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SummaryThe objective of this study was to evaluate the safety and tolerability of DS-1205c, an oral AXL-receptor inhibitor, in combination with osimertinib in metastatic or unresectable EFGR-mutant non-small cell lung cancer (NSCLC) patients who developed disease progression during EGFR tyrosine kinase inhibitor (TKI) treatment. An open-label, non-randomized phase 1 study was conducted in Taiwan, in which 13 patients received DS-1205c monotherapy at a dosage of 200, 400, 800, or 1200 mg twice daily for 7 days, followed by combination treatment with DS-1205c (same doses) plus osimertinib 80 mg once daily in 21-day cycles. Treatment continued until disease progression or other discontinuation criteria were met. At least one treatment-emergent adverse event (TEAE) was reported in all 13 patients treated with DS-1205c plus osimertinib; with ≥ 1 grade 3 TEAE in 6 patients (one of whom also had a grade 4 increased lipase level), and 6 patients having ≥ 1 serious TEAE. Eight patients experienced ≥ 1 treatment-related AE (TRAE). The most common (2 cases each) were anemia, diarrhea, fatigue, increased AST, increased ALT, increased blood creatinine phosphokinase, and increased lipase. All TRAEs were non-serious, with the exception of an overdose of osimertinib in 1 patient. No deaths were reported. Two-thirds of patients achieved stable disease (one-third for > 100 days), but none achieved a complete or partial response. No association between AXL positivity in tumor tissue and clinical efficacy was observed. DS-1205c was well-tolerated with no new safety signals in patients with advanced EGFR-mutant NSCLC when administered in combination with the EFGR TKI osimertinib. ClinicalTrials.gov; NCT03255083.

Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic-phenotypic databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world's population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption. Agency for Science, Technology and Research (A*STAR) Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) We thank all investigators, staf members and study participants of the contributing cohorts and studies: (1) the HELIOS study at the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; (2) the GUSTO study jointly hosted by the National University Hospital, KK Women’s and Children’s Hospital, the National University of Singapore and the Singapore Institute for Clinical Sciences, the Agency for Science Technology and Research (A*STAR); (3) the SEED cohort at the Singapore Eye Research Institute; (4) the MEC, National University of Singapore; (5) the PRISM cohort; and (6) the TTSH Personalised Medicine Normal Controls cohort. We also thank the National Supercomputing Centre, Singapore (https://www.ncss.sg) for computation resources. The SG10K_Health project is funded by the Industry Alignment Fund (Pre-Positioning) (IAF-PP, H17/01/a0/007); the project made use of participating study cohorts supported by the following funding sources: (1) the HELIOS study by grants from a Strategic Initiative at Lee Kong Chian School of Medicine, the Singapore MOH under its Singapore Translational Research Investigator Award (NMRC/STaR/0028/2017) and the IAF-PP (H18/01/a0/016); (2) the GUSTO study by the Singapore National Research Foundation under its Translational and Clinical Research Flagship Program and administered by the Singapore MOH’s National Medical Research Council Singapore (NMRC/TCR/004-NUS/2008, NMRC/ TCR/012-NUHS/2014) with additional funding support available through the A*STAR and the IAF-PP (H17/01/a0/005); (3) the SEED study by NMRC/CIRG/1417/2015, NMRC/CIRG/1488/2018 and NMRC/OFLCG/004/2018; (4) the MEC by individual research and clinical scientist award schemes from the Singapore National Medical Research Council (including MOH-000271-00) and the Singapore Biomedical Research Council, the Singapore MOH, the National University of Singapore and the Singapore National University Health System; (5) the PRISM cohort study by NMRC/CG/ M006/2017_NHCS, NMRC/STaR/0011/2012, NMRC/STaR/0026/2015, the Lee Foundation and the Tanoto Foundation; and (6) the TTSH cohort study by NMRC/CG12AUG2017 and CGAug16M012. This research is also supported by the National Research Foundation Singapore under its NPM program Phase II funding (MOH-000588) and administered by the Singapore MOH’s National Medical Research Council.

