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During the COVID-19 pandemic, contact tracing was used to identify individuals who had been in contact with a confirmed case so that these contacted individuals could be tested and quarantined to prevent further spread of the SARS-CoV-2 virus. Many countries developed mobile apps to find these contacted individuals faster. We evaluate the epidemiological effectiveness of the Dutch app CoronaMelder, where we measure effectiveness as the reduction of the reproduction number R. To this end, we use a simulation model of SARS-CoV-2 spread and contact tracing, informed by data collected during the study period (December 2020 - March 2021) in the Netherlands. We show that the tracing app caused a clear but small reduction of the reproduction number, and the magnitude of the effect was found to be robust in sensitivity analyses. The app could have been more effective if more people had used it, and if notification of contacts could have been done directly by the user and thus reducing the time intervals between symptom onset and reporting of contacts. The model has two innovative aspects: i) it accounts for the clustered nature of social networks and ii) cases can alert their contacts informally without involvement of health authorities or the tracing app., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, whereas supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome, and congenital anomalies. Inositol status can be influenced by diet, synthesis, transport, utilization, and catabolism., Objectives: We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites., Methods: GC-MS was used to determine plasma MI concentration of >2000 healthy, young adults (aged 18-28 y) from the Trinity Student Study. Genotyping data were used to test association of plasma MI with single nucleotide polymorphisms (SNPs) in candidate genes, encoding inositol transporters and synthesizing enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with d-chiro-inositol (DCI), glucose, and other metabolites by Spearman rank correlation., Results: Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 μM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11 (solute carrier family 5 member 11), encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (P < 5 × 10 -8 ). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (P < 1 × 10 -5 ), 3 of which were located within or close to genes: MTDH (metadherin), LAPTM4B (lysosomal protein transmembrane 4 β), and ZP2 (zona pellucida 2). We found significant positive correlation of plasma MI concentration with concentration of dci and several other biochemicals including glucose, methionine, betaine, sarcosine, and tryptophan., Conclusions: Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11, which is worthy of further investigation., (Copyright © 2022 American Society for Nutrition.)

Antenatal diagnosis of placenta accreta spectrum (PAS) disorders allows planned management by a multidisciplinary team in a tertiary center, and thus can reduce hemorrhagic morbidity, compared with intrapartum diagnosis. Previous Cesarean section and placenta previa are the two most common risk factors. Prenatal ultrasound is a promising diagnostic tool for PAS in the second or third trimester. Recent evidence shows sonographic markers of PAS can be present in the first trimester. Prenatal ultrasound may help predict the depth and topography of placental invasion which are the major determinants of maternal morbidity. The presence of increased vascularity in the inferior part of the lower uterine segment and the parametrial region is associated with a more severe disorder according to a newly proposed staging system. In this chapter, we will discuss how to improve the prediction of PAS, the depth, and topography of placental invasion., Competing Interests: Declaration of Competing interest The authors have no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Pregnancy presents a teachable moment to engage male smokers whose partners are pregnant in smoking cessation. Evidence on how to approach and help these smokers quit smoking in antenatal settings has remained scarce. This paper presents the rationale and study design of a trial which aims to evaluate the effectiveness of a brief intervention model for promoting smoking cessation in expectant fathers., Methods: BANSAR is a pragmatic randomised controlled trial conducted in antenatal clinic in seven public hospitals in Hong Kong, China. An estimated 1148 fathers who smoke at least one cigarette daily and whose partners are pregnant and non-smoking will be randomised (1:1) to receive brief advice combined with 1-week sample of nicotine replacement therapy (NRT) and active referral to smoking cessation services, or brief advice only (usual care). Outcome will be assessed at 3 and 6 months after treatment initiation. The primary outcome is carbon monoxide-verified (<4 part per million) abstinence at 6 months post-treatment initiation. Secondary outcomes include self-reported 7-day point-prevalence abstinence and 24-week continuous abstinence, use of smoking cessation service and NRT and quit attempt, and smoking reduction, change in nicotine dependence and intention to quit in continuing smokers., Comment: This trial will provide real-world evidence on the effectiveness of a combined brief intervention model for smoking cessation in expectant fathers, an understudied population. The findings may be particularly relevant to low and middle-income countries, where male-to-female smoking ratios and birth rates tend to be higher than higher-income countries., Trial Registration: ClinicalTrials.gov, number NCT03671707., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Redox signaling and homeostasis are essential for cell survival and the immune response. Peroxiredoxin (Prx) modulates the level of H 2 O 2 as a redox signal through H 2 O 2 decomposition. The redox activity of thioredoxin (Trx) is required as a reducing equivalent to regenerate Prx. Edwardsiella piscicida is an opportunistic Gram-negative enteric pathogen that secretes a novel Trx-like effector protein, ETAE&#95;2186 (Trxlp). Trxlp has unique structural properties compared with other Trx proteins. In enzymatic and binding assays, we confirmed Trxlp to be redox-inactive due to the low reactivity and flexibility of the resolving cysteine residue, C35, at the active site motif " 31 WCXXC 35 ". We identified key residues near the active site that are critical for reactivity and flexibility of C35 by site-directed mutagenesis analysis. NMR titration experiment demonstrated prolong inhibitory interaction of Trxlp with Prx1 resulting in the repression of Prx1-mediated H 2 O 2 decomposition leading to increased ROS accumulation in infected host cells. Increased ROS in turn prevented nuclear translocation of NF-κB and inhibition of NF-κB target genes, leading to bacterial survival and enhanced replication inside host cells. Targeting Trxlp-mediated virulence promises to attenuate E. piscicida infection., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

