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OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. METHODS: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a. ispartof: ANNALS OF NEUROLOGY vol:90 issue:6 pages:887-900 ispartof: location:United States status: published

This study endeavours to investigate empirically how Information and Communications Technology (ICT) usage affects the bounded rationality and business performance of Small and Medium Enterprises (SMEs) in Sri Lanka. The data collection has been done with 400 owners of SMEs in Sri Lanka by employing telephone and face to face interviews using a structured questionnaire. The Partial Least Squares-Structural Equation Modelling (PLS-SEM) was utilized to analyse the data. The empirical results discovered that the different dimensions of ICT usage such as infrastructure, applications, policy, human resources, and mobile technology have a negative impact on bounded rationality and positive effects on the business performance of SMEs in Sri Lanka. Thus, the study recognizes that several dimensions of ICT usage make proper information flow to pull out information asymmetry and reduce the bounded rationality of SMEs, thereby increasing the business performance of SMEs in Sri Lanka.

Objectives: Telehealth implementation is a complex systems-based endeavour. This paper compares telehealth responses to (COrona VIrus Disease 2019) COVID-19 across ten countries to identify lessons learned about the complexity of telehealth during critical response such as in response to a global pandemic. Our overall objective is to develop a health systems-based framework for telehealth implementation to support critical response. Methods: We sought responses from the members of the International Medical Informatics Association (IMIA) Telehealth Working Group (WG) on their practices and perception of telehealth practices during the times of COVID-19 pandemic in their respective countries. We then analysed their responses to identify six emerging themes that we mapped to the World Health Organization (WHO) model of health systems. Results: Our analysis identified six emergent themes. (1) Government, legal or regulatory aspects of telehealth; (2) Increase in telehealth capacity and delivery; (3) Regulated and unregulated telehealth; (4) Changes in the uptake and perception of telemedicine; (5) Public engagement in telehealth responses to COVID-19; and (6) Implications for training and education. We discuss these themes and then use them to develop a systems framework for telehealth support in critical response. Conclusion: COVID-19 has introduced new challenges for telehealth support in times of critical response. Our themes and systems framework extend the WHO systems model and highlight that telemedicine usage in response to the COVID-19 pandemic is complex and multidimensional. Our systems-based framework provides guidance for telehealth implementation as part of health systems response to a global pandemic such as COVID-19.

Introduction: Type 2 Diabetes mellitus (T2DM) is a chronic illness, caused due to resistance to insulin or poor production. FBS, PPBS and Glycated Haemoglobin (HbA1c) are the major tests that are used to monitor chronic glycemia worldwide. HbA1c level remains the gold standard test for assessment of glycemic control at follow up and it reflects the mean glucose values in the previous three - month period. HbA1c is expressed as a percentage, whereas the day-to-day monitoring and treatment of diabetes are based on blood glucose levels expressed as milligrams per deciliter (mg/dl) or millimoles per liter (mmol/L). Due to the difference in the denominators of FBS/PPBS with HbA1c, it causes confusion to the patients regards their glycaemic control. “Estimated average glucose” or eAG derived from HbA1c has been promoted by the American Diabetes Association (ADA). American Association of Clinical Chemists concludes that the correlation (r =0.92) is strong enough to justify reporting both HbA1c and eAG which indicate the 3- month control of the average sugar of the patient. This is easy for the patient as both FBS/PPBS and eAG are expressed with the same denominator for daily glucose checks and long-term control respectively, enhancing the glycaemic control. Objectives: To determine the statistical correlation between eAG derived from HBA1C using the Nathan’s regression equation with FBS and PPBS in patients with T2DM. To analyze the significance of eAG as opposed to HbA1C as a marker of long-term glycemic control in T2DM. Methodology: A retrospective analytical study done at the Department of Haematology of the Sri Jayewardenepura General Hospital, Sri Lanka. A simple random sampling technique was used, over a period of one year commencing June 2019 to June 2020, to obtain the laboratory records through laboratory information system of 201 adult patients both males and females who were diagnosed with T2DM. HbA1c, FBS, PPBS done on the same day were recorded. The eAG(mg/dl) was calculated using the Nathan’s regression equation (eAG = 28.7 x HbA1c – 46.7). Three groups were generated according to the patients’ levels of FBS and PPBS. Statistical Analysis: Data were double entered and analyzed using (SPSS) version 20. Descriptive statistical methods were used to calculate the median, mean standard deviation of age, HBA1c, FBS, and PPBS. Correlations between study variables were done with Pearson’s correlation method. The p value, lower than 0.05 was considered as statistically significant. Coefficient of determination (R Sq) was used to a statistical measure of how close the data are to the fitted regression line. Results: The total population of patients in both the FBS and PPBS groups showed a significant statistical correlation with eAG. The individual subgroups did not conform to this correlation. The results reveal no statistical correlation in both FBS and PPBS with eAG in patients with good glycaemic control. There was a significant statistical correlation in both FBS and PPBS with eAG in the groups of patients with moderately poor control. In those with markedly poor control the FBS did not show a statistical correlation with eAG, as opposed to the PPBS. Conclusion: The clinical importance of HbA1C/eAG in diagnosis and management of T2DM can be re-emphasized by this study. HbA1C along with eAG may be added as a test in the management of T2DM, for the better understanding and maintenance of good glycemic control. As eAG values, derived by the Nathan’s regression equation in our study scattered very close to the regression line, it provided a more complete and representative measure of average glucose in past 3 months. We conclude that HbA1c values were reliably translated into eAG measurements which would be easily understood by the patients being of the same denominator as the FBS/PPBS.

Fluoride is a beneficial trace element for human health as its deficiency and excess levels can cause detrimental health effects. In Sri Lanka, dry zone regions can have excessive levels of fluoride in drinking water and can cause dental and skeletal fluorosis. In addition to drinking water, traditional habits of tea consumption can cause an additional intake of fluoride in the population. A total number of 39 locally blended black tea samples were collected from a village where chronic kidney disease with undetermined origin (CKDu) is prevalent. In addition, unblended tea samples were obtained from tea-producing factories. The fluoride contents in infusions of 2% weight per volume (w/v) were measured using calibrated ion-selective fluoride electrodes. The mean fluoride content was 2.68±1.03 mg/L in loose tea, 1.87±0.57mg/L in packed tea samples, and 1.14±0.55 mg/L in unblended tea. Repeated brewing of the same tea leaves showed that over 50% of fluoride leached into the solution in the first infusion. An estimate of the daily total average fluoride intake via tea consumption per person is 2.68 mg per day. With groundwater in many dry zone regions in Sri Lanka showing high fluoride levels that exceed 0.5 mg/L, the additional daily intake can rapidly exceed recommended thresholds of 2 mg/day. This can add to adverse health impacts that might also relate to CKDu.

