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Abstract Background Coffee and tea consumption account for most caffeine intake and 2–3 billion cups are taken daily around the world. Caffeine dependence is a widespread but under recognized problem. Objectives To conduct a systematic review on the genetic susceptibility factors affecting caffeine metabolism and caffeine reward and their association with caffeine intake. Methodology We conducted PubMed and Embase searches using the terms “caffeine”, “reward”, “gene”, “polymorphism”, “addiction”, “dependence” and "habit" from inception till 2024. The demographics, genetic and clinical data from included studies were extracted and analyzed. Only case-control studies on habitual caffeine drinkers with at least 100 in each arm were included. Results A total of 2552 studies were screened and 26 studies involving 1,851,428 individuals were included. Several genes that were involved with caffeine metabolism such as CYP1A2, ADORA2A, AHR, POR, ABCG2, CYP2A6, PDSS2 and HECTD4 rs2074356 (A allele specific to East Asians and monomorphic in Europeans, Africans and Americans) were associated with habitual caffeine consumption with effect size difference of 3% to 32% in number of cups of caffeinated drink per day per effect allele. In addition, ALDH2 was linked to the Japanese population. Genes associated with caffeine reward included BDNF, SLC6A4, GCKR, MLXIPL and dopaminergic genes such as DRD2 and DAT1 which had around 2–5% effect size difference in number of cups of caffeinated drink for each allele per day. Conclusion Several genes that were involved in caffeine metabolism and reward were associated with up to 30% effect size difference in number of cups of caffeinated drink per day, and some associations were specific to certain ethnicities. Identification of at-risk caffeine dependence individuals can lead to early diagnosis and stratification of at-risk vulnerable individuals such as pregnant women and children, and can potentially lead to development of drug targets for dependence to caffeine.

Summary: Background: Impaired mitochondrial protein import machinery leads to phenotypically heterogeneous diseases. Here, we report a recurrent homozygous missense variant in the gene that encodes the translocase of outer mitochondrial membrane 7 (TOMM7) in nine patients with microcephaly, short stature, facial dysmorphia, atrophic macular scarring, and moyamoya disease from seven unrelated families. Methods: To prove the causality of the TOMM7 variant, mitochondrial morphology, proteomics, and respiration were investigated in CRISPR/Cas9-edited iPSCs-derived endothelial cells. Cerebrovascular defects and mitochondrial respiration were also examined in CRISPR/Cas9-edited zebrafish. Findings: iPSC-derived endothelial cells with homozygous TOMM7 p.P29L showed increased TOM7 stability, enlarged mitochondria, increased senescence, and defective tube formation. In addition, proteomic analysis revealed a reduced abundance of mitochondrial proteins involved in ATP synthesis or coordinating TCA cycle and gluconeogenesis. Moreover, mitochondrial respiration was slightly decreased while ATP production from glycolysis was significantly increased. Furthermore, deletion of tomm7 in zebrafish caused craniofacial and cerebrovascular defects that recapitulated human phenotypes. Notably, homozygous iPSCs differentially expressed genes involved in glycolysis and response to hypoxia. Finally, the metabolic imbalance was evidenced by decreased oxygen consumption, increased level of hexokinase 2, and enhanced glycolysis in endothelial cells derived from the patient's iPSCs. Interpretation: These results revealed the essential role of TOMM7 in balancing cellular sources of energy production at both proteomic and transcriptomic levels and provided the molecular mechanisms through which TOMM7 p.P29L variant leads to an autosomal recessive microcephalic osteodysplastic dwarfism with moyamoya disease. Funding: This work is supported by National Science and Technology Council grants and National Cheng Kung University Hospital.

Abstract The study aimed to investigate alterations in gray matter volume in individuals undergoing regular soccer training, using high-resolution structural data, while also examining the temporal precedence of such structural alterations. Both voxel-based morphometry and source-based morphometry (SBM) methods were employed to analyze volumetric changes in gray matter between the soccer and control groups. Additionally, a causal network of structural covariance (CaSCN) was built using granger causality analysis on brain structural data ordering by training duration. Significant increases in gray matter volume were observed in the cerebellum in the soccer group. Additionally, the results of the SBM analysis revealed significant increases in gray matter volume in the calcarine and thalamus of the soccer group. The analysis of CaSCN demonstrated that the thalamus had a prominent influence on other brain regions in the soccer group, while the calcarine served as a transitional node, and the cerebellum acted as a prominent node that could be easily influenced by other brain regions. In conclusion, our study identified widely affected regions with increased gray matter volume in individuals with regular soccer training. Furthermore, a temporal precedence relationship among these regions was observed.

