A Literature Review of the Effects of Air Pollution on COVID-19 Health Outcomes Worldwide: Statistical Challenges and Data Visualization.

Several peer-reviewed papers and reviews have examined the relationship between exposure to air pollution and COVID-19 spread and severity. However, many of the existing reviews on this topic do not extensively present the statistical challenges associated with this field, do not provide comprehensive guidelines for future researchers, and review only the results of a relatively small number of papers. We reviewed 139 papers, 127 of which reported a statistically significant positive association between air pollution and adverse COVID-19 health outcomes. Here, we summarize the evidence, describe the statistical challenges, and make recommendations for future research. To summarize the 139 papers with data from geographical locations around the world, we also present anopen-source data visualization tool that summarizes these studies and allows the research community to contribute evidence as new research papers are published.

Hepatic Cystic Echinococcosis (Hydatid Cyst) in a Six Year Old.

Presentation To describe a case of cystic echinococcosis (CE) in a previously healthy child and review epidemiology of CE in Ireland. Diagnosis A previously healthy 6 year old girl was found to have a cystic lesion in the right lobe of her liver. Serology for Echinococcus granulosus was positive, and radiological features were suggestive of CE. Treatment The patient was pre-treated with anti-helminthic medications before undergoing a liver segmentectomy to remove the cyst, and received further treatment with albendazole after surgery. Histological findings were consistent with CE due to E. granulosus, likely acquired during travel to continental Europe. Conclusion CE should be considered in the differential of children with asymptomatic cysts in the liver and/or lung, and a travel history elucidated in such cases.

Varicella Related Hospital Admissions in Ireland

Aim The aim of this study was to evaluate trends in admissions for patients with primary varicella infection in Irish hospitals. Methods The Hospital Inpatient Enquiry System was evaluated from Irish hospitals from 2005-2016 for patients with primary varicella infection. Results There were 2717 admissions with primary varicella infection. The average annual number of admissions was 226 for an incidence of 4.87/100,000. Average length of stay (ALOS) was 5-days. Sixty-two (2.5%) patients required intensive-care with an ALOS of 26-days. The most common secondary diagnoses were cellulitis, volume-depletion and streptococcal infection. The number of admissions due to streptococcal infection and cellulitis significantly increased over the period. Conclusion Chickenpox places a consistent burden on Irish healthcare, accounting for in excess of 1100 acute and 160 intensivecare bed days annually. This study adds weight to the argument that universal varicella vaccine should be considered and provides baseline epidemiology to determine vaccine effectiveness in the future.

Benefit of Sequential Audit Cycles in Improving Management of Vitamin D Deficiency in the HIV Infected Paediatric Population

Aims Lifelong HIV infection has an unknown impact on bone health in children. In view of this, we aimed to improve management of vitamin D deficiency. Methods Three audits over 8 years (2009-2017) were performed with interventions introduced intermittently in an effort to improve vitamin D deficiency. The interventions included education, a change in vitamin D dose and brand to increase compliance and a shift to nursing led management. Results The most striking result was the eradication of patients with deficient vitamin D levels (<25nmol/L) in 2017. In 2009 and 2015, 15% and 9% were deficient. In the earlier two studies, only 15% had 'sufficient' (>50nmol) vitamin D levels. This increased to 71% in 2017. 10% of patients had levels greater than >120nmol/L, increasing risk of vitamin D toxicity. 67% of patients with insufficient vit D (25-50nmol/L) were prescribed a stat high dose vitamin D (120,000 IU) to help avoid adherence issues. Conclusions Sequential audits along with a shift to nurse led management were the most likely reasons for sustained improvement. Similar projects in all medical departments could improve clinical outcomes.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

A Cluster of Paediatric Invasive Group A Streptococcal and Chicken Pox Infections.

