COVID-19 cases were extracted from open source. A computer simulation design in conjunction with the susceptible-exposed-infected-recovered (SEIR) type model was applied to evaluating confinement measures in Italy with adjustment for underreported cases; isolation and quarantine in Taiwan; and NPIs and vaccination in Israel. Results In Italy scenario, the extents of confinement measures were 34% before the end of March and then scaled up to 70% after then. Both figures were reduced to 22-69% after adjusting for underreported cases. Approximately 44% of confinement measures was implemented in the second surge of pandemic in Italy. Fitting the observational data on Taiwan assuming the initial outbreak similar to Wuhan, China, 44% of isolation and quarantine was estimated before 23th March 2020. Isolation and quarantine were scaled up to 90% and at least 60% to contain community-acquired outbreaks from March 24th 2020 onwards. Given 15% monthly vaccination rate from December 2020 in Israel, the effectiveness estimates of reducing the infected toll were 36%, 56%, and 85% for NPIs alone, vaccination alone, and both combined, respectively. Conclusion We demonstrated how various NPIs stamp out and delay the epidemic curve of COVID-19. The optimal implementation of these NPIs has to be planned before wide vaccine uptake worldwide.

Introduction Efficient evaluation with an early surrogate endpoint, taking into account the process of disease evolution, may not only clarify inconsistent or underpowered results but also provide a new insight into the exploration of a new antiviral therapy for treating COVID-19 patients. Methods We assessed the dynamics of COVID-19 disease spectrum, commencing from low-risk (no or low oxygen supplement), medium-risk (non-invasive ventilator or high oxygen supplement), and high-risk (extracorporeal membrane oxygenation or invasive ventilator) risk state on enrollment, and then the subsequent progression and regression of risk states until discharge or death. The efficacy of antiviral therapy in altering the dynamics was assessed by using the high-risk state as a surrogate endpoint based on the data retrieved from the two-arm Adaptive Covid-19 Treatment Trial. Results Using the high-risk state as a surrogate endpoint, remdesivir treatment led to a decrease in the high-risk COVID-19 state by 34.8% (95% CI 26.7–42.0%) for a 14-day period and 29.3% (95% CI 28.8–29.8%) up to 28 days, which were consistent with a statistically significant reduction of death by 30.5% (95% CI 6.6, 50.9%) up to a 28-day period. The estimates of numbers needed to be treated were 100.9 (95% CI 88.1, 115.7) for using the high-risk COVID-19 state as a surrogate endpoint for a 14-day period and 133.3 (95% CI 112.5, 158.0) were required for averting one death from COVID-19 up to 28 days. Conclusions We demonstrate the expedient use of the high-risk COVID-19 disease status as a surrogate endpoint for evaluating the primary outcome of the earliest death. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00431-9.

Background Toll‐like receptor (TLR)‐7‐associated rhinovirus (RV) activation is involved in the pathogenesis of asthma. Plasmacytoid dendritic cells (pDCs) are the main interferon‐α‐producing cells against viruses. Objective To determine whether asthmatic patients and control subjects differ in terms of interferon‐α expression in pDCs under TLR‐7 or RV stimulation. Methods pDCs were identified in BDCA‐2+ and HLA‐DR+ peripheral blood mononuclear cells. Interferon‐α expression of pDCs was analyzed after TLR‐7 stimulation with or without interleukin 4 (IL‐4)/IL‐13 pretreatment. Interferon‐α expression was also analyzed after RV stimulation over periods of 24, 48, or 96 h with or without IL‐4 pretreatment. RV detection and molecular typing were assayed from throat swabs. Results Following TLR‐7 stimulation, the expression of intracellular interferon‐α was higher in the pDCs of normal subjects than those of asthmatic patients; however, pretreatment with IL‐4 was shown to reduce this effect. After 48‐ and 96‐h RV stimulation, we observed a notable increase in the production of interferon‐α of pDCs in normal subjects but not in asthmatic patients. Baseline interferon‐α expression in pDCs and the incidence of asthma exacerbation to emergency was higher among the 13% of patients identified as rhinovirus+ than among their RV counterparts. Conclusion Our study discovered the response to TLR‐7 stimulation in pDCs was compromised and the sustainability of interferon‐α expression to RV stimulation was reduced in pDCs of asthmatic patients, which provide further evidence of defective innate response and subspeciality to RV infection in asthma. The high exacerbation history founded in RV+ patients agrees with these findings. Further research is required for the modulatory effect of IL‐4 on TLR‐7 stimulated pDCs., Our study discovered the response to TLR‐7 stimulation in pDCs was compromised and the sustainability of interferon‐a expression to RV stimulation was reduced in pDCs of asthmatic patients, which provide further evidence of defective innate response and subspeciality to RV infection in asthma. The high exacerbation history founded in RV+ patients agrees with these findings.