The incidence of Tourette syndrome and chronic tic disorders has seldom been evaluated in Asia.Using the National Taiwan Insurance Research Database, the annual standardized incidence and prevalence of Tourette syndrome (TS) and chronic tic disorders were estimated from 2007 to 2015. The pre-existing comorbidity at disease diagnosis was also evaluated.From 2007 to 2015, the age- and sex-standardized incidence increased from 5.34 (95% confidence interval [CI] 5.06-5.62) per 100,000 person-years to 6.87 (95% CI 6.53-7.21) per 100,000 person-years. In children and adolescents, the age- and sex-standardized incidence increased from 19.58 (95% CI 18.42-20.75) per 100,000 person-years to 31.79 (95% CI 30.09-33.49) per 100,000 person-years. In adults, the age- and sex-standardized incidence decreased from 2.01 (95% CI 1.79-2.23) per 100,000 person-years to 1.24 (95% CI 1.07-1.42) per 100,000 person-years. The incidence rate ratio (IRR) between males and females was 3.74 (95% CI 3.32-4.22). The age- and sex-standardized prevalence increased from 37.51 (95% CI 36.75-38.27) per 100,000 people in 2007 to 84.18 (95% CI 83.02-85.35) per 100,000 people in 2015. The rate risk (RR) between males and females was 3.65 (95% CI 3.53-3.78).The annual incidence rates of TS and chronic tic disorders increased in childhood and adolescence but decreased in adulthood from 2007 to 2015. The prevalence rates increased over the same period.

Renal defects in maturity onset diabetes of the young 3 (MODY3) patients and Hnf1a-/- mice suggest an involvement of HNF1A in kidney development and/or its function. Although numerous studies have leveraged on Hnf1α-/- mice to infer some transcriptional targets and function of HNF1A in mouse kidneys, species-specific differences obviate a straightforward extrapolation of findings to the human kidney. Additionally, genome-wide targets of HNF1A in human kidney cells have yet to be identified. Here, we leveraged on human in vitro kidney cell models to characterize the expression profile of HNF1A during renal differentiation and in adult kidney cells. We found HNF1A to be increasingly expressed during renal differentiation, with peak expression on day 28 in the proximal tubule cells. HNF1A ChIP-Sequencing (ChIP-Seq) performed on human pluripotent stem cell (hPSC)-derived kidney organoids identified its genome-wide putative targets. Together with a qPCR screen, we found HNF1A to activate the expression of SLC51B, CD24, and RNF186 genes. Importantly, HNF1A-depleted human renal proximal tubule epithelial cells (RPTECs) and MODY3 human induced pluripotent stem cell (hiPSC)-derived kidney organoids expressed lower levels of SLC51B. SLC51B-mediated estrone sulfate (E1S) uptake in proximal tubule cells was abrogated in these HNF1A-deficient cells. MODY3 patients also exhibit significantly higher excretion of urinary E1S. Overall, we report that SLC51B is a target of HNF1A responsible for E1S uptake in human proximal tubule cells. As E1S serves as the main storage form of nephroprotective estradiol in the human body, lowered E1S uptake and increased E1S excretion may reduce the availability of nephroprotective estradiol in the kidneys, contributing to the development of renal disease in MODY3 patients.

Blastocystis is a species complex that exhibits extensive genetic diversity, evidenced by its classification into several genetically distinct subtypes (ST). Although several studies have shown the relationships between a specific subtype and gut microbiota, there is no study to show the effect of the ubiquitous Blastocystis ST1 on the gut microbiota and host health. Here, we show that Blastocystis ST1 colonization increased the proportion of beneficial bacteria Alloprevotella and Akkermansia, and induced Th2 and Treg cell responses in normal healthy mice. ST1-colonized mice showed decreases in the severity of DSS-induced colitis when compared to non-colonized mice. Furthermore, mice transplanted with ST1-altered gut microbiota were refractory to dextran sulfate sodium (DSS)-induced colitis via induction of Treg cells and elevated short-chain fat acid (SCFA) production. Our results suggest that colonization with Blastocystis ST1, one of the most common subtypes in humans, exerts beneficial effects on host health through modulating the gut microbiota and adaptive immune responses.