An increase in invasive group A streptococcus (GAS) cases referred to the paediatric infectious disease (PID) department of the Children's University Hospital (CUH), Temple Street, prompted review of all invasive GAS cases in 2016. All of the 10 cases identified occurred over a 16-week period from February to June, of which 6 (60%) required admission to the paediatric intensive care unit. The median length of stay was 21.5 days. Seven had active chickenpox infection at diagnosis. This study highlights the significant morbidity of invasive GAS in children in Ireland. Most cases were associated with a vaccine preventable illness, which should prompt reappraisal of the absence of varicella vaccine from the national immunisation schedule in Ireland.

Kawasaki Disease - A Review of Treatment and Outcomes in an Irish Paediatric Cohort 2010-14.

Diagnosis of Kawasaki Disease (KD) can be challenging due to lack of a diagnostic test, and some children present with 'incomplete' KD when not all diagnostic criteria are met. Treatment with intravenous immunoglobulin (IVIG) and aspirin reduces the risk of coronary artery complications. There is sub-group of patients who are resistant to IVIG/aspirin therapy and are at increased risk of complications. Recent evidence suggests that additional treatment of this high-risk group with corticosteroids is beneficial in reducing this risk. We examine the treatment and coronary artery outcomes, by retrospective review of medical records, of a cohort of 32 paediatric patients with KD admitted to a single Irish tertiary centre from January 2010-December 2014. Twenty-eight percent of patients (9/32) had an incomplete diagnosis of KD; these patients received IVIG later compared to those with a complete KD diagnosis. 15/32 (47%) had abnormal echocardiogram findings in the acute phase, 8/32 (25%) had echocardiogram abnormalities at 6-week follow-up, and 4/32 (12.5%) had persisting abnormalities. This study highlights the potential for adverse outcome in KD, the difficulty in diagnosis in 'incomplete' cases, and the need to identify children at higher risk for adverse outcome where adjunctive therapies would be most beneficial.

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.

OBJECTIVES: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. METHODS: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15-29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. RESULTS: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4-111) vs. 8 (IQR 2-38) weeks, respectively], and highest in perinatally infected participants aged 10-14 years [49 (IQR 9-267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0-12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9-5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10-14 years when starting ART (27.7%; 95% CI 13.2-42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10-14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. CONCLUSIONS: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk. METHODS: We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib. RESULTS AND DISCUSSION: Incidence of MI was increased by rofecoxib in all comparison categories [all NSAIDs (OR: 1·811, 95% CI: 1·379-2·378), placebo (OR: 1·655: 95% CI: 1·029-2·661), nsNSAIDs (OR: 2·155, 95% CI: 1·146-4·053), and COXIBs (OR: 1·800, 95% CI: 1·217-2·662)], but was decreased by celecoxib and naproxen in the COXIB comparison [(OR: 0·583, 95% CI: 0·396-0·857) and (OR: 0·609, 95% CI: 0·375-0·989, respectively]. Incidence of stroke was increased by rofecoxib in comparisons with all NSAIDs and other COXIBs [(OR: 1·488, 95% CI: 1·027-2·155) and (OR: 1·933, 95% CI: 1·052-3·549), respectively]. Incidence of stroke was decreased by celecoxib when compared with all NSAIDs, nsNSAIDs, and COXIBs [(OR: 0·603, 95% CI: 0·410-0·887), (OR: 0·517, 95% CI: 0·287-0·929), and (OR: 0·509, 95% CI: 0·280-0·925), respectively]. No NSAID reached statistical significance in regard to CV death. Incidence of the composite endpoint was increased by rofecoxib when compared against all NSAIDs, placebo, and other COXIBs [(OR: 1·612, 95% CI: 1·313-1·981), (OR: 1·572, 95% CI: 1·123-2·201) and (OR: 1·838, 95% CI: 1·323-2·554), respectively]. Incidence of composite endpoint was decreased by celecoxib in the all NSAIDs and COXIBs comparisons [(OR: 0·805, 95% CI: 0·658-0·986) and (OR: 0·557, 95% CI: 0.404-0.767), respectively]. When rofecoxib was removed from the COXIBs group, no difference was found with any comparison, suggesting rofecoxib skewed the data. WHAT IS NEW AND CONCLUSION: This instead of the meta-analysis suggests that COX-2 selectivity may not play a role in the CV risk of NSAIDs. Rofecoxib was the only drug to demonstrate harm and skewed the data of the COX-2 selective group.