HIV is a sexually transmitted infection (STI) whose transmission process is highly dependent on the sexual network structure of the population under consideration. Most sexual behaviour data is egocentric in nature. We develop a stochastic dynamic sexual network model that utilises this type of egocentric network data. The model incorporates both steady and casual sex partners, and can be seen as a stochastic form of a generalised pair-formation model. We model the spread of an infection where individuals are susceptible, infectious, or successfully treated (and unable to transmit) and derive analytical expressions for several epidemiological quantities. We use sexual behaviour and HIV prevalence data that was gathered among 403 MSM at an STI clinic in Stockholm. To accurately capture transmission dynamics for this population, we need to explicitly model both casual sex partners and steady partnerships. Our model yields an estimate for the mean time until diagnosis followed by successful treatment that is in line with literature. This study indicates that small reductions in the time to diagnosis, and thereby, beginning of treatment, may substantially reduce HIV prevalence. Moreover, we find that moderate increases in condom use with casual sex partners have greater impact on reducing prevalence than the same increases in condom use with steady sex partners. This result demonstrates the relative importance of casual contacts on the HIV transmission dynamics among MSM in Sweden. Our results highlight the importance of HIV testing and condom-use interventions, and the role that casual and steady partners play in this, in order to turn the epidemiological trend in Sweden towards decreased HIV incidence., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Oral pills, including tablets and capsules, are one of the most popular pharmaceutical dosage forms available. Compared to other dosage forms, such as liquid and injections, oral pills are very stable and are easy to be administered. However, it is not uncommon for pills to be misidentified, be it within the healthcare institutes or after the pills were dispensed to the patients. Our objective is to develop groundwork for automatic pill identification and verification using Deep Convolutional Network (DCN) that surpasses the existing methods., Materials and Methods: A DCN model was developed using pill images captured with mobile phones under unconstraint environments. The performance of the DCN model was compared to two baseline methods of hand-crafted features., Results: The DCN model outperforms the baseline methods. The mean accuracy rate of DCN at Top-1 return was 95.35%, whereas the mean accuracy rates of the two baseline methods were 89.00% and 70.65%, respectively. The mean accuracy rates of DCN for Top-5 and Top-10 returns, i.e., 98.75% and 99.55%, were also consistently higher than those of the baseline methods., Discussion: The images used in this study were captured at various angles and under different level of illumination. DCN model achieved high accuracy despite the suboptimal image quality., Conclusion: The superior performance of DCN underscores the potential of Deep Learning model in the application of pill identification and verification., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The structure of the sexual network of a population plays an essential role in the transmission of HIV. Concurrent partnerships, i.e. partnerships that overlap in time, are important in determining this network structure. Men and women may differ in their concurrent behavior, e.g. in the case of polygyny where women are monogamous while men may have concurrent partnerships. Polygyny has been shown empirically to be negatively associated with HIV prevalence, but the epidemiological impacts of other forms of gender-asymmetric concurrency have not been formally explored. Here we investigate how gender asymmetry in concurrency, including polygyny, can affect the disease dynamics. We use a model for a dynamic network where individuals may have concurrent partners. The maximum possible number of simultaneous partnerships can differ for men and women, e.g. in the case of polygyny. We control for mean partnership duration, mean lifetime number of partners, mean degree, and sexually active lifespan. We assess the effects of gender asymmetry in concurrency on two epidemic phase quantities (R 0 and the contribution of the acute HIV stage to R 0 ) and on the endemic HIV prevalence. We find that gender asymmetry in concurrent partnerships is associated with lower levels of all three epidemiological quantities, especially in the polygynous case. This effect on disease transmission can be attributed to changes in network structure, where increasing asymmetry leads to decreasing network connectivity., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