STUDY OBJECTIVES: Polysomnography is the gold standard in identifying sleep stages; however, there are discrepancies in how technicians use the standards. Because organizing meetings to evaluate this discrepancy and/or reach a consensus among multiple sleep centers is time-consuming, we developed an artificial intelligence system to efficiently evaluate the reliability and consistency of sleep scoring and hence the sleep center quality. METHODS: An interpretable machine learning algorithm was used to evaluate the interrater reliability (IRR) of sleep stage annotation among sleep centers. The artificial intelligence system was trained to learn raters from 1 hospital and was applied to patients from the same or other hospitals. The results were compared with the experts’ annotation to determine IRR. Intracenter and intercenter assessments were conducted on 679 patients without sleep apnea from 6 sleep centers in Taiwan. Centers with potential quality issues were identified by the estimated IRR. RESULTS: In the intracenter assessment, the median accuracy ranged from 80.3%–83.3%, with the exception of 1 hospital, which had an accuracy of 72.3%. In the intercenter assessment, the median accuracy ranged from 75.7%–83.3% when the 1 hospital was excluded from testing and training. The performance of the proposed method was higher for the N2, awake, and REM sleep stages than for the N1 and N3 stages. The significant IRR discrepancy of the 1 hospital suggested a quality issue. This quality issue was confirmed by the physicians in charge of the 1 hospital. CONCLUSIONS: The proposed artificial intelligence system proved effective in assessing IRR and hence the sleep center quality. CITATION: Liu G-R, Lin T-Y, Wu H-T, et al. Large-scale assessment of consistency in sleep stage scoring rules among multiple sleep centers using an interpretable machine learning algorithm. J Clin Sleep Med. 2021;17(2):159–166.

The novel coronavirus disease 2019 (COVID-19), with first presentation of atypical pneumonia, has spread rapidly from Wuhan, China, on December 12, 2019 to over 200 countries, caused 2 310 572 infected individuals and 158 691 mortalities, updated on April 19, 2020. Many studies have published timely to help global healthcare workers to understand and control the disease. Vulnerable patients with risk factors such as elderly, cardiovascular diseases (eg, hypertension, coronary disease, or cardiomyopathy), diabetes, and chronic kidney disease have worse outcomes after COVID-19 infection. COVID-19 could directly cause cardiovascular injuries such as pericarditis, myocarditis, myocardial infarction, heart failure, arrhythmias, or thromboembolic events, which urge cardiologists to be involved in the frontline to practice. Here, we provide a review of COVID-19 on cardiovascular system to assist clinical cardiologists to better understand the disease and being capable of providing comprehensive medical support.

Purpose The purpose of this study was to evaluate the efficacy of a novel double-docking technique, incorporating the use of femtosecond laser arcuate keratotomy (FSAK) in correcting low-degree astigmatism and Malyugin ring, in a patient with intraoperative floppy iris syndrome (IFIS). Methods A case report of a 72-year-old man with grade 4 cataract, low-degree astigmatism (

Uremic pericarditis and pericardial effusion are possible complications among patients with end-stage renal disease. The accumulation of toxic metabolites may contribute to the pathogenesis of uremic pericarditis. Bleeding diathesis in peritoneal dialysis patients raises the risk of hemorrhagic pericardial tamponade, which is a fatal complication of peritoneal dialysis. We report a case of hemorrhagic pericardial tamponade who was non-adherent to peritoneal dialysis with initial presentation of hypotension and syncope. Transthoracic echocardiogram revealed septated, fibrinoid pericardial effusion and right ventricular diastolic compression. A massive bloody pericardial effusion was drained when he underwent the pericardial window procedure. There was a significant improvement both in his clinical condition and in the echocardiogram images after the procedure. Hemorrhagic pericardial tamponade occurs in uremic patients but is rarely seen in those undergoing peritoneal dialysis. Early diagnosis, immediate surgical drainage, and regular follow-up with echocardiography are crucial to achieve better prognoses in future similar clinical scenarios.

Background: Traffic-related pollution is associated with the onset of asthma and the development of different phenotypes of asthma. Few studies have investigated the association between traffic proximity and late-onset of asthma (LOA) and early-onset asthma (EOA). This study was conducted to investigate the associations of LOA phenotypes with a function of the distance between residence and heavy traffic roads (HTRs).Methods: The study group consisted of 280 patients who were (LOA: 78.4%) recruited consecutively from a pay-for-performance asthma program to clarify the patient characteristics and proximity to HTRs within 1,000 m from their residences between EOA and LOA in three urban centers in Taiwan. The subsequent analysis focused on patients with LOA (n = 210) linking phenotypes and distance to HTRs.Results: Subjects with LOA tended to be older than those with EOA and had shorter asthma duration, poorer lung function, lower atopy, and less exposure to fumes or dust at home. Patients with LOA were more likely than those with EOA to live within 900 m of two or more HTRs (14.3 vs. 3.4%, p = 0.02). Among patients with LOA, minimum distance to an HTR was negatively associated with numbers of specific IgE as well as positively associated with the age of onset and body weight significantly. A higher proportion of patients with atopy (26.3 vs. 20.6%, p = 0.001. odds ratio [OR]: 2.82) and anxiety/depression (21.0 vs. 18.1%, p = 0.047. OR: 1.81) and a trend of lower proportion of patients with obese (5.7 vs. 12.4%, p = 0.075) were found to be living within 900 m from HTRs.Conclusions: Late-onset of asthma (LOA) tended to live in areas of higher HTR density compared to EOAs. Among patients with LOA living close to HTRs, the interaction between traffic-related pollution, allergy sensitization, and mood status were the factors associated with asthma onset early. Obesity may be the factor for later onset who live far from HTRs.