Photobacterium angustum and Photobacterium kishitanii, Psychrotrophic High-Level Histamine-Producing Bacteria Indigenous to Tuna.

Scombrotoxin fish poisoning (SFP) remains the main contributor of fish poisoning incidents in the United States, despite efforts to control its spread. Psychrotrophic histamine-producing bacteria (HPB) indigenous to scombrotoxin-forming fish may contribute to the incidence of SFP. We examined the gills, skin, and anal vents of yellowfin (n = 3), skipjack (n = 1), and albacore (n = 6) tuna for the presence of indigenous HPB. Thirteen HPB strains were isolated from the anal vent samples from albacore (n = 3) and yellowfin (n = 2) tuna. Four of these isolates were identified as Photobacterium kishitanii and nine isolates as Photobacterium angustum; these isolates produced 560 to 603 and 1,582 to 2,338 ppm histamine in marine broth containing 1% histidine (25°C for 48 h), respectively. The optimum growth temperatures and salt concentrations were 26 to 27°C and 1% salt for P. kishitanii and 30 to 32°C and 2% salt for P. angustum in Luria 70% seawater (LSW-70). The optimum activity of the HDC enzyme was at 15 to 30°C for both species. At 5°C, P. kishitanii and P. angustum had growth rates of 0.1 and 0.2 h(-1), respectively, and the activities of histidine decarboxylase (HDC) enzymes were 71% and 63%, respectively. These results show that indigenous HPB in tuna are capable of growing at elevated and refrigeration temperatures. These findings demonstrate the need to examine the relationships between the rate of histamine production at refrigeration temperatures, seafood shelf life, and regulatory limits.

Long-term psychosocial and behavioral adjustment in individuals receiving genetic test results in Lynch syndrome.

A cross-sectional study of 155 participants who underwent genetic testing for Lynch syndrome (LS) examined long-term psychosocial and behavioral outcomes. Participants completed standardized measures of perceived risk, psychosocial functioning, knowledge, and a questionnaire of screening activities. Participants were on average 47.3 years and had undergone testing a mean of 5.5 years prior. Eighty four (54%) tested positive for a LS mutation and 71 (46%) negative. For unaffected carriers, perceived lifetime risk of colorectal cancer was 68%, and surprisingly, 40% among those testing negative. Most individuals demonstrated normative levels of psychosocial functioning. However, 25% of those testing negative had moderate depressive symptoms, as measured by the Center for Epidemiologic Studies for Depression Scale, and 31% elevated state anxiety on the State-Trait Anxiety Inventory. Being female and a stronger escape - avoidant coping style were predictive of depressive symptoms. For state anxiety, similar patterns were observed. Quality of life and social support were significantly associated with lower anxiety. Carriers maintained higher knowledge compared to those testing negative, and were more engaged in screening. In summary, most individuals adapt to genetic test results over the long term and continue to engage in screening. A subgroup, including some non-carriers, may require added psychosocial support.

The effect of desmopressin on bleeding time and platelet aggregation in healthy volunteers administered ticagrelor.