Background Mixed evidence exists regarding the effectiveness of the Chronic Care Model (CCM) with patient outcomes. The aim of this review is to examine the effectiveness of CCM interventions on hemoglobin A1c (HbA1c), systolic BP (SBP), diastolic BP (DBP), LDL cholesterol and body mass index (BMI) among primary care adults with type 2 diabetes. Methods PubMed, Embase, CINAHL, Cochrane Central Registry of Controlled Trials, Scopus and Web of Science were searched from January 1990 to June 2021 for randomized controlled trials (RCTs) comparing CCM interventions against usual care among adults with type 2 diabetes mellitus in primary care with HbA1c, SBP, DBP, LDL cholesterol and BMI as outcomes. An abbreviated search was performed from 2021 to April 2022. This study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for data extraction and Cochrane risk of bias assessment. Two reviewers independently extracted the data. Meta-analysis was performed using Review Manager software. Heterogeneity was evaluated using χ2 and I2 test statistics. Overall effects were evaluated using Z statistic. Results A total of 17 studies involving 16485 patients were identified. Most studies had low risks of bias. Meta-analysis of all 17 studies revealed that CCM interventions significantly decreased HbA1c levels compared to usual care, with a mean difference (MD) of −0.21%, 95% CI −0.30, −0.13; Z = 5.07, p1c ≥8% (MD −0.36%, 95% CI −0.51, −0.21; Z = 5.05, pZ = 4.85, pZ = 3.75, p=0.0002) and DBP (MD −1.35 mmHg, 95% CI −2.05, −0.65, Z = 3.79, p=0.0002) compared to usual care but there was no impact on LDL cholesterol levels or BMI. Conclusions CCM interventions, compared to usual care, improve glycaemic control among adults with type 2 diabetes in primary care, with greater reductions when the mean baseline HbA1c is ≥8% and with interventions containing four or more CCM elements. Systematic review registration PROSPERO CRD42021273959

In the existing literature, the dynamic characteristics of the spinning shaft-disk systems are usually evaluated using the transfer matrix method (TMM), the finite element method (FEM) or the differential quadrature method (DQM). The results of the above-mentioned TMM, FEM or DQM are the approximate solutions and the exact solution concerned is rare. For this reason, this paper aims at presenting an analytical method to yield the exact whirling speeds and mode shapes of a “multi-span” continuous shaft mounted by arbitrary rigid disks. In theory, the whirling motion of a rotating shaft-disk system is three-dimensional (3-D), however, if the transverse displacement in the vertical principal xy-plane and that in the horizontal principal xz-plane for the cross-section of the rotating shaft located at axial coordinate x are combined using a complex number, and the effects of each rigid disk i mounted on the shaft are replaced by a lumped mass together with a frequency-dependent “equivalent” mass moment of inertia, then the whirling motion of a rotating shaft-disk system will be similar to the two-dimensional (2-D) transverse free vibration of a stationary beam. After the foregoing manipulations, the techniques for the free vibrations of a stationary beam carrying various concentrated elements (including the intermediate supports) will be available for the whirling motions of a rotating “multi-span” shaft mounted by arbitrary rigid disks. To confirm the reliability of presented theory and developed computer programs, most results obtained from the presented method are compared with the available literature or the results of FEM and good agreements are achieved. The presented method has the following merits: (a) The complicated 3-D whirling motions of a rotating shaft can be solved with the approaches for the simple 2-D free vibrations of a stationary beam, so that much computer time can be saved. (b) The damping matrix is eliminated so that the computer programming is easier. (c) The obtained results are the “exact” solutions and may be the benchmark for evaluating the accuracy of the other approximate methods.