Background Queensland, Australia has been successful in containing the COVID-19 pandemic. Underpinning that response has been a highly effective virus containment strategy which relies on identification, isolation, and contact tracing of cases. The dramatic emergence of the COVID-19 pandemic rendered traditional paper-based systems for managing contact tracing no longer fit for purpose. A rapid digital transformation of the public health contact tracing system occurred to support this effort. Objectives The objectives of the digital transformation were to shift legacy systems (paper or standalone electronic systems) to a digitally enabled public health system, where data are centered around the consumer rather than isolated databases. The objective of this paper is to outline this case study and detail the lessons learnt to inform and give confidence to others contemplating digitization of public health systems in response to the COVID-19 pandemic. Methods This case study is set in Queensland, Australia. Universal health care is available. A multidisciplinary team was established consisting of clinical informaticians, developers, data strategists, and health information managers. An agile “pair-programming” approach was undertaken to application development and extensive change efforts were made to maximize adoption of the new digital workflows. Data governance and flows were changed to support rapid management of the pandemic. Results The digital coronavirus application (DCOVA) is a web-based application that securely captures information about people required to quarantine and creates a multiagency secure database to support a successful containment strategy. Conclusion Most of the literature surrounding digital transformation allows time for significant consultation, which was simply not possible under crisis conditions. Our observation is that staff was willing to adopt new digital systems because the reason for change (the COVID-19 pandemic) was clearly pressing. This case study highlights just how critical a unified purpose, is to successful, rapid digital transformation.

Prior studies suggest a strong genetic influence on breast cancer prognosis. Six genome-wide association studies (GWAS) on breast cancer prognosis have been published to date. However, none of the reported loci was replicated across studies and only two passed genome-wide significance (P < 5 x 10-8). In the Pathways Study, a prospective cohort of breast cancer survivors begun in Kaiser Permanente Northern California (KPNC) in 2006, we carried out a GWAS of overall survival (OS) in 3,973 patients. Trans-ethnic meta-GWAS identified an association with OS of a locus on chromosome 15 that almost reached genome-wide significance (P = 9.42 x 10-8). This locus spanned the UACA gene, a key regulator of tumor suppressor Par-4. We found that receipt of chemotherapy modified the effect of the UACA locus on OS (Pinteraction = 2.4 x 10-4). This observation led us to hypothesize that the UACA locus effect on OS may be specific to Par-4 dependent chemotherapies, which include anti-HER2 therapy and doxorubicin. We stratified patients into two groups, those who received Par-4 dependent chemotherapy agents versus other patients. In separate trans-ethnic meta-GWAS, the UACA locus was significantly associated with OS in patients taking Par-4 dependent chemotherapies (P = 1.27 x 10-9), while no association was observed in the other patients (P = 0.21). To evaluate whether the UACA gene may be responsible for this association, we performed a transcriptome-wide association study (TWAS) of OS in White patients taking Par-4 dependent chemotherapies. Higher UACA gene expression was significantly associated with OS (P = 4.68 x 10-7), the only gene reaching transcriptome-wide significance (P < 4.34 x 10-6). These results suggest that higher UACA expression may inhibit Par-4 induced apoptosis and lead to stronger chemoresistance and worse survival. We attempted to validate our findings in the independent KPNC Genetic Epidemiology Research on Aging (GERA) cohort. The GERA cohort included only 168 White patients with incident breast cancer after DNA collection who received Par-4 dependent chemotherapies. We found a non-significant association (hazard ratio (HR) = 1.46, P = 0.66) consistent with Pathways Study findings. However, the GERA cohort also included 1,983 prevalent breast cancer patients with biospecimen collection after diagnosis. In this group, the risk allele frequency in breast cancer survivors receiving Par-4 dependent chemotherapies was significantly lower than that in the White population (P = 5.50 x 10-3) while the risk allele frequency in the those not receiving these chemotherapies was similar to the population (P = 0.07). This is consistent with Pathways Study observations that the UACA locus risk allele significantly increased risk of mortality in patients taking Par-4 dependent chemotherapies. A higher mortality in breast cancer survivors carrying the risk allele would result in decreased risk allele frequency. We further validated our findings in Shanghai Breast Cancer Survival Study (SBCSS)and Shanghai Breast Cancer Study, which were conducted from 1996 to 2006 in urban Shanghai and recruited 5,575 breast cancer patients. In this independent Asian breast cancer population, the UACA locus was modestly associated with OS in the overall population (HR = 1.18, P = 0.012), and more significantly in 1,289 SBCSS patients who received anthracyclines (HR = 1.66, P = 1.55 x 10-4). This is the first human study suggesting the Par-4 pathway affects breast cancer patient survival with UACA a key modulator of treatment outcomes by anti-Her2 therapy and doxorubicin. Our findings suggest a path toward new predictive pharmacogenetic markers for personalized medicine targeting the Par-4 pathway for breast cancer treatment. Citation Format: Lawrence H Kushi, Qianqian Zhu, Emily Schultz, Jirong Long, Janise M Roh, Emily Valice, Cecile A Laurent, Li Yan, Isaac J Ergas, Warren Davis, Dilrini K Ranatunga, Marilyn L Kwan, Ping-Ping Bao, Wei Zheng, Xiao-Ou Shu, Christine B Ambrosone, Song Yao. Genome-wide association study identifies UACA as a modulator of breast cancer chemoresistance and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-05.

The study empirically examined how the use of mobile technology affects the opportunism and business performance of Small and Medium-sized Enterprises (SMEs) in Sri Lanka. The Partial Least Squares-Structural Equation Modelling (PLS-SEM) was utilized to analyze the data that was collected from 400 SMEs by utilizing a structured questionnaire having face-to-face and telephony inter-views. Results revealed that mobile technology generates a significant positive effect on business performance and, consequently, a negative effect on opportunism while opportunism makes a negative impact on the business performance of SMEs. Simultaneously, the study revealed that opportunism considerably interposes in the relationship between mobile technology and SME business performance. Finally, the study has made a strong recommendation to strengthen the use of mobile technology and its applications which highly relate to solving the issues faced by SMEs in the current imperfect market mechanism.

Introduction Congenital disorders of glycosylation (CDG) are inborn errors of glycan metabolism with high clinical variability. Only a few antenatal cases have been described with CDG. Due to a lack of reliable biomarker, prenatal CDG diagnostics relies primarily on molecular studies. In the presence of variants of uncertain significance prenatal glycosylation studies are very challenging. Case report A consanguineous couple had a history of second-trimester fetal demise with tetralogy of Fallot and skeletal dysplasia. In the consecutive pregnancy, the second trimester ultrasonography showed skeletal dysplasia, vermian hypoplasia, congenital heart defects, omphalocele and dysmorphic features. Prenatal chromosomal microarray revealed a large region of loss of heterozygosity. Demise occurred at 30 weeks. Fetal whole exome sequencing showed a novel homozygous likely pathogenic variant in ALG3 and a variant of uncertain significance in COG5. Methods Western blot was used to quantify ALG3, COG5, COG6, and the glycosylation markers ICAM-1 and LAMP2. RT-qPCR was used for ALG3 and COG5 expression in cultured amniocytes and compared to age matched controls. Results ALG3 and COG5 mRNA levels were normal. ICAM-1, LAMP2, ALG3 and COG5 levels were decreased in cultured amniocytes, suggesting the possible involvement of both genes in the complex phenotype. Conclusion This is the first case of successful use of glycosylated biomarkers in amniocytes, providing further options of functional antenatal testing in CDG.