WHAT IS KNOWN AND OBJECTIVE: Ticagrelor is a reversibly binding and selective P2Y12 -receptor antagonist approved for the prevention of atherothrombotic events in patients with acute coronary syndromes. As bleeding events remain a hazard with antiplatelet therapy, this study investigated the effect of the vasopressin agonist, desmopressin, on ticagrelor-induced bleeding time prolongation. Desmopressin has previously been shown to improve primary haemostasis and is widely used as first-line therapy for individuals with bleeding disorders. METHODS: In a randomized, double-blind, 2-period crossover study, healthy volunteers received ticagrelor (270 mg loading dose; 180 mg bid) for 5 days. On Day 5, desmopressin (0·3 µg/kg) or saline intravenous infusions were administered. The impact of desmopressin on bleeding time, inhibition of platelet aggregation (IPA), platelet function and ticagrelor pharmacokinetic parameters was investigated. RESULTS: Twenty-one volunteers (81% male) were enrolled. Median [range] bleeding times were slightly reduced with ticagrelor plus desmopressin compared with ticagrelor alone (7·50 [3-17] vs. 10·50 [3-25] min at 2·5 h). Median reductions in bleeding time from baseline were generally similar between ticagrelor plus desmopressin compared with ticagrelor alone at all time points. Co-administration of desmopressin had no impact on IPA, although platelet reactivity was significantly increased (von Willebrand Factor antigen: GLS mean AUEC was 4667%.h for ticagrelor plus desmopressin compared with 2750%.h for ticagrelor alone). Desmopressin did not influence the pharmacokinetics of ticagrelor. WHAT IS NEW AND CONCLUSION: Desmopressin had no significant effect on bleeding time or inhibition of platelet aggregation by ticagrelor, although primary haemostatic activity was significantly increased. Ticagrelor pharmacokinetic parameters were not affected by co-administration with desmopressin. Therefore, desmopressin is unlikely to be an effective therapeutic agent for control of the potential bleeding events associated with ticagrelor.

Early human contact and housing for pigs - part 1: responses to humans, novelty and isolation.

The development of fear and stress responses in animals can be influenced by early life experiences, including interactions with humans, maternal care, and the physical surroundings. This paper is the first of three reporting on a large experiment examining the effects of the early housing environment and early positive human contact on stress resilience in pigs. This first paper reports on the responses of pigs to humans, novelty, and social isolation. Using a 2 × 2 factorial design, 48 litters of pigs were reared in either a conventional farrowing crate (FC) where the sow was confined or a loose farrowing pen (LP; PigSAFE pen) which was larger, more physically complex and allowed the sow to move freely throughout the farrowing and lactation period. Piglets were provided with either routine contact from stockpeople (C), or routine contact plus regular opportunities for positive human contact (+HC) involving 5 min of scratching, patting and stroking imposed to the litter 5 days/week from 0-4 weeks of age. The positive handling treatment was highly effective in reducing piglets' fear of humans, based on +HC piglets showing greater approach and less avoidance of an unfamiliar person at 3 weeks of age. There was evidence that this reduction in fear of humans lasted well beyond when the treatment was applied (lactation), with +HC pigs showing greater approach and less avoidance of humans in tests at 6, 9 and 14 weeks of age. The +HC treatment also reduced piglets' fear of a novel object at 3 weeks of age, and for pigs in FC, the cortisol response after social isolation at 7 weeks of age. Rearing in FC compared to LP reduced piglets' fear of novelty at 3 weeks of age, as well as their vocalisations and cortisol response to isolation at 7 weeks of age. The FC pigs showed greater approach and less avoidance of humans compared to LP pigs at 3, 4 and 6 weeks of age, but not at 9 and 14 weeks of age. These results show that positive handling early in life can reduce pigs' fear of humans, fear of novelty and physiological stress response to social isolation. The LP pigs were reared in a more isolated environment with less overall contact with stockpeople and other pigs, which may have increased their fear responses to humans and novel situations, suggesting that different housing systems can modulate these pigs' responses.

Early human contact and housing for pigs - part 3: ability to cope with the environment.