Abstract Background Androgenetic alopecia (AGA), one of the most common types of hair loss, is associated with oxidative stress, inflammation and aging. Derinat, a transient receptor potential canonical channels (TRPCs) inhibitor, restrains TRPCs-mediated increase intracellular Ca2+ signaling, which initiates the skin aging process with intracellular reactive oxygen species (ROS) accumulation. This study investigated whether Derinat protected skin from oxidative stress-induced damage and aging, thus inhibiting AGA pathogenesis. Methods The lifespan of Caenorhabditis elegans was measured to examine the capacity of Derinat to oppose the oxidative stress induced-aging process, which drives the hair cycle from anagen to catagen phase. The experiments that used BALB/c-nu and C57BL/6 mice determined the effects of Derinat on hair cycle and oxidative stress in skin. To further apply Derinat to clinical study, the resulting relationship between AGA pathogenesis and TRPCs-regulated oxidative stress was confirmed using the bioinformatics approach. We consequently used the parameters of hair density, hair diameter, hair recovery and quality of life index to evaluate the effect of Derinat treatment on AGA subjects. Results Derinat restrained the oxidative stress induced-aging process sufficiently to extend the lifespan of worms. Derinat also changed the hair growth patterns of mice by maintenance of the hair cycle at the anagen phase. This efficacy was due to reduction of TRPCs-mediated ROS accumulation. Because the bioinformatics analysis found that AGA pathogenesis is associated with TRPCs-regulated oxidative stress and inflammation, treatment with Derinat in AGA subjects increased positive outcomes of oral medication while mitigating the impairment of AGA subjects’ quality of life. Conclusions Derinat restrains AGA pathogenesis and may provide a new therapeutic approach for treating AGA. ClinicalTrials.gov Identifier NCT05450861, https://register.clinicaltrials.gov , date of registration 07/11/2022. Trial registration ClinicalTrials.gov Identifier NCT05450861, https://register.clinicaltrials.gov , date of registration 07/11/2022

Abstract Objective Sociodemographic factors play a crucial role in shaping the health-seeking behaviors of individuals residing in slum areas, particularly in their choice of healthcare facilities. Recognizing the importance of strengthening the existing healthcare systems, this research project was undertaken with the primary objective of comprehending the health-seeking behaviors among residents of Mumbai’s slum dwellings in India. To achieve this goal, a comprehensive cross-sectional community needs assessment was conducted spanning from October 2018 to January 2019. Results 432 respondents reported utilizing at least one health facility in the past year. They reported using private hospitals (172), public hospitals (208), Community Health clinics [23], or other healthcare services (29). To gain further insights into the factors influencing these choices, logistic regression analysis was conducted. The analysis revealed that being female was found to be negatively associated with the selection of a general practitioner as a preferred healthcare provider. On the other hand, higher levels of education and income were found to have a positive association with the preference for private hospitals. Conversely, these factors were negatively associated with the choice of government hospitals.

Abstract Background Gaucher disease (GD) is a lysosomal storage disorder characterized by deficient glucocerebrosidase activity that results from biallelic mutations in the GBA1 gene. Its phenotypic variability allows GD to be classified into 3 subtypes based on the presence and extent of neurological manifestations. Enzyme replacement therapy (ERT) has been available for all patients with GD in Taiwan since 1998. Newborn screening (NBS) for GD has been available since 2015. This study attempted to unveil the clinical features of patients diagnosed with GD during different eras in Taiwan. Materials and methods Data from the health records of two tertiary hospitals responsible for two-thirds of the patients with GD in Taiwan were used. The study population included all patients identified as having GD between 1998, and April 2022, in these two hospitals for review. A total of 42 individuals were included, six of whom were diagnosed by NBS. Results Our cohort presented a higher proportion of GD3 individuals, both by clinical suspicion and by NBS diagnosis, than that reported worldwide. The major subtypes that were recognized following NBS diagnosis were GD2 and GD3. The majority of GD patients carry at least one p.Leu483Pro variant. The 5-year survival rates were 0% for GD2 patients and 100% for patients with other subtypes. Patients diagnosed during the post-NBS era were free of symptoms on initial presentation, except for those with the GD2 subtype. For those diagnosed earlier, ERT was shown to be effective in terms of improved hemograms and prevented bone crises. However, the neurological symptoms in GD3 patients progressed despite ERT intervention. Conclusion ERT is essential in reversing the hematological presentations and preventing the skeletal complications of GD. Timely diagnosis of GD with NBS allows for early intervention with ERT to prevent disease progression and complications. However, the need for effective intervention for neurological dysfunction remains unmet.

Abstract Electroplated Cu has been extensively applied in advanced electronic packaging, and its mechanical properties are critical for reliability. In this study, Cu foils fabricated through electroplating with various bis-(3-sulfopropyl) disulfide (SPS) concentrations are examined using tensile tests. The SPS concentration affects the grain size of the electroplated Cu foils, resulting in different mechanical properties. A significant Hall–Petch effect, $${\sigma }_{y} = 197.4 + 0.12{d}^{\frac{-1}{2}}$$ σ y = 197.4 + 0.12 d - 1 2 , is demonstrated for the electroplated Cu foils. The different concentrations of impurities identified through time-of-flight secondary ion mass spectrometry correspond to the different grain sizes, determining the transgranular and intergranular fracture during the tensile test. The results demonstrate that the SPS concentration controlling the microstructures of the electroplated Cu results in a Hall–Petch effect on the mechanical properties of the electroplated Cu foils.

Abstract Alzheimer’s disease (AD) is the most common late-onset neurodegenerative disorder. Identifying individuals at increased risk of developing AD is important for early intervention. Using data from the Alzheimer Disease Genetics Consortium, we constructed polygenic risk scores (PRSs) for AD and age-at-onset (AAO) of AD for the UK Biobank participants. We then built machine learning (ML) models for predicting development of AD, and explored feature importance among PRSs, conventional risk factors, and ICD-10 codes from electronic health records, a total of > 11,000 features using the UK Biobank dataset. We used eXtreme Gradient Boosting (XGBoost) and SHapley Additive exPlanations (SHAP), which provided superior ML performance as well as aided ML model explanation. For participants age 40 and older, the area under the curve for AD was 0.88. For subjects of age 65 and older (late-onset AD), PRSs were the most important predictors. This is the first observation that PRSs constructed from the AD risk and AAO play more important roles than age in predicting AD. The ML model also identified important predictors from EHR, including urinary tract infection, syncope and collapse, chest pain, disorientation and hypercholesterolemia, for developing AD. Our ML model improved the accuracy of AD risk prediction by efficiently exploring numerous predictors and identified novel feature patterns.