The role of cytochrome P450 (CYP)2C9 and CYP2C19 genetic variation in risk for phenytoin‐induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B (HLA‐B)*15:02 risk allele. In the multi‐ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self‐identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non‐Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin‐induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64–11.69; P

Background Accidental awareness during general anaesthesia (AAGA) is a complex and rare outcome to investigate in surgical patient populations, particularly obstetric patients. We report the protocol of the Direct Reporting of Awareness in Maternity patients (DREAMY) study, illustrating how the research was designed to address practical and methodological challenges for investigating AAGA in an obstetric cohort. Methods This is the trial protocol of a prospective, multicentre cohort study of patients undergoing obstetric surgery under general anaesthesia. Accidental awareness during general anaesthesia will be detected using three repetitions of standardised direct questioning over 30 days, with responses indicating memories during general anaesthesia verified using structured interviews. Reports will be adjudicated, then classified, in accordance with pre-defined and pre-validated structures, including the Michigan Awareness Classification tool. Quantitative data will be collected on general anaesthesia conduct for all participants. This descriptive study is being conducted in England and aims to recruit a minimum of 2015 patients. Results The DREAMY study was prospectively registered (ClinicalTrials.gov Identifier: NCT03100396) and ethical approval granted. Participant recruitment began in May 2017 and one year follow up concluded in August 2019. Publication of the results is anticipated in 2020. Conclusions The DREAMY study will provide data on incidence, experience and implications of AAGA for obstetric patients, using a robust methodology that will reliably detect and translate subjective AAGA reports into objective outcomes. In addition, the study is expected to improve vigilance for AAGA in participating hospitals and encourage adoption of recommendations for support of patients experiencing AAGA.

BackgroundIn type 2 Diabetes Mellitus (T2DM) chronic hyperglycemia leads to multi-organ damage. It is a chronic low-grade inflammation resulting in reduced antioxidants leading to many complications. Hyperglycemia causes glycation of serum proteins forming advanced glycation end products (AGEs). HBA1c is an AGE of haemoglobin. Bilirubin considered a waste product of the heme catabolic pathway, has proven to be a natural antioxidant associated with a lower prevalence of oxidative stress-mediated diseases. Bilirubin prevents glycation of proteins providing benefit in T2DM. General objective - To evaluate the association of serum bilirubin levels with HBA1c, FBS, PPBS in diabetes patients. Specific objectives - 1) To compare the serum bilirubin levels in diabetes patients with good and poor control. 2) To evaluate the association of HbA1c with FBS, PPBS and age in controlled and uncontrolled diabetes mellitusMethodology -A retrospective analytical study done at the department of Haematology of the Sri Jayewardenepura General Hospital.Sample selection and sample size -A random sampling technique used. Data obtained through laboratory information system of 201 adult patients diagnosed with T2DM. The study population grouped as poorly and well controlled using HbA1c value over and below 7% respectively. Normal ranges for serum bilirubin, FBS and PPBS was (0.3-1.2) mg/dl, (75- 110) mg/dl and (80-140) mg/dl respectively. Data were entered and analyzed using statistical package for social sciences (SPSS) version 20. Descriptive statistics used to calculate the median, mean and the standard deviation of age, serum bilirubin, HBA1c, FBS, and PPBS. Correlations between variables were done using Pearson’s Correlation method. The p value Results. A negative correlation between total bilirubin and HbA1c (r = -0.234, p value = 0.001) with a low linear relationship (R Sq of 0.055, figure 02) observed. No statistical significance between total bilirubin level with FBS, PPBS and age (p value >0.05) but the mean values of these in the two groups were statistically significant (p value < 0.05). A statistically positive co-relation observed between HbA1c with FBS and PPBS, not with age. Conclusion. The significant negative correlation between total bilirubin and HbA1c, infers that a lower blood glucose level will result in reducing the oxidant stress mediated damage by the antioxidant and anti- inflammatory action of the increased oxygen free radicals produced by a high bilirubin.

sBackgroundRandomized-controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction, but it is unknown if the association extends to statin users undergoing routine care.ObjectivesThe primary objective was to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of primary prevention participants.MethodsWe determined polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Cox regression models were used to compare the risk of the cardiovascular outcomes between statin users and matched nonusers.ResultsThe hazard ratio (HR) for statin effectiveness on incident myocardial infarction was similar within 10-year atherosclerotic cardiovascular disease (ASCVD) risk score groups at 0.65 (95% confidence interval [CI] 0.39-1.08; P=0.10), 0.65 (95% CI 0.56-0.77; P=2.1E-7), and 0.67 (95% CI 0.57-0.80; P=4.3E-6) for borderline, intermediate, and high ASCVD groups, respectively. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (HR 0.62, 95% CI 0.50-0.77; P=1.4E-5), intermediate in the intermediate polygenic risk score group (HR 0.70, 95% CI 0.61-0.80; P=5.7E-7), and smallest in the low polygenic risk score group (HR 0.86, 95% CI 0.65-1.16; P=0.33). ASCVD risk and statin LDL-C lowering did not differ across polygenic risk score groups.ConclusionsIn primary prevention patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of statin LDL-C lowering. Our findings extend prior work by identifying a subset of patients with attenuated clinical benefit from statins.

Introduction Portal hypertension (PH) is associated with complications including refractory ascites and variceal haemorrhage and can be treated endovascularly with a Transjugular Intrahepatic Portosystemic Shunt (TIPS). Portal vein puncture during TIPS using real-time transabdominal ultrasound guidance is one of many portal vein puncture techniques and is seldom used compared with other methods. The purpose of this manuscript is to describe this technique and its associated procedural outcomes at a quaternary liver transplant hospital. Methods Clinical data of all patients who underwent ultrasound-guided TIPS at our institution between 1 January 2009 and 1 January 2019 were retrospectively obtained from electronic medical records and reviewed. Patient demographics, indications, procedural outcomes and complications were recorded. Results Forty-four ultrasound-guided TIPS procedures were performed during the study period. The most common indication for TIPS was refractory ascites (n = 26; 57%) and variceal haemorrhage (n = 12; 26%). Technical success rate was 100%. No intraprocedural complications occurred. Periprocedural complication rate was 35% (n = 16) with encephalopathy (n = 8; 17%) and sepsis (n = 5; 11%) the most common. One patient with sepsis died. No other TIPS-related deaths occurred. Median fluoroscopy time, contrast volume, air kerma and dose area product values for all procedures were 35 minutes (IQR 24-51), 100 ml (IQR 70-160), 0.95 Gy (IQR 0.50-1.53) and 127 Gycm2 (IQR 68.75-206), respectively. Conclusion Transabdominal ultrasound-guided portal vein puncture during TIPS is safe and technically feasible. When compared to fluoroscopically guided methods, it is associated with lower intraprocedural complication rates, fluoroscopy times, contrast volumes and radiation doses in our experience. Radiation doses, FTs and contrast volumes were also considerably lower than recommended limits.