Medium-chain triacylglycerides (MCTs) are dietary supplements that can induce ketosis without the need for a traditional ketogenic diet or prolonged fasting. They have the potential to marginally delay the progression of neurodegenerative diseases, such as Alzheimer's disease. However, there have been inconsistencies in reports of the MCT dose–response relationship, which may be due to differences in MCT composition, participant characteristics, and other factors that can influence ketone generation. To resolve these discrepancies, we reviewed studies that investigated the ketogenic effect of MCTs in healthy adults. Aside from the treatment dose, other factors that can influence the ketogenic response, such as accompanying meals, fasting duration, and caffeine intake, were assessed. Based on the available literature, four practical recommendations are made to optimize the ketogenic effect of MCTs and reduce unwanted side effects (primarily gastrointestinal discomfort and diarrhea). First, the starting dose should be either 5 g of octanoic acid [caprylic acid (C8); a component of MCTs] or 5 g of a combination of C8 and decanoic or capric acid (C10; another component of MCTs), and the dose should be progressively increased to 15–20 g of C8. Second, MCTs should be consumed after an overnight fast, without an accompanying meal if tolerable, or with a low-carbohydrate meal. Third, the addition of caffeine may slightly increase the ketogenic response. Fourth, emulsifying the MCTs might increase their ketogenic effect and alleviate side effects.

ObjectivesTwo kinds of epidemic surveillance models are presented for containing the spread of SARS-CoV-2 variants so as to avert and stamp out a community-acquired outbreak (CAO) with non-pharmaceutical interventions (NPIs), tests, and vaccination.DesignThe surveillance of domestic cluster infections transmitted from imported cases with one-week time lag assessed by the Poisson model and the surveillance of whether, how and when NPIs and test contained the CAO with the SEIR model.SettingsBorder and Community of Taiwan.Main Outcome MeasurementsThe expected number and the upper bound of the 95% credible interval (CrI) of weekly covid-19 cases compared with the observed number for assessing the threshold of a CAO; effective reproductive number (Rt) and the effectiveness of NPIs for containing a CAO.ResultsFor the period of January-September 2020 when the wild type and the D614G period were prevailing, an increase in one imported case prior to one week would lead to 9.54% (95% CrI 6.44% to 12.59%) higher risk of domestic cluster infection that provides a one-week prior alert signal for more stringent NPIs and active testing locally. Accordingly, there was an absence of CAO until the Alpha VOC period of February 2021. However, given level one of NPI alert the risk of domestic cluster infections was gradually elevated to 14.14% (95% CrI 5.41% to 25.10%), leading to the Alpha VOC CAOs of six hotspots around mid-May 2021. It took two-and-half months for containing this CAO mainly with level three of NPI alert and rapid test and partially by the rolling out of vaccination. By applying the SEIR model, the Rt decreased from 4.0 at beginning to 0.7 on 31 July 2021 in parallel with the escalating NPIs from 30% to 90%. Containing a small outbreak of Delta VOC during this CAO period was also evaluated and demonstrated. After controlling the CAO, it again returned to imported-domestic transmission for Delta VOC from July until September 2021, giving an estimate of 10.16% (95% CrI: 7.01% to 13.59%) for the risk of several small cluster infections. However, there was an absence of CAO that resulted from the effectiveness of NPIs and tests, and the rapid expansion of vaccination.ConclusionsAverting and containing CAOs of SARS-CoV-2 variants are demonstrated by two kinds of epidemic surveillance models that have been applied to Taiwan scenario. These two models can be accommodated to monitor the epidemic of forthcoming emerging SARS-CoV-2 VOCs with various circumstances of vaccine coverage, NPIs, and tests in countries worldwide.

Seeing double can be a good thingMany human breast cancers harbor activating mutations inPIK3CA, the gene coding for the catalytic subunit of phosphoinositide 3-kinase (PI3K). Clinical trials are underway to evaluate the efficacy of PI3K inhibitors in cancer patients. Vasanet al.found unexpectedly that a subset of breast cancers harbor not one—but two—PIK3CAmutations, and the mutations occur on the same allele (see the Perspective by Toker). In model systems, the double mutations hyperactivate PI3K signaling and enhance tumor growth. Preliminary analysis of clinical trial data suggests that breast cancers with double mutations are more responsive to PI3K inhibitors than those with a single mutation.PIK3CAmutational status could help identify the breast cancer patients most likely to benefit from these drugs.Science, this issue p.714; see also p.685