Early experiences can have long-term impacts on stress adaptability. This paper is the last of three in a series on early experiences and stress in pigs, and reports on the effects of early human contact and housing on the ability of pigs to cope with their general environment. Using a 2 × 2 factorial design, 48 litters of pigs were reared in either a farrowing crate (FC) or a loose farrowing pen (LP; PigSAFE pen) which was larger, more physically complex and allowed the sow to move freely. Piglets were provided with either routine contact from stockpeople (C), or routine contact plus regular opportunities for positive human contact (+HC) involving 5 min of scratching, patting and stroking imposed to the litter 5 days/week from 0 to 4 weeks of age. At 4 weeks of age (preweaning), C piglets that were reared in FC had considerably lower concentrations of serum brain-derived neurotrophic factor (BDNF) than piglets from the other treatment combinations. Compared to C pigs, +HC pigs had fewer injuries at 4 weeks of age. There were no clear effects of human contact on BDNF concentrations or injuries after weaning, or on basal cortisol or immunoglobulin-A concentrations, behavioural time budgets, tear staining, growth, or piglet survival. Compared to FC piglets, LP piglets showed more play behaviour and interactions with the dam and less repetitive nosing towards pen mates during lactation. There was no evidence that early housing affected pigs' behavioural time budgets or physiology after weaning. Tear staining severity was greater in LP piglets at 4 weeks of age, but this may have been associated with the higher growth rates of LP piglets preweaning. There was no effect of lactation housing on growth after weaning. Preweaning piglet mortality was higher in the loose system. The findings on BDNF concentrations, injuries and play behaviour suggest improved welfare during the treatment period in +HC and LP piglets compared to C and FC piglets, respectively. These results together with those from the other papers in this series indicate that positive human interaction early in life promotes stress adaptability in pigs. Furthermore, while the farrowing crate environment deprives piglets of opportunities for play behaviour and sow interaction, there was no evidence that rearing in crates negatively affected pig welfare or stress resilience after weaning. Whether these findings are specific to the two housing systems studied here, or can be generalised to other housing designs, warrants further research.

Early human contact and housing for pigs - part 2: resilience to routine husbandry practices.

The ability of pigs to cope with routine farming practices can affect their welfare. This paper is part of a series on early experiences and stress, and reports on the effects of early human contact and housing on the responses of pigs to routine husbandry practices. Using a 2 × 2 factorial design, 48 litters of pigs were raised in either a conventional farrowing crate (FC) or a loose farrowing pen (LP; PigSAFE pen) which was larger, more physically complex and allowed the sow to move freely. Piglets were provided with either routine contact from stockpeople (C), or routine contact plus regular opportunities for positive human contact (+HC) involving 5 min of scratching, patting and stroking imposed to the litter 5 days/week from 0 to 4 weeks of age. At 4 weeks of age, piglets were weaned and re-housed with controlled mixing of litters within treatment. At 4 days of age, after only 3 bouts of the handling treatment, +HC pigs showed less escape behaviour than C pigs after capture by a stockperson for vaccinations and tail docking, and shorter durations of vocalisations throughout the procedures. The  +HC pigs also showed less escape behaviour when captured by a stockperson at 3 weeks of age. The FC pigs showed less escape behaviour than LP pigs after capture by a stockperson at 4 days of age but not at 3 weeks of age. Serum cortisol concentrations were lower in FC pigs than LP pigs 2 h after weaning but not at 49 h after weaning, whereas serum cortisol concentrations were lower in  +HC pigs than C pigs at 49 h after weaning but not at 2 h after weaning. In the period from 0 to 1 h after weaning, C pigs from LP performed the most escape attempts, although escape attempts were rare overall. When being moved out of the home pen by a stockperson at 21 weeks of age, FC pigs showed less baulking than LP pigs, but there were no detected effects of human contact treatment. In conclusion, both housing system and human contact during lactation affected the stress responses of pigs to routine husbandry practices. The +HC and FC pigs appeared to cope better than C and LP pigs, based on lower responses indicative of stress including escape behaviour, vocalisations and cortisol concentrations. These findings are consistent with corresponding reductions in fear that were reported in Part 1 of this series of papers.

Paediatric HIV: the experience in Ireland 2004-2011.