There have been a variety of attempts to model and quantify the amount of land-based waste entering the world’s oceans, most of which rely heavily on global estimates of population density as the key driving factor. Using empirical data collected in seven different countries/territories (China, Kenya, South Africa, South Korea, Sri Lanka, Taiwan and Vietnam), we assessed a variety of different factors that may drive plastic leakage to the environment. These factors included both globally available GIS data as well as observations made at a site level. While the driving factors that appear in the best models varied from country to country, it is clear from our analyses that population density is not the best predictor of plastic leakage to the environment. Factors such as land use, infrastructure and socio-economics, as well as local site-level variables (e.g., visible humans, vegetation height, site type) were more strongly correlated with plastic in the environment than was population density. This work highlights the importance of gathering empirical data and establishing regular monitoring programs not only to form accurate estimates of land-based waste entering the ocean, but also to be able to evaluate the effectiveness of land-based interventions.

Advances in interventional radiology have seen the adaptation of urological endoscopic laser techniques to treat biliary tract calculi. Percutaneous transhepatic biliary laser lithotripsy provides an effective alternative procedure for the management of intrahepatic or conventionally refractory choledocholithiasis which would otherwise require invasive and high-risk surgical intervention. Several small studies have validated the procedure for management in this subset of patients, with most achieving 100% calculi clearance with minimal complications. Most patients are suitable for percutaneous transhepatic biliary laser lithotripsy. Preprocedural imaging is useful for evaluating stone burden and planning percutaneous access. Holmium lasers are commonly used and act by vaporising water particles on and in the calculi, fragmenting the stone via thermal expansion. A series of catheters, wires, sheaths and dilators are used to allow introduction of the choledochoscope and laser so that calculi can be targeted. Percutaneous transhepatic biliary laser lithotripsy is often used in conjunction with balloon dredging and biliary stricture dilatation. Only experienced interventionalists should perform this procedure, and users should be aware of associated hazards. Repeat percutaneous transhepatic cholangiography is routinely performed to confirm eradication of stones. Treatment of biliary calculi and obstruction is important in preventing diseases such as cholangitis and cirrhosis. For patients unsuitable for conventional treatment, percutaneous transhepatic laser lithotripsy is a safe and effective alternative when performed by experienced interventional radiologists. Preprocedural planning is imperative to procedure success.

Allopurinol, which lowers uric acid (UA) concentration, is increasingly being recognized for its benefits in cardiovascular and renal disease. However, response to allopurinol is variable. We gathered samples from 4,446 multiethnic subjects for a genome-wide association study of allopurinol response. Consistent with previous studies, we observed that the Q141K variant in ABCG2 (rs2231142), which encodes the efflux pump breast cancer resistance protein (BCRP), associated with worse response to allopurinol. However, for the first time this association reached genome-wide level significance (P=8.06×10-11 ). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, P=3.22×10-6 ). In vitro studies identified oxypurinol, the active metabolite of allopurinol, as an inhibitor of the UA transporter GLUT9, suggesting that oxypurinol may modulate UA reabsorption. These results provide strong evidence for a role of BCRP Q141K in allopurinol response, and suggest that allopurinol may have additional hypouricemic effects beyond xanthine oxidase inhibition.

The increasing specialisation of medical care in larger centres is contributing to the declining use of rural hospitals that are close to larger centres, risking bed closures or even facility closure. An allied health-led model of care supported by telehealth geriatrician services was developed and implemented in eight beds in a rural hospital to manage older patients needing geriatric evaluation and management. The project was set in Kilcoy Hospital, a small facility north of Caboolture in Queensland, Australia. The feeder hospital was Caboolture Hospital, the regional centre. Occupancy rates at the rural hospital along with length of stay, discharge destination and functional independence measure. A project officer was employed 1 day a week to facilitate the implementation of the new model of care. Training and education were provided to medical and nursing staff to understand and implement the geriatric evaluation and management model of care. Over the project time frame, 93 patients were successfully managed in the rural hospital with improved occupancy rates. Outcomes were as effective and safe as compared to the group managed at the regional centre. The model of care is now routine practice. Using excess capacity in rural hospitals by employing a geriatric evaluation and management approach is a viable strategy to address declining rural hospital usage.

BackgroundThe prevalence of the oral-systemic relationship has accounted for potentially preventable chronic conditions and morbidity worldwide. Health literacy is a large contributing factor. This systematic review investigates the knowledge and awareness of patients with major systemic conditions, regarding the oral associations to their condition.MethodsElectronic databases including Medline (Ovid), CINAHL, The Cochrane Library, Web of Science, Informit Health Databases and Scopus were searched. All articles from 2011 to 2020, investigating knowledge of the oral-systemic link, of adult patients with the following major system conditions were searched: diabetes mellitus (DM), respiratory disease, cardiovascular disease (CVD), pregnancy and bone disease. Two independent reviewers completed screening, data extraction and quality assessment. A synthesis without meta-analysis was conducted. Twenty-four studies, from 14 different countries, were included in the systematic review.ResultsAnalysis showed that globally, patients with major systemic conditions have poor knowledge and awareness (ConclusionTo improve the global burden of preventable chronic conditions, it is essential to address inequalities in the dissemination of health education to at-risk populations. Improvements in patient education rely on an increase in patient-practitioner communication on the oral-systemic link, implementation of oral health educational programs and greater interdisciplinary collaboration.

Pathogenic alterations in the DPM2 gene have been previously described in patients with hypotonia, progressive muscle weakness, absent psychomotor development, intractable seizures, and early death. We identified biallelic DPM2 variants in a 23-year-old male with truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting. His clinical presentation was much less severe than that of the three previously described patients. This is the second report on this ultra-rare disorder. Here we review the characteristics of previously reported individuals with a defect in the DPM complex while expanding the clinical phenotype of DPM2-Congenital Disorders of Glycosylation. In addition, we offer further insights into the pathomechanism of DPM2-CDG disorder by introducing glycomics and lipidomics analysis. ispartof: MOLECULAR GENETICS AND METABOLISM vol:132 issue:1 pages:27-37 ispartof: location:United States status: published

To design aeronautical composite multi-stringer panels that can safely operate in a postbuckled state, it is important to identify the parameters that can influence the different modes in which skin-stringer separation might occur. A methodology is under development to study the interaction between the skin-stringer separation and the postbuckling deformation using the building block approach and single-stringer specimens. In particular, the methodology can identify whether the skin-stringer separation occurs due to bending or twisting, so that these two possible modes can be studied separately. For bending, a simple criterion that can predict the location of initiation is presented. This procedure has the potential to reduce the overall development cost and allows the investigation of the design parameters that influence the skin-stringer separation.