Objective To investigate the predictive function of miR-200c level in peripheral blood on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation. Methods Fifty-one patients who received allo-HSCT in hematology department of our hospital from January 2014 to October 2018 were selected as the research subjects. According to the principle of whether agVHD occurred after transplantation, 33 patients were in the experimental group (with aGVHD) and 18 patients were in the control group (without aGVHD). RT-qPCR was used to detect miR-200c in two groups and the differences in miR-200c expression between the two groups were analyzed. Results The transplantation was successful in both groups, and the hematopoietic function was restored. The recovery time was 18 days, among which 33 patients developed aGVHD and 18 patients did not develop aGVHD, with an incidence of 64.71%. The expression of miR-200c in experimental group was lower than that in control group before transplantation and 7, 14, and 72 d after transplantation (P＜0.05). MiR-200c in peripheral blood after the occurrence of aGVHD was significantly lower than that before the occurrence(P＜0.001). Compared with aGVHD Ⅱ, the expression of miR-200c in peripheral blood of aGVHD Ⅱ patients was down-regulated (P＜0.05); as compared with aGVHD Ⅲ patients, the expression of miR-200c in peripheral blood of aGVHD Ⅲ patients was down-regulated (P＜0.001); the 2-year survival rate in the high expression group of miR-200c was higher than that in the low expression group (P＜0.05). Conclusions The reduced level of miR-200c is associated with the occurrence of aGVHD after allogeneic hematopoietic stem cell transplantation. With the increase of the severity of aGVHD the expression level of miR-200c is decreased, and the survival rate of patients with low miR-200c expression is low, so the expression of miR-200 is a potential marker for early diagnosis and prediction of aGVHD.

Abstract Miniature pigs are an ideal animal model for translational research to evaluate stem cell therapies and regenerative applications. While the derivation of induced pluripotent stem cells (iPSCs) from miniature pigs has been demonstrated, there is still a lack of a reliable method to generate and maintain miniature pig iPSCs. In this study, we derived iPSCs from fibroblasts of Wisconsin miniature swine (WMS), Yucatan miniature swine (YMS), and Göttingen minipigs (GM) using our culture medium. By comparing cells of the different pig breeds, we found that YMS fibroblasts were more efficiently reprogrammed into iPSCs, forming colonies with well-defined borders, than WMS and GM fibroblasts. We also demonstrated that YMS iPSC lines with a normal pig karyotype gave rise to cells of the three germ layers in vitro and in vivo. Mesenchymal stromal cells expressing phenotypic characteristics were derived from established iPSC lines as an example of potential applications. In addition, we found that the expression level of the switch/sucrose nonfermentable component BAF60A regulated by STAT3 signaling determined the efficiency of pig iPSC generation. The findings of this study provide insight into the underlying mechanism controlling the reprogramming efficiency of miniature pig cells to develop a viable strategy to enhance the generation of iPSCs for biomedical research.

Objective To derive the probability distribution formula of combined identity by state （CIBS） score among individuals with different relationships based on population data of autosomal multiallelic genetic markers. Methods The probabilities of different identity by state （IBS） scores occurring at a single locus between two individuals with different relationships were derived based on the principle of ITO method. Then the distribution probability formula of CIBS score between two individuals with different relationships when a certain number of genetic markers were used for relationship identification was derived based on the multinomial distribution theory. The formula was compared with the CIBS probability distribution formula based on binomial distribution theory. Results Between individuals with a certain relationship, labelled as RS, the probabilities of IBS=2, 1 and 0 occurring at a certain autosomal genetic marker x （that is, p2（RSx）, p1（RSx） and p0（RSx））, can be calculated based on the allele frequency data of that genetic marker and the probability of two individuals with the corresponding RS relationship sharing 0, 1 or 2 identity by descent （IBD） alleles （that is, φ0, φ1 and φ2）. For a genotyping system with multiple independent genetic markers, the distribution of CIBS score between pairs of individuals with relationships other than parent-child can be deducted using the averages of the 3 probabilities of all genetic markers （that is, p2（RS）, p1（RS） and p0（RS））, based on multinomial distribution theory. Conclusion The calculation of CIBS score distribution formula can be extended to all kinships and has great application value in case interpretation and system effectiveness evaluation. In most situations, the results based on binomial distribution formula are similar to those based on the formula derived in this study, thus, there is little difference between the two methods in actual work.

Abstract The COVID-19 pandemic has led to widespread shortages of personal protective equipment (PPE) for healthcare workers, including of N95 masks (filtering facepiece respirators; FFRs). These masks are intended for single use but their sterilization and subsequent reuse has the potential to substantially mitigate shortages. Here we investigate PPE sterilization using ionized hydrogen peroxide (iHP), generated by SteraMist equipment (TOMI; Frederick, MD), in a sealed environment chamber. The efficacy of sterilization by iHP was assessed using bacterial spores in biological indicator assemblies. After one or more iHP treatments, five models of N95 masks from three manufacturers were assessed for retention of function based on their ability to form an airtight seal (measured using a quantitative fit test) and filter aerosolized particles. Filtration testing was performed at a university lab and at a National Institute for Occupational Safety and Health (NIOSH) pre-certification laboratory. The data demonstrate that N95 masks sterilized using SteraMist iHP technology retain filtration efficiency up to ten cycles, the maximum number tested to date. A typical iHP environment chamber with a volume of ~ 80 m3 can treat ~ 7000 masks and other items (e.g. other PPE, iPADs), making this an effective approach for a busy medical center.