Despite effective prevention strategies paediatric HIV infection remains an important condition in Ireland. To characterise presentation and identify barriers to optimal management a retrospective chart review of HIV-infected children presenting in Ireland, 2004-2011 was undertaken. Forty-two HIV-infected children were identified; (25 male). Median age at presentation was 6 years (range 0-16 years). 38 children (90%) were born to African mothers. Eleven (26%) were born in Ireland. Twenty-five (59%) were late diagnoses; 11 were symptomatic. Ten of 12 foreign born HIV-infected children had antiretroviral exposure with frequent resistance associated mutations. Seven of 8 children with stage C disease had previously been admitted to hospital in Ireland before diagnosis. Maternal non-adherence to recommendations and seroconversion in pregnancy challenge the goal of paediatric HIV eradication. Targeted strategies for women at risk of infection in pregnancy are required. Late HIV diagnosis remains common, highlighting the need for a more proactive approach to HIV testing.

Pathogenic aberrations revealed exclusively by single nucleotide polymorphism (SNP) genotyping data in 5000 samples tested by molecular karyotyping.

BACKGROUND: Several recent studies have demonstrated the use of single nucleotide polymorphism (SNP) arrays for the investigation of intellectual disability, developmental delay, autism or congenital abnormalities. In addition to LogR 'copy number' data, these arrays provide SNP genotyping data for gene level autozygosity mapping, estimating low levels of mosaicism, assessing long continuous stretches of homozygosity (LCSH), detection of uniparental disomy, and 'autozygous' regions. However, there remains little specific information on the clinical utility of this genotyping data. METHODS: Molecular karyotyping, using SNP array, was performed on 5000 clinical samples. RESULTS: Clinically significant 'LogR neutral' genotyping abnormalities were detected in 0.5% of cases. Among these were a single case of chimerism, 12 cases with low level chromosome mosaicism, and 11 cases with an LCSH associated with uniparental disomy. In addition, the genotyping data revealed several LCSH associated with clinically relevant 'recessive type' genetic defects. CONCLUSIONS: These results demonstrate the utility of SNP genotyping data for detection of clinically significant abnormalities, including chimerism/mosaicism and recessive Mendelian disorders associated with autozygosity. The incidence of clinically significant low level mosaicism inferred from these cases suggests that this has hitherto been underestimated and chromosome mosaicism frequently occurs in the absence of indicative clinical features. The growing appreciation among clinicians and demand for SNP genotyping data poses significant challenges for the interpretation of LCSH, especially where there is no detailed phenotypic description to direct laboratory analysis. Finally, reporting of unexpected or hidden consanguinity revealed by SNP array analysis raises potential ethical and legal issues.

Lack of clinically significant pharmacological interactions between ticagrelor and enoxaparin or unfractionated heparin in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: Patients with acute coronary syndromes (ACS) receive several pharmacological therapies concomitantly, including antiplatelet and anticoagulant agents. As unfractionated heparin (UFH) activates platelets in vitro and in vivo, co-administration with an antiplatelet agent may lead to decreased clinical effectiveness of the latter. The aim was therefore to determine any potential drug-drug interactions between the new oral antiplatelet agent ticagrelor, and UFH or enoxaparin. METHODS: In two open-label, three-period, crossover trials, healthy subjects were randomized to receive ticagrelor alone or with enoxaparin (study 1) or UFH (study 2), or enoxaparin or UFH alone. Ticagrelor plasma concentrations, inhibition of platelet aggregation (IPA), anti-factor Xa levels, activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) were measured. RESULTS: Thirty and 28 subjects completed studies 1 and 2, respectively. Study drugs were generally well tolerated, with no significant bleeding or serious adverse events. Co-administration with enoxaparin or UFH had no significant effect on ticagrelor pharmacokinetics. The effect of ticagrelor on IPA was unimpaired by co-administration of enoxaparin, except for a marginal (-2.9%; 908.7%.h, 881.9%.h) reduction in final extent area under the effect curve (AUEC)(2-12) (95% CI: -51.6%.h, -2.0%.h). Co-administering UFH with ticagrelor caused small decreases in IPA(max) (-3.8%; 94.6%, 91.0%) and AUEC(2-12) (-6.8%; 888.6%.h, 828.3%.h) vs. ticagrelor alone (95% CI: final extent IPA(max) -5.7%, -1.6%; AUEC(2-12) -109.8%.h, -10.8%.h). Ticagrelor had no clinically significant effects on enoxaparin as assessed by anti-factor Xa (study 1), or UFH as assessed by aPTT or ACT (study 2). WHAT IS NEW AND CONCLUSIONS: Enoxaparin and UFH had no effect on the pharmacokinetics and no clinically significant effect on the pharmacodynamics of ticagrelor. Ticagrelor had no clinically significant effects on the pharmacodynamics of enoxaparin or UFH.