Introduction: Classical Hairy Cell Leukaemia (cHCL) and Hairy Cell Leukaemia variant (HCL-v) are both rare and slow-growing mature B cell neoplasms. According to flowcytometry data, they fall into the group classified as CD5- CD10- B cell lymphoproliferative disorders. Methods: Two cases with features atypical to two neoplasms at the time of diagnosis were studied. Results: Case 1 was a 15 year old male with right cervical lymph nodes (1x1 cm) in the posterior triangle, a few ecchymotic patches on the arm and a massive splenomegaly. C-reactive protein (CRP) level was 53 mg/dL. Erythrocyte Sedimentation Rate (ESR) was 98 mm/1 st hour. Full Blood Count (FBC) revealed typical features of pancytopenia with monocytopenia. The liver and renal profiles were normal. Morphology of bone marrow was suggestive of cHCL. Flowcytometry and BRAF V600E mutation was positive confirming the diagnosis of cHCL. Case 2 was a 55 year old male presenting with moderate splenomegaly and absolute lymphocytosis. The FBC revealed leukocytosis which is commonly seen with monocytopenia. Blood pictures revealed many hairy cells with moderately basophilic cytoplasm and visible nucleoli suggesting HCL-v. Flowcytometry findings and negative BRAF V600E mutation confirmed HCL-v. Conclusions: Clinical findings, blood images, morphology of bone marrow, flowcytometric findings and positive BRAF V600E mutation confirmed the diagnosis of cHCL in case 1 (15 year old boy) making it as a very rare case. The morphological findings on blood, the presence of characteristic CD markers on flowcytometry and negativity of BRAF V600E confirmed the case 2 as HCL-v, despite having CD10 positivity and monocytopenia.Keywords: Flowcytometric immunophenotyping, Hairy cell leukaemia, Hairy cell leukaemia variant

Objective: Mid-maxillary osteodistraction (MMOD) is a novel technique. This study seeks to assess the occlusal and functional improvement of patients with midfacial hypoplasia secondary to cleft lip and palate. Design: This was done as a retrospective study at the Regional Cleft Centre of the Teaching Hospital-Karapitiya (THK). Participants: A total of 81 patient records were accessed on those who underwent MMOD with a tooth-borne intraoral device from January 1, 2007, to December 31, 2016, at THK. Methods: Records of the patients included pre- and post-treatment lateral cephalograms, study models, speech assessments, and photographs. Results: An advancement ranging from 5 to 12 mm (mean, 8.14 mm) was achieved in all patients; 80% (n = 63) and 87.65% (n = 71) showed improvement in consonant production and quality of speech. These were statistically significant (P < .05). With regard to the Peer Assessment Rating score assessing the occlusal improvement, 97.6% showed an improvement whereas only 2 patients showed no improvement. There was a significant improvement in sella (S), nasion (N), and point A (SNA) angle; point A, the nasion, and point B (ANB) angle; and the maxillary length over the treatment period (P < .05). The change in the ANB angle and maxillary length significantly differed between genders with males having a comparatively higher improvement. The profile improvements were noteworthy on the profile photographs. Conclusion: This relatively novel approach to maxillary advancement by maxillary distraction using a combined surgical and modified orthodontic technique has proven to be successful. This protocol and the technique have improved function, occlusion, and the aesthetics.

Solid tires are utilized for excessive material handling purposes. They experience excessive stresses and high internal energy generation. These factors are not easy to be captured using experimental methods due to complex experimental setup and high cost. Hence, this study is focused on development of a detailed three-dimensional (3D) Finite Element (FE) model of a three-layered forklift solid resilient tire to investigate its characteristics at static conditions. Mooney-Rivlin, Ogden and Yeoh materials model were identified as the best suited hyper-elastic material models that have good agreement with base, cushion and tread of this tire respectively. The developed FE model was validated and its characteristics were investigated at different loads and grade levels of ramp. The results emphasized that, localized high stresses are mainly distributed in the base layer and reinforcements. Cushion layer was identified as the highest energy dissipation area. Furthermore, Forklift gradeability analysis results show that higher-grade values lead to poor tire performances with high wear rate. This study can be further extended to investigate the dynamic behavior of the solid resilient tire.

There are no current descriptions of general anaesthesia characteristics for obstetric surgery, despite recent changes to patient baseline characteristics and airway management guidelines. This analysis of data from the direct reporting of awareness in maternity patients' (DREAMY) study of accidental awareness during obstetric anaesthesia aimed to describe practice for obstetric general anaesthesia in England and compare with earlier surveys and best-practice recommendations. Consenting patients who received general anaesthesia for obstetric surgery in 72 hospitals from May 2017 to August 2018 were included. Baseline characteristics, airway management, anaesthetic techniques and major complications were collected. Descriptive analysis, binary logistic regression modelling and comparisons with earlier data were conducted. Data were collected from 3117 procedures, including 2554 (81.9%) caesarean deliveries. Thiopental was the induction drug in 1649 (52.9%) patients, compared with propofol in 1419 (45.5%). Suxamethonium was the neuromuscular blocking drug for tracheal intubation in 2631 (86.1%), compared with rocuronium in 367 (11.8%). Difficult tracheal intubation was reported in 1 in 19 (95%CI 1 in 16-22) and failed intubation in 1 in 312 (95%CI 1 in 169-667). Obese patients were over-represented compared with national baselines and associated with difficult, but not failed intubation. There was more evidence of change in practice for induction drugs (increased use of propofol) than neuromuscular blocking drugs (suxamethonium remains the most popular). There was evidence of improvement in practice, with increased monitoring and reversal of neuromuscular blockade (although this remains suboptimal). Despite a high risk of difficult intubation in this population, videolaryngoscopy was rarely used (1.9%).

Background: Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported. Methods: Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts. Results: A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: TMEM40 on chromosome 3p25 (rs11719526; β=0.47 and P =3.10×10 −8 ) that replicated in Biobank Japan and confirmed recent findings implicating the BAG3 locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (β=−0.83 and P =8.24×10 −17 ). Although the minor allele frequencies of TMEM40 rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, BAG3 rs17617337 was rare (minor allele frequenciesTMEM40 or BAG3 on EF are largely independent of these conditions. Conclusions: In this large and multiethnic study, we identified 2 loci, TMEM40 and BAG3 , associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.