A noninvasive approach by serial ultrasound examination at 12-15, 18, and 30 weeks of gestation can be used to exclude homozygous α 0 -thalassemia-induced fetal anemia. At 12-15 weeks of gestation, the predictive values for the fetal cardio-thoracic ratio were better than that for the placental thickness. At 16-20 weeks of gestation, measuring middle cerebral artery peak systolic velocity is associated with a low false-positive rate. However, the false-positive rate of this noninvasive approach can be about 3%, requiring an invasive test to confirm the diagnosis. A false-negative may result in a delay in diagnosis. The success of this noninvasive approach depends on an accurate measurement of the fetal cardiothoracic ratio which can be improved by adequate training and subsequent quality control. Currently, there is a lack of data reporting the performance of a noninvasive approach before 12 weeks of gestation., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions., Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism., Design: Folic acid-supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined., Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr(+/-) livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr(+/-) mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile., Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient.

Human Edwardsiella tarda infections often manifest as gastroenteritis, but can become systemic and potentially lethal. E. tarda uses virulence factors that include type III and type VI secretion systems, quorum sensing, two-component systems, and exoenzymes to gain entry into and survive within the host. Better understanding of interactions between these factors will lead to the development of novel antimicrobials against E. tarda and other enterics., (Copyright © 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Myo-inositol plays key physiological functions, necessitating development of methodology for quantification in biological matrices. Limitations of current mass spectrometry-based approaches include the need for a derivatisation step and/or sample clean-up. In addition, co-elution of glucose may cause ion suppression of myo-inositol signals, for example in blood or urine samples. We describe an HPLC-MS/MS method using a lead-form resin based column online to a triple quadrupole tandem mass spectrometer, which requires minimum sample preparation and no derivatisation. This method allows separation and selective detection of myo-inositol from other inositol stereoisomers. Importantly, inositol was also separated from hexose monosaccharides of the same molecular weight, including glucose, galactose, mannose and fructose. The inter- and intra-assay variability was determined for standard solutions and urine with inter-assay coefficient of variation (CV) of 1.1% and 3.5% respectively, while intra-assay CV was 2.3% and 3.6%. Urine and blood samples from normal individuals were analysed., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Spinal cord regenerative ability is lost with development, but the mechanisms underlying this loss are still poorly understood. In chick embryos, effective regeneration does not occur after E13, when spinal cord injury induces extensive apoptotic response and tissue damage. As initial experiments showed that treatment with a calcium chelator after spinal cord injury reduced apoptosis and cavitation, we hypothesized that developmentally regulated mediators of calcium-dependent processes in secondary injury response may contribute to loss of regenerative ability. To this purpose we screened for such changes in chick spinal cords at stages of development permissive (E11) and non-permissive (E15) for regeneration. Among the developmentally regulated calcium-dependent proteins identified was PAD3, a member of the peptidylarginine deiminase (PAD) enzyme family that converts protein arginine residues to citrulline, a process known as deimination or citrullination. This post-translational modification has not been previously associated with response to injury. Following injury, PAD3 up-regulation was greater in spinal cords injured at E15 than at E11. Consistent with these differences in gene expression, deimination was more extensive at the non-regenerating stage, E15, both in the gray and white matter. As deimination paralleled the extent of apoptosis, we investigated the effect of blocking PAD activity on cell death and deiminated-histone 3, one of the PAD targets we identified by mass-spectrometry analysis of spinal cord deiminated proteins. Treatment with the PAD inhibitor, Cl-amidine, reduced the abundance of deiminated-histone 3, consistent with inhibition of PAD activity, and significantly reduced apoptosis and tissue loss following injury at E15. Altogether, our findings identify PADs and deimination as developmentally regulated modulators of secondary injury response, and suggest that PADs might be valuable therapeutic targets for spinal cord injury., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The analysis of echocardiograms, whether visual or automated, is often hampered by ultrasound artifacts which obscure the moving myocardial wall. In this study, a probabilistic framework for tracking the endocardial surface in 3D ultrasound images is proposed, which distinguishes between visible and artifact-obscured myocardium. Motion estimation of visible myocardium relies more on a local, data-driven tracker, whereas tracking of obscured myocardium is assisted by a global, statistical model of cardiac motion. To make this distinction, the expectation-maximization algorithm is applied in a stationary and dynamic frame-of-reference. Evaluation on 35 three-dimensional echocardiographic sequences shows that this artifact-aware tracker gives better results than when no distinction is made. In conclusion, the proposed tracker is able to reduce the influence of artifacts, potentially improving quantitative analysis of clinical quality echocardiograms., (Copyright 2010 Elsevier B.V. All rights reserved.)