Toxic stress caused by autotoxins is a common phenomenon for cucumber under monoculture condition. A previous study demonstrated that grafting could enhance the resistance of cucumber to cinnamic acid (CA) stress, but the underlying mechanism behind this enhanced resistance is still unclear. In the present study, we reconfirmed the stronger resistance of grafted rootstock (RG) compared to the non-grafted (NG) cucumber as measured though plant biomass accumulation. In addition, we focused on the phenolic and other aromatic acids metabolism in hydroponic culture model system using a combination of qRT-PCR (to measure gene expression of relevant genes) and HPLC (to detect the presence of phenolic and other aromatic acids). The results showed that the exogenous CA lead to the expression of four enzymes involved in phenolic and other aromatic acids biosynthesis, and a larger increase was observed in grafted rootstock (RG). Specifically, expression of six genes, involved in phenolic and other aromatic acids biosynthesis (PAL, PAL1, C4H, 4CL1, 4CL2 and COMT), with the exception of 4CL2, were significantly up-regulated in RG but down-regulated in NG when exposed to CA. Furthermore, six kinds of phenolic and other aromatic acids were detected in leaves and roots of NG and RG cucumber, while only benzoic acid and cinnamic acid were detected in root exudate of all samples. The CA treatment resulted in an increase of p-hydroxybenzonic acid, benzoic acid and cinnamic acid contents in RG cucumber, but decrease of p-coumaric acid and sinapic acid contents in NG cucumber. Surprisingly, the type and amount of phenolic and other aromatic acids in root exudate was improved by exogenous CA, particularly for RG cucumber. These results suggest that a possible mechanism for the stronger resistance to CA of RG than NG cucumber could involve the up-regulation of key genes involved in phenolic and other aromatic acids metabolism, and that the excessive phenolic compounds released to surroundings is a result of the accumulation of phenolic compounds in a short time by the plant under stress.

Abstract Background Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, which are characterized by the accumulation of glycosaminoglycans, and eventually lead to the progressive damage of various tissues and organs. Methods An epidemiological study of MPS in Taiwan was performed using multiple sources. The survival and diagnostic age for different types of MPS between 1985 and 2019 were evaluated. Results Between 1985 and 2019, there were 175 patients diagnosed with MPS disorders in the Taiwanese population, with a median diagnostic age of 3.9 years. There were 21 (12%), 78 (45%), 33 (19%), 32 (18%) and 11 (6%) patients diagnosed with MPS I, II, III, IV and VI, respectively, with median diagnostic ages of 1.5, 3.8, 4.7, 4.5 and 3.7 years, respectively. Diagnosis of MPS patients was significantly earlier in recent decades (p

Abstract Background Surgeon suturing technology plays a pivotal role in patient recovery after laparoscopic surgery. Intracorporal suturing and knot tying in minimally invasive surgery are particularly challenging and represent a key skill for advanced procedures. In this study, we compared the application of multidirectional stitching technology with application of the traditional method in a laparoscopic suturing instructional program. Methods We selected forty residents within two years of graduation to assess the specialized teaching of laparoscopic suturing with laparoscopic simulators. The forty students were randomly divided into two groups, a control group and an experimental group, with twenty students in each group. The control group was scheduled to learn the traditional suture method, and the experimental group applied multidirectional stitching technology. The grades for suturing time, thread length, accuracy of needle entry, stability of the knot, tissue integrity, and tightness of the tissue before and after the training program were calculated. Results There was no significant difference between the two groups before the learning intervention. After the program, both groups significantly improved in each subject. There were significant differences between the control group and the experimental group in suture time (P = 0.001), accuracy of needle entry and exit (P = 0.035), and whether the suture tissue had cracks (P = 0.030). However, the two groups showed non-significant differences in thread length (P = 0.093), stablity of the knot (P = 0.241), or tightness of the tissue (P = 0.367). Conclusions Multidirectional stitching technology improves the efficiency and effectiveness of traditional laparoscopic suture instructional programs. It might be a practicable, novel training method for acquiring proficiency in manual laparoscopic skills in a training setting.

Background Low temperature is a type of abiotic stress that threatens the growth and yield of asparagus bean. However, the key genes and regulatory pathways involved in low temperature response in this legume are still poorly understood. Methodology. The present study analyzed the transcriptome of seedlings from two asparagus bean cultivars—Dubai bean and Ningjiang 3—using Illumina RNA sequencing (RNA-seq). Correlations between samples were determined by calculating Pearson correlation coefficients (PCC) and principal component analysis (PCA). Differentially expressed genes (DEGs) between two samples were identified using the DESeq package. Transcription factors (TF) prediction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs were also performed. Results Phenotypes and physiological indices indicated that Ningjiang 3 seedlings tolerated cold better than Dubai bean seedlings, in contrast to adult stage. The transcriptome dynamics of the two cultivars were closely compared using Illumina RNA-seq following 0, 3, 12, and 24 h of cold stress at 5 °C and recovery for 3 h at 25 °C room temperature. Global gene expression patterns displayed relatively high correlation between the two cultivars (>0.88), decreasing to 0.79 and 0.81, respectively, at 12 and 24 h of recovery, consistent with the results of principal component analysis. The major transcription factor families identified from differentially expressed genes between the two cultivars included bHLH, NAC, C2H2, MYB, WRKY, and AP2/ERF. The representative GO enrichment terms were protein phosphorylation, photosynthesis, oxidation-reduction process, and cellular glucan metabolic process. Moreover, KEGG analysis of DEGs within each cultivar revealed 36 transcription factors enriched in Dubai bean and Ningjiang 3 seedlings under cold stress. Conclusions These results reveal new information that will improve our understanding of the molecular mechanisms underlying the cold stress response of asparagus bean and provide genetic resources for breeding cold-tolerant asparagus bean cultivars.