Introduction: Iron deficiency anemia (IDA) is the commonest nutritional deficiency in all parts of the world. In developing countries, the commonest cause is inadequate dietary intake [1]. The red cell indices raise the suspicion of iron deficiency state due to the microcytic, hypochromic changes and the wide red cell distribution width. The iron studies are confirmatory of an iron deficiency state, but are not accurate in the presence of infection, inflammation or malignancy as they are acute phase proteins and are affected in these states making the serum iron studies unreliable under these conditions. The reticulocyte haemoglobin content (CHr) indicates the iron available in the marrow for the production of Hb and are not affected by the above-mentioned situations and therefore has been recommended as a reliable marker of iron status in the body. The value for CHr given in the literature was 25pg [3]. Objectives: General objective was to evaluate the significance of CHr in the diagnosis of IDA. The Specific objectives were to compare CHr with the other conventional iron parameters including serum iron, serum ferritin, TS and TIBC and evaluate any significance of CHr with RBC indices (MCV, MCH and MCHC) and age. Methodology: A retrospective analytical study performed at the Department of Haematology of a Tertiary care hospital in Sri Lanka. Data was obtained from the patient records of those referred to the Haematology department for management of iron deficiency during the period of 9 months commencing from April 2019 to January 2020. Data from 178 adult patients both males and females (16 to 84 years) diagnosed with IDA (S. Ferritin < 20ng/ml) (Hb < 12g/dl in men and Hb

Background Visceral and renal artery aneurysms (VRAAs) are uncommon but are associated with a high mortality rate in the event of rupture. Endovascular treatment is now first line in many centres, but preservation of arterial flow may be difficult in unfavourable anatomy including wide necked aneurysms, parent artery tortuosity and proximity to arterial bifurcations. Endovascular stenting, and in particular flow-diversion, is used in neurovascular intervention to treat intracranial aneurysms but is less often utilised in the treatment of VRAAs. The CASPER stent is a low profile dual-layer braided nitinol stent designed for carotid stenting with embolic protection and flow-diversion properties. We report the novel use of the CASPER stent for the treatment of VRAAs. We present a case series describing the treatment of six patients with VRAAs using the CASPER stent. Results Six patients with unruptured VRAAs were treated electively. There were three splenic artery aneurysms and three renalartery aneurysms. Aneurysms were treated with the CASPER stent, with or without loose aneurysm coil packing or liquid embolic depending on size and morphology. All stents were successfully deployed with no immediate or periprocedural complications. Four aneurysms completely occluded after serial imaging follow up with one case requiring repeat CASPER stenting for complete occlusion. In one patient a single aneurysm remained patent at last follow up, A single case was complicated by delated splenic infarction and surgical splenectomy. Conclusion Preliminary experience with the CASPER stent suggests it is technically feasible and effective for use in the treatment of VRAAs.

The potential association between rare germline genetic variants and prostate cancer (PrCa) susceptibility has been understudied due to challenges with assessing rare variation. Furthermore, although common risk variants for PrCa have shown limited individual effect sizes, their cumulative effect may be of similar magnitude as high penetrance mutations. To identify rare variants associated with PrCa susceptibility, and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we analyzed large population-based cohorts, custom genotyping microarrays, and imputation reference panels in an integrative study of PrCa genetic etiology. In particular, 11,649 men (6,196 PrCa cases, 5,453 controls) of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health, ProHealth Study, and California Men’s Health Study were genotyped and meta-analyzed with 196,269 European-ancestry male subjects (7,917 PrCa cases, 188,352 controls) from the UK Biobank. Six novel loci were genome-wide significant in our meta-analysis, including two rare variants (minor allele frequency < 0.01, at 3p21.31 and 8p12). Gene-based rare variant tests implicated a previously discovered PrCa gene (HOXB13) as well as a novel candidate (ILDR1) highly expressed in prostate tissue. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants atHOXB13and other loci, reflecting their evolutionary history. Furthermore, a polygenic risk score (PRS) of 187 known, largely common PrCa variants was strongly associated with risk in non-Hispanic whites (90thvs. 10thdecile OR = 7.66,P= 1.80*10-239). Many of the 187 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a six-fold difference in log-probability of Androgen Receptor binding at the variant rs2680708 (17q22). Our finding of two novel rare variants associated with PrCa should motivate further consideration of the role of low frequency polymorphisms in PrCa, while the considerable effect of PrCa PRS profiles should prompt discussion of their role in clinical practice.

Spinal decompression procedures require a mode of anaesthesia which should facilitate prone positioning, muscle relaxation for ease of retraction and effective, lengthy analgesia. In such cases, spinal anaesthesia is associated with numerous advantages over general anaesthesia. But precise case selection is of utmost importance. The cases presented here are single-level, unilateral decompressions in healthy young adults. The successful outcomes in these cases, both anaesthetically and surgically, suggest integration to local practice elsewhere as well.

Solid tires are often utilized to bear excessive loads. Therefore, sidewall cracks and internal heat build-up affect their durability more significantly. It is a challenge to minimize these factors and improve tire performance while maintaining the functionality of the solid tire. Moreover, there are no specific standard guidelines for modifying the solid tire design to achieve this objective. This study proposes several design and performance improvements to the solid resilient tire and investigates the performance of these modified designs using the Finite Element (FE) method under static and dynamic conditions. For these FE simulations, suitable hyperelastic models are obtained using curve fitting combined with three standard error measures. The results show that the Mooney-Rivlin, Ogden, and Yeoh material models show good agreement with experimental data for modelling the base, cushion, and tread layers of the tire, respectively. The developed FE models are validated using experimental data obtained from a leading tire manufacturing company in Sri Lanka. The validated model is used to develop and analyse two distinct tire models which have two different cavity geometries (circular and elliptical) in their cushion layers to minimize heat build-up and sidewall cracks. The tire reinforcements are also rearranged to further improve the performance of the models. The introduction of cavities helps to reduce strain energy dissipation and to increase the dissipation of internal heat by convection. Furthermore, the stress intensity on the side walls is also reduced, thereby minimizing sidewall cracks. Numerical experiments show that the modified designs have a lower strain energy density, lower stress concentration, and less material utilization when compared to the basic tire design.