The influences of different pre-treatment approaches, comprising sandblasting, grinding, chemical polishing, and plowing, and various anodizing parameters, including electrolyte composition, temperature, current density, time, and final voltage, on the quality of anodized aluminum oxide (AAO) film on AA 6061 were studied in the present research. It was found that, during both mild and hard anodization treatment, the thickness and microhardness of AAO film increased as the anodization current density increased. Under mild anodization treatment, when the current density increased from 0.5 to 2.0 A/dm2, the anodization efficiency decreased from 90 to 52% and 71 to 44% during the mild anodization treatment performed at 22°C and 0°C, respectively. However, on the other hand, the anodization efficiency increased from 55 to 56% and 57 to 64% when the current density increased from 7.0 to 8.0 A/dm2 during the hard anodization treatment carried out at 22°C and 0°C, respectively. Therefore, different AAO film formation mechanisms prevail during the mild and hard anodization treatment. Moreover, the microhardness of AAO film formed at 22°C or 0°C dropped heavily when the current density was higher than 9.0 A/dm2 due to the burning reaction. In addition, the AAO film can achieve higher hardness and resistance to corrosion through the sealing process, which can effectively decrease the size of the tubes due to the volume expansion effect (23%) after the sealing treatment.

Funder: Kjell och Märta Beijers Stiftelse (Kjell and Marta Beijer Foundation); doi: https://doi.org/10.13039/501100006353, Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

In recent years, research on image authentication and recovery using convolutional neural networks (CNNs) has attracted tremendous attention. Most existing studies on this topic treat such authentication and recovery simply as a type of pixel-wise annotation and prediction, that is, annotation of true/false labels on each pixel and predicting the value of each tampered pixel. However, such machine learning mechanisms show unstable performance and effectiveness. Classical digital watermarking techniques can secure the integrity of the data; thus, they can leverage the data to stabilize the machine-learning-based image authentication and recovery performance . Accordingly, this paper proposes a model that combines CNNs and classical digital watermarking techniques (DWTs); this assures the integrity of data by using the traditional image authentication method in the DWT domain. We examined the effectiveness and performance of the proposed approach against a few of the most popular image tampering attacks. We also compared our approach with several state-of-the-art works. Experimental results show that our proposal provides predominant tampering recognition. In addition, our proposed method can precisely recover tampered regions of a image.

Aims/hypothesisDiabetes progression and complication risk are different in Asian people compared with those of European ancestry. In this study, we sought to understand the epidemiology of diabetes-related lower extremity complications (DRLECs: symptomatic peripheral arterial disease, ulceration, infection, gangrene) and amputations in a multi-ethnic Asian population.MethodsThis was a retrospective observational study using data obtained from one of three integrated public healthcare clusters in Singapore. The population consisted of individuals with incident type 2 diabetes who were of Chinese, Malay, Indian or Other ethnicity. We examined incidence, time to event and risk factors of DRLECs and amputation.ResultsBetween 2007 and 2017, of the 156,593 individuals with incident type 2 diabetes, 20,744 developed a DRLEC, of whom 1208 underwent amputation. Age- and sex-standardised incidence of first DRLEC and first amputation was 28.29/1000 person-years of diabetes and 8.18/1000 person-years of DRLEC, respectively. Incidence of both was highest in individuals of Malay ethnicity (DRLEC, 36.09/1000 person-years of diabetes; amputation, 12.96/1000 person-years of DRLEC). Median time from diabetes diagnosis in the public healthcare system to first DRLEC was 30.5 months for those without subsequent amputation and 10.9 months for those with subsequent amputation. Median time from DRLEC to first amputation was 2.3 months. Older age (p p p p = 0.014), chronic comorbidities (nephropathy [p p p p p 1c(p p p = 0.002) eGFR, greater or missing BMI (p p p p p 1c(p p = 0.009) or missing (p p = 0.008) were associated with higher hazard of amputation in those with DRLEC. Indian ethnicity (p = 0.007) was associated with significantly lower hazard of amputation.Conclusions/interpretationThis study has revealed important ethnic differences in risk of diabetes-related lower limb complications, with Malays most likely to progress to DRLEC. Greater research efforts are needed to understand the aetiopathological and sociocultural processes that contribute to the higher risk of lower extremity complications among these ethnic groups.Graphical abstract