Objective: Adult bone marrow mononuclear cells (BMMNCs) can restore cardiac function following myocardial necrosis. Protocols used to date have administered cells relatively late after ischaemia/reperfusion injury, but there is the opportunity with elective procedures to infuse cells shortly after restoration of blood flow, for example after angioplasty. Our aim was therefore to try and quantify protection from myocardial injury by early infusion of BMMNCs in a rat ischaemia reperfusion (I/R) model., Methods and Results: Male Wistar rats underwent 25 min of ischaemia followed by 2 h reperfusion of the left anterior descending coronary artery. Ten million BMMNCs were injected i.v. at reperfusion. We found BMMNCs caused a significant reduction in infarct size at 2 h when assessed by staining the area at risk with p-nitro blue tetrazolium (42% reduction, P<0.01). Apoptosis and necrosis of isolated cardiomyocytes was significantly reduced in the area at risk. Functional assessment at 7 days using echocardiography and left ventricular catheterisation showed improved systolic and diastolic function in the BMMNC treatment group (LVEF: BMMNC 71 ± 3% vs. PBS 48 ± 4%, P<0.0001). In functional studies BMMNC injected animals showed increased activation of Akt, inhibition of GSK-3β, amelioration of p38 MAP kinase phosphorylation and NF-κB activity compared to control myocardium. Inhibition of PI3K with LY294002 abolished all beneficial effects of BMMNC treatment. Proteomic analysis also demonstrated that BMMNC treatment induced alterations in proteins within known cardioprotective pathways, e.g., heat shock proteins, stress-70 protein as well as the chaperone protein 14-3-3 epsilon., Conclusions: Early BMMNC injection during reperfusion preserves the myocardium, with evidence of reduced apoptosis, necrosis, and activation of survival pathways., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: High density single nucleotide polymorphism (SNP) genotyping array is widely applied on genome-wide association study of common diseases. In these studies, a fixed batch-size of 48 or 96 samples allows high-throughput analysis. To enhance the clinical application of microarray analysis on personalized medicine, we describe a modified PCR purification protocol without batch-size limitation for whole-genome scan using ultra-high density SNP microarray., Methods: Enzyme-digested PCR products were purified with the use of magnetic beads. Separation of the magnetic particles applies magnetic stand devices instead of vacuum pumps. With no batch-size limitation, we genotyped 17 genomic samples and 3 whole genome amplified samples in order to examine the performance of the modified protocol., Results: Our method is simple and fast, provides sufficient amount and high quality PCR products for subsequent fragmentation and labeling procedures prior to GeneChip hybridization. We show that the purified DNA can be genotyped with good QC call rate of >93% in average similar to standard protocol. With the use of the short protocol, we successfully identified the breakpoint localization of a ring chromosome in a female and located the disease gene in a consanguineous family affected by limb-girdle muscular dystrophy., Conclusion: By modifying a single step in the original protocol, we are able to speed up the overall genotyping analysis and change the batch-wise analysis to random-access analysis for ultra-high density whole-genome scan for personalized medicine, positional mapping, and cytogenetic analysis.