To meet the growing demand for interventional radiology (IR), more hospitals are investing in state-of-the-art angiography suites, but these are expensive investments. Both the initial construction cost and the ongoing operational costs are significant. For health services, it is important to commission an angiography suite that can satisfy both present and future healthcare demands to maximize the value of the initial expenditure and the opportunities provided by this ongoing investment. Smart angiography suites (SAS) could be the solution that future-proof angiography services. Similar to the smart operating theatre, SAS refers to the incorporation of audio-video technology and internet connectivity into the angiography suite.1 SAS has the ability to record high resolution audio-visual data from the angiography suite and stream it to a remote audience at low latency to enable bi-directional communication and collaboration. SAS, alongside other telemedicine concepts, have also gained new-found interest and relevance in light of the global coronavirus pandemic and the travel restrictions associated with this. We reviewed the current literature to provide an overview of the SAS, its potential, and associated legal and ethical considerations. For hospitals, SAS can be as rudimentary as a webcam or as advanced as a comprehensive commercial solution such as Olympus MedPrescence, Proximie, Tegus Medical, Sony Nucleus or InTouch Health VisitOR. In general, commercial solutions will include audio-video equipment setup, internet streaming and broadcasting setup, and an end-user viewing software. Most commercial solutions are compatible with pre-existing equipment (vendor neutral) (see figure 1 for an example solution). Different solutions also offer varying features of different video layouts, video freezing, telestration with or without augmented reality, integration with picture archiving and communication system, and security. The cost of a commercial SAS solution varies with each company offering a different type of license. Figure 1 An example of a smart angiography suite solution, from …

Introduction In 2010, British Columbia (BC) introduced new traffic laws designed to deter impaired driving, speeding, and distracted driving. These laws generated significant media attention and were associated with reductions in fatal crashes and in ambulance calls and hospital admissions for road trauma. Objective To understand the extent and type of media coverage of the new traffic laws and to identify how the laws were framed by the media. Methods We reviewed a database of injury related news coverage (May 2010–December 2012) and extracted reports that mentioned distracted driving, impaired driving, or speeding. Articles were classified according to: (i) Type, (ii) Issue discussed, (iii) ‘Reference to new laws’, and (iv) ‘Pro/anti traffic law’. Articles mentioning the new laws were reread and common themes in how the laws were framed were identified and discussed. Results Over the course of the study, 1848 articles mentioned distraction, impairment, or speeding and 597 reports mentioned the new laws: 65 against, 227 neutral, and 305 supportive. Reports against the new laws framed them as unfair or as causing economic damage to the entertainment industry. Reports in favor of the new laws framed them in terms of preventing impaired driving and related trauma or of bringing justice to drinking drivers. Growing evidence of the effectiveness of the new laws generated media support. Conclusions BC's new traffic laws generated considerable media attention both pro and con. We believe that this media attention helped inform the public of the new laws and enhanced their deterrent effect.

No abstract available

Utilization of renewable sources can reduce the impact of increasing global energy demand on the rate of depletion of fossil fuels. One of the most studied and implemented routes to meet this energy demand is to harvest solar energy. Among solar-energy harvesting devices, dye-sensitized solar cells have been recognized as some of the cheapest and most environment friendly technologies, since they do not require high purity of starting materials or advanced fabrication techniques. A dye-sensitized solar cell is composed of a working electrode, in which the light absorbing sensitizer is chemisorbed onto the surface of a wide bandgap semiconductor; a redox electrolyte, that is placed in between two electrodes and functions to regenerate the sensitizer; and a counter electrode, which is a catalyst which accelerates a redox reaction with the electrolyte. Titanium dioxide (anatase phase) is the most widely used semiconductor material in dye-sensitized solar cells due to its low cost, chemical stability and optical properties. In this chapter, the literature on optimizing TiO2 as a semiconductor material for n-type DSCs is reviewed. The evolution of TiO2 nanostructures and techniques such as doping, composite preparation and surface modification are elaborated on. These methods have enhanced both the chemical and physical properties of TiO2 nanostructures. Moreover, despite good overall performance, rapid recombination kinetics are a major disadvantage inherent in TiO2. Thus, research has been carried out to substitute TiO2 with alternative semiconductors. In view of this, other potential competitors for photo-anode material are reviewed and assessed. Finally, the prospects of an ideal semiconductor material for dye-sensitized solar cells is discussed.

The energy crisis is a global problem that drives investment on renewable energy sources worldwide. Utilization of solar energy has become an effective strategy for sustainable energy generation, as it has the potential to fill the energy gap created due to the depletion of fossil fuel. On the ever-extending ladder of solar harvesting technologies, third generation dye-sensitized solar cells (DSCs) have the advantages of better cost effectiveness and environmental footprint when compared to the first-generation silicon solar cells and second-generation thin film photovoltaics. The ultimate goal of constructing high-efficiency multi-junction devices has set the target of improving single junction components of DSCs (n- and p-type), separately. The pace of development of single junction p-DSCs has been much slower than that of n-DSCs. Discovery of suitable materials and techniques have lifted the performance of n-DSCs to more than 14% since it was first reported in 1991. On the other hand, p-DSCs have a maximum efficiency of 2.51%. It is important to bridge the gap between the efficiencies of these single junction configurations, in order to adopt the concept of multi-junction/tandem-DSCs that have the potential to reach higher efficiencies by harvesting a larger fraction of the solar spectrum. This chapter focuses on reviewing literature on development of p-DSCs. First, as an introduction, the structure, function and kinetics of p-DSCs are described. Next, the two main factors that affect the overall performance of a p-DSC; light harvesting capacity, and energy loss within the device, are comprehensively discussed.

ObjectiveTo assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment.MethodsA retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response.ResultsAmong 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin.ConclusionCYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.

In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.

Introduction Diabetic patients with peripheral arterial disease (PAD) are challenging to assess. Non-contrast magnetic resonance angiography (MRA) offers a safe alternative in patients with renal impairment. The study objective is to evaluate accuracy of lower limb quiescent-interval single-shot (QISS) MRA and pedal QISS-arterial spin-labelled (ASL) MRA for detection of significant stenosis in diabetic patients with PAD. Methods Combined QISS and QISS-ASL MRA was performed in 32 diabetic PAD patients (20 male, 12 female; mean 69 years; 8 with critical ischaemia). Two readers assessed haemodynamically significant (>50%) stenosis and diagnostic confidence on MRA, against digital subtraction angiography (DSA) as the reference standard, with subgroup analysis of patients with severe renal impairment (n = 7). Inter-reader agreement of stenosis and diagnostic confidence were evaluated. Test-retest reproducibility was evaluated in 10 subjects who underwent repeat MRA on a different day. Results At DSA, 262/645 segments (40.6%) had haemodynamically significant stenoses. MRA accuracy was 78.1% (478/612) and 75.6% (464/614), sensitivity 64.7% (161/249) and 77.5% (193/249), and specificity 87.3% (317/363) and 74.2% (271/365) for 2 readers. MRA accuracy was 80.9% and 80.7% for readers 1 and 2, respectively, in patients with severe renal impairment. QISS MRA but not pedal QISS-ASL MRA was considered of diagnostic image quality. Inter-reader agreement was moderate for stenosis (ĸ = 0.60) and diagnostic confidence (ĸ = 0.41). Test-retest reproducibility was high (ĸ = 0.87) and moderate (ĸ = 0.54) for individual readers. Conclusions Quiescent-interval single-shot MRA has reasonable accuracy in a diabetic PAD population with high burden of disease, providing a non-contrast option in patients with renal impairment. QISS-ASL MRA requires further optimisation to be clinically feasible.