Sorafenib is a multikinase inhibitor used for treatment of advanced hepatocellular carcinoma. Sorafenib resistance may be related to Src-induced cell migration and angiogenesis, which are regulated by cancer stem cell activation and release of vascular endothelial growth factor. Dasatinib is a Src inhibitor that inhibits Src phosphorylation and suppresses Src-associated cell migration and angiogenesis. This study investigated whether combined treatment with dasatinib can overcome sorafenib resistance. Hepatoma cell lines were used for sorafenib and/or dasatinib treatment. Cell viability, cell migration, molecular expressions, and release of vascular endothelial growth factor by hepatoma cells were evaluated. Hepatoma cell culture medium was applied on human umbilical vein endothelial cells to monitor angiogenesis promoted by the hepatoma cells. Sorafenib and dasatinib combined therapy suppressed cell viability of hepatoma cells synergistically. Dasatinib suppressed sorafenib-induced cell migration via inhibiting sorafenib-induced Src/FAK phosphorylation, cell-to-cell contact and cancer stem cell activation. Culture medium from Chang liver and PLC/PRF/5 cells suppressed angiogenesis of human umbilical vein endothelial cells with any treatment, whereas sorafenib-treated medium of HepG2 cells induced angiogenesis. This sorafenib-induced angiogenesis was then suppressed by dasatinib. Vascular endothelial growth factor released from hepatoma cells was also inhibited by combined treatment. Src/FAK phosphorylation and cancer stem cell activation inducing cell migration and angiogenesis may be the key factors of sorafenib resistance. Sorafenib and dasatinib combined treatment suppresses cell migration and angiogenesis by inhibiting the Src/FAK phosphorylation, cell-to-cell contact, cancer stem cell activation, and release of vascular endothelial growth factor.

Along with the annually increasing elderly population, the issues particularly regarding the elderly care are gaining inevitable attention. Nursing and taking care of the elderly people is now the emphasized issue. Besides, the social phenomena of large urban–rural gap and population emigration cause serious shortage of nursing manpower. Among the needs for good care, falls present extreme risks in the elderly population. The shortage of nursing manpower causes the impossible provision of real-time-care for the elderly fall accidents. This study uses the three-axis accelerometer in Apple watch to measure the movement and to input it to the High-Level Fuzzy Petri Net (HLFPN) prediction model. Based on the HLFPN model, fuzzy reasoning is performed to predict the users’ daily motions including walking, sitting down, and falls. With the application to elderly exercise model, this system would transmit real-time positioning datasets when there are falls for the rapid and proper treatment so as to minimize the elderly injury caused by falls. Based on the experimental datasets regarding forward fall, backward fall, right-sided fall, and left-sided fall, the obtained precision values are 95.45%, 97.72%, 94.67%, and 95.12%, respectively. Walking, running, and falls could also be distinguished in this study. It is expected that this study could assist in solving the problem of nursing manpower shortage, providing immediate assistance for the elderly on the occasion of falls.

Adequate control of pharmacoresistant epilepsy continues to be a challenge. Multiple studies have reported the benefits of epilepsy surgery and vagus nerve stimulation for children with pharmacoresistant epilepsy. Little is known about the role of vagus nerve stimulation for children with failed epilepsy surgeries. The aim of this study was to examine the effects of vagus nerve stimulation on seizure frequency reduction for children with failed epilepsy surgeries. We retrospectively reviewed 85 children with pharmacoresistant epilepsy who underwent vagus nerve stimulation. Six of these patients underwent epilepsy surgery before vagus nerve stimulation (group I) and 79 patients received only vagus nerve stimulation (group II). We recorded seizure frequency at 3, 12, 24 and 36 months after vagus nerve stimulator implantation. Both groups had reduced seizure frequencies at the 3-, 12-, 24- and 36-month follow-up (p = 0.044 for group I trends and 0.008 for group II trends). Vagus nerve stimulator implantations significantly improve seizure frequency for children with or without previous epilepsy surgery at 3, 12, 24 and 36 months. These findings suggest that vagus nerve stimulation should be considered an alternative therapy for pediatric patients with previous failed surgeries.