Peritoneal dissemination is the most frequent metastatic route of ovarian cancer. However, due to the high heterogeneity in ovarian cancer, most conventional studies lack parental tumor controls relevant to metastases and, thus, it is difficult to trace the molecular changes of cancer cells along with the selection by the abdominal microenvironment. Here, we established an in vivo mouse peritoneal dissemination scheme that allowed us to select more aggressive sublines from parental ovarian cancer cells, including A2780 and SKOV‐3. Microarray and gene profiling analyses indicated that autophagy‐related genes were enriched in selected malignant sublines. Detection of LC3‐II, p62 and autophagic puncta demonstrated that these malignant variants were more sensitive to autophagic induction when exposed to diverse stress conditions, such as high cell density, starvation and drug treatment. As compared with parental A2780, the selected variant acquired the ability to grow better under high‐density stress; however, this effect was reversed by addition of autophagic inhibitors or knockdown of ATG5. When analyzing the clinical profiles of autophagy‐related genes identified to be enriched in malignant A2780 variant, 73% of them had prognostic significance for the survival of ovarian cancer patients. Taken together, our findings indicate that an increase in autophagic potency among ovarian cancer cells is crucial for selection of metastatic colonies in the abdominal microenvironment. In addition, the derived autophagic gene profile can not only predict prognosis well but can also be potentially applied to precision medicine for identifying those ovarian cancer patients suitable for taking anti–autophagy cancer drugs.

Cannulation in low birth weight (LBW) neonates using larger sheaths could increase the risk of vascular injury. This study investigated the relationship between body weight (BW) and diameter of femoral vessels in LBW neonates and whether BW can be used to predict femoral vessel diameter.The cohort included 100 neonates weighing 2.5 kg (.57-2.42 kg) with a gestational age of 24-39 weeks. Vascular ultrasonography was used to measure diameters of the bilateral femoral arteries (FA) and veins (FV). The cohort was divided into four groups according to weight: group-A, 2-2.49 kg (n = 28); group-B, 1.5-1.99 kg (n = 38); group-C, 1-1.49 kg (n = 21); and group-D, 1 kg (n = 13); or according to BSA: group-A, BSA .16 mThe median vessel diameters (mm) in groups A-D according to weight were FA, 1.96, 1.86, 1.78, and 1.53, and FV, 2.30, 2.28, 2.13, and 1.87, respectively. The median vessel diameters (mm) in groups A-D according to BSA were FA, 1.96, 1.86, 1.76, and 1.53, and FV, 2.30, 2.28, 2.05, and 1.87, respectively. There were positive correlations between BW and femoral vessel diameter (correlation coefficient: .56 and .55 between BW and FA and FV, respectively) (p 0.001), and between BSA and femoral vessel diameter (correlation coefficient: .56 and .55 between BSA and FA and FV, respectively) (p 0.001).BW is a predictor of femoral vessel diameter in LBW newborns. This finding may help to avoid using larger sheath in smaller vessels.

Background Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of trinucleotide CAG repeat in the Huntingtin (Htt) gene. The major pathogenic pathways underlying HD involve the impairment of cellular energy homeostasis and DNA damage in the brain. The protein kinase ataxia-telangiectasia mutated (ATM) is an important regulator of the DNA damage response. ATM is involved in the phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK plays a critical role in response to DNA damage. Herein, we demonstrated that expression of polyQ-expanded mutant Htt (mHtt) enhanced the phosphorylation of ATM. Ginsenoside is the main and most effective component of Panax ginseng. However, the protective effect of a ginsenoside (compound K, CK) in HD remains unclear and warrants further investigation. Methods This study used the R6/2 transgenic mouse model of HD and performed behavioral tests, survival rate, histological analyses, and immunoblot assays. Results The systematic administration of CK into R6/2 mice suppressed the activation of ATM/AMPK and reduced neuronal toxicity and mHTT aggregation. Most importantly, CK increased neuronal density and lifespan and improved motor dysfunction in R6/2 mice. Conversely, CK enhanced the expression of Bcl2 protected striatal cells from the toxicity induced by the overactivation of mHtt and AMPK. Conclusions Thus, the oral administration of CK reduced the disease progression and markedly enhanced lifespan in the transgenic mouse model (R6/2) of HD.

The TGF-β superfamily members and their antagonists comprise an indispensable system that controls mammalian ovarian development in a sophisticated manner. In contrast to a plethora of studies on the ovary-expressed TGF-β superfamily members, knowledge regarding their antagonists, including their expression profiles and antagonism preferences, is still lacking. Using quantitative PCR in rats and transcriptomic dataset comparisons in mice and humans, we set out to characterize the relative expression levels of most antagonists in the mammalian ovary. We found that Twsg1 and Nbl1 are the most abundant BMP antagonists expressed in the rodent and human ovaries, respectively. TWSG1 has been reported to have synergistic action with the chordin subfamily, including CHRD and CHRDL1, the genes of which also showed moderate expression in the mammalian ovary. Therefore, their ovarian expression profiles and antagonisms against the ovary-expressed TGF-β superfamily members were further characterized. Bioactivity tests indicated that TWSG1 alone can directly inhibit the signaling of BMP6 or BMP7. In addition, it can further enhance the antagonizing ability of CHRD towards BMP2, BMP4, BMP7 and GDF5, or CHRDL1's antagonism towards BMP2, BMP4, GDF5 and activin A. In combination with their distinct transcript profiles in ovarian compartments, our findings suggest that TWSG1 may work coordinately with CHRD within theca/interstitial shells and also with CHRDL1 in developing granulosa cells; these interactions would modulate the intraovarian functions of the TGF-β superfamily members, such as the control of progesterone production.