Background Unplanned pregnancy is a significant public health issue in both low- and high-income countries. The burden of unplanned pregnancy is reflected in women opting for pregnancy terminations and it can be detrimental to the women and her family as well as the health system and society. Solid data on the proportion of unplanned pregnancies are using more specific tools such as the London Measure of Unplanned Pregnancy (LMUP) needed to address the issue in Sri Lankan contexts. The objective was to describe the proportion of unplanned pregnancies, their determinants and the health outcomes of women delivering at Colombo North Teaching Hospital-Ragama (CNTH). Methods A cross-sectional study was carried out among 494 consecutive pregnant women selected by non-probability consecutive sampling who were admitted for the confinement at CNTH. A pre-tested structured interviewer-administered questionnaire was used to collect data on antenatal women and intentionality measured by self-administered six-item LMUP. Maternal and newborn health outcomes were ascertained in each post-partum women before discharge. Data were analyzed with the Mann-Whitney U tests, Kruskal-Wallis tests and spearman rank correlation. We also evaluated the psychometric properties of the Sinhalese version of LMUP. Results The response rate was 97.8 and 17.2% of pregnancies ending at birth were unplanned, 12.7% were ambivalent and 70.1% were planned. Associated factor profile of women with unplanned pregnancies includes; not married women (p = 0.001), educated up to the passing of GCE ordinary level by women (p p p = 0.002) and inadequate knowledge on emergency contraceptives (p = 0.037). Less planned pregnancies were also significantly associated with anemia (p = 0.004), low mood for last 2 weeks (p p p p p Conclusions A sizeable proportion of pregnancies were unplanned. Teenage pregnancies, non-marital relationships and inadequate knowledge on emergency contraceptives, maternal anemia, low mood, and GBV were modifiable associated factors which could be prevented by evidence-based locally applicable approaches.

Background Flow diverting stents have been used safely and effectively for the treatment of intracranial aneurysms, particularly for large and wide necked aneurysms that are not amenable to conventional endovascular treatment with coiling. The Surpass Streamline device (Stryker Neurovascular, MI, USA) is a relatively new and unique flow diverting stent which maintains constant device mesh density over varying vessel diameters. This may potentially provide advantages compared to other flow diverting stents in achieving aneurysmal occlusion. Case presentation Two patients with VRAA were treated using the Surpass Streamline device. The first patient was a 65-year-old male with an incidental 2.4 cm aneurysm originating from the hepatic artery near the gastroduodenal artery (GDA). The second patient was a 56-year-old male with an incidental 1.9 cm renal aneurysm arising from an anterior inferior segmental branch of the left renal artery. A Surpass flow diverting stent was used to successfully exclude the aneurysm neck in both cases. Reduced flow was achieved in one patient (equivalent to O’Kelly-Marotta [OKM] Grade B1). Preserved flow and stagnation (equivalent to OKM Grade A3) was achieved in the other. There was preserved distal flow in the parent arteries. No immediate complications were encountered in either case. Complete occlusion of both aneurysms was seen on follow up CT angiographic imaging within 8-weeks. Conclusions The Surpass flow diverting stent can be used safely and effectively to treat VRAA. It should be considered in unruptured large and giant wide necked VRAAs aneurysms. Additional large prospective studies are required for further validation.

Purpose To report the technical success, complications and long-term outcomes of patients with intrahepatic cholelithiasis not amenable to endoscopic retrograde cholangiopancreatography (ERCP) who were treated with percutaneous transhepatic biliary Laser lithotripsy (PTBLL). Patients and methods A retrospective review of 12 patients who underwent PTBLL for intrahepatic cholelithiasis was performed. There were 5 men and 7 women with a mean age of 46 ± 18 (SD) years (range: 23–75 years). PTBLL was performed when stone clearance using ERCP had previously failed or was not appropriate due to unfavourable anatomy or the presence of multiple stones or a large stone. Percutaneous biliary access into intrahepatic ducts was obtained if not already present and lithotripsy was performed using a HolmiumYAG 2100 nM Laser. Patients files were analyzed to determine the technical success, complications and long-term outcomes. Results Eleven patients (11/12; 92%) had a history of previous hepatobiliary surgery and nine (9/12; 75%) had multiple stones confirmed on preprocedure imaging. A 100% success rate in fragmenting the target stone(s) was achieved and 11/12 patients (92%) had successful first pass extraction of target stone fragments. Two patients (2/12; 17%) required repeat lithotripsy. One patient (1/12; 8%) experienced a major complication in the form of cholangitis. Of patients with long-term follow-up, 4/10 (40%) had recurrence of intrahepatic calculi with a mean time interval of 31 months (range 3–84 months). Conclusion For patients with intrahepatic biliary calculi not amenable to ERCP, PTBLL provides an effective and safe alternate treatment.

Vertebral compression fractures (VCFs) are a common cause of back pain and disability and are usually osteoporotic in nature. Therapy aims to adequately control pain and allow early mobilisation and return of function while preventing additional fractures. A proportion of patients do not achieve adequate pain relief using conservative measures alone. Unwanted adverse effects from medications may also ensue. Vertebroplasty represents an alternative treatment option for VCFs. Patients with acute VCFs (≤6 weeks old) may gain the most benefit from vertebroplasty as healed fractures are not as amenable to cement injection. High-quality studies have reported conflicting results regarding the use of vertebroplasty in the treatment of acute VCFs. Despite high-quality evidence, varying study designs and heterogenous patient cohorts make interpretation of this data difficult. Only one sham-controlled randomised controlled trial (RCT) has evaluated vertebroplasty exclusively in patients with acute VCFs, reporting favourable results. Pooled data from RCTs also suggest vertebroplasty to be safe. This article provides a concise and critical review of the current literature regarding vertebroplasty for the treatment of acute VCFs.

Tea is the most popular beverage, prepared with leaves of Camellia sinensis (L.) O. Kuntze, consumed by almost all communities and has economic, medicinal and cultural importance. The tea plant originated in southwestern China around 5000 years ago and is now grown in over 52 countries. Tea-breeding activities first started in ancient China and the selection of promising plants from natural variability of heterogeneous populations was practiced in the early years. This chapter highlights limitations in the traditional crop improvement programs and the necessity for adopting novel biotechnological tools to overcome them. The role of tea genetic resources in crop improvement, an overview of tea genetic resources in the world and conservation attempts made to date are discussed. Molecular markers have been used to improve the crop in tea-growing countries. The progress and significant achievements of marker-assisted selection for important traits are highlighted. A comprehensive account is given of genetic linkage maps constructed. The recent developments in functional genomic research and the progress of the omics approaches in tea are discussed. Several attempts have been made to identify functional genes associated with important traits. The progress of transgenic research in tea during the last two decades is summarized. The first genome sequence of tea was reported in 2017, which is a milestone in genome research. Mutation breeding has the potential to be used as an alternative tool to develop new cultivars in tea. The progress on controlled hybridization between selected parents, the most preferred strategy for tea crop improvement to date, is discussed. The chapter provides an overview of the current status and future prospective on the application of new technologies to combat global climate change.