Background The sign of contrast agent pooling (C.A.P.) in dependent part of the venous system were reported in some case reports, which happened in the patients before sudden cardiac arrest. Until now, there is no solid evidence enough to address the importance of the sign. This study aimed to assess the accuracy of the C.A.P. sign in predicting imminent cardiac arrest and the association of the C.A.P. sign with patient’s survival. Methods This is a retrospective cohort study. The study included all patients who visited the emergency department, who received contrast computed tomography (CT) scan and then experienced cardiac arrest at the emergency department (from January 1, 2016 to December 31, 2018). We evaluated the occurrence of the C.A.P. sign on the chest or abdominal CT scan, patients with ECMO were excluded. With positive C.A.P. sign, the primary outcome is whether in-hospital cardiac arrest happens within an hour; the accuracy of C.A.P. sign was calculated. The secondary outcome is survival to discharge. Results In the study, 128 patients were included. 8.6% (N = 11) patients had positive C.A.P. sign and 91.4% (N = 117) patients did not. The accuracy of C.A.P. sign in predicting cardiac arrest within 1 h was 85.94%. The C.A.P. sign had a positive association with IHCA within 1 h after the CT scan (adjusted odds ratio 7.35, 95% confidence interval [CI] 1.27 – 42.69). The relative risk (RR) of survival to discharge was 0.90 with positive C.A.P. sign (95% CI 0.85 – 0.96). Conclusions The C.A.P. sign can be considered as an alarm for imminent cardiac arrest and poor prognosis. The patients with positive C.A.P. sign were more likely to experience imminent cardiac arrest; in contrast, less likely to survive. Trial registration IRB No.108107-E.

Ectopic ceramide accumulation in insulin-responsive tissues contributes to the development of obesity and impairs insulin sensitivity. Moreover, pharmacological inhibition of serine palmitoyl transferase (SPT), the first enzyme essential for ceramide biosynthesis using myriocin in rodents reduces body weight and improves insulin sensitivity and associated metabolic indices. Myriocin was originally extracted from fruiting bodies of the fungus Isaria sinclairii and has been found abundant in a number of closely related fungal species such as the Cordyceps. Myriocin is not approved for human use but extracts from Cordyceps are routinely consumed as part of traditional Chinese medication for the treatment of numerous diseases including diabetes. Herein, we screened commercially available extracts of Cordyceps currently being consumed by humans, to identify Cordyceps containing myriocin and test the efficacy of Cordyceps extract containing myriocin in obese mice to improve energy and glucose homeostasis. We demonstrate that commercially available Cordyceps contain variable amounts of myriocin and treatment of mice with a human equivalent dose of Cordyceps extract containing myriocin, reduces ceramide accrual, increases energy expenditure, prevents diet-induced obesity, improves glucose homeostasis and resolves hepatic steatosis. Mechanistically, these beneficial effects were due to increased adipose tissue browning/beiging, improved brown adipose tissue function and hepatic insulin sensitivity as well as alterations in the abundance of gut microbes such as Clostridium and Bilophila. Collectively, our data provide proof-of-principle that myriocin containing Cordyceps extract inhibit ceramide biosynthesis and attenuate metabolic impairments associated with obesity. Moreover, these studies identify commercially available Cordyceps as a readily available supplement to treat obesity and associated metabolic diseases.

ispartof: SCIENTIFIC REPORTS vol:10 issue:1 ispartof: location:England status: published