Acinetobacter baumannii is an emerging nosocomial, opportunistic pathogen with growing clinical significance globally. A. baumannii has an exceptional ability to rapidly develop drug resistance. It is frequently responsible for ventilator-associated pneumonia in clinical settings and inflammation resulting in severe sepsis. The inflammatory response is mediated by host pattern-recognition receptors and the inflammasomes. Inflammasome activation triggers inflammatory responses, including the secretion of the pro-inflammatory cytokines IL-1β and IL-18, the recruitment of innate immune effectors against A. baumannii infection, and the induction programmed cell death by pyroptosis. An important knowledge gap is how variation among clinical isolates affects the host’s innate response and activation of the inflammasome during A. baumannii infection. In this study, we compared nine A. baumannii strains, including clinical locally-acquired isolates, in their ability to induce activation of the inflammasome and programmed cell death in primary macrophages, epithelial lung cell line and mice. We found a variation in survival outcomes of mice and bacterial dissemination in organs among three commercially available A. baumannii strains, likely due to the differences in virulence between strains. Interestingly, we found variability among A. baumannii strains in activation of the NLRP3 inflammasome, non-canonical Caspase-11 pathway, plasmatic secretion of the pro-inflammatory cytokine IL-1β and programmed cell death. Our study highlights the importance of utilising multiple bacterial strains and clinical isolates with different virulence to investigate the innate immune response to A. baumannii infection.

Background The incidence of follicular lymphoma (FL) in Taiwan has not been well investigated since its inclusion as a histological subtype in the Taiwan Cancer Registry in 2008. The purpose of this study was to describe the incidence patterns of FL in Taiwan and compare the trends with those in other racial groups in the United States. Materials and methods We conducted an epidemiological study using population-based data from the Taiwan Cancer Registry, Ministry of Health and Welfare, and the 18 Surveillance, Epidemiology, and End Results (SEER) registries to evaluate the FL incidence from 2008 to 2017. We calculated the annual percent change (APC) to describe the trends in the incidence of FL in subpopulations defined by race and sex over time. Results The annual age-adjusted incidence rate of FL in Taiwan increased significantly from 0.59 per 100,000 persons in 2008 to 0.82 per 100,000 persons in 2017, with an APC of 3.2. By contrast, the incidence rate in whites in the United States during the same period decreased from 3.42 to 2.74 per 100,000 persons, with an APC of −2.1. We found no significant change for the blacks (APC, −1.5%), Hispanics (APC, −0.7%), and Asians or Pacific Islanders (APC, +0.7%). The temporal trend was similar between the males and females. The relative frequency of FL among the incident non-Hodgkin lymphoma (NHL) cases also increased significantly in Taiwan from 7.64% in 2008 to 11.11% in 2017 (APC = 3.8). The relative frequency of FL among the incident NHL cases in the whites decreased from 2008 to 2012 (APC, −3.8%) and then stabilized after 2012 (APC, −0.2%). By contrast, little change in relative frequency of FL among the incident NHL cases was observed in the blacks, Hispanics, and APIs between 2008 and 2017. Conclusion We found increases in the incidence of FL and the relative frequency of FL among the incident NHL cases in both males and females in Taiwan from 2008 to 2017. The FL incidence rates were unchanged for all races and sex groups in the United States, except for the decreases in the whites.

The Syrian crisis has had a devastating impact on displaced populations and among host communities in neighboring countries such as Jordan. Many of these individuals are at risk for non-communicable diseases (NCD) and mental health disorders, yet do not have access to services designed to manage or prevent these conditions. The purpose of this study was to examine the efficacy of a non-communicable disease (NCD) awareness educational intervention and an integrated NCD and mental health education intervention on reducing cardiovascular disease (CVD) risk among Jordanians and displaced Syrians.This natural experiment study was conducted in three health centers in Irbid, Jordan with 213 Syrian participants and 382 Jordanians. Participants were assigned to one of three study conditions: the Healthy Community Clinic (HCC), a non-communicable disease educational intervention; the HCC with added mental health awareness sessions; standard healthcare. CVD risk factors were assessed at baseline, 12 and 18 months.The HCC education group yielded significant improvements in three CVD risk factors including: body mass index (BMI) −1.91 (95% CI: −2.09, −1.73); systolic blood pressure (SBP) −12.80 mmHg (95% CI: −16.35, –9.25); and diastolic blood pressure (DBP) −5.78 mmHg (95% CI: −7.96, −3.60) compared to standard care. The HCC-mental health treatment arm also demonstrated significant improvements in BMI, SBP, and DBP compared to standard care. Significant improvements in fasting blood glucose −20.32 (CI: −28.87, −11.77) and HbA1c −0.43 (−0.62, −0.24) were also illustrated in the HCC-mental health treatment arm. The HCC-mental health group sustained greater reductions in CVD risk than the HCC education group at 18-months.This study is among the first to our knowledge illustrating an integrated health and mental health educational intervention can reduce CVD risk among Syrian refugees and Jordanians. Continued investment and research in CVD prevention interventions is needed to enhance health, reduce costs, and have lasting benefits for conflict-affected individuals and communities.