Background Global burden of COVID-19 has not been well studied, disability-adjusted life years(DALYs) and value of statistical life(VSL) metrics were therefore proposed to quantify its impacts on health and economic loss globally. Methods The life expectancy, cases, and death numbers of COVID-19 until 30th April 2021 were retrieved from open data to derive the epidemiological profiles and DALYs (including years of life lost (YLL) and years loss due to disability (YLD)) by four periods. The VSL estimates were estimated by using hedonic wage method(HWM) and contingent valuation method(CVM). The estimate of willingness to pay using CVM was based on the meta-regression mixed model. Machine learning method was used for classification. Results Globally, DALYs (in thousands) due to COVID-19 was tallied as 31,930 from Period I to IV. YLL dominated over YLD. The estimates of VSL were US$591 billion and US$5,135 billion based on HWM and CVM, respectively. The estimate of VSL increased from US$579 billion in Period I to US$2160 billion in Period IV using CVM. The higher the human development index(HDI), the higher the value of DALYs and VSL. However, there exits the disparity even at the same level of HDI. Machine learning analysis categorized eight patterns of global burden of COVID-19 with a large variation from US$0.001 billion to US$691.4 billion. Conclusions Global burden of COVID-19 pandemic resulted in substantial health and value of life loss particularly in developed economies. Classifications of such health and economic loss is informative to early preparation of adequate resource to reduce impacts.

BACKGROUND: As Coronavirus disease 2019 (COVID-19) pandemic led to the unprecedent large-scale repeated surges of epidemics worldwide since the end of 2019, data-driven analysis to look into the duration and case load of each episode of outbreak worldwide has been motivated. METHODS: Using open data repository with daily infected, recovered and death cases in the period between March 2020 and April 2021, a descriptive analysis was performed. The susceptible-exposed-infected-recovery model was used to estimate the effective productive number (Rt). The duration taken from Rt > 1 to Rt

Rationale: The progression of prostate cancer (PCa) to castration-resistant PCa (CRPC) despite continuous androgen deprivation therapy is a major clinical challenge. Over 90% of patients with CRPC exhibit sustained androgen receptor (AR) signaling. KDM4B that removes the repressive mark H3K9me3/2 is a transcriptional activator of AR and has been implicated in the development of CRPC. However, the mechanisms of KDM4B involvement in CRPC remain largely unknown. Here, we sought to demonstrate the molecular pathway mediated by KDM4B in CRPC and to provide proof-of-concept evidence that KDM4B is a potential CRPC target. Methods: CRPC cells (C4-2B or CWR22Rv1) depleted with KDM4B followed by cell proliferation (in vitro and xenograft), microarray, qRT-PCR, Seahorse Flux, and metabolomic analyses were employed to identify the expression and metabolic profiles mediated by KDM4B. Immunoprecipitation was used to determine the KDM4B-c-Myc interaction region. Reporter activity assay and ChIP analysis were used to characterize the KDM4B-c-Myc complex-mediated mechanistic actions. The clinical relevance between KDM4B and c-Myc was determined using UCSC Xena analysis and immunohistochemistry. Results: We showed that KDM4B knockdown impaired CRPC proliferation, switched Warburg to OXPHOS metabolism, and suppressed gene expressions including those targeted by c-Myc. We further demonstrated that KDM4B physically interacted with c-Myc and they were co-recruited to the c-Myc-binding sequence on the promoters of metabolic genes (LDHA, ENO1, and PFK). Importantly, KDM4B and c-Myc synergistically promoted the transactivation of the LDHA promoter in a demethylase-dependent manner. We also provided evidence that KDM4B and c-Myc are co-expressed in PCa tissue and that high expression of both is associated with worse clinical outcome. Conclusions: KDM4B partners with c-Myc and serves as a coactivator of c-Myc to directly enhance c-Myc-mediated metabolism, hence promoting CRPC progression. Targeting KDM4B is thus an alternative therapeutic strategy for advanced prostate cancers driven by c-Myc and AR.