Polymorphonuclear leukocyte (PMN)-derived microparticles display inhibitory properties on target cells as assessed in vitro; since PMNs contain abundant amounts of the endogenous anti-inflammatory protein annexin 1 (AnxA1), we tested here whether biologically active AnxA1 could be present in PMN-derived microparticles. PMN adhesion to human umbilical vein endothelial cell (HUVEC) monolayers led to the generation of microparticles that contained AnxA1, as detected by Western blotting, flow cytometry, and mass spectrometry analyses. Addition of these microparticles to recipient PMNs prior to flow over HUVEC monolayers significantly inhibited cell adhesion, an effect abrogated by a neutralizing anti-AnxA1 antibody, or an antibody raised against the AnxA1 receptor, that is termed lipoxin A(4) receptor or ALX. Intravenous delivery of human PMN-derived microparticles markedly inhibited PMN recruitment to an air pouch inflamed with IL-1beta. This anti-inflammatory effect was also dependent on endogenous AnxA1, since injection of microparticles produced from wild-type PMNs (bone marrow derived), but not from AnxA1-null PMNs, inhibited IL-1beta-induced leukocyte trafficking. In conclusion, PMN-derived microparticles contain functionally active AnxA1 that confers them anti-inflammatory properties; generation of these microparticles in the microcirculation could promote inflammatory resolution by time-dependent dampening of cell recruitment.

Alpha-thalassaemia is one of the most common human genetic disorders. Couples in which both partners carry alpha(0)-thalassaemia traits have a 25% risk of having a fetus affected by homozygous alpha-thalassaemia or haemoglobin Bart's disease, with severe fetal anaemia in utero, hydrops fetalis, stillbirth or early neonatal death, as well as causing various maternal morbidities. This disorder is common in southeast Asia and southern China, and the expanding populations of southeast Asian immigrants in the US, Canada, UK and Europe mean that this disorder is no longer rare in these countries.

Enteropathogenic Escherichia coli (EPEC), a major gastrointestinal pathogen, causes infantile diarrhea in many developing countries. EPEC is an attaching and effacing (A/E) pathogen that utilizes a LEE-encoded type III secretion system (TTSS) to deliver effector proteins into host cells. These effectors have been identified as potential virulence factors in A/E pathogens including EPEC, enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium (CR). We used a proteomics approach to identify a new non-LEE-encoded effector, NleI, from the EPEC sepL and sepD mutants. The nleI gene, located in a prophage-associated island with nleBCD, is also present in EHEC and CR but not in E. coli K-12. In EPEC, the transcription of nleI was increased upon sepD inactivation but remained unaffected in ler and sepL mutants. We demonstrated that NleI is secreted and translocated into HeLa cells in a TTSS-dependent manner and that the CesT chaperone is required for efficient NleI translocation. Nevertheless, under overexpression conditions, the first 20 amino acids of NleI are sufficient to support both secretion and translocation. After translocation, NleI can be detected in the cytoplasmic and membrane of HeLa cells.

Because of their invasive properties, Salmonella species are uniquely suited for use as live oral vaccines, and mutants attenuated in general metabolic functions show promise as vaccine strains. We have identified a Salmonella choleraesuis transposon mutant which is deficient in abilities to attach to, invade or penetrate through animal cells. This mutant is avirulent in mice, yet is able to persist within the liver, spleen and gut-associated lymphoid tissue for periods which may be adequate for induction of secretory, humoral and cell-mediated immunity. This and other strains attenuated in factors specifically required for Salmonella pathogenesis may have potential as vaccine strains.