Personal protective equipment (PPE) is crucially important to the safety of both patients and medical personnel, particularly in the event of an infectious pandemic. As the incidence of Coronavirus Disease 2019 (COVID-19) increases exponentially in the United States and many parts of the world, healthcare provider demand for these necessities is currently outpacing supply. In the midst of the current pandemic, there has been a concerted effort to identify viable ways to conserve PPE, including decontamination after use. In this study, we outline a procedure by which PPE may be decontaminated using ultraviolet (UV) radiation in biosafety cabinets (BSCs), a common element of many academic, public health, and hospital laboratories. According to the literature, effective decontamination of N95 respirator masks or surgical masks requires UV-C doses of greater than 1 Jcm-2, which was achieved after 4.3 hours per side when placing the N95 at the bottom of the BSCs tested in this study. We then demonstrated complete inactivation of the human coronavirus NL63 on N95 mask material after 15 minutes of UV-C exposure at 61 cm (232 μWcm-2). Our results provide support to healthcare organizations looking for methods to extend their reserves of PPE.

ObjectivesThis study examined the mediating or moderating relationship of social health on physical health and post-traumatic stress symptoms among displaced Syrians and Jordanians at high risk for physical and mental health ailments. Frequency of mental health symptoms stratified by demographic factors was also explored. We hypothesized social health would mediate and/or moderate the relationship between physical and post-traumatic stress symptoms (PTSS).MethodsThis cross-sectional study includes 598 adults between 18 and 75 years old recruited from three health centers in the city of Irbid, Jordan, 20 km away from the Syrian border. Post-traumatic stress symptoms (PTSS) were measured through the primary care post-traumatic stress disorder checklist. Physical and social health were assessed through the Duke Health Profile. One-way ANOVA and independent samples T-tests examined mean scores of social health, PTSS, physical health stratified by age, gender, nationality, education level, and trauma exposure. Bivariate correlations explored the relationship between social health, PTSS, and physical health. PROCESS macro tested social health as a moderator and mediator on the association of the physical health and PTSS.ResultsSocial health moderated and mediated the relationship between physical health and PTSS. Males reported (t = 2.53, p < .05) better physical health scores than females. Those who had less than a high school education reported lower social health (F = 13.83, p < .001); higher PTSS (F = 5.83, p < .001); and lower physical health (F = 5.76, p < .01) than more educated individuals. Syrians reported significantly higher PTSS (F = 4.13, p < .05) than Jordanians, however, there was no significant differences between nationality for physical or social health. Social health was positively associated with better physical health (r = 0.10, p < .01) and negatively with PTSS (r = -.293, p < .01).ConclusionsOur results support our primary hypothesis suggesting social health mediates and moderates PTSS and physical health. Secondary findings illustrate gender, educational, and income differences in physical health and PTSS.Clinical trials registryNCT03721848.

Abstract Background Neurofibromatosis type 1 (NF1) is a dominantly inherited tumor predisposition syndrome that targets the peripheral nervous system. It is caused by mutations of the NF1 gene which serve as a negative regulator of the cellular Ras/MAPK (mitogen-activated protein kinases) signaling pathway. Owing to the complexity in some parts of clinical diagnoses and the need for better understanding of its molecular relationships, a genetic characterization of this disorder will be helpful in the clinical setting. Methods In this study, we present a customized targeted gene panel of NF1/KRAS/BRAF/p53 and SPRED1 genes combined with Multiple Ligation-Dependent Probe Amplification analysis for the NF1 mutation screening in a cohort of patients clinically suspected as NF1. Results In this study, we identified 73 NF1 mutations and two BRAF novel variants from 100 NF1 patients who were suspected as having NF1. These genetic alterations are heterogeneous and distribute in a complicated way without clustering in either cysteine–serine-rich domain or within the GAP-related domain. We also detected fifteen multi-exon deletions within the NF1 gene by MLPA Analysis. Conclusions Our results suggested that a genetic screening using a NGS panel with high coverage of Ras–signaling components combined with Multiple Ligation-Dependent Probe Amplification analysis will enable differential diagnosis of patients with overlapping clinical features.

Abstract Background Mucopolysaccharidosis type II (MPS II) is the most frequently occurring MPS in Taiwan, with an incidence of 2.05 per 100,000 live male births, but little is known about clinical characteristics and surgical history in Taiwanese patients. Methods Medical history, demographics, signs and symptoms, and surgical history were analysed in all patients from Taiwanese centres in the Hunter Outcome Survey (HOS; NCT 03292887), a global, multicentre registry that collects real-world data on patients with MPS II. Results As of January 2016, 61 male Taiwanese patients were enrolled; 49% (24/49) had received at least one infusion of idursulfase. Median (10th, 90th percentiles) ages at signs and symptom onset and at diagnosis were 2.5 (0.2, 5.5) years (n = 55) and 3.5 (1.2, 11.9) years (n = 56), respectively. Hernia, facial features consistent with MPS II and claw hands were the earliest presenting signs and symptoms (median ages of 3.2 [0.4, 12.0] years, 4.3 [1.1, 12.0] years and 4.7 [2.5, 12.2] years [n = 45, 53 and 50], respectively). More than 75% of patients had undergone a surgical procedure, most commonly hernia repair (57% of patients). Median age at first surgery for hernia repair was 4.2 (0.5, 9.8) years (n = 35). Almost one-third (31.1%) of patients had at least one surgical procedure before diagnosis, and of the 20 procedures before diagnosis, 16 were hernia repair. Conclusions This information from patients in HOS highlights the importance of both medical and surgical history in diagnosing MPS II in Taiwanese patients.