Lack of significant food effect on the pharmacokinetics of ticagrelor in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist and has been approved in the European Union and the USA for the reduction of clinical thrombotic events in patients with acute coronary syndromes. This study aimed to assess the effect of food on ticagrelor pharmacokinetics. METHODS: The study was an open-label, randomized, 2-period crossover single-centre trial; 26 healthy volunteers received a single 270 mg (3×90 mg tablets) ticagrelor dose orally following: (i) a 10-h overnight fast; and (ii) after a standard high-fat, high-calorie breakfast. Ticagrelor and AR-C124910XX (a major pharmacologically active metabolite) plasma concentrations were quantified for pharmacokinetic analysis. RESULTS: Ticagrelor median time to maximum concentration (t(max); 2·5 h vs. 1·5 h) was slightly delayed in the fed vs. fasting state. Maximum concentration of ticagrelor (C(max)) was comparable between the two states with 95% confidence intervals (CI) of the geometric least-squares (GLS) mean ratio (0·85-1·03) being within no-effect limits (0·80-1·25). Ticagrelor exposure was slightly higher with food intake; area under the plasma concentration-time curve from zero to infinity (AUC) was 21% higher compared with fasting state (95% CI of GLS mean ratio=1·13-1·30). For AR-C124910XX, AUC (95% CI of GLS mean ratio=0·93-1·07) was unaffected by food consumption. Median t(max) of the metabolite was slightly longer in the fed than fasting state (3·5 h vs. 1·5 h). Mean C(max) for AR-C124910XX was slightly lower (22%) with food intake vs. fasting (95% CI of GLS mean ratio 0·69-0·88). WHAT IS NEW AND CONCLUSION: Food effects on ticagrelor AUC and AR-C124910XX C(max) were small and are considered to be of minimal clinical significance. Thus, ticagrelor can be administered with or without food.

Development and validation of an instrument to measure the impact of genetic testing on self-concept in Lynch syndrome.

A positive genetic test result may impact on a person's self-concept and affect quality of life. The purpose of the study was to develop a self-concept scale to measure such impact for individuals carrying mutations for a heritable colorectal cancer Lynch syndrome (LS). Two distinct phases were involved: Phase 1 generated specific colorectal self-concept candidate scale items from interviews with eight LS carriers and five genetic counselors, which were added to a previously developed self-concept scale for BRCA1/2 mutation carriers, Phase II had 115 LS carriers complete the candidate scale and a battery of validating measures. A 20-item scale was developed with two dimensions identified through factor analysis: stigma/vulnerability and bowel symptom-related anxiety. The scale showed excellent reliability (Cronbach's α = 0.93), good convergent validity by a high correlation with impact of event scale (r(102) = 0.55, p < 0.001) and Rosenberg self-esteem scale (r(108) = -0.59, p < 0.001), and a low correlation with the Fear questionnaire (r(108) = 0.37, p < 0.001). The scale's performance was stable across participant characteristics. This new scale for measuring self-concept has potential to be used as a clinical tool and as a measure for future studies.