Background The interaction between the pulmonary function and cardiovascular mechanics is a crucial issue, particularly when treating patients with chronic obstructive pulmonary disease (COPD). Synchrogram index is a new parameter that can quantify this interaction and has the potential to apply in COPD patients. Our objective in this study was to characterize cardiorespiratory interactions in terms of cardiorespiratory coupling (CRC) using the synchrogram index of the heart rate and respiratory flow signals in patients with chronic obstructive pulmonary disease. Methods This is a cross-sectional and preliminary data from a prospective study, which examines 55 COPD patients. K-means clustering analysis was applied to cluster COPD patients based on the synchrogram index. Linear regression and multivariable regression analysis were used to determine the correlation between the synchrogram index and the exercise capacity assessed by a six-minute walking test (6MWT). Results The 55 COPD patients were separated into a synchronized group (median 0.89 (0.64–0.97), n = 43) and a desynchronized group (median 0.23 (0.02–0.51), n = 12) based on K-means clustering analysis. Synchrogram index was correlated significantly with six minutes walking distance (r = 0.42, p = 0.001) and distance saturation product (r = 0.41, p = 0.001) assessed by 6MWT, and still was an independent variable by multivariable regression analysis. Conclusion This is the first result studying the heart–lung interaction in terms of cardiorespiratory coupling in COPD patients by the synchrogram index, and COPD patients are clustered into synchronized and desynchronized groups. Cardiorespiratory coupling is associated with exercise capacity in patients with COPD.

Malaria persists as a major health problem due to the spread of drug resistance and the lack of effective vaccines. DNA gyrase is a well-validated and extremely effective therapeutic target in bacteria, and it is also known to be present in the apicoplast of malarial species, including Plasmodium falciparum. This raises the possibility that it could be a useful target for novel antimalarials. To date, characterization and screening of this gyrase have been hampered by difficulties in cloning and purification of the GyrA subunit, which is necessary together with GyrB for reconstitution of the holoenzyme. To overcome this, we employed a library of compounds with specificity for P. falciparum GyrB and assessed them in activity tests utilizing P. falciparum GyrB together with Escherichia coli GyrA to reconstitute a functional hybrid enzyme. Two inhibitory compounds were identified that preferentially inhibited the supercoiling activity of the hybrid enzyme over the E. coli enzyme. Of these, purpurogallin (PPG) was found to disrupt DNA binding to the hybrid gyrase complex and thus reduce the DNA-induced ATP hydrolysis of the enzyme. Binding studies indicated that PPG showed higher-affinity binding to P. falciparum GyrB than to the E. coli protein. We suggest that PPG achieves its inhibitory effect on gyrase through interaction with P. falciparum GyrB leading to disruption of DNA binding and, consequently, reduction of DNA-induced ATPase activity. The compound also showed an inhibitory effect against the malaria parasite in vitro and may be of interest for further development as an antimalarial agent.

While the efficacy of population-based screening for colorectal cancer (CRC) with the fecal occult blood test (FOBT) has been demonstrated in several randomized controlled trials the results on cost-effectiveness analysis using a probabilistic approach has been barely investigated. In this chapter, we first proposed the framework of economic evaluation for population-based screening for CRC and then reviewed the results in literature on various screening methods. We also demonstrate a case study with the application of the analytical Markov decision model to evaluating different screening strategies with particular emphasis on fecal immunochemical test (FIT) that has been implemented in Taiwan since 2000. The probabilistic cost-effectiveness analysis was performed to evaluate annual, biennial, and triennial FIT as opposed to no screening. We found biennial FIT was cost saving compared with the annual g-FOBT test. The probability of being cost-effective was up to 80% given 20,000 WTP. Performing cost-effective analysis with a probabilistic approach plays a crucial in evidence-based medicine for population-based screening policy.

Background and aim Appropriate sedation is important to the success of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Dexmedetomidine is a sedative agent that operates via the α2 adrenergic agonist, which provides sleep-like sedation with little respiratory suppression. This study compared the efficacy and safety of dexmedetomidine sedation with propofol in cases of EBUS-TBNA. Methods Patients requiring EBUS-TBNA were randomly assigned dexmedetomidine sedation (D, n=25) or propofol sedation (P, n=25). Vital signs, diagnostic yield and the bispectral index (BIS) were recorded throughout the bronchoscopic procedure and recovery period. The tolerance and cooperation of the patients were evaluated using questionnaires. Measurements and results The lowest mean arterial blood pressure in group D (79.2±9.9 versus 72.5±12.9 mmHg, p=0.049) exceeded that in group P, the lowest heart rate was lower (60.9±10.2 versus 71.4±11.8 beats·min−1, p=0.006) and the mean BIS during sedation was significantly higher (84.1±8.3 versus 73.6±5.7, p, Compared to propofol sedation for EBUS-TBNA, dexmedetomidine provided patients lighter sedation with lower heart rates and less decrease in blood pressure. The recovery times, hypoxaemia, cooperation and diagnostic yield in the two groups were similar. https://bit.ly/33qgEj3

While vaccines are vital for preventing COVID-19 infections, it is critical to develop new therapies to treat patients who become infected. Pharmacological targeting of a host factor required for viral replication can suppress viral spread with a low probability of viral mutation leading to resistance. In particular, host kinases are highly druggable targets and a number of conserved coronavirus proteins, notably the nucleoprotein (N), require phosphorylation for full functionality. In order to understand how targeting kinases could be used to compromise viral replication, we used a combination of phosphoproteomics and bioinformatics as well as genetic and pharmacological kinase inhibition to define the enzymes important for SARS-CoV-2 N protein phosphorylation and viral replication. From these data, we propose a model whereby SRPK1/2 initiates phosphorylation of the N protein, which primes for further phosphorylation by GSK-3α/β and CK1 to achieve extensive phosphorylation of the N protein SR-rich domain. Importantly, we were able to leverage our data to identify an FDA-approved kinase inhibitor, Alectinib, that suppresses N phosphorylation by SRPK1/2 and limits SARS-CoV-2 replication. Together, these data suggest that repurposing or developing novel host-kinase directed therapies may be an efficacious strategy to prevent or treat COVID-19 and other coronavirus-mediated diseases.

Background Postoperative positive pressure lung expansion is associated with decreased pulmonary complications and improved clinical outcomes. The aim of the present study was to compare the differences in post-operative pulmonary complications and clinical outcomes between two groups of study subjects who underwent cardiac surgery; one included subjects who received mechanical insufflation-exsufflation (MI-E) and the other included subjects who received intermittent positive pressure breathing (IPPB) therapy. Methods This retrospective study included 51 subjects, who underwent cardiac surgery in an intensive care unit of a tertiary hospital during the time period from June 2017 to February 2018. After liberation from mechanical ventilation, the subjects received lung expansion therapy by means of two types of positive pressure devices, MI-E (n = 21) or IPPB (n = 30). The pulmonary complications, lung function, and clinical outcomes were compared between the two groups. Results Subjects in both groups displayed similar baseline characteristics and underwent similar types of surgical procedures. Compared to subjects who received non-oscillatory therapy, those who received MI-E therapy had higher post-operative force vital capacity (58.4 ± 4.74% vs. 46.0 ± 3.70%, p = 0.042), forced expiratory volume in one second (62.4 ± 5.23% vs. 46.8 ± 3.83%, p = 0.017), and peak flow rate (67.1 ± 5.53 L vs. 55.7 ± 4.44 L p = 0.111). However, the incidence of chest pain was higher in the MI-E group (n = 13, 61.9%) than in the IPPB group (n = 4, 16.7%; odds ratio, 0.123, 95% confidence interval, 0.03–0.45; p = 0.002). The length of hospital and ICU stay, development of atelectasis, pneumonia, and pleural effusion were similar in both the groups. Conclusion Both IPPB and MI-E therapies have similar effects on preventing post-operative complications in cardiac surgery patients. However, compared to IPPB therapy, MI-E therapy was associated with better-preserved pulmonary function and higher incidence of chest pain.

Few studies quantify a cascade of dynamic transitions on the detailed components of metabolic syndrome (MetS) and subsequent progressions to cardiovascular disease (CVD) and its death. A total of 47,495 subjects repeatedly attending a community-based integrated screening program in Taiwan were recruited. The refined MetS-related classification (RMRC) in relation to five criteria of MetS was defined as free of metabolic disorder (FMD, none of any criteria), mild metabolic disorder (MMD, 1–2 criteria) and MetS. A multistate Markov model was used for modelling such a multistate process. The estimated progression rate from FMD to MMD was 44.82% (95% CI 42.95–46.70%) whereas the regression rate was estimated as 29.11% (95% CI 27.77–30.45%). The progression rate from MMD to MetS was estimated as 6.15% (95% CI 5.89–6.42%). The estimated annual incidence rates of CVD increased with the severity of RMRC, being 1.62% (95% CI 1.46–1.79%) for FMD, 4.74% (95% CI 4.52–4.96%) for MMD, to 20.22% (95% CI 19.52–20.92%) for MetS. The estimated hazard rate of CVD death was 6.1 (95% CI 4.6–7.7) per thousand. Elucidating the dynamics of MetS-related transition and quantifying the incidence and prognosis of CVD provide a new insight into the design and the evaluation of intervention programs for CVD.

Background: The impact of remdesivir on length of stay of hospitalization, high-risk state, and death stratified by the severity of COVID-19 at enrollment is controversial. Methods: We applied a simulated two-arm controlled study design to the data on compassionate use of remdesivir as a secondary analysis. Dynamics of risk states and death from COVID-19 patients defined by the six-point disease severity recommended by the WHO R&D and the time to discharge from hospital were used to evaluate the efficacy of remdesivir treatment compared with standard care. Results: Stratified by the risk state at enrollment, low-risk patients exhibited the highest efficacy of remdesivir in reducing subsequent progression to high-risk state by 67% (relative risk (RR)=0.33,95% CI: 0.30-0.35) and further to death by 55% (RR=0.45, 95%CI: 0.39-0.50). For the medium-risk patients, less but still statistically significant efficacy results were noted in reducing progression to high-risk state by 52% (RR=0.48, 95% CI: 0.45-0.51) and further to death by 40% (RR=0.60, 95% CI:0.54-0.66). High-risk state patients treated with remdesivir led to a 25% statistically significant reduction in death (RR=0.75, 95% CI: 0.69-0.82). Regarding the outcome of discharge, remdesivir treatment was most effective for medium-risk patients at enrollment (RR: 1.41, 95% CI: 1.35-1.47) followed by high- (RR=1.34, 95% CI: 1.27-1.42) and low-risk patients (RR=1.28, 95% CI: 1.25-1.31). Conclusion: Our results with a simulated two-arm controlled study have provided a new insight into the precision treatment of remdesivir for COVID-19 patients based on risk-stratified efficacy.

Among many cancers, breast cancer is the second most common cause of death in women. Early detection and early treatment reduce breast cancer mortality. Mammography plays an important role in breast cancer screening because it can detect early breast masses or calcification region. One of the drawbacks in breast mammography is breast cancer masses are more difficult to be found in extremely dense breast tissue. We select 106 breast mammography images with masses from INbreast database. Through data augmentation, the number of breast mammography images was increased to 7632. We utilize data augmentation on breast mammography images, and then apply the Convolutional Neural Networks (CNN) models including AlexNet, DenseNet, and ShuffleNet to classify these breast mammography images.

The aim of this study was to develop a simplified screening questionnaire to detect the existence of severe obstructive sleep apnea (OSA) in chronic obstructive pulmonary disease (COPD) patients to reduce mortality and hospitalization rates. Seventy-seven stable Asian COPD patients aged 69.2 ± 11.5 years were retrospectively analyzed into the development group. The simplified screening questionnaire was developed from factors identified from sleep surveys and demographic data to predict severe OSA. Receiver operating characteristic (ROC) curve analysis was used to validate the simplified screening questionnaire. Data from another 78 stable COPD patients were used for validation. The apnea-hypopnea index was similar between the development and validation groups (26.3 ± 21.9 and 27.6 ± 21.1, respectively). After logistic regression analysis in the development group, snoring, body mass index ≥27.5 kg/m2, witnessed apnea and coronary artery disease were incorporated into the screening questionnaire to predict OSA. When this questionnaire was applied to the validation group, the results were similar. The simplified screening questionnaire developed is useful in identifying severe OSA in COPD patients.

// Chien-Ying Liu 1, 2 , Chih-Liang Wang 1, 2 , Shih-Hong Li 1 , Ping-Chih Hsu 1 , Chih-Hung Chen 1 , Ting-Yu Lin 1, 2 , Chih-Hsi Kuo 1, 2 , Yueh-Fu Fang 1, 2 , How-Wen Ko 1 , Chih-Teng Yu 1, 2 , Tai-Yun Yang 1, 2 and Cheng-Ta Yang 1, 2 1 Division of Pulmonary Oncology, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan 2 School of Medicine, Chang Gung University, Taoyuan, Taiwan Correspondence to: Cheng-Ta Yang, email: yang1946@cgmh.org.tw Keywords: afatinib, dose de-escalation, epidermal growth factor mutations, lung adenocarcinoma, therapeutic efficacy Received: January 12, 2017 Accepted: March 22, 2017 Published: June 27, 2017 ABSTRACT The choice of a first-line therapy for lung cancer is a crucial decision that can impact the survival as well as the quality of life of a patient. Inhibitors of epidermal growth factor receptor (EGFR) such as afatinib, erlotinib, and gefitinib have previously been used to treat non-small cell lung cancer harboring favorable EGFR mutations. Although afatinib has greater efficacy than other EGFR inhibitors, adverse events related to its use can result in the discontinuation of the therapy. In this study, we compared the therapeutic efficacy in lung cancer patients of a regimen of 40 mg/day of afatinib with that of a lower dose regimen of

The tautomeric pair of garcinielliptone FC (GFC) is a novel tautomeric pair of polyprenyl benzophenonoid isolated from the pericarps of Garcinia subelliptica Merr. (G. subelliptica, Clusiaceae), a tree with abundant sources of polyphenols. Our previous report demonstrated that GFC induced apoptosis on various types of human cancer cell lines including chemoresistant human colorectal cancer HT-29 cells. In the present study, we observed that many autophagy-related genes in GFC-treated HT-29 cells were up- and down-regulated using a cDNA microarray containing oncogenes and kinase genes. GFC-induced autophagy of HT-29 cells was confirmed by observing the formation of acidic vesicular organelles, LC3 puncta, and double-membrane autophagic vesicles using flow cytometry, confocal microscopy, and transmission electron microscopy, respectively. Inhibition of AKT/mTOR/P70S6K signaling as well as formation of Atg5-Atg12 and PI3K/Beclin-1 complexes were observed using Western blot. Administration of autophagy inhibitor (3-methyladenine and shRNA Atg5) and apoptosis inhibitor Z-VAD showed that the GFC-induced autophagy was cytotoxic form and GFC-induced apoptosis enhanced GFC-induced autophagy. Our data suggest the involvement of autophagy and apoptosis in GFC-induced anticancer mechanisms of human colorectal cancer.

Traditional hydrodissection may cause posterior capsule rupture (PCR) if excessive fluid accumulates. In this study, we describe the successful application of a novel minimal fluid hydrodissection technique in 100 consecutive cataract surgery cases. This technique separates the nucleus from the capsule utilizing low hydrostatic pressure and precise kinetic movement of a small volume (around 0.2 cc) of balanced salt solution. There were no instances of PCR. This technique is suitable for a range of cases, including femtosecond laser-assisted cataract surgery and posterior subcapsular cataract.