Abstract Cells respond to many signals with a limited number of signaling components. Heterotrimeric G proteins and MAPK cascades are universally used by eukaryotic cells to transduce signals in various developmental processes or stress responses by activating different effectors. MAPK cascade is integrated with G proteins by scaffold protein during plant immunity. However, the molecular relationship between G proteins and MAPK modules in plant development is still unclear. In this study, we demonstrate that Arabidopsis Gβ protein AGB1 interacts with MPK3 and 6, MKK4 and 5, as well as the regulatory domains of YODA (YDA), the upstream MEKK of MKK4/5. Remarkably, YDA interacts with the plasma membrane associated SHORT SUSPENSOR (SSP) through its N- and C-terminal region in vitro and in vivo. Additionally, genetic analysis shows that AGB1 functions together with MPK3/6 signaling cascade during the asymmetric division of the zygote. These data indicate that Gβ may function likely as a scaffold, through direct physical interaction with the components of the MPK signaling module in plant development. Our results provide new insights into the molecular functions of G protein and will advance the understanding of the complex mechanism of kinase signaling cascades.

Abstract Clinical management of Clostridium difficile infection is still far from satisfactory as bacterial spores are resistant to many chemical agents and physical treatments. Certain types of nanoparticles have been demonstrated to exhibit anti-microbial efficacy even in multi-drug resistance bacteria. However, most of these studies failed to show biocompatibility to the mammalian host cells and no study has revealed in vivo efficacy in C. difficile infection animal models. The spores treated with 500 µg/mL Fe3-δO4 nanoparticles for 20 minutes, 64% of the spores were inhibited from transforming into vegetative cells, which was close to the results of the sodium hypochlorite-treated positive control. By cryo-electron micro-tomography, we demonstrated that Fe3-δO4 nanoparticles bind on spore surfaces and reduce the dipicolinic acid (DPA) released by the spores. In a C. difficile infection animal model, the inflammatory level triple decreased in mice with colonic C. difficile spores treated with Fe3-δO4 nanoparticles. Histopathological analysis showed a decreased intense neutrophil accumulation in the colon tissue of the Fe3-δO4 nanoparticle-treated mice. Fe3-δO4 nanoparticles, which had no influence on gut microbiota and apparent side effects in vivo, were efficacious inhibitors of C. difficile spore germination by attacking its surface and might become clinically feasible for prophylaxis and therapy.

We propose a set of family-based burden and kernel tests for censored traits (FamBAC and FamKAC). Here, censored traits refer to time-to-event outcomes, for instance, age-at-onset of a disease. To model censored traits in family-based designs, we used the frailty model, which incorporated not only fixed genetic effects of rare variants in a region of interest but also random polygenic effects shared within families. We first partitioned genotype scores of rare variants into orthogonal between- and within-family components, and then derived their corresponding efficient score statistics from the frailty model. Finally, FamBAC and FamKAC were constructed by aggregating the weighted efficient scores of the within-family components across rare variants and subjects. FamBAC collapsed rare variants within subject first to form a burden test that followed a chi-squared distribution; whereas FamKAC was a variant component test following a mixture of chi-squared distributions. For FamKAC, p-values can be computed by permutation tests or for computational efficiency by approximation methods. Through simulation studies, we showed that type I error was correctly controlled by FamBAC for various variant weighting schemes (0.0371 to 0.0527). However, FamKAC type I error rates based on approximation methods were deflated (max 0.0376) but improved by permutation tests. Our simulations also demonstrated that burden test FamBAC had higher power than kernel test FamKAC when high proportion (e.g. ≥ 80%) of causal variants had effects in the same direction. In contrast, when the effects of causal variants on the censored trait were in mixed directions, FamKAC outperformed FamBAC and had comparable or higher power than an existing method, RVFam. Our proposed framework has the flexibility to accommodate general nuclear families, and can be used to analyze sequence data for censored traits such as age-at-onset of a complex disease of interest.

[This corrects the article DOI: 10.1371/journal.pone.0103060.].

Objective: To summary the recent advances in molecular research of glioblastoma (GBM) and current trends in personalized therapy of this disease. Data Sources: Data cited in this review were obtained mainly from PubMed in English up to 2015, with keywords “molecular”, “genetics”, “GBM”, “isocitrate dehydrogenase”, “telomerase reverse transcriptase”, “epidermal growth factor receptor”, “PTPRZ1-MET”, and “clinical treatment”. Study Selection: Articles regarding the morphological pathology of GBM, the epidemiology of GBM, genetic alteration of GBM, and the development of treatment for GBM patients were identified, retrieved, and reviewed. Results: There is a large amount of data supporting the view that these recurrent genetic aberrations occur in a specific context of cellular origin, co-oncogenic hits and are present in distinct patient populations. Primary and secondary GBMs are distinct disease entities that affect different age groups of patients and develop through distinct genetic aberrations. These differences are important, especially because they may affect sensitivity to radio- and chemo-therapy and should thus be considered in the identification of targets for novel therapeutic approaches. Conclusion: This review highlights the molecular and genetic alterations of GBM, indicating that they are of potential value in the diagnosis and treatment for patients with GBM.

BACKGROUND:International medical donation programs can help alleviate the burden of illness and serve as a safety net for the global health care system. However, to our knowledge no studies have assessed the number of individuals served through medical donation programs. As such, this study aimed to evaluate the impact of the Americares Foundation's (Americares) medical donation program in terms of the number of patients served. METHODS:We conducted an outcome evaluation study in 34 health facilities in 10 countries that receive medical donations from Americares. Medical records were randomly sampled at each participating facility and evaluated for types of medications and number of courses of prescribed treatments. Facility level data and donation inventory data were also collected. We developed an algorithm for converting quantities of donated medicines into the number of individuals served at the facility level. These estimates were then extrapolated to the country and region levels to assess the total impact of medications donated in 2015. Probabilistic sensitivity analysis was conducted to derive 95% credible ranges for projected estimates and to assess model uncertainty. RESULTS:Records of 3,205 unique patients were reviewed, encompassing 10,449 medical visits. The average number of medications and courses of treatments prescribed per visit were 2.63 and 2.68, respectively. The average medication destruction rate ranged from 0% to 24% at facilities, with a cross-country average of 7%. For the 10 countries included in the study, we project that 700,377 unique individuals were served through the program (95% credible range: 518,401-905,982). Scaled across all regions receiving Americares donations, we project that the program supported an estimated 5.1 million beneficiaries, including 484,188 chronic care and 4.65 million acute care patients. CONCLUSIONS:This study provides a novel methodology for medical donation programs seeking to estimate one of their key outcomes-patients served-and global reach. Rigorous assessments of program outcomes can provide important insights into the value of medical donation initiatives. TRIAL REGISTRATION:Human subjects approval was received from the University of Washington Institutional Review Board (Approval #52316; 7/19/2016).

Licorice (Glycyrrhiza) species have been widely used as a traditional medicine and a natural sweetener in foods. The 18β-glycyrrhetinic acid (18β-GA) is a bioactive compound in licorice that exhibits potential anti-cancer, anti-inflammatory, and anti-microbial activities. Many synthesized derivatives of 18β-GA have been reported to be cytotoxic and suggested for the treatment of malignant diseases. In this study, we explored the possible pharmacological roles of an 18β-GA derivative in skin biology using primary human dermal fibroblasts and HaCaT keratinocytes as cell models. We found that this 18β-GA derivative did not cause cell death, but significantly enhanced the proliferation of dermal fibroblasts and HaCaT keratinocytes. A scratch wound healing assay revealed that the 18β-GA derivative promoted the migration of fibroblasts. Due to the important role of aquaporin-3 in cell migration and proliferation, we also investigated the expression of aquaporin-3 and found this compound up-regulated the expression of aquaporin-3 in dermal fibroblasts and HaCaT keratinocytes. In dermal fibroblasts, the 18β-GA derivative induced the phosphorylation of Akt, ERK, and p38. The inhibitor of Akt predominantly suppressed the 18β-GA derivative-induced expression of aquaporin-3. Collectively, this compound had a positive effect on the proliferation, migration, and aquaporin-3 expression of skin cells, implying its potential role in the treatment of skin diseases characterized by impaired wound healing or dermal defects.

A region-specific method, NTR (non-threshold rare) variant detection method, was developed-it does not use the threshold for defining rare variants and accounts for directions of effects. NTR also considers linkage disequilibrium within the region and accommodates common and rare variants simultaneously. NTR weighs variants according to minor allele frequency and odds ratio to combine the effects of common and rare variants on disease occurrence into a single score and provides a test statistic to assess the significance of the score. In the simulations, under different effect sizes, the power of NTR increased as the effect size increased, and the type I error of our method was controlled well. Moreover, NTR was compared with several other existing methods, including the combined multivariate and collapsing method (CMC), weighted sum statistic method (WSS), sequence kernel association test (SKAT), and its modification, SKAT-O. NTR yields comparable or better power in simulations, especially when the effects of linkage disequilibrium between variants were at least moderate. In an analysis of diabetic nephropathy data, NTR detected more confirmed disease-related genes than the other aforementioned methods. NTR can thus be used as a complementary tool to help in dissecting the etiology of complex diseases.

The association between off-hours presentation and mortality in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. We performed a meta-analysis to assess the impact of off-hours presentation on short- and long-term mortality among STEMI patients.We searched PubMed, EMBASE, and the Cochrane Library from their inception to 10 July 2016. Studies were eligible if they evaluated the relationship of off-hours (weekend and/or night) presentation with short- and/or long-term mortality.A total of 30 studies with 33 cohorts involving 192,658 STEMI patients were included. Off-hours presentation was associated with short-term mortality (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.02-1.12, P = 0.004) but not with long-term mortality (OR 1.00, 95% CI 0.94-1.07, P = 0.979). No significant heterogeneity was observed. The outcomes remained the same after sensitivity analyses and trim and fill analyses. Subgroup analyses showed that STEMI patients undergoing primary percutaneous coronary intervention do not have a higher risk of short-term mortality (OR 1.061, 95% CI 0.993-1.151). In addition, higher mortality was observed only during hospitalization (OR 1.072, 95% CI 1.022-1.125), not at the 30-day, 1-year or long-term follow-ups.Off-hours presentation was associated with an increase in short-term mortality, but not long-term mortality, among STEMI patients. Clinical approaches to decrease short-term mortality regardless of the time of presentation should be evaluated